This is my final set of notes. I was never planning ever to submit this document online because it’s far too long and it was too large to send by email, so I’ve had to delete most of the pictures. However due to popular demand, I caved in, and here they are. Please use my notes sensibly just reading them will not do, and as comprehensive as they may seem Leicester Medical School manages to chuck a random question in the paper.

Anyway I hope, as you’ve managed to get this far in the course, and you’ve bothered to download my final set of notes, that you found them helpful.

Have fun,

Mark Sims

Clinical Pharmacology

Session 1- Safe Prescribing1100 deaths occur from medication errors every year. Its occurring more because:

Medical o Shift work and reduced hourso Lower exposure to teachingo Working alone more ofteno Less ward teaching and feedbacko Poor moraleo Lack of continuity of careo Too many studentso Lack of pharmo training

Pharmaceuticalo Vast numbers of new drugso Clinical evidence is usually with drug used in isolation in:

Selected relatively healthier patients And/or young volunteers initially

o Some side effects come to light only during post marketing surveillanceo Blind adherence to guidelines leads to prescription where contraindications or

serious interactions exists Population

o Increasing numberso Elderly patients with many co-morbidities, multiple drugs, ↑risk of side effects

Extended prescribingo More doctorso Nurse practitionerso Pharmacistso Devolvement of prescribing

Process of error

Reason’s model of accident causationPerson approach – aberrant mental processes ‘bad things happen to bad people’ – countermeasures centred on person e.g. Fear, retaining, litigation, naming and shamingOrSystem approach – errors seen as consequences, unable to change human condition, countermeasures centred on barriers and safeguards.

Latent conditions – processes inherent to an organisation or factors as a result of management decisionsError-producing conditions – poor environment, lack of individual or team communicationActive failures

Person making error knowingly did soSlips – erroneous performanceLapse - erroneous memoryMistakes – error in planning of action

‘Swiss cheese model Successive layers of defences, barriers and safeguards

DEFENSES – senior review, near-patient pharmacy checks, reviews of prescriptions, electronic systems, patient identifiers Prevention – knowledge, meticulous, the environment, formulary development, do your own work

Meticulous – use your mind and not just pen, legible writing, no abbrevs, review, clarify instructionsEnvironment – time management, prioritisations, neat and tidy, use tech GFR calcs, toxbase, eBNF

FormulariesTypes of formulary – traditionally as a list of compounded medicines

Now means list of recommended first-line drugs for common medical conditions.

– Leicestershire medicines formulary. Factors for local formularies Efficacy (how effective is it, compared with other drugs or placebo) Safety (major and minor effects) Cost, but only if efficacy and safety of two drugs are equivalent

eBNF - lists all the drugs currently licensed in the UK. Lists some drugs that were used but which now been identified as less suitable for prescribing, either because lack of efficacy or ↑toxicity

Role of pharmacist in reducing prescription error

Pharmacists understand pharmacology better than most medics. They occupy a pivotal position in the NHS overseeing that prescriptions are correctly made out. In some hospitals pharmacists are also able to write discharging prescriptions. However, the primary role they play in detecting prescription error does not mean they take the responsibility for what is written on the prescription. This always lies with the prescribing medic; the legal responsibility of the pharmacist is to dispense according to prescription

Consequently if they suspect an error has been made in the prescription then they must refer this back to the doc. There is evidence that some junior doctors overly rely on the specialist knowledge and experience of the pharmacist as a short cut to check over errors, instead of spending time carefully consulting the BNF prior to prescription.

Instead of a short cut, unprofessional reliance on the pharmacist brings additional pressure in the system. The formal recording of error and querying the Hx behind a prescription means the short cut turns into a waste of time. Moreover, this may additionally compromise patient welfare, especially if the condition needs to be treated within a short time frame.

Check list for avoiding medical error

Along with the active application of your skill and knowledge, the use of an appropriate formulary provides the first and most important line of defence against serious prescription error.

1. Consider the patient2. correct chart for the patient? – do not use the wrong chart and get the right patient3. What is your diagnosis and therapeutic aim?4. Is it the right drug for the patient?

a. Avoid therapeutic duplication (co-codamol and paracetamol)b. Any serious interaction that could lead to failure of treatment of other unintended

consequence – ANTICOUGULANTSc. Any allergy to this agent or group of drugs that is already documented for the

patient e.g. tazocin does not tell you it contains a penicillind. The drug name is spelt correctly e. NO ABBREVSf. The form of the drug is correct for the patient. E.g. liquids for children

5. Will the patients illness affect drug distribution/elimination?6. Are there any alternatives to your choice?7. Is the patient on any other non-prescription medication that may interact

a. Eg. Antacids and statins. St. John’s wort used as an antidepressant has documented interactions with around forty drugs and OCP

8. route of administration appropriate – oral preferred to IV where possible for antibiotics9. Is the correct dose prescribed? Check body weight, check decimal point, write out nano, and

micro not n and m10. Is the correct freq. And timing of drug given –diuretics in the morning, some drugs once

weekly11. What is the likely duration of treatment – how long for12. What are the most serious side effects associated with the drug13. Is drug/therapeutic monitoring required14. How much information/explanation does the patient need? – compliance15. Are there any special prescribing requirements for this drug? E.g. controlled drug

prescriptions require total quantity in words and figures on TTO.

Pharmacovigilance/ ADRSPharmacovigilance is the process of identifying and then responding to safety issues about marketed drugs. Therefore the survey the safety of drugs and develop strategies to ↓risk and optimise benefits

Why? The granting of a product licence for a new drug merely means that any hazards unacceptable to the licensing authority have not been identified. It does not ensure that a medicine will be safe in subsequent prescribing practice

Frequency of adverse events: Very common > 1 in 10 common <1 in 10 > 1 in 100 Uncommon/less commonly <1 in 100 > 1 in 1000 Rare - <1 in 1000 >1 in 10000 Very rare <1 in 100000

What is an adverse drug reaction? It is an unwanted or harmful reaction experienced following the administration of a drug(s)

It is suspected to be related to the drug(s) – the reaction may be a known SE of the drug or it may be new and previously unrecognised.

Limitations of pre-marketing clinical studies in identifying ADRs Relatively small number of patients treated The freq. Of exclusion of sub-groups of patients who may be at greater risk of ADRs

o Clinical trials are not representative of the clinical population Clinical studies

o Limited duration of treatmento Restricted doseso Experienced, specialist investigatorso Freq. Of doc-patient contact and opportunities to intervene

CLASSIFICATION OF ADRS later

Determining causality: Strength of association (temporal relationship, lack of confounding factors, certainty of the

diagnosis Dose-response relationship Supporting evidence

Approaches to pharmocovigilance

Organised studies – cohort or case control

Whole population – GP, or yellow card scheme

Cohort study Advantages –

o ability to study multiple outcomes

o study a temporal sequence of eventso calculation of both absolute rates and relative rates

Disadvantageso Biaso Time taken (take years)o Huge studies would be required to study rare outcomeso Usually expensive

Case control Advantages –

o Study rare ADRSo Multiple exposureso Can give a quick answer if a suitable database is availableo Low cost

Disadvantageso Requires a prior hypothesiso Suitable database often not availableo Often more susceptible to bias than cohorto Only allows calculation of odds ratio

General practicePrescription event monitoring studies – drug safety research unit, independent academic

unit, used to study selected, newly licensed medsThe patient cohort is identified from NHS prescriptions giving exposure data

Yellow card scheme Voluntary, ADR reporting scheme Report suspected ADRs on yellow cars Created 1964 following thalidomide Doctors, dentists, coroners, optometrists, pharmacists, health visitors, nurses, midwives can

report and patient reporting It identifies very rare events (<1 in 10,000) To act as an alerting or signalling system – individual cases, cluster of cases, continuous

monitoring REPORT – any therapeutic agent, including herbal products

o Recent produces report all suspected ADRS even minoro All reactions to vaccineso Established products – serious or unusual reactionso All serious ADRs should be Yellow Card reported. These include all ADRs leading to

hospital admission, including ADRs which are already well-recognized e.g. aspirin and GI bleeding.

o Yellow Card reports should sent regardless of whether they refer to ADRs to prescription medicines, herbal remedies or OTC (over the counter) medicines.

o Serious ‘medically significant’ ADRs

Previously unrecognised SE especially rare or delayed effects may still be identified after many years of use. Need to investigate in detail well known SE

Risk factors for patients such as age or concurrent disease How medicines can be used more safely

To compare medicines in the same therapeutic class to investigate their relative safety

Delayed drug effects – some reactions may become manifest months or years after exposure

The elderly – particular vigilance is required to identify adverse reactions in the elderly.

Congenital abnormalities – when an infant is born with one or malformed aborted fetus- consider ADRS

Children particular vigilance

Regulatory action

If risk/benefit analysis indicates an unacceptable risk

The marketing authorisation may be withdrawn

Company may voluntarily suspend or withdraw the product

If a particular group of patients at risk, product license may be amended

Limitations – poor compliance, under reporting, association not causality, poor/variable date quality, cannot accurately calc incidence, comparisons are difficult (no control), insensitive for reactions which mimic commoner conditions, delays

Advantages – cheap, easy, concurrent, covers all patients and doctors, detects common and rare, useful for generating hypotheses, can characterise ADR

Session 2- PharmacokineticsPharmacokinetics: study of the movement of a drug into and out of the body. ‘what the body does to the drug’

Pharmacodynamics – study of drug effect and mechanisms of action ‘what the drug does to the body’

Pharmacogenetics – the effect of genetic variability on the pharmacokinetics or dynamics of a drug on an individual

Importance of pharmacokinetics:

To appreciate how dosing regimens are devised To tailor an appropriate dosing regimen to an individual patient To determine why a patient may fail to respond to treatment To determine why a drug has caused toxicity To elucidate the mechanisms of drug interactions

The main factors effecting entry and removal of the drug can be remembered using the mnemonic acronym ADME:

Absorption = Distribution DRUG In Metabolism Excretion drug out

Administration routes:

Enteral – orally peg, NG tube, enema, PR, suppository Pros – cheap, no assistance required, no needle phobia Cons – metabolised by the liver, slower action, slow drugs have poor uptake

Parenteral - IV, intra-arterial, IM, intracerebral, intra-cardiac, subcutaneous, intra-oseous, Intrathecal

Pros – faster uptake, 100% BA, potentially longer lasting, continuous medication Cons – requires medical assistance, more addictive, risk of needle contamination, air

boluses, needle phobia.

Topical sites – skin, cornea, vagina, nasal mucosa, transdermal, inhalation High dose where it matters May have some systemic affects, not good for systemic delivery, can be expensive.

Bioavailability: the fraction of a dose which finds its way into a body compartment, usually the circulation. For an IV bolus, bioavailability is 100%. For other routes, compare amount reaching the body compartment by that route with IV bioavailability.

Oral bioavailability (F) = area under curve (oral)/ area under curve IV)

Factors affecting F Absorption - drug formulation, age, food (lipid-soluble> water-soluble), vomiting/malabsorption

First pass metabolism – can be a key determinant of how much drug is available for systemic effect. FPM includes that carried out by both the gut and the liver. As virtually all molecules absorbed via the gut will travel via the portal circulation to the liver, hepatic FPM can again significantly reduce the amount of available drug as measured by its extraction ratio.

The gut lumen – gastric acid, proteolytic enzymes, grapefruit juice can affect drugs (benzylpenicillin, insulin, ciclosporin)

The gut wall – P-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into lumen (ciclosporin

The liver – propranolol is extensively metabolised.

Drug Distribution the distribution of a drug refers to its ability to ‘dissolve’ in the body. There are two key factors: - protein binding and volume of distribution

Once in the systemic circulation, many drugs are bound to circulating proteins: Albumin (acidic drugs) Globulins (hormones) Lipoproteins (basic drugs) Acid glycoproteins (basic drugs)

Most drugs must be unbound to have a pharmacological effect. Only the fraction of the drug that is not protein-bound can bind to cellular receptors, pass across tissue membranes, gain access to cellular enzymes etc.

Free drug determines its action at receptor. Displacement of drugs from binding sites causes protein binding drug interactions.

Changes in protein binding can occur, causing changes in drug distribution. These are only important if 3 criteria are met:

1. High protein binding2. Low Vd3. Has a narrow therapeutic ratio

Factors affecting protein binding: hypoalbuminaemia, pregnancy, renal failure, displacement by other drugs

Tissue distribution drug that is not bound to plasma proteins is available for distribution to the tissues of the body. Some are distributed only to the body fluids, while others are bound extensively in body tissues. One measure of distribution is the apparent volume of distribution

Vd is a measure of how widely a drug is distributed in body tissues:

Vd ≈ Dose/[drug]t0

It is a hypothetical measure, but it can be useful in understanding dosing regimens e.g. 100mg gentamicin dose, peak plasma concentration 5mg/l, then the Vd will be 20 litres

T1/2 α Vd and clearance

Tissue distribution can also be affected by: specific receptor sites in tissues; regional blood flow; lipid solubility; active transport; disease states; drug interactions

The end products of conjugation are water-soluble enabling rapid elimination from the body. They are usually pharmacologically inactive.

Metabolism of a pharmacologically inactive compound to one with pharmacological activity (pro-drugs): inactive enalaprilat to active enalapril OR L-dopa is metabolised to a more active metabolite to improve distribution (crosses blood-brain barrier)

Metabolism of a pharmacologically active compound (codeine) to other active compounds morphine

Phase 1 drug metabolism: oxidation and reduction are in part dependent on the cytochrome p450 family of enzymes. The activity of theses can be influenced by enzyme-inducing and enzyme-inhibiting drugs that alter the rate of metabolism of other drugs.

Cytochrome p450: present mainly in the liver (some gut and lung) super family of isoforms is responsible for 90ish% human drug metabolism through oxidative reactions. Metabolise toxins such as carcinogens and pesticides. Genetic differences in

Cytochrome P450 3A: roles metabolism of:

Calcium channel blockers Benzodiazepines HIV protease inhibitors Most statins Cyclosporin Most non-sedating antihistamines

CYP 450 2D6: absent in 7% Caucasians and hyperactive in 30% of east Africans

Metabolises: codeine, B-blockers, tricyclics

Inhibited by: fluoxetine, paroxetine, haloperidol, quinidine

CYP 450 2C9 absent in 1% of Caucasians and blacks

Metabolises: most NSAIDs, s-warfarin, phenytoin, tolburamide

Inhibited by: fluconazole

Induced by: carbamazepine and ethanol

CYP 450 2C19: absent in 30% asains & 5% of Caucasians

Metabolises: diazepam, phenytoin, omeprazole

Inhibited by: ketoconazole, omeprazole, isoniazis, fluoxetine, ritonavir

Induced by: rifampicin.

Other factors: Race – development of pharmacogenetics Age – reduced metabolism in aged patients & children Sex – women have slower ethanol metabolism

Inhibitors of 3A

Anti fungals: ketoconazole, fluconazole, itraconazole

Cimetidine

Erthromycin

Grape fruit juice

Inducers

Carbamazepine

Phenytoin

Rifampicin

Ritonavir

St. John’s wort

Species – drug development Clinical or physiological condition

Drug Elimination

The main route of drug elimination is the kidney. Other routes include the lungs, breast milk, sweat, tears, genital secretions, bile, saliva

3 processes determine the renal excretion of drugs: Glomerular filtration Passive tubular reabsorption Active tubular secretion

If the GFR is ↓then clearance is ↓. T1/2 is inversely proportional to clearance ↑t1/2

1 st order kinetics - linear – rate of elimination is proportional to drug level. Constant fraction of drug eliminated in unit time. T1/2 can be defined

Linear when log y axis plotted against time

Zero order kinetics – Non-linear – rate of elimination is constant

Straight line when linear y axis scale plotted against time zero order kinetics.

Most drugs exhibit zero order kinetics at high doses because of enzyme/receptor saturation

Some Maths:

K= elimination rate constant = Cl/Vd

In plot of linear kinetics gives a straight-line

Ln [Drug]t = ln [drug]t0 – kt

T1/2 = ln2/k

T1/2 – 0.693vd/Cl

Phenytoin Toxicity – phenytoin follows zero order kinetics. Fixed rate of elimination per unit time. High risk of toxicity. Small dose changes may produce large increments in dose lead to toxicity. Drug monitoring essential, no t1/2 is calculable

Drug pharmacokinetics – during repeated drug administration, a new steady state is achieved in 3-5 half lives. This is irrespective of dose or frequency of administration.

Digoxin prescribing large apparent Vd – predominantly excreted by kidneys. Relatively long t1/2 = 40 hours. Thus 5 half-lives to steady state will be > 1 week. Therefore

Needs loading doses to achieve a rapid therapeutic effect Maintenance doses need reducing if renal failure leads to reduced clearance Loading dose can remain much the same in renal failure unless renal failure is very severe.

Loading dose = Vd X [drug]target

First order elimination the clinical effectiveness of the drug (after it is stopped) will depend on the therapeutic window and the minimal effective plasma drug concentration

Pharmacodynamics, Drug interaction and ToxicologyPart of pharmacology that explores the effects of drugs and their mechanism of action on the body. Essentially the study of what drugs do to the body.

Drugs exert their effects, either by physicochemical effects e.g. Antacids or interaction with enzymes, transport systems, second messengers, hormone or ion channels

Drug receptor theory: Agonists and antagonists Partial agonists/antagonists Competitive antagonism and non-competitive antagonism Specificity and selectivity

Partial signal

An ideal drug would mimic the action of the endogenous controlling molecule. Real drugs act at more than one binding site.

Specificity relates to complementary drug and receptors

Selectivity relates to clinical effect of drug and can be measured with specific therapeutic index.

Affinity defines the tendency of a drug to bind to a specific receptor type. Use notation Kd for agonist and Ki for antagonist

Kd and Ki values are the concentration at which half the available receptors are bound.

Concentration and responseDrug response is generally proportional to number of receptor sites bound by the drug. Target receptors can exist at different tissues throughout the body. Drug response curve

Effectmax is the maximum response of the system to the drug

EC50 is the concentration of the drug that brings on half of the maximum response of the drug

Concentration on a logarithmic scale to ease calculation of EC50

Potency is a measure of the amount of drug required to produce an effect of a given intensity

Efficacy is a measure of the maximum effect of a drug or treatment regardless of dosage

Drug A and B are more effective than drug C, Drug A is more potent than drug B.

Therapeutic index is the relationship between concentrations causing adverse effects and concentrations causing desirable effects.

Therapeutic index = EC50 (adverse effect)/EC5- (desired effect)

Therapeutic window is the range of dosages that can effectively treat a condition while still remaining safe. It is the range between the

lowest dose that has a positive effect, and the highest dose before the negative effects outweigh the positive effects. Narrow windows: digoxin, warfarin

Drug-drug interaction –PD

Interactions either enhance or reduce therapeutic outcome through actions on the receptors

Drug interactions can occur via different receptors or different tissues

Agonism/Antagonism at same R e.g. opiate analgesics and naloxone. β-blockers and β2 agonist

Agonism/antagonism at different R. – warfarin and aspirin

Non-selective nature of drug e.g. antidepressants interact with many receptor subtypes

Drugs can be enhanced by other means e.g. digoxin toxicity enhanced by hypoK caused by a loopy D

The same drugs account for the common significant drug-drug interactions time after time:

Anticonvulsants Anticoagulants Antidepressants Antibiotics Antiarrhythmics Infected depressed epileptic (with) AF [AF Rx both anticoagulants and antiarrhythmics] IDEA

QTc interval prolongation – drugs may prolong the QT interval and cause ‘torsade des pointes’: genetic and acquired forms; ion channel and sympathetic abnormalities; QTc lengthened by many antiarrhythmics; other drugs also prolong QT. Any drug that impairs metabolism of QTc prolonging drug may cause Long QT syndrome.

Renal disease – falling GFR – ↓CL of renally excreted drugs and disturbances of electrolytes may predispose to toxicity. Nephrotoxins will further damage kidney

Hepatic disease – ↓CL of hepatic metabolised drugs, ↓CYP 450 activity, long T1/2, toxicity, classic – opiates in cirrhosis.

Cardiac disease – low CO will lead to: excessive response to hypotensive agents. ↓organ perfusion – ↓hepatic blood flow and CL, reduced renal blood flow and clearance

Drug-food interaction – grapefruit juice inhibits several cYP450 isoenzymes affects CL. May lead to ↑exposures to drug of up to 16 fold

Cranberry juice used to treat UTI, inhibits bacterial adherence to urothelium. Inhibits CYP2C9 isoform, ↓warfarin CL. Enhanced anticoagulant effect risk of haemorrhage.

Drug monitoring – other changes likely to affect levels – prescription changes bad renal/hepatic function

Or drug itself e.g. phenytoin due to low therapeutic index

OR surrogate markers of effect/ADRS

CYPS and drug response

Several polymorphisms that affect genes encoding cytochrome P450 have been described

The CYP 2D6 isoform is responsible for the metabolism of 25% of drugs (including antidepressants, antipsychotics, β-blockers, opioids), variability in the rate of metabolism between people is > 100-fold. 6% of the Caucasian population carrying two null alleles at the CYP 2D6 gene locus 19. There are >70 variant alleles of the CYP 2D6 locus. Other variants that ↓activity, alter substrate specificity or ↑activity have also been described.

Absent or reduced CYP 2D6 activity can lead to ADRs by the following mechanisms:1. ↓FPM and drug elimination2. Accumulation of the drug as a result of reduced metabolism3. Re-routing of metabolism

Not a straight forwarded test for CYP 2D6 activity, random DNA testing has ethical issues too

In the future patients may be screened for how effective the drug will be for them and their likelihood or a ADR.

Types of ADR

Type A dose dependent: ‘On target’ ADR– are due to an exaggerated therapeutic effect of the drug most likely due to

↑dosing or factors affecting drug PK (e.g. ↓ GFR) and PD (e.g. inhibit cytochrome P450) ‘Off target’ ADR – virtually all drugs will interact with other receptor type secondarily to the

one intended for therapeutic effect. They can also occur with metabolites that subsequently act as a toxin e.g. paracetamol in overdose.

Type B (20% of ADRs) – Idiosyncratic responses ADRs are due to unique individual disposition. Inappropriate immune responses also form another category of ‘off target’ ADRs. However much less predictable.

Hospital patients are often on a cocktail of six or more drugs, which takes the overall chance of an ADR to 80%!

HLA associated histocompatibility complexes these provide a wide range of ADR associated targets. Example is carbamazepine hypersensitivity causing idiosyncratic severe blistering and rash.

PharmacogeneticsPharmacogenetics is the science of understanding how different individual genotypes relate to different drug. This enables physicians to know which drugs will therefore be safe and effective for an individual patient

Pharmacogenomics is pharmacogenetics applied to the entire genome.

Some drugs aren’t effective for some people and more toxic to others.

6-7% patients have ADRs not all due to genetics but some. 30% of patients do not respond to statins.

An everyday example – blacks/whites given Lisinopril. ACEi less effective in blacks.

An individual’s response to ACEi/ARB is dependent on their own RAS activity. Young whites have higher RAS activity – therefore ACEi/ARB treatment will lower the BP more effectively. Older and blacks have lower RAS activity – first line therapy includes Thiazide diuretics/CCB. But genetic variation in races. Blacks more likely to get angioedema from ACEi/ARB.

Genetic polymorphisms can affect PK and PD. Toxicity can occur due to someone having impaired metabolism (e.g. different CYP enzyme), and impaired efficacy can occur if the person say has an abnormal receptor.

Haemolytic anaemia: in RBCs, glucose-6-phosphate dehydrogenase (G6DP) deficit results in loss of protection against oxidative damage. Sulphonamides and antimalarials can induce RBC oxidative stress resulting in severe idiosyncratic haemolytic anaemia.

10% of blacks have glucose-6phosphate dehydrogenase deficiency and will get severe haemolytic anaemia when they receive one of the drugs.

Hepatic porphyria due to deficiency in haem synthesis capability – hepatic porphyrias are proteolytic rare pharmacogenetic disorders. Well intended use of sedatives, antipsychotics or analgesics in patients with undiagnosed hepatic propria can be lethal, however with appropriate support management most recover completely. These disorders are characterised by ↓of one of the enzymes required for haem synthesis, with the result that porphyrin containing haem precursors accumulate, causes rash, GI disturbance, behavioural disorders.

Inducers of CYP450 can precipitate acute attacks in susceptible individuals. Conditions: sleeping disorders, hypothyroidism, schizophrenia

The future – test Px for markers of disease, and the ability to detect how a Px will respond to a drug.

Session 3- The Gonadal Steroids and InhibitorsSex steroids: oestrogen, progesterone’s and androgens All derived from cholesterol

Oestrogens: Actions – mild anabolic, Na and H2O retention, ↑HDL, ↓LDL, ↓bone reabsorption, impair

glucose tolerance, ↑blood coagulability, improve mood and concentration, ↓Alzheimer’s, SE– breast tenderness, nausea, vomiting, water retention, ↑coagulability, thromboembolism,

↓glucose tolerance, endometrial hyperplasia and cancer

Progesterones Actions – secretory endometrium, anabolic, ↑bone mineral density, fluid retention, mood

changes SE – weight ↑, fluid retention, anabolic, acne, nausea, vomiting, irritability, depression, PMS,

lack of concentration

Testosterone Actions/SE – male secondary sex characteristics, anabolic, acne, voice changes, aggression,

metabolic adverse effects on lipids. Routes of administration

Oralo O – synthetic derivatives: ethinyloestradial, methoxy derivative, valerateo P – synthetic derivatives

P derivatives: medroxyprogesterone, dihydrogesteroneo Testosterone derivatives: norethisterone, norgestrel, ethynodiol

OTHER: Transdermal, Implants, Nasal and Vaginal

Transport of steroid – Transport bound to SHBG (except P) and albumin. Liver metabolism, P almost totally metabolised in one passage through liver. Metabolites excreted in urine (as glucuronides and sulphates)

COCP – oestrogens high/low dose: 50, 35, 30, 20mg/day combined with a 1st-4th generation progesterone. Regime: either monophasic – 21, triphasic (varied doses across cycle) – 21, or every day = 21 +7 placebo.

Mode of action – suppression of ovulation inhibit FSH, LH Adverse effect on cervical mucous Adverse effect on the endometrium

Adverse effects: Venous thromboembolism MI, HTN – in small % in women) ↓glucose tolerance ↑risk of stroke in women with focal migraine Headaches

Mood swings Cholestatic jaundice ↑incidence of gallstones Precipitate porphyria.

Serious ADRs are rare e.g. thromboembolism in 2nd gen pills: 1.5/1000 users vs 1/1,000 in non-pregnant control vs 6/1000 pregnant non-users per year.

Drug interactions – they undergo metabolism by both phase 1 and 2 hepatic pathways and are affected by CYP inducers including rifampicin, carbamazepine and St John’s wort. Use of broad-spectrum antibiotics can result in ↓efficacy due to effects on intestinal flora. These play a part in enterohepatic recycling as they ↓so does the amount of drug re-entering the systemic circulation. Risk of CV event higher in smokers

Monitoring of BP and enquiry about other ADRs should continue over the period of prescription

The POP28 days of P, it primarily acts to thicken cervical mucus, secondarily hindering ovulation and endometrial implantation. Efficacy is about 96-98% and is usually offered to women for whom the COCP is contraindicated. A number of P implants (IM, SC or IUD) provide long term contraception. Causes: poor cycle control

Postmenopausal HRT

HRT to control symptoms of menopause e.g. hot flushes/sweats Can ↓osteoporosis, ↓ mood changes may have a negative effect on CVS. There are issues with long term use of single or combined HRT as clinical trial evidence points to ↑risk of ADR. Currently it is proposed to treat these symptoms with lower dose of HRT for shortest time.

Steroids in HRT – oestradial 1-2mg/day premarin 0.625-1.25 mg/day with/without Medroxyprogesterone acetate, tibolene (O, P some T mix)

Combined HRT either: continuous same dose or only O for 14 days then O, P for 12-14

Base line tests – LH, FSH, GnRH, P, O sonogram.

Monitoring – hormone levels, breast cancer screening, possible hysterectomy

Risks of HRT Unopposed O: ↑endometrial cancer, and ovarian cancer ↑breast Ca ↑IHD, and stroke ↑risk of venous thromboembolism Uterine bleeding Adverse effect on lipid profile Adverse effect on thrombophilia profile

Administration: oral, transdermal, implant, transvaginal, nasal.

Anti- progestogens

Partial agonist to P receptor, inhibits P action Sensitises the uterus to prostaglandins Used for medical termination of pregnancy, and induction of labour. ‘

E.g. mifepristone

Anti – androgen

Cyproterone: progesterone derivative

Weak progestogenic effect. Partial agonist to P receptor competes with dihydrotestosterone used in COCP.

Selective Oestrogen Receptor Modulators

Raloxifene: protects against osteoporosis, no proliferative effects on endometrium, no proliferative affect on breast, ↑hot flushes

This group of drugs exhibit mixed agonist/antagonist properties on the PD of which are tissue dependent. The specific action is dependent on: tissue specific expression of the nuclease O receptors: the genes associated with these receptors; presence of transcription co-factors.

Weak oestrogens that block receptors:

Clomiphene – ovulation induction, inhibit O binding to ant pituitary, in negative feedback, results in ↑GnRH and FSH, LH

Tamoxifen – Rx of Breast ca and ovulation induction. ADR proliferation of endometrium

Corticosteroids: Corticosteroids are from the adrenal cortex, widespread metabolic effects, and important role in maintaining life. Negative feedback control system via the hypothalamic-pituitary-adrenal axis.

GFR = MGA (mineralocorticoids, glucocorticoids and androgens)

Adrenal steroids- based on cholesterol molecule: mineralocorticoids, glucocorticoids, sex steroids

Steroid hormone action – intracellular receptors form complexes which enter nucleus and alter DNA transcription. Different to peptide hormones (Cell surface receptors)

Mechanism of GC action – GC receptors are intracellular, GC-receptor complexes bind to DNA, glucocorticoid response element gene regulation – fundamental change in physiology

Mineralcorticoid action – fluid retention, HT, hypokalaemia

Aldosterone acts – promotes active Na and Cl reabsorption and secretion of K and H in DCT and CD. Receptor bound aldosterone ↑transcription of ENaC results in ↑extrusion of Na from cells into interstitium and secretion of K, H into lumen. Also more ATP and ↑expression of Na/K pump

MC deficiency – hyponatraemia, hyperK and hypotension

MC excess – hypernatraemia, hypoK and HT (conn’s tumour)

Glucocorticoid actionThe broad and systemic effects of glucocorticoids on intermediary metabolism are manifest as ↑in nutrient availability, ↑blood [glucose],[ AA], and TGA levels. In response to stress, this ensures critical organs receive adequate substrate supply. Effects of excess glucocorticoids however, ↑ in AA levels are bought at the expense of protein synthesis, which can lead to fast twitch muscle wastage over time/ They can also lead to negative Ca balance, affecting absorption in the GI. Over time they can reduce bone resorption, affecting skeletal integrity and significantly ↑ risk of fracture in the elderly and retarding linear bone growth in kids. Prolonged elevation of corticoid levels and the tendency to hyperG can lead to DM in susceptible individuals. Effects on the CNS are reported ranging from euphoria to psychosis in some people.

↑glucose productiono ↑glycogen breakdown in livero ↑hepatic gluconeogenesiso ↓glucose uptake by peripheral tissues

↑protein breakdowno Protein breakdown to AAo Catabolic effecto Particularly proximal muscles.

Direct activation of lipolysis and redistribution of fat deposition. Central obesity and dorso-cervical fat pad.

Inhibition of B and T cell responses ↓transcription of cytokines ↓cell adhesion by leucocytes ↓phagocytic function Immune suppression

Endogenous GCs can also act as anti-inflammatory and immunosuppressant drugs. It is these properties that are therapeutically exploited through deliberate amplification of these effects in exogenous steroids. Widely used in many inflammatory disease and immunosuppression. Also used to replace in adrenal insufficiency and malignancy.

Inhibition of osteoblast formation

↑osteoclast proliferation ↓Ca absorption in gut ↓sex steroid production osteoporosis

Relative CG and MC action:

Drug GC MC Reason for use:Hydrocortisone 1 1 Corticosteroid replacementPrednisolone 4 0.8 Inflammatory DiseaseDexamethasone 25 0 Tumour/oedema Betamethasone 25 0 Eczema topical treatmentFludrocortisone 10 125 Aldosterone replacement

Pharmacokinetics – Oral steroids, similar rates of absorption and similar bioavailability. T1/2 8-72 hours. Endogenous corticosteroids are about 90% bound in plasma; however synthetic ones vary in their degree of plasma binding. After crossing the cell membrane, they first bind with intracellular receptors. The hormone receptor complex forms a dimer with another HR complex. The dimer than translocates to the nucleus where it binds with a glucocorticoid response element. The bound form of the GRE then modulates transcription of the associated genes. This has profound effects on mRNA expression, as it appears at least 1% of nuclear genes can be regulated by the above pathways. Therapeutic effects of changes in gene expression may only be apparent some hours after administration. Inhaled steroids – 80% swallowed, lipophilic compounds retained longer in lungs.

Hepatic and renal CL: CL ↓with age and ↑ hyperthyroidism. Small amounts excreted in breast milk.

Intravenous – IV methylprednisolone Oral - oral prednisolone; oral dexamethasone, oral hydrocortisone, oral fudrocortisone Inhaled – inhaled beclomethasone, inhaled fluticasone (high 1st pass metabolism) Topical - Flexor > forehead > scalp > face > forearm – topical betamethasone Intra-articular – intra-articular triamcinolone, intra-articular depo-medrone

With ↑systemic dosing PKs become no-linear, as plasma GC binding sites become saturated with resultant ↑in unbound plasma levels.

Summary of clinical use – adrenal insufficiency, Inflammatory disease, immune-suppression, malignancy, diagnosis of Cushing’s

Adrenal insufficiency – primary adrenal failure, Rx – hydrocortisone/fludrocortisone. Mimic normal physiology.

Inflammatory disease – vasculitis, sarcoidosis, RA, asthma, GI disease (crohn’s UC), inflammatory skin conditions, nephritic syndrome, haematological conditions, cerebral oedema

Immuno-suppression – acute transplant rejection, acute leukaemia, pemphigus, exfoliative dermatitis

Malignancy – hypocalcaemia, improve appetite, malignancy oedema (inhibit cytotoxic cytokines)

Diagnosis of Cushing’s Syndrome – Dexamethasone suppression test, 2 days dexamethasone, measure cortisol levels before and after, normal individuals suppress < 50nmol/l). Failure to suppress in Cushing’s syndrome. Dexamethasone negatively feedbacks on hypothalamus and pituitary so no CRH and ACTH should be made respectively and thus cortisol.

SE of Steroids

Mineralocorticoid effectso Effects on MC receptoro Fluid retention – HTo Hypokalaemia

Glucocorticoid effectso Osteoporosiso Avascular necrosiso Peptic Ulcers reduced arachidonic acid productiono ↑infectionso HT

Adrenal suppression – Exogenous steroids all act on the HPA axis like cortisol, so CRH, ACTH and cortisol release all reduced. This occurs after 3 weeks. A dose of prednisolone > 20mg will suppress HPA axis and may persist for years if long term treatment. Abrupt withdrawal may lead to a hypo-adrenal crisis.

Hypoadrenal crisis – hypotension, hypoglycaemia, hypokalaemia, severe dehydration, DEATH Treatment – give fluid, glucose, steroids

Subtle effects – fever, myalgia, arthralgia, weight loss, conjunctivitis, rhinitis

Patients on long term steroid cannot mount an endogenous stress response risk of peri-operative hypoadrenal crisis. Inform anaesthetist and surgical seniors early.

Laparotomy or major procedure – hydrocortisone 100mg IM at induction. Hydrocortisone 100 mg IM 6 hourly until eating and drinking. Double normal oral steroids until full recovery

Less invasive surgery – HC 100mg at time of procedure, double normal oral dose until full recovery

Intercurrent illness – double oral dose, IM injection if diarrhoea or vomiting, may need admission

Drug interactions

Patients on steroids often on numerous medications enzyme inducers (phenytoin, primidone and rifampicin) may ↓steroid effects. Enzyme inhibitors (OCP) may ↑effects

‘Steroid sparing agents’ reduce steroid requirement, Azathioprine, cyclophosphamide, biological therapies, important for reducing steroid side effects.

Can cause peptic ulcer, diabetes mellitus?, intercurrent infection

Guidelines for use

Should be published evidence that steroids help the condition you are treating.

Steroids are beneficial in asthma, this is less clear-cut in COPD. No beneficial effect on exacerbation rate. NICE – inhaled steroids indicated in COPD if low peak flow and more than two exacerbations per year otherwise risks of steroids outweigh benefits.

Glucocorticoid effectso Diabeteso Impaired growtho Skin Atrophyo Cataractso Corneal damageo Cushingoid features.

Generally

Have a specific Rx objective. Use only if other Rx fail. Administer for a sufficient time to allow response and do not administer for longer than necessary.

Stop steroids if no response when expected or maximum benefit achieved. Stop if complications occur that are worse than the disease. Consider agents to prevent osteoporosis. Use of objective measure of response where possible (peak flow, ALT, CRP)

Abrupt cessation of GCS due to SE or other reasons is not normally undertaken due to the risk of adrenal insufficiency. Even short term (> 3 weeks) Rx with greater than 20mg of prednisolone can lead to suppression of the HPA axis. Gradual tapering of doses allows reactivation of the HPA and return to its normal function. Failure to do this can lead to chronic adrenal atrophy, which can be fatal.

Advice to patients – don’t top immediately, glucose/HTN will need to be monitored, need to carry a steroid card and to tell HCW’s they are on steroids if needed, go and see GP if any ADRs

Session 4 Diabetes mellitus – insulin, other hypoglycaemia agents and obesity drugsElevated glucose leads to acute symptoms – polyuria, polydipsia and weight loss

Chronically elevated glucose leads to complications

Microvascular – renal, retinal, neurological

Macrovascular – cerebrovascular, cardiovascular and peripheral vascular

In a normal person, the rate of insulin production is continuous and very fine, governed by the ATP/ADP ratio in the β-cells. This in turn directly reflects the variations in blood glucose. Allied with a very short t1/ of endogenous insulin of 10 minutes, normal homeostatic control of glucose is very efficient.

Type 1 - characterised by ketonuria absence of insulin

Type 2 – endogenous insulin does not work to control sugar adequately – insulin resistance and relative insulin deficiency. Insulin levels can be very high. Type II typically presents in those above 40 with obesity. Can go undiagnosed for years as it is a gradual disease.

Insulin’s actions: Fuel metabolism

o Glucose- action about which we are concerned Inhibits liver glycogen breakdown ↑uptake of glucose by liver ↑uptake by muscle and adipose tissue

o Free fatty acids Insulin promotes clearance of free fatty acids

o Amino acids

Active transport of AA into cells Inhibits catabolism of proteins Inhibits gluconeogenesis in liver

Diabetes is a state of premature CV death associated with hyperglycaemia

Management – glycaemia control – aim to achieve HbA1c target (<7% to minimise microvascular outcomes)

Treatments – diet and exercise, oral hypoglycaemic drugs, insulins, Obesity drugs (in the absence of success by diet and weight control, some clinicians consider them)

Limiting CV risk – targeting of traditional risk factors

Type 1 diabetes

Insulin – intermediate, rapid, mixtures, analogues, numerous devices for administration Adequate patient education

o Home blood glucose monitoring and making use of resultso Dose adjustment for normal eating (DAFNE) course o Regular HbA1c testing – HbA1c >7% exponentially causes vascular complicationso Detect damage to renal, hepatic, cardiovascular and neurological function.

Human insulin is made up of 2 polypeptide chains linked by 2 disulphide bridges

Fast acting native insulin – actrapid, humulin S

Fast acting analogues – novorapid, humalog

Intermediate – acting native insulin – insulatard, humulin I

Intermediate/long acting analogues – levemir, glargine

Insulin Type Onset Peak Duration UsageUltra rapid 0.2-0.5 1 3-4 Meals/acute hyperGShort acting 0.5-1 2-5 6-12Intermediate 1.5-3 4-10 16-24 Basal insulin/

overnight controlLong acting 4-6 8-30 18-36

Pre-mixed insulin regimeno Humalog mix 25, novomix 30, mixtard 30 – taken twice a day with or before meals,

lacks flexibility but only twice a day Basal bolus regimen – intermediate or long acting insulin as background, fast acting insulin

with meals, flexible but up to 5 times a day

Type 2 diabetes Diet and exercise – around 90% are overweight/obese Anti obesity drugs Oral hypoglycaemia drugs Newer agents Insulin is needed in the end if the patient lives long enough as type 2 is a progressive disease

Benefits of 10% weight lossMortality >20% ↓in total mortality

>30% ↓in diabetes related deaths>40% ↓in obesity related deaths

Blood pressure ↓of 10mmHg/20mmHg systolic/diastolic Diabetes 50% ↓in FBS

15% ↓in HbA1c (60% reduction in progression to diabetes)Lipids 10% ↓total cholesterol

15% ↓in LDL30% ↓in triglycerides8% ↑in HDL

Diet Reduced energy intake in overweight Carbohydrate (>55%), Fat (<30%, saturated fat < 10%), protein (10-15%) Encourage complex carbs Limit salt intake (<6g/day) Limit alcohol intake (m <21 units, f<14 units) ↑exercise STOP SMOKING

Therapy should be escalated when previous management has started to fail (HbA1c levels) patients should be made aware this will occur. Lifestyle discussed on every occasion. Start with oral agents (each lower HbA1c by 2%)

Metformin first, unless contraindicated Progress to multiple oral agents Progress to insulin

Improvements in micro-vascular diseases were not matched by similar improvements in macro-vascular disease. There is thus a need for a therapy which provides continued and sustained glucose control and an improved SE profile. Insulin resistance should be a target of therapy which has the potential to provide improved glycaemic control, improved SE profile, and may benefit the macrovascular complications of the disease.

Metformin (class – biguanides) – action is not fully understood – receptor unknown

↓hepatic gluconeogenesis mitochondria can reduce HbA1c by 2% ↑glucose uptake in skeletal muscle and fat – GLUT 1 and GLUT 4 Metformin ↑insulin sensitivity so ↑skeletal and adipose glucose uptake. Special benefits in overweight patients

o Weight-neutral or weight- reducing (stimulates appetite)o Improvement in CV outcomes (↓LDL and VLDLS)

SE mitigated by slow dose titrationo Usual maximum dose is 1g bd

Contraindicated in metabolic failure – stop before radiocontrast media and surgery Does not cause hypoglycaemia. T1/2 2-3 hours so given 2/3 times a day prior to meals to provide acute negative feedback on

top of a basal endogenous insulin signal. GI disturbances are common but can be ameliorated by slow dose titration. Use is

contraindicated in patients with compromised HRH and resp disease.

SulphonylureasDrugs: tolbutamide, glibenclamide and glipizide. Vary PK and PD. Are chosen for use to supplement endogenous insulin accordingly. Tolbutamide shortest T1/2/ 4 hours acts for 6-12 hours. Offers better short term post prandial control of glucose and is given about 30 mins before eating. The other two are much more potent but not therapeutically superior. T1/2 and duration of action for glibenclamide is 10 hours and 18-24 hours. Glipizide 7 hours and 16-24 hours. These will provide a longer duration of negative feedback on top of any basal endogenous insulin signal. Reduces HbA1c by 1-2% given once a day. They act by binding to and antagonising β-cell K+/ATP (efflux) channel activity. The ↓ in K+ current results in depolarisation, as K+ accumulates in the β-cell. This is turn results in ↑ Ca2+ entry which governs the fusion rate of insulin vesicles with the β-cell membrane and their release into circulation.

Enhances insulin secretion (irrespective of ambient glucose level) Reduces fasting and postprandial glucose Half-life important

o Glibenclamide long T1/2 – can lead to prolonged hypoglycaemia, especially in elderlyo Gliclazide short T1/2 and therefore, preferred agent

Common ADRs – GI disturbance Can cause hypoglycaemia

Associated with weight gain.

Repaglinide (class – meglitidines) Non-sulphonylurea insulin secretagogue Three receptors

o Similar action to sulphonylureas. Identical efficacyo Requires glucose to have effect taken before meals

Short plasma half-life T1/2 0 1-3 hours –o 0.5 mg with meals, max 16mg/day – weekly increase in dose if required

Weight neutral ++++ Less severe hypoglycaemia

Acarbose Α-glucoside inhibitor

o Delays absorption of carbs – allows beta- cell time to augment responseo ↓HbA1c by 1%, fasting plasma glucose by 1.5 mmol

No change in weight Modest ↓in triglyceride Dosage schedule – with first bite, start low, ↑every 2 weeks Contraindicated in renal failure, IBD and cirrhosis Rarely used owing to poor efficacy and significant GI side effects

Thiazolidinedionese.g. Rosiglitazone and pioglitazone, relatively new. Peak effect after 1-2 months, which include reduction of gluconeogenesis and ↑glucose uptake into muscle. ↓ HbA1c by 1-1.5%.

PPARγ-agonists – improve insulin sensitivity – liver, skeletal muscle and adipocytes. The known action does not fully explain its effect. They agnostically bind to the nuclear hormone receptor site the peroxisome proliferator-activated receptor- γ. This binds with another nuclear receptor the Retinoid X receptor. The complex then appears to upregulate a wide set of genes with products important in insulin signalling which govern glucose and lipid metabolism. Receptor high presence in adipose and low in liver and skeletal, it is suggested that the signalling element that causes the effects observed in muscle and liver is due to a reduction of FA release into the blood.

T1/2 = 7 hours, but metabolites can have some degree of pharmacological activity and have prolonged t1/2 up to 150 hours. Given once a day, do not offer as fine glycaemia control as Metformin. 99% bound in plasma (DDI’S)

Improve beta-cell function Do not induce hypoglycaemia. Associated with weight gain – part of action of these drugs. ADRs: ↑LDLs ↑HDLs oedema Contraindicated in heart failure Recent controversy about CV effects and ↑risk of bone fractures

Pharmacology of type 2 diabetes Metformin – first choice in overweight or obesity unless contraindicated Sulphonylureas and their derivatives (when HbA1c above 7%) Thiazolidinediones (HbA1c above 7.5%) Insulin’s (HbA1c above 7.5% and other drugs not working)

Newer agentso GLP 1

analogues – GLP1 is produced by L cells of the small intestineo DPP4 inhibitors – DPP4 is the enzyme that breaks down GLP1

ADRs of diabetic drugs hypoglycaemia leading to coma.

Obesity is a growing problemThree specific drugs:

Orlistato Gastric and pancreatic lipase inhibitor – theoretical deficiency of fat soluble vitaminso ADRs – Gi disturbance and fatty stools, flatus and faecal discharge

Sibutramine – appetite suppression ↓in hyperG and rate of glucose metabolism ↑ thermogenesis

NA and 5-HT reuptake inhibitor Contraindicated in depression Blood pressure must be closely monitored causes ↑HR and BP

o Rimonabant Endocannabinoid antagonist – newest agent Contraindicated in depression

All drugs have appropriate support programmes

Cholesterol PharmacologyAtheroma Sequence of Events:

Endothelial injury (due to HTN/LDLS/DM) platelet adhesion PDGF release SMC proliferation and migration LDL oxidation by macrophages uptake of lipid by SMC and macrophages SMC produce matrix Foam cells produce cytokines further SMC stimulation + ↑ recruitment of inflammatory cells fibrosis cap ruptures haemorrhage thrombosis ARTERY OCCLUSION

Cholesterol is a major risk factor in CHD and a 10% reduction in total cholesterol results in: 15% ↓in CHD mortality 11% ↓in total mortality

Statins

Synthesis of LDL Receptor Serum LDL Cholesterol

Reduced VLDL

Cholesterol

LDL is the primary target to prevent CHD/ Intensity of intervention depends on total CV risk.

HTN, smoking and cholesterol level as risk factors act in synergy multiplying the effect.

TC <5.0mmol/L. Fasting LDL should be < 3mmol/L HDL >1.2mmol/L TG 0.5-1.9mmol. Once treatment with lipid lowering drugs target TC < 4.0 fasting LDL <2.0 HDL > 1.4Pro-atherogenic effects of ox-LDL:

Inhibits macrophage motility Induces T-cell activation and

VSMC division/differentiation Toxic to endothelial cells

Enhances platelet

aggregationStatinsInhibit cholesterol synthesis in hepatocytes. ↑CL of LDL and LDL also

↓production of VLDL and LDL. Is ↑because depleted [cholesterol] in hepatocytes causes upregulation of LDL receptors. Statins ↓LDL by 5-35% and ↑HDL by 5% and ↓TGA’s by 10- 35%. indications CV risk prevention (CVD + DM) and familial hypercholesterolaemia. CV risk of > 20% over 10 years. PK – intestinal absorption varies between 30-85%. Hepatic FPM is extensive, but may occur by diffusion or active transport by OATP3. Due to this and the requirement by some statins for activation, systemic availability may be 5-30% of administered dose. Hepatic elimination includes CRP3A4 for some statins whilst others are only metabolised by phase 2 pathways.

ADRs of statins ↑transaminase levels

o 0.1% - 2.5% of treated patients develop ↑of > 3 X upper-normal limit, especially at higher doses/ Rapidly reversible, no evidence of chronic liver disease

Myopathy

Oxidation

o Diffuse muscle pain and CPK > 10 X upper-normal limit. Primary seen when higher doses of statins are used in combination with cyclosporine, gemfibrozil and occasionally erythromycin and niacin 0.01%

Miscellaneous – GI complaints, arthralgias and headaches. 5% get muscle ache of which half is due to the statins

Other benefits of statins: anti-inflammatory, plaque reduction, improved endothelial cell function, ↓thrombotic risk.

They are the preferred lipid lowering agent.

Mean Total cholesterol ↓

CHD events ↓

Number needed to treat for 5 years for one person to benefit

T1/2

Simvastatin 27.5% 126 19 1-4 given at night*Pravastatin 26.8% 123 20Fluvastatin 27.0% 124 19Cerivastatin 27.2% 125 19Atorvastatin 31.6% 145 17 20 (greater efficacy)

Cerivastatin banned for killing people if used in combination with a fibrate.

*cholesterol metabolism peaks in the early hours.

Atorvastatin long t1/2 so can be used either day or night, unlike other statins which are only at night. Mnemonic any time day OR night.

Statins as a group also exhibit non-linear PD where for any statin, a doubling of dose results in =6% ↓in LDL.

Drug-drug – affected by CYP inducers (rifampicin and St. Johns wort)/inhibitors (grapefruit juice and verapamil).

Fibric acid DerivativesAmpipathic carboxylic acidsPPARα agonist (peroxisome proliferators – activated receptor) – ↑production of lipoprotein lipase.

- ↓triglyceride production- Improved postprandial triglyceridemia- Some ↓(10-20%) in LDL but variable, depending on specific drug.

↑FA uptake and oxidation, ↓triglyceride levels. ↑LDL particle size and HDL-C levels direct vascular effects.

Indications – adjunctive therapy to diet, hypertriglyceridemia, combined hyperlipidaemia with low HDL who do not respond to NA

Efficacy – ↓TG 25-50%, LDL ↓, ↑HDL 15-25% in hypertriglyceridemia

Side effects – GI upset (8%), cholelithiasis (gallstones), myositis, abnormal LFTs

Contraindications – hepatic or renal dysfunction, pre-existing gallbladder disease/

Examples: gemfibrozil (also inhibits both OATP2 and statin glucoridination) this ↑statin plasma levels but also synergistically ↑the risk of myopathy.

Nicotinic Acid

Relatively new, rarely used

↓VLDL and ↑HDL at high doses. Best agent to raise HDL-C. Lipid lowering effect by inhibition of lipoprotein lipase. Reduces coronary events

SE: flushing, itching, headache, hepatotoxicity, GI, activation of peptic ulcer, hyperglycaemia and ↓insulin sensitivity.

Contraindications – active liver disease or unexplained LFT elevations and peptic ulcer disease.

Ezetimide – mechanism of action

It selectively inhibits intestinal cholesterol absorption blocks NPC1L1 in the brush border stopping uptake.

- ↓ intestinal delivery of cholesterol to the liver- ↑ expression of hepatic LDL receptors

Fibrate

- ↓ cholesterol content of atherogenic particlesEzetimide and its active glucuronide metabolite circular enterohepatically – delivers agent back to the site of action – limits systemic exposure. Can ↓LDLs by 15-20%. Ezetimide + statin works better than doubling the statin dose and ↓statin ADRs.

ADRs = headache, abdominal pain and diarrhoea.

Combination therapy

Combination fibrate and statin therapy may significantly improve triglyceride, LDL-C and HDL-C levels. But fibrates plus statins are associated with ↑risk for myopathy and rhabdomyolysis

Not thought due to cytochrome P450 drug interaction. Gemfibrozil may impair glucuronidation of statins (with Cerivastatin being more susceptible than other statins such as Simvastatin and Atorvastatin). Fenofibrate appears to have less potential for impairment of statin metabolism, and thus this may account for the reduced reports

Plant sterols –found in low fat spread – prevent the cholesterol uptake through gut wall.

Positive dietary factors: fish oils, fibre, vitamin C/E, alcohol (HDL)

Negative – dietary cholesterol/fat and alcohol.

Drug/class LDL HDL TGsStatins ↓5-35% ↑5% ↓10-35%.Ezetimibe ↓15-20% ↓3% ↓8%Nicotinic acid ↓8% ↑8-25% ↓14-35%Bile acid sequesterants ↓8-24% ↑8-25% -Omega-3 FA = = ↓Fibrate ↓5 ↑5-15% ↓35-70%

Session 5 – AntibioticsAntibiotic targets:

DNA synthesis – Quinolones (ciprofloxacin), folic acid antagonists (trimethoprim, sulphonamides)

Protein synthesis – aminoglycosides (gentamicin), macrolides (erythromycin), tetracyclines Cell wall synthesis – Beta-lactams (penicillins, cephalosporins, carbapenems), glycopeptides

(vancomycin)

Prophylaxis of bacterial infections People at ↑risk of infection: Peri-operative – prevention of surgical site infections Short term – meningitis contacts Long term – asplenia, immunodeficiency

Therapy of significant bacterial infectionsRx of culture proven infection or empirical Rx of suspected organism. This involves either following the local antibiotic formulary or the thoughtful way (likely cause of infection? Which antibiotics are likely to be effective? Which one is best?)

Likely organisms can be ascertained from a good history, and anatomical site, and time of year

Community of healthcare onset? Severity of infection? Baseline rate of resistance? Immune statuses of patient- THINK likely susceptibility, and consequences of wrong choice.

Best choice think: cost, efficacy, age, toxicity, drug interactions, allergies, pregnancy breast feeding, organ function, administration route, cost.

Judicious antibiotic therapy: ideal clean kill of infecting bacteria with minimal impact on commensal organisms and no resistance in any surviving pathogens. Along with no unwanted effects in patient such as drug interactions and no toxicities (pharmacological, immunological, and idiosyncratic)

Cephalosporins are linked to clostridium difficile infection!!!

Measure antibiotic activity via disc testing on an agar plate

Bacteria can gain resistance by chromosomal gene mutation or horizontal gene transfer.

ANTIBIOTIC RESISTANCE:

Antibiotic inactivation – e.g. beta-lactamase Alteration of target site – e.g. penicillin binding protein Alteration of metabolic pathway – para-aminobenzoic acid is normally required by bacteria

but some can use preformed folate instead ↓intracellular antibiotic accumulation via ↓permeability OR active efflux mechanisms

Some super-bugs: Methicillin resistant staphylococcus aureus (MRSA Glycopeptide intermediate susceptibility staphylococcus aureus (GISA) Glycopeptide resistant enterococci (GRE) Extended spectrum beta lactamase enterobacteriaceae (ESBLs) Extensively drug resistant klebsiella pneumonia (XDR-KP)

Minimum inhibitory concentration – the minimum concentration of antibiotic required to inhibit growth of bacterium in vitro. Units are mg/l – antibiotic and isolate specific

Breakpoint considers the MIC, antibiotic PK. Thus predicting the likely response from susceptible intermediate resistant

Preventing antibiotic resistance – infection control AND judicious antibiotic use

Prevent bacterial exposure to antibiotics – minimise risk of infection, monitor and control antibiotic prescribing

Preventing the spread of recognised resistant bacteria – isolation or cohorting, hand hygiene, decolonisation of patients

Judicious antibiotic therapy (right antibiotic, Right dose, right frequency, right duration)

Pharmacodynamics

Time dependent killingo Successful treatment requires prolonged antibiotic presence at the site of infectiono But not high concentration

Concentration dependent killingo Successful treatment requires high antibiotic concentration at site of infectiono But not for long

PK– administration (oral or IV), distribution, elimination/metabolism

Therapeutic drug monitoring is used to ensure there is an adequate dose which is non-toxic. Aminoglycosides/vancomycin

AntiviralsInfections treated with antiviral agents:

DNA viruseso Herpes simplex I and IIo Varicella-zostero CMVo EBVo Human herpes virus – 8o Hepatitis B

Antiviral drug development- there needs to be a burden of disease and clinical need. The virology of what to target needs to be understood, drug development clinical trials and impact adverse effects resistance and monitoring

The Flu

Most complications occur in otherwise healthy persons these are bronchitis, pneumonia, sinusitis, exacerbation of underlying disease

Three types: Influenza A – multiple host species, antigenic drift and shift

o Naturally occurs in aquatic birds and a range of other species. There are 15 subtypes of haemagglutinin and 9 subtypes of neuraminidase. These surface glycoproteins are the antigenic determinants to man. Only 3 HA lineages have become established in man suggesting a degree of host specificity. Cross species transfer does occur

Influenza B – no animal reservoir, lower mortality Influenza C – common cold like

To gain entry into a host cell, the invading virion first attaches to a neuraminic or sialic acid residue on a membrane glycoprotein. The complex then allows the virus to gain entry by endocytosis. Following uptake of the virion into a host cell by endocytosis: There are two steps that must go ahead uncoating and successful transcription of viral RNA. The 1st step involves ATP driven proton entry into the endosome to allow fusion of the viral membrane with the internal endosomal membrane.

RNA viruseso Influenzao HIVo Hep Co Polio

The second step involves entry of protons into the virus itself via a viral ion channel known as M2. The low pH inside the virus then results in the breakdown of the viral coat of the nucleocapsid. The RNA can then escape out into the host cell cytoplasm. This then is used to form viral proteins RNA replicates and virion assembly then occurs and it is shed from the cell.

Influenza viruses are enveloped RNA viruses with segmented genome belonging to the family of orthomyxoviridae. Both A and B viruses contain 8 RNA segments each individually encapsidated by the viral nucleoprotein and possess two surface glycoproteins embedded into the membrane: the HA and NA, which are capable of eliciting antibody responses in humans. Influenza C viruses contain 7 RNA segments. HA is involved with receptor binding and membrane fusion. The NA catalyses the cleavage of viral progeny from infected cells. It also prevents virus clumping so that each virion can function as an independent infectious unit. It facilitates cleavage of sugar residues on HA, and by modifying HA carbohydrate side chains may be implicated in virulence. It also facilitates movement of virus through inhibitory mucopolysaccharides coating the respiratory tract epithelium allowing cell to cell spread through the respiratory mucosa. A third surface protein, the M2 ion channel, is a tetrameric membrane channel important in the regulation of internal pH of the virion.

Amantadanes: M2 ion channel

Amantadine and rimantadine – anti-parkinsonism activity, available since 1960’s. Tricyclic amines block M2 channel to inhibit viral uncoating. Active against influenza A including non-human subtypes. Amantadine has more marked ADR risk than rimantadine of about 5-10% ADRs include dizziness, GI disturbance and hypotension. More serious are confusion and insomnia and hallucination which can be problematic in the elderly whom these symptoms may be present and further exacerbated. For this reason rimantadine is used more.

There are a number of limitations. Amantadine will only affect A subtypes. There are a number of side effects on the CNS (usually minor and transient. These symptoms are predominately in the elderly. It can lower epileptic seizure threshold and accumulates in renal failure.

VACCINE

Neuraminidase inhibitor

M2 inhibi

tor

Single point mutation in M2 gene: S31N leads to the rapid emergence of drug resistant strains. High-level ,rapid emergence resistance Transmissible H5N1 isolates 2003-present: resistant H3N2 (> 60% Asia 2003-04, >90% US 2005-6

They use gene sequencing of protein, X-ray crystallography of Nuclear magnetic resonance to try and work out the structure of target sites for drugs and to evaluate them.

Neuraminidase is essential for replication. Surface of influenza highly variable. Active site is conserved across subtypes. The existence of an unchanging molecular structure present in nature suggests a site that is essential to survival. Subsequent research demonstrates that this pocket is indeed the active site through which neuraminidase cleaves sialic acid (membrane glycoprotein residues on the cell membrane. Without this, the virus cannot break the cellular bond and is unable to spread. Ideal target for antivirals

Human and non-human influenza A Influenza B M2 resistant viruses Avian strains including H5N1 Reconstructed 1918 pandemic H1N1

Neuraminidase inhibitors (sialic acid derivatives) stop the cleaving of viruses effectively stop viral replication. The selectivity donates their lack of activity against human neuraminidase.

Zanamavir – low bioavailability, dry powder aerosol, remains detectable in sputum up to 24 hours post dosing and is renally excreted

Oseltamivir (tamiflu) – prodrug, 80% bioavailability

Tamiflu if treatment commenced within 24hr of symptom onset it ↓the duration of the illness by 36%, and if given within 36hr the duration is 25%. Also ↓in severity of illness in influenza-infected patients. Is effective given up to 48hr after symptom onset. Even if the patient receives tamiflu after As seasonal prophylaxis – there is a 76% reduction in the number of patients with flu as compared with placebo 70% reduction in risk of mortality even 64 hours after symptom onset.

48 hours there chance of surviving is ↑. Little benefit after this time.

Prophylaxis treatment for six weeks with 75mg significantly ↓incidence of flu in both healthy adults and frail elderly subjects.

ADRs of both – generally not serious – GI disturbance, headache, nose bleed, rarely resp depression bronchospasm. Well tolerated in children.

There is oseltamivir resistance in H5N1.

Surveillance for resistance: Influenza WHO system Neuraminidase inhibitor susceptibility network

National and European surveillance Detailed evaluation of post treatment isolates.

Viruses tend to stay Zanamavir sensitive. This is because mutations around the active site does not affect binding it is smaller so more easily fits into the active site. Oseltamivir has a longer stalk. Tight fit into a pocket of active site. N1 has a smaller pocket than N2. Mutations around the site close it, oseltamivir no longer fits. The neuraminidase enzyme also appears to be evolutionary conservative, which is a great advantage for any antimicrobial therapeutic.

So far very little resistance in swine flu H1N1

Session 6 – Pharmacology of Airway ControlAsthma is a heterogeneous disease characterised by smooth muscle dysfunction (↑ contraction↑ cytokines/chemokines) , airway remodelling (mucus hyper-secretion, subepithelial fibrosis, epithelium desquamation, airway wall thickening) and lastly inflammation (T cells and mast cells)

There are a symptom patterns and triggers of exacerbations.

Bronchoconstriction leads to increased lower airway resistance. Normally about 40-50% of flow resistance is in the URT where no gaseous exchange takes place. The remainder of resistance is provided by the trachea and down to the 7th generation bronchi.

Bronchial hyperresponsiveness – a factor contributing to airway dysfunction. Defined as an exaggerator bronchoconstrictor response to direct pharmacological stimuli such as histamine, or indirect stimuli such as exercise. These indirect stimuli cause bronchoconstriction at least in part through the direct and indirect activation of airway mast cells. Mast cell mediators then induce bronchoconstriction.

Asthma attack: Immediate phase in allergic asthma, is due to interaction with mast cell fixed IgE. This results

in the release of histamine and a host of potent spasmogens leading the immediate bronchospasm

Late phase – Co-release of a range of mediators and chemotaxins activate a complex immune system response that bring leucocytes to the area this causes exacerbated bronchospasm and congestion due to epithelial damage, thickening of the BM, oedema and mucus production. Additionally, the epithelial damage leads to ↑exposure of the sensory irritant receptors, which further exacerbates bronchial hyperactivity and sensitivity. While this dual response to allergen challenge is relevant to symptoms in some atopic individuals, the Pathophysiology of ongoing day-to-day symptoms and asthma exacerbations is undoubtedly much more complex and the mechanisms are poorly defined.

Burden High prevalence rate (10% in 13-14 yr olds) 5.1 million : 0.5 who are refractory to therapy 74,000 emergency hospital admissions/yr 1500 deaths

Asthma control means: Minimal symptoms during day and night Minimal need for reliever medication No exacerbations No limitation of physical activity Normal lung function (FEV1 and PEF > 80% predicted)

Aim for early control, with stepping up or down as required.

Before initiating a new drug therapy check compliance with existing therapies and inhaler technique and attempt to eliminate trigger facts.

Step 1 – mild intermittent asthma

Short-acting β2-agonists such as salbutamol or terbutaline. Uses:

Symptom relief through reversal of bronchoconstriction. Prevention of bronchoconstriction i.e. before exercise Used on an as-required basis If used regularly, they reduce asthma control. Also cause reduced histamine release and increased mucociliary clearance

Its action is predominantly on airway smooth muscle, and potentially inhibits mast cell degranulation if only used intermittently. On regular use of β2-agonists, mast cell degranulation in response to

allergen ↑.

STEP 1 β2 - Agonist binds at Receptor the β2 - adrenoreceptor (Gs GPCR). STEP 2 Intermediate signalling via Gs a -sub unit to ↑cAMP production via adenyl cyclase STEP 3 ↑cAMP production results in ↑activation of Protein Kinase A STEP 4 Protein Kinase A directly ↓Ca binding by myosin in SM therefore inducing relaxation β2 – Agonists binding will lead to ↑K+ efflux (Calcium activated) augmenting the relaxation.

SE of β2- agonists – adrenergic i.e. tachycardia, palpitations, tremor etc even though B2 agonists are very selective (?approx. 200-40 of B1) they can still agonist cardiac B1 receptors sufficiently to

induce tachycardia and dysrhythmias. The most notable negative interaction is with β blockers which bind to both β1 and β2. This can lead to severe asthma refractive to any treatment with β2 agonists.

Step 2 – Regular preventer therapy

Inhaled corticosteroids – ↓mucosal oedema,↓ bronchoconstriction and↓ mucus plugging. Also ↓inflammation and stop airway remodelling so ↓bronchial hyperresponsiveness

They improve symptoms improve lung function ↓exacerbations prevent death

Lipophilic substituent’s on D-ring lead to combination of 3 key properties (they are added to the steroid. )

A very high affinity for the GCS receptor ↑uptake and dwell time in tissue on local application Rapid inactivation by hepatic biotransformation following systemic absorption.

Patients with eosinophilic asthma have a better treatment response to inhaled steroids than non-eosinophilic patients. Additionally, they act to ↑the expression of β2-receptors and anti-inflammatory interleukin proteins. Optimal effects are seen after weeks/months of therapy.

Some of the drug is swallowed and absorbed in the gut and some is absorbed from the lungs into the systemic circulation. From the gut it enters the liver which most of it is inactivated in FPM

Systemic absorption of ICS – beclomethasone absorbed through gut and lungs, budesonide and fluticasone undergo extensive FPM. Lung absorption is still relevant and at high doses all ICS have the potential to produce systemic SE.

STEP 3- Add on therapy

Re-check patient’s medication compliance and inhaler technique and eliminate risk factors. Typical indication of moving up to step 3 is if the patient still wakes up a night due to asthma.

First choice – long-acting β2 – agonists such as (formoterol, salmeterol)

Formoterol SalmeterolUsual dosage 12 g μ 50 gμOnset of action 1-3 min 10-20Duration of action 12hr 12hrIntrinsic B2-agonist activity 0.85 0.71Molecular properties Moderately lipophilic Highly lipophilic

The lipophilic characteristic means they sit in the membrane. Formoterol is 5 times more potent than salmeterol and 400 times more than terbutaline Salmeterol is a partial agonist and can only achieve 40% of maximal relaxation. Salmeterol is less efficient at activating the receptor.

Therefore: LABA Reduce asthma exacerbations Improve symptoms Improve lung function Not anti-inflammatory on their own, and must always be prescribed in conjunction with an

inhaled steroid.

Combined inhalers: Budesonide/formoterol (symbicort) Fluticasone/formoterol (seretide) Beclomethasone/formoterol (fostair)

Why? – Easier to use, greater compliance, only 1 prescription, potentially cheaper than 2 inhalers, safety as patient can’t take LABA on their own. Shown combinations ↓freq of severe exacerbations

Step 4 High dose ICS Leukotriene receptor antagonist Theophylline (methylxanthines)

LRA’s LTC4 released by mast cells and eosinophils can induce bronchoconstriction, mucus secretion and mucosal oedema and promote inflammatory cell recruitment. LRAs block the effect of cysteinyl leukotrienes in the airways at the CysLT1 receptor. Some anti-asthma activity but only useful in about 15% patients as off-on therapy. It’s not a wonder drug.

Side effects: angioedema, dry mouth, anaphylaxis, arthralgia, fever, GI disturbances. All rare

Administration - orally

Methylxanthines 1. Antagonise adenoside receptors2. Inhibit phosphodiesterase – so ↑cAMP – unlikely to be relevant in vivo3. As with LTRAs, often poorly efficacious4. Narrow therapeutic window5. Frequent side-effects – nausea, headache, agitation tachycardia. 6. Potentially life-threatening toxic complications – arrhythmias, fits7. Important drug interactions – levels ↑by cytochrome P450 inhibitors e.g. erythromycin,

ciprofloxacin.

8. Can be used in COPD and status asthmaticus.

They are administered orally.

Step 5 Oral steroids – (side effects)/ IV hydrocortisone Step 5+ anti-IgE therapy – strict criteria for use, very expensive, potentially reduces

exacerbation rates in patients not controlled on oral steroids (however many patients don’t get any effect from it)

Asthma is a variable disease – many factors that contribute to the development and persistence of asthma also lead to variability. This variability is often beyond the control of either the patient or physician. The variable nature of asthma means that most patients experience periods of good control and periods of worsening symptoms.

Bronchial hyperresponsiveness is a characteristic feature of asthma and leads to episodes of coughing, wheezing, chest tightness and breathing difficulties. Asthma exacerbations can be triggered by various stimuli including allergens, infections, environmental factors and exercise.

During exacerbations, patients tend to use their reliever medication to control their symptoms without also ↑their anti-inflammatory medication as they should. Changes to the controlled medication dose are usually only made if asthma worsening persists long enough for the patient to make a visit to the physician. However, without additional controller therapy, inflammation may ↑– leading to airway obstruction that, in turn, may lead to the patient to be hospitalised or seek ER treatment, which often involves a course of oral steroids.

Stepping down – once asthma is controlled stepping down is recommended. This stops patients receiving higher doses than necessary. Should aim for lowest possible dose of inhaled steroid.

Self-management plans – every asthmatic should have a self-management plan with written instructions on when and how to step-up and step down treatment. This leads to better outcomes in terms of day-to-day control, frequency and severity of exacerbations.

Drug delivery via inhaler: 10 μ particles – deposited in the mouth and oropharynx 1-5 μ particles- most effective as they settle in small airways 0.5 μ – too small inhaled to alveoli and exhaled without being deposited in the lungs.

Inhaler devices – if a patient is unable to use a device satisfactorily an alternative should be found. The patient should have their ability to use the inhaler device assessed by a competent HCP. The medication needs to be titrated against clinical response to ensure optimum efficacy. Re-assess inhaler technique as part of a structured clinical review.

Acute severe asthma in adultsSevere

1. Unable to complete sentences2. Pulse > 110 beats3. Respiration > 25/min

Severe + any of the below = life threatening attack PEF < 33% SpO2 < 92 PaO2 < 8 kpa PaCO2 > 4.5 kpa Silent chest Cyanosis Feeble respiratory effort Hypotension, bradycardia, arrhythmia Exhaustion, confusion, coma.

4. Peak flow 33-50% of best or predicted

Near fatal CO2 > 6 kPa

Treatment of acute severe asthma1. Oxygen, high flow2. Nebulised salbutamol – continuous if necessary O2 driven3. Oral prednisolone – 20mg daily for 10-14 days4. If not responding add nebulised ipratropium bromide5. Consider I.V MgS 1.2 – 2 g over 20min6. Consider IV aminophylline if no improvement and life threatening features not responding

to above treatment

Anticholinergic – ipratropium bromide – a quaternary anticholinergic agent. Bronchodilation develops more slowly and less intense than adrenergic agonists (acts on M3). Response may last up to 6 hours. Useful add-on in acute severe asthma not responding to high dose β2- agonist. Drug is not well absorbed across the lung, avoiding many systemic side effects. Used in COPD where the major bronchoconstrictive component is mediated via cholinergic innervation.

Immunosuppression and disease-modifying therapy – Rheumatology Rheumatology - inflammatory arthritis, SLE and systemic vasculitis

RA is an autoimmune multi-system disease with a UK prevalence of 1%. Initially localised to the synovium, inflammation and proliferation of synovium leads to dissolution of cartilage and bone

Diagnosis:

Morning stiffness > 1 hour Arthritis of > or = 3 joints Arthritis of hand joints Symmetrical arthritis

Treatment goals – symptomatic relief and prevention of joint destruction

Strategy – early use of disease-modifying drugs, aim to achieve good disease control. Use adequate dosages and a combination of drugs, avoidance of long-term corticosteroids

Rheumatoid nodules Serum rheumatoid factor X-ray changes Typical person – women of child

bearing age.

Treatment goals in SLE and vasculitis Symptomatic relief e.g arthralgia, Raynaud’s phenomenon in SLE ↓mortality – induction of disease remission then maintenance (Wegener’s vasculitis) Prevention of organ damage e.g. renal failure in SLE Reduction in long term morbidity caused by disease and drugs

Immunosuppressants Corticosteroids Azathioprine Ciclosporin Tacrolimus Mycophenolate mofetil

Corticosteroids Prevent IL-1 and IL 6 production by macrophages and inhibit all stages of T-cell activation. However have key adverse effects:Weight gain, fat redistribution, striae, growth retardation, osteoporosis, avascular necrosis, glucose intolerance, adverse lipid profile, infection risk, cataract formation

Azathioprine in practice SLE and vasculitis as maintenance therapy RA – weak evidence for efficacy IBD Bullous skin disease Atopic dermatitis Many other uses as ‘steroid sparing’ drug.

Action – cleaved to 6-mercaptopurine (6-MP) functions as an anti-metabolite to ↓DNA and↓ RNA synthesis

Rheumatoid arthritispathogenesis

B cellsT cells

macrophages

cytokines

IL-1IL-6TNF-Etc etc

Il-4TGF-Etc etc

metalloproteinases

Rheumatoid factor

neuropeptides

Pro-inflammatory

Anti-inflammatory

Other disease-modifying anti-rheumatic drugs (DMARDs)

Methotrexate Sulphasalazine Anti-TNF agents Rituximab Cyclophosphamide

PD – 6-MP is metabolised by thiopurine methyltransferase, TPMT gene highly polymorphic. Individuals vary markedly in TPMT activity. Those with low or absent TPMT levels are likely to develop myelosuppression. Therefore test this before prescribing

ADRs – common – bone marrow suppression (monitor FBC), ↑risk of malignancy (all immunosuppressants) (-ESP transplant patients), ↑risk of infection. Rarely hepatitis (monitor LFT)

Calcineurin inhibitorsActive against helper T cells preventing the production of IL-2 via calcineurin inhibition. Ciclosporin binds to cyclophilin protein. Tacrolimus binds to tacrolimus-binding protein. Drug/protein complexes bind calcineurin. Calcineurin normally exerts phosphatise activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription. Micro-emulsion formulation (Neoral) is standard preparation – more predictable absorption.

Tacrolimus is more popular.

USES: Transplant medicine Also indicated for atopic dermatitis and psoriasis Pimecrolimus only available as topical formulation-use in atopic dermatitis Not commonly used in rheumatology – concerns about toxicity Ciclosporin useful in RA/SLE patients with cytopenias as it has no clinical effect on bone

marrow Monitor for toxicity – check BP and eGFR

Adverse effects – nephrotoxic, hypertension, hyperlipidaemia, N&V diarrhoea, hypertrichosis (shaking), gingival hyperplasia (gum hypertrophy), hyperuricaemia. Multiple drug interactions are possible, primarily with agents affecting the cytochrome P450 system.

People told not to drink grapefruit juice in the hour before taking dose of ciclosporin. Also medicine can cause K ↑so told to avoid high K foods such as bananas.

Mycophenolate MofetilAction – it is a prodrug derived from fungus Penicillium stoloniferum. It inhibits the enzymes inosine monophosphate dehydrogenase (required for guanosine synthesis). Impairs B and T-cell proliferation and spares other rapidly dividing cells (because of the presence of guanosine salvage pathways in other cells)Adverse effects – commonly N&V diarrhoea. Serious – myelosuppression

USES: Transplantation Good efficacy as induction of maintenance therapy for lupus nephritis In transplantation medicine drug levels of the active metabolite mycophenolic acid may be

monitored Toxicity may be precipitated in by both renal and liver disease

CyclophosphamideAn alkylating agent – cross links DNA so that it cannot replicate so suppresses T cells and B cells

USES: Lymphoma, leukaemia Lupus nephritis Wegener’s granulomatosis Polyarteritis nodosa

PD – it is a prodrug, converted in the liver by oxidase enzymes and cytochrome P450 to active forms that have chemotherapeutic activity. The main active metabolite is 4-hydroxycyclophosphamide. This exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is oxidised to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard.

Cyclophosphamide is excreted by the kidney. Acrolein, another metabolite is toxic to the bladder epithelium and can lead to haemorrhagic cystitis. This can be prevented through the use of aggressive hydration and/or mesna.

Considerations – significant toxicity – ↑risk of bladder cancer, lymphoma and leukaemia,- Infertility – risk relates to cumulative dose and patient age

o Monitor FBC and adjust dose in renal impairment- MMF may supersede cyclophosphamide in lupus nephritis (a trial is underway)

Methotrexate

Gold standard treatment for RA. Other indications include malignancy, psoriasis and crohn’s. Also unlicensed roles in: inflammatory myopathies, maintenance therapy in vasculitis, steroid-sparing agent in asthma.

Action – methotrexate competitively and reversibly inhibits dihydrofolate reductase. The affinity of methotrexate for DHRF is 1000x that of folate for DHRF. DHRF catalyses the conversion of the dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in purine (A, G) and thymidine synthesis. Methotrexate therefore inhibits the synthesis of DNA, RNA and proteins. Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. It therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI and oral mucosa) which replicate their DNA more frequently.

However its mechanism of active in non-malignant disease e.g. RA, psoriasis is not clear. Mechanism is not via anti-folate action. Possible action – inhibition of enzymes causing ↑[ adenosine]

Mean oral bioavailability is 33%

Mean intramuscular bioavailability is 76%

Administered, PO, IM or S/C

Weekly not daily dosing, metabolised to polyglutamates with long half lives

50% protein bound – NSAIDs displace

Renal excretion

USES- Well tolerated- 50% of patients continue the drug for >5 years, longer than any other DMARD- Improved QoL- Retardation of joint damage- Anchor drug for DMARD combinations

Adverse effects- Mucositis- Marrow suppression both respond to folate supplementation- Hepatitis, cirrhosis- Pneumonitis- Infection risk- Highly teratogenic, abortifacient

Methotrexate- toxicity monitoring – ACR and BSR recommendation. Baseline chest X-ray, FBC, LFT, U+E, regular e.g. monthly FBC, LFT, U+E + creatinine

SulfasalazineA conjugate of salicylate and a sulfapyridine moleculeAction

- T cello Inhibition of proliferationo Possible T cell apoptosiso Inhibition of IL-2 production

- Neutrophilo ↓chemotaxis and ↓degranulation

ADR –myelosuppression, hepatitis, rash. Milder SE N&V, abdo pain

In practice- Effective- Favourable toxicity- Long term blood monitoring not always needed- Very few drug interactions- No carcinogenic potential- Safe in pregnancy

ANTI TNFNICE – a patient with RA is prescribed anti-TNF only if they have had an adequate trial of MTX and at least one other standard DMARD, both with at least 2 months at target dose. A patient with RA is prescribed anti-TNF only if there is evidence of clinically active RA. Rx is withdrawn if patient experiences an ADR or fails to response.

Expensive £9000 per annum

Drugs: Adalimumab, entanercept and infliximab

Effects of blocking TNF-α- ↓ inflammation

o Cytokine cascade – recruitment of leucocytes to joint. Elaboration of adhesion molecules and production of chemokines

- ↓ angiogenesis – VEGF and IL-levels- ↓joint destruction – MMPs and other destructive enzymes bone resorption and erosion,

cartilage breakdown

ADR – does not ↑overall risk of malignancy. Risk of serious infections is similar to other DMARDs. Anti-TNF ↑risk of skin/soft tissue infections. TB reactivation and other intracellular bacterial infections – post marketing surveillance.

Rituximab binds specifically to a unique cell-surface marker CD20, which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type. B cells – present antigen to T cells and produce cytokines and antibodies. Rituximab works in three ways- activation of complement mediated B cell lysis; initiation of cell mediated cytotoxicity via macrophages, induction of apoptosis.

Long term – development of hypogammaglobulinaemia and ↑risk of infection. Development of hypersensitivity or blocking immune responses

Session 7 – Non-steroidal Anti-inflammatory DrugsAbout 50 drugs – significant structural heterogeneity, principle action key enzymes in prostaglandin synthesis/ 3 primary therapeutic effects: analgesia, anti- inflammatory, antipyretic

The inflammatory response Fundamental response of body to injurious stimuli – includes wide variety of noxious agents:

o Physical/chemical injury – structural straino Infectionso Many diseases – Autoimmune conditions

Normally a protective response to reduce risk of further damage to organism Alerts body through signalling pain – ↓risk of further damage through continued use/activity

A wide range of local molecular mediators and signalling agents employed – the Autacoids including

Bradykinins, Histamine, cytokines, leukotrienes, nitric oxide, neuropeptides and the eicosanoids (includes PGs)

Signalling overlap to ensure robust anti-inflammatory response

Key feature is localised release and short T1/2 allows fine control in signalling response

Prostaglandins are synthesised from Arachidonic Acid

Eicosanoids are 20C phospholipid derivatives used as signalling molecules. Variations in synthetic routes give rise to different classes.

Prostanoids prostaglandins (PGs), prostacyclins, thromboxanes,

All eicosanoid classes derived from arachidonic acid which is cleaved from cell membrane phospholipids.

Specific PG enzymes an example is prostaglandin desynthase.

COX-1 ISOFORM is constitutively expressed. It is in a wide range of tissue types. PG synthesis by COX-I has major cytoprotective role (Gastric mucosa, myocardium, renal parenchyma, ensures local perfusion – reduces ischemia)

PG t1/2 short = 10 mins – need constant synthesis. Due to its constitutive expression, most ADRs causes by NSAIDS effects are due to COX-I inhibition.

COX-2 isoform expression is induced by injurious stimuli. Expression induced by inflammatory mediators such as Bradykinin. COX-2 appears to be constitutively expressed in parts of the brain and kidney. Main therapeutic effects of NSAIDs occur via COX-2 inhibition. COX-1 and 2 do not work independently and PG synthesis of both dependent on tissue and organ type.

COX-1/COX-2 specificity NSAIDs exhibits a range of selectivity for the two forms. Generally NSAID action on COX-1 is rapid and competitive, on COX-2 is slower and often irreversible.

PGs: general pharmacology. PGs bind with GPCRs specific actions depends on PG receptor types. E.g. PG E at lease four main types: EP 1-4. Often action includes synergising effects of other autacoids e.g. bradykinin/histamine.

Inflammatory Response Mediators: Range of autacoids and prostanoids released post injury esp. PGE2 – also PGD2 released from local tissues and blood vessels. Autacoid release also induces expression of COX-2. Synergise with

other autacoids – bradykinin/histamine. PGs act as potent vasodilators – but doesn’t ↑capillary permeability directly – synergise permeating effects of bradykinin/histamine.

EP1 receptor – making response more sensitive, ↑C fibre activity

EP 2 – vasodilation

Pain: sensitising afferent nerve nociception. GPCr activation results in: ↑ neuronal sensitivity to bradykinin and inhibition of K+ channels/↑Na channels sensitivity. In combination these act to ↑C fibre activity. PGs may also activate previously silent C fibres. By reducing synthesis of PGs that sensitise nociceptors to inflammatory mediators, thought to ↓headache pain by cerebral

vasodilation mediated by prostaglandins. May also have a secondary effect on PG facilitation of afferent pain signal in spinal cord dorsal horn neurones.

Sensitising central nociception:

↑sustained nociceptive signalling peripherally result in ↑cytokine levels in the dorsal horn cell body/ this causes ↑ COX-2 synthesis and ↑ PGE2 synthesis. PGE2 acts via local GPCR receptor to ↑sensitivity and discharge rate of secondary sensory neurones.

Central sensitisation by PGE2 thus causes ↑perception of pain, central sensitisation in dorsal horn of spinal cord

Pyrexia – in infected and inflammatory states bacterial endotoxins stimulate macrophage release of IL-1. IL-1 within the hypothalamus (via induction of COX2?) stimulates PGE2 synthesis. PGE2 via EP3 receptor ↑cAMP levels in neurones regulating temperature ↑ heat production and ↓ heat loss

Therapeutic Effects

Main therapeutic effects achieved via COX-2 inhibition. Pharmacological action for nearly all NSAIDS via competitive inhibition of COX-1 and COX-2. Occupation of COX1/COX2 hydrophobin channel by NSAID competes with AA site occupation. With 50ish different NSAIDs wide variation in affinity

Nearly all have therapeutic efficacy as analgesics, anti-inflammatory and antipyretics. Often dominant disease state and individual patient response determine physician choice.

PK typically given orally but many topical preparations for soft tissue injury. Linear PKs within therapeutic dose range.

T1/2 mainly 2 groups <6 or >10. Many heavily bound to plasma protein 90-99%

Anti-inflammatories very wide use in musculoskeletal disorders (RA/OA)

Analgesia – mild to moderate pain though less effective than opiates but better ADR profile. Moderate pain accompanies many disease states very common with many medical procedures.

ADRs

Inhibition of COX-1 constitutive PG synthesis leads to many side effects. Long term use in elderly particularly associated with iatrogenic morbidity and mortality. Majority ADRs are seen in stomach/GI tract.

Renal ADRs occur in compromised individuals HRH or Hypovolaemia. HRH is heart failure, renal disease, hepatic cirrhosis

GI ARDS – stomach pain, nausea, heartburn, gastric bleeding, ulceration

Gastric COX-1 PGE2 stimulates cytoprotective mucus secretion throughout GI tract, reduce acid secretion and promote mucosal blood flow. NSAIDs especially long term have high incidence of GI ADRs between 10-30%. PGE2 inhibition increases mucosal permeability and decrease mucosal blood flow and protection. Clinical burden due to ulceration, haemorrhage and even perforation.

Renal/neovascular ADRS

Renal ADRs in HRH compromised patients due to renal perfusion and blood flow. PGE2 and PGI2 maintain renal blood flow. If reduced by NSAIDs then GFR ↓ further risk of renal compromise. Na/K/Cl and H2O retention follow with ↑likelihood of HTN

Vascular – ↑risk of prolonged bleeding time bruising and haemorrhage

Hypersensitivity

Skin rashes (up to 15% for some NSAIDs) range from mild to rare Stevens Johnson syndrome. Bronchial asthma and anaphylaxis. Particular care when prescribing to asthmatics. Aspirin also associated with risk of post-viral Reye’s syndrome in children.

NSAIDS- specific COX-2 INHIBITORS

Large research effort put into developing highly selective COX-2 inhibitors Rofecoxib (Vioxx) and celecoxib. Theoretically overcome ADRs due to COX-1 inhibition with equal efficacy to standard NSAIDs. Not completely free of GI ADRs. Clinical trials show significant ↑of CVD ADRs with long term use. US/EU approval for short term use only. More expensive so rarely used.

Therapeutic in combination with low dose opiates (all NSAIDs) – extends therapeutic range for treating pain and reduces ADRs seen with opiates along.

NSAIDS in combination NSAIDS given in combination ↑risk of ADRs, often occurs due to self medication with NSAIDS. NSAIDS together can affect each other PK/PDs due to competition for plasma protein

binding sites – many NSAIDS heavily bound up to 90-99% NSAIDS + low dose aspirin – compete for COX1 binding sites – may interfere with cardio

protective action of aspirin. NSAID protein binding can affect PK/PDS

o Highly protein bound drugs such as sulphonylurea, Warfarin and methotrexate can all be displaced, so may require dose adjustment to avoid changes in PK and PG

o ↑ sulphonylurea – hypoglycaemiao ↑ Warfarin – ↑bleedingo ↑ methotrexate – wide ranging serious ADRs

ASPIRINAspirin used as reference NSAID for efficacy and ADR severity. Still in very widespread esp. acute self medication. Relatively higher long term risk of ADRs. The only NSAID to irreversibly inhibit COX enzymes by acetylation. Unique PK profile. T-half less the 30 mins rapidly hydrolysed in plasma to salicylate.Salicylate PKs dose dependent. At lower doses first order T1/2 – 4 hours. At higher doses – 12 X 300mg tablets/ day zero order kinetics apply. Widespread use as cardio protective (@75mb) increasing trial evidence as prophylactic for GI/breast other cancers – trials continue.

Artero-thrombotic disease use of low dose aspirin (75mg) in reducing platelet aggregation is very widespread in treating a range of conditions with a vascular component. The irreversible inhibition

of COX-1 stops its activity that usually drives pro-aggregative activity in both platelets and the vessel wall therefore ↓thrombotic formation.

PARACETAMOL

Unique NSAID as it has virtually no anti-inflammatory action. Very effective for mild to moderate analgesia and fever. At therapeutic doses has a much better ADR profile than other NSAIDs. It is agent of choice for these moderate pain and fever. Therapeutic doses 8 X 500mg/day

Currently unknown mechanism of action weak COX1/Cox 2 inhibitor. Considered to primarily act in CNS possibly on a COX3 isoform. Metabolite in CNS can combine with AA to block binding with COX1/COX2? T-half – 2-4 hours. Caution in those with compromised hepatic function or alcoholism.

Toxicology single doses in excess of 10g potentially fatal, at high doses paracetamol PKs become zero order. Elimination involves both phase 1 and phase 2 metabolism and production of highly reactive intermediate. The intermediate is conjugated with glutathione and is then made non-toxic. At very high doses glutathione is depleted. When it is depleted a reactive intermediate is formed (NAPQI) exerting its toxic effect. This occurs by binding to many cellular macromolecules that result in necrotic cell death. Rx for OD must be given as soon as possible and guided by blood levels of drug. This additionally ↑a systemic burden as the liver is less able to cope with the normal levels of free radicals generated by the body. This results in further apoptotic damage and further compromise of hepatic function. OD should be treated within 8 hours, Rx. IV N-acetylcysteine or oral Methionine that ↑glutathione levels. Is still treatable up to 48 hours but if this is missed then the patient is very likely to die of liver failure. RTN and hypoglycaemic coma may follow.

Drug interactions – patients may be self-medicating with NSAIDs. So ask. Aspirin also interacts with Warfarin, displacing it from plasma proteins. NSAIDS can interact with ACEi and attenuate their action blocking the production of vasodilation PGs

NSAIDS can cause severe bronchospasm, angioedema and/or anaphylactoid reactions in about 2 of the population. These individuals are said to be aspiring/NSAID hypersensitive. If they take these drugs, the COX pathway is completely blocked and all AA metabolism occurs via the lipoxygenase pathway. The production of high levels of leukotrienes causes severe and prolonged bronchospasm, and the activation of cytokines from inflammatory cells can cause widespread mast cell degranulation.

Opioid AnalgesicsPain has a physiological and psychological component.

GATE THEORY

Pain transmission substania gelatinosa in the dorsal horn of the spinal cord

Neurotransmitter: substance P

Inhibitory descending pathways from higher centres of the brain synapse with substania gelatinosa and block pain transmission. mind over matter

Opioid drugs inhibit the release of substance P from nerve terminals.

Pain pathway:

Sensory signals integrated and filtered then sent to primary sensory cortex conscious awareness of pain. Not fully understood

Endogenous opioid peptides

Prokephalins enkephalins

Pro-opiomelanocortin endorphins

Prodynorphin dynorphins

Met- enkephalin (tyr-gly-gly-phe-met) Leu- enkephalin (tyr-gly-gly-phe-leu) Dynorphin Β-endophin – pain relief, award system in brain (exercise), immunosuppressant, regulating

labour, (smooth muscle relaxant) Opioid receptors

Evidence in CNS for, all GPCR μ – analgesia (supraspinal) binding causes ↑ outward flux of K hyperpolarisation ↓

excitability AND causes ↓ cAMP k – analgesia (spinal cord) ↓ influx of Ca via channels d – enkephalins (widely distributed) present in neuromuscular junction ↓ cAMP

synthesis

Receptor subtypes: μ1 – main effect –analgesia main target of opioids μ2 ADRS –

o Nausea, vomiting, constipation, drowsiness, miosis, o Respiratory depressiono Hypotensiono Also dependence and tolerance

k – pentazocine – dysphoria

Pharmacodynamics

Nociceptor

Type A - myelinated

Type C - Non-myelinated

(predominant)

Dorsal root of spinal cord

Interneurones in substantia Gelatinosa

Thalamus and pimary sensory

cortex<<<<< inhibitory signal back via

descending pathway

substance P --> /Glutamate <--

Agonist – e.g morphine Partial agonist e.g nalbuphine Antagonist e.g. naloxone – at μ receptor

Morphine – ‘the best’

Metabolism – glucuronidation makes either morphine-6-glucuronide (still active) or morphine-3-glucuronide which are both in urine. It goes straight into phase 2 metabolism

Heroin/diamorphine – is more lipid soluble version of morphine with a 5 minute t1/2. However hydrolysis converts the molecule to morphine with a 4 hour t1/2.

Clinical uses of opioids

Analgesic – chronic visceral pain (not stabbing pain) Morphine – analgesic (terminal illness) and can be used as diarrhoea Diamorphine – analgesic (terminal illness)

Epidural analgesia (not licensed) Codeine – mild analgesic (oral) (metabolised to morphine) 50% bioavailability cytochrome

P450 changes it to morphine Methadone – post-operative analgesia OR maintenance of dependence. Long term pain

relief Fentanyl Alfentanil Remifentanil – all 3 use in anaesthetics and cause histamine release (causing itching) Pethidine – analgesia in labour (IM) however slows labour and slows inflammatory

mediators and crosses the placenta so baby needs naloxone when born. Other uses sickle-cell crisis. (norpethidine (metabolite) convulsions) do not give frequent repeat disease

Opioid agonists-antagonists – pentazocine, nalbuphine, butorphanl, buprenorphine, meptazinol all analgesic e.g antagonist at μ, partial agonist at k, weak agonist at d

Opioid antagonists

μ receptor antagonists: Naloxone T1/2 1- 1.5h injection Naltrexone T1/2 4 h – orally

/Uses: opioid toxicity, reverse respiratory depression, treatment of dependence. However naloxone not long enough to keep opioids at bay (shorter T1/2)

New endogenous opioid peptides and receptors

Peptides – nociceptin, nocistatin (blocks effects of nociceptin), endomorphin-1 and 2

Receptor – ORL 1 (opioid receptor like 1 – nociceptin binds to it)

Drug Half-life (hrs)Morphine 1.3-6.7Diamorphine 0.08Methadone 15-30Buprenorphine 2-4Codeine 1.9-3.9Dihydrocodeine 3.4-4.5Fentanyl 3-12Pethidine 2-5Nalbuphine 1.9-7.7Tramadol 4.3-6.7

Medico legal aspects opioid analgesics are class A controlled drugs. The misuse of drugs act 1971, misuse of drugs regulation 2001.

Session 8 Antiarrhytmic DrugsTypes of Arrhythmias

Too fast: AF, atrial flutter, AV re-entry tachycardia, ventricular tachycardia, torsades de pointes

Too slow – heart block

Vaughan Williams ClassificationClass 1 Class 2 Class 3 Class 4Na channel Blockers Beta blockers Prolonged AP (K

channel blockers)Ca channel blockers

Ia Quinidine Atenolol Amiodarone DiltiazemIb Lidocaine Bisoprolol Sotalol (also β-

blocker)Verapamil

Ic Flecainide MetoprololNBKC – never buy Kellog’s cornflakes

Class Myocardial contractility

AV conduction

AP duration Effective refractory period

Ia ↓ ↓ ↑ ↑Ib - - ↓ ↑↑Ic ↓↓ ↓↓ - -II ↓↓ -/↓ - -III - ↑ ↑↑↑ ↑↑↑IV ↓↓↓ ↓↓ ↓↓ -

Class 1 drugsMainly block fast Na channels, weak K+ channel block. Therefore:

↓ conduction velocity ↓ depolarisation amplitude ↓ automaticity ↓ phase 4 slope ↑ depolarisation threshold Alter duration of AP

Lidocaine – class Ib agent. Rapid dissociation t1/2- 0.1s. Binds open and inactive Na channels.

PK – extensive FPM, IV admin, short T1/2

Adverse effects – negatively inotropic, seizures, nystagmus

Clinical use – ventricular tachycardia post MIFlecainide class 1c agent, also blocks outward K channels, long dissociation t1/2 10 s. Binds open Na channels only

↑PR, QRS and QT intervals at normal rates ↑ AP in atrial tissue at fast rates

PK – well absorbed orally, metabolised by CYP2D6 & renal elimination. Elimination t1/2 10-18 hours

Clinical use – prophylaxis and Rx of SVT/ Paroxysmal AF

Adverse effects- contraindicated with Hx of IHD/HF – causes lethal dysrhythmias

Beta Blockers Non selective – propranolol, sotalol β1 selective – Longer acting atenolol, bisoprolol Shorter acting metoprolol, nebivolol,

esmolol Mixed β1α1 – Carvedilol, labetalol

Adverse effects – HF, bradycardia, bronchospasm, peripheral limb ischaemia, loss of hypoglycaemic symptoms, fatigue

Clinical use: Rate control of AF/atrial flutter Cardioversion AVRT/ AVNRT Secondary prevention of VT/VF Heart failure Hypertension IHD

Class 3 ↑ AP duration Block slow outward K+ channels ↑ refractory period ↑ QT interval Suppress re-entry circuits However can ↑ risk of early after depolarisation leading to torsade de pointes Most commonly used are Amiodarone and sotalol

They ↑prolongation of AP ↑ wavelength, ↓ excitable gap

Amiodarone all classes of action:

Acute - blocks fast Na and Ca channels – class 1 and 4 action, use dependent, blocks Ach gate K channels (class 2 action), less negatively inotropic than class 1/2/4 agents

Chronic – blocks outward K channels – class 3 actiono Inhibits cell-cell couplingo Prolongs AP duration and refractory periodo Slows AVN conductiono Prolongs QT interval

PK – 30% bioavailability. Large Vd = 66 L/kg (approx 5000L in a 70kg individual) IV or oral loading dosing required. Elimination T1/2 10- 100 days. Hepatic metabolism by CYP450 3A4 to desethylamiodarone. Dose adjustments not required in renal/hepatic/cardiac dysfunction

Adverse effects – Short term – phlebitis & hypotension wit IV administration

Requires central access when given IV Long term – pulmonary fibrosis, hypo/hyperthyroidism, hepatic dysfunction, corneal

microdeposits, slate grey skin/photosensitivity, peripheral neuropathy, proximal myopathy, ↑defibrillation threshold for ICDs

Drug interactions inhibits CYP3A4 and CYP2C9 and P-glycoprotein dose reductions of Warfarin, Digoxin and Flecainide may be required.

Use:

Acute – AF, atrial flutter, VT, when other antiarrhythmics contraindicated

Chronic indications – secondary prevention of VT/VF when other antiarrhythmics not tolerated

Sotalol Racemate D-sotalol pure class 3 agent, I-sotalol has β-blocker and class 3 action Blocks outward K+ channels Reverse use dependence Lowers defibrillation threshold for ICDs Doses < 120mg bd has mainly β blocker action Higher doses have class 3 action

Adverse effects – β blocker adverse effects, Torsade de pointes

Clinical use = paroxysmal AF

Class 4

Diltiazem & verapamil block slow inward Ca channels on SAN and AVN. Slow phase 4 depolarisation, slow conduction velocity, ↑refractory period on AVN.

Dihydropyridine CCB (e.g. nifedipine, amlodipine) acts on vascular smooth muscle and have no antiarrhthymic effects.

Block L type Ca channel

Verapamil – IV or oral, sustained release preparations, negatively inotropic, drug interactions with Digoxin and Amiodarone

Diltiazem – less negatively inotropic than verapamil sustained release preparations

Adverse effects (both)- bradycardia, HF, constipation

Clinical use (both) – rate control of AF, cardioversion of AVRT/AVNRT, antianginal/antihypertensive

Other antiarrhythmics

AdenosineMain action as an AV node blocker: activates α1 receptor in the heart. α1 receptors are Gi linked inhibits adenylate cyclase ↓ cAMP levelsActivates Ach K channels in SAN and AVN hyperpolarises cells

Reduces automaticity, ↑AVN refractory period’

T1/2 – few seconds

Associated with transient chest tightness, and used as an IV bolus to diagnose/treat AVTs

Digoxin – inhibits Na/K ATPase. Direct cardiac effects + inotrope CNS mediated effects - ↓ SNS outflow, ↑ PNS outflow, sensitises baroreceptors reflex Combined effect - ↓ automaticity of SAN and AVN, ↑ refractory period of AVN, ↓ conduction

velocity of AVN

PK – oval bioavailability 70-80%, large Vd (4 – 7 L/kg), 20-30% protein bound, loading dose required for rapid onset of action. 2 compartment model kinetics, T1/2 36-48 hours with normal renal function. Renal excretion unchanged by P-glycoprotein. Digoxin clearance proportional GFR. Reduce dose in elderly & renal impairment.

Loading usually in 2 divided doses to minimise risk of toxicity. Plasma Digoxin levels checked 6-8 hours after dosing

Drug interactions ↑ Digoxin levels – propafenone,

Quinidine, Amiodarone, verapamil, Spironolactone, cyclosporine, likely mediated by P-glycoprotein

↑Digoxin levels – erythromycin, tetracycline

3Na+

3Na+ C

a2+

Ca2+

2H+

Sarcoplasmic

Reticulum

ATP

ATP

2H+

Ca2+C

a2

+

ATP

2K+

PD – beta blockers, verapamil, Diltiazem, Flecainide, diuretics

Adverse effects – narrow therapeutic index – plasma level 1-2.6 nmol/L, toxicity enhanced with ↓ plasma K

Cardiac toxicity – bradycardia, atrial/ventricular/functional ectopicso AVN blocko Atrial tachycardia with AVN blocko Accelerated idioventricular tachycardia

Signs and symptoms – delirium, fatigue, confusion, nausea, vomiting, anorexia, diarrhoea, blurred and yellow vision (xanthopsia)

Severe toxicity can be treated with antibody fragment therapy (digibind)

Clinical use – main use is rate control in AF; heart failure however no mortality benefit

Magnesium IV mg2+ used to treat Torsades de Pointes; Digoxin toxicity’ mechanism of action is unknown, no benefit to chronic administrationClinical use of Antiarrhythmics

Identify & treat precipitating factors – ischaemia, drug therapy, electrolyte/endocrine disturbance, sepsis

Establish goals of Rx – rhythm control, rate control, prevention

Minimise risks – avoid multiple antiarrhythmics, drug-drug interactions, short and long term adverse effects

DiureticsRenal physiology

Regulatory – fluid balance, acid-base balance, electrolyte balance Excretory – waste products, drug elimination Endocrine – RAAS, erythropoietin, prostaglandins Metabolism – Vitamin D, polypeptides (insulin, PTH)

Pharmacology

Drugs acting on the renal tubules Carbonic anhydrase inhibitors – cause NaHCO3 diuresis, excretion of Na, K and PO3 causes

metabolic acidosis/hypokalaemia Osmotic diuretics – filtered at glomerulus, ↑osmotic gradient through nephron, excessive

water loss, hypernatraemia Loop diuretics – thick ascending limb of henle inhibits NaCl/2k and reabsorption, concurrent

Ca/Mg excretion, causes hypokalaemia in the collecting duct Thiazides – inhibit NaCl reabsorption in DCT, promotes Ca reabsorption however causes

hypokalaemia and hyperuricaemia K sparing diuretics

Aldosterone antagonists – Spironolactone inhibits, Na retention (NA/K ATPASE activity↓ and ENaC expression ) blunt K and H secretion, androgenic cross reactivity, hyperkalaemia

ADH antagonists – include lithium/demeclocycline – ↓concentrating ability of urine in CD

Other drugs with diuretic activity: Digoxin - inhibit tubular Na/K ATPase Amiloride – inhibits Na channels in DCT/ CD, K sparing

Generic ADRs for diuretics

Anaphylaxis/rash etc- Hypovolaemia & hypotension leading to ARF, electrolyte disturbance, metabolic abnormalities

Common specific ADRs Thiazides – gout, erectile dysfunction Spironolactone – hyperkalaemia, painful gynaecomastia Frusemide – ototoxicity Bumetanide – myalgia

Drug interactions

Interacting drugs Potential interactions

ACE inhibitors/K sparing diuretics

↑hyperkalaemia

Aminoglycosides/loop d Ototoxicity and nephrotoxicityDigoxin/Thiazide & loop D Hypokalaemia ↑ Digoxin binding and toxicity

-blockers/Β Thiazide diuretics Hyperglycaemia, hyperlipidaemia, hyperuricaemia

Steroids/Thiazide and loop D ↑ risk of hypokalaemiaCarbamazepine/Thiazide diuretics

↑ risk of hyponatraemia

Diuretic Resistance = incomplete treatment of the primary disorder. Continuation of high Na intake, patient non-compliance, poor absorption, volume depletion ↓filtration of diuretics, volume depletion ↑serum aldosterone which expresses ENaC. NSAIDs – can reduce renal blood flow

DIURETIC USEHeart failure – loop D, Thiazide D, Spironolactone ACEi/ang II antagonists, β-blockersHypertension – Thiazide D, Spironolactone, ACEi/ARBs, B-blockers

Decompensated liver disease – Spironolactone, loop diuretics

Conn’s Syndrome – Spironolactone

Drugs may reduce kidney function by direct or indirect toxicity. Drugs may accumulate to toxic levels if they are excreted through the kidneys and renal function is impaired.

Potentially nephrotoxic drugs

ACEi- do not use ACEi with renal artery stenosis – under these conditions GFR↓ causing RAAS to ↑ BP and vasoconstriction affects renal output. ACEi and ARBs preferentially dilate efferent arteriole ↓↓ GFR as no pressure over glomerulus

Aminoglycosides – e.g. gentamicin Penicillins Cyclosporin A Metformin NSAIDs Loads more – double whammy if renal function is impaired

Prescribing in CRF- Avoid nephrotoxins- Reduce dosages in line with GFR metabolism or eliminated via the kidneys- Monitor renal function and drug levels- Hyperkalaemia is more likely- Uraemic patients have greater tendency to bleed- BNF

Prescribing in the elderly- Renal function is over-estimated as creatinine is dependent on body mass- So start low, titrate cautiously- Polypharmacy more likely

Management of hyperK- Indentify cause- ECG- Rx – calcium gluconate, insulin/dextrose, calcium resonium, NaHCO3, salbutamol

Session 9 - Treatment for Hypertension and Heart Failure

Blood pressurePhysiological control by the ANS, RAAS and others such as Bradykinin, endothelin, nitric oxide, ANP

Angiotensin converting enzyme is also involved in the breakdown of Bradykinins which vasodilate. Therefore ACEi potentiate bradykinin action causing an additional vasodilation.

HTN ↑arterial thickening SMC hypertrophy accumulation of vascular matrix, loss of arterial compliance target organ damage heart, kidneys, brain, eyes CV morbidity and mortality

Epidemiology – defined as 140/90mmHg, 40% of the adult population of England are hypertensive although the proportion ↑with age.

Lowering diastolic BP by 10mmHg is associated with reductions in stoke of 58% and CHD of 37%

Primary (essential) HTN – high BP without any single evident cause, 90% hypertensive population

Secondary HTN – high BP with a discrete, identifiable underlying cause, 10% hypertensive population

Rx – identify and Rx underlying cause if present. Identify and treat other CV risk factors or co-morbidities. Lifestyle advice/non-pharmacological therapy, Drugs

Category Systolic BP (mmHg) Diastolic BP (mmHg)Blood pressureOptimal <120 <80Normal <130 <85High normal 130-139 85-89H Y P E R T E N S I O N Grade 1 (mild) 140-159 90-99Grade 2 (moderate) 160-179 100-109Grade 3 (severe) >180 >110Isolated systolic HTGrade 1 140-159 <90Grade 2 >160 <90

Thresholds for drug Rx: sustained pressure >160/>100 justify drugs. At levels of 140-159/90-99 the decision depends on the overall CV risk profile (is there >15% of CV event in the next 10 years) and the presence or absence of end organ damage in the heart, eye or kidney. In the presence of diabetes the Rx threshold is 140/90 with a target level of <130/80. Lifestyle therapy:

Patient education Maintain normal body weight (BMI 20-25) Reduce salt intake to <6g/day Limit alcohol consumption to <3 units/day for men, <2 units/day for women Engage in regular aerobic physical exercise for >30 mins/day Consume >5 portions of fresh fruit/veg daily Reduce intake of total and saturated fat (smoking cessation) (relaxation therapies)

1st line pharmacological therapy: ACE/ARB CCB Diuretics

ACEi ↓in formation of ang II (up to 70%) mainly arteriolar vasodilators, some venodilation, circulating aldosterone is ↓

e.g. Lisinopril, Ramipril,

Potentiate the action of bradykinin. Main SE – dry cough (10-15%), important SE are angio-oedema (rare, more common in black pop), renal failure (incl. Renal artery stenosis), hyperkalaemia

ARBs e.g. losartan, valsartan, bind to angiotensin AT1 receptor. Inhibit vasoconstriction and aldosterone stimulation caused by ang2. Well tolerated few SE. Serious SE renal failure, hyperK

CCBs – bind to specific αsubunit of L-type Ca channel, reducing cellular Ca entry. Three main groups:

Dihydopyridines (nifedipine, amlodipine) Benzothiazepines (Diltiazem) – works mainly as a negative chronotrope Phenylalkylamines (verapamil) – should not be given with a beta blocker (severe

hypotension and bradycardia can occur) works mainly as a negative chronotrope

They vasodilate peripheral, coronary and pulmonary arteries, no significant effect on veins - Short acting Dihydopyridines baroreflex mediated tachycardia. Verapamil depresses SAN and slows A-V conduction

Dihydropyridine – CCB

Properties: good oral absorption, protein bound > 90%, metabolised by the liver, few have active metabolites. Works as a vasodilator

Adverse effects – SNS activation - tachycardia and palpitations

Also flushing, sweating, throbbing headache, oedema, gingival hyperplasia

Phenylalkylamines – verapamil

Properties – impeded ca transport across the myocardial and vascular SMC membrane. Class IV anti-arrhythmic agent/prolongs the AP/ effective refractory period

Peripheral vasodilatation and a reduction in cardiac preload and myocardial contractility

Adverse effects – constipation, risk of bradycardia, reduced myocardial contractility (negative inotrope) = can worsen HF

Benzothiazepines – Diltiazem

Properties – impedes ca transport across the myocardial and vascular SMC membrane. Prolongs the AP/effective refractory period. Peripheral vasodilatation and a reduction in cardiac preload and myocardial contractility.

Adverse effects – risk of bradycardia, less negative inotropic effect than verapamil – can worsen HF

Thiazide diuretics (bendroflumethiazide)

Reduce distal tubular Na reabsorption, sustained action. BP reduction, several mechanisms initial blood volume↓, with later – TPR↓ (vasodilating effects). Dose-BP response curve flat

Adverse effects – hypokalaemia, ↑urea and uric acid levels. Impaired glucose tolerance (esp. With beta-blockers), cholesterol and triglyceride levels ↑. Activates RAAS

Class Indication Caution ContraindicationThiazide/diuretics Elderly, ISH*, HF GoutBeta blockers MI./angina HF, Peripheral vascular

disease, diabetes (except with CHD)

Asthma, COPD, heart block

CCB (Dihydopyridines)

elderly, ISH

CCB (rate limiting) Angina Combination with BB Heart block, HFACEi HF, LV dysfunction, MI,

diabetes (type 1), nephropathy

Renal impairment, PVD,

Pregnancy, renovascular HTN

ARBS ACEi intolerance, HTN with LVH, type 2 DM

Renal impairment, PVD Pregnancy, renovascular HTN

Alpha blockers Benign prostatic hyperplasia

Postural hypotension, HF

Urinary incontinence

*isolated systolic hypertension

Other anti-hypertensive drugs Alpha blockers

o Selective antagonism at post-synaptic alpha 1 adrenoceptors, and antagonise the contractile effects of NA on vascular SM

o Reduce peripheral vascular resistanceo More effect in upright positiono Benign effect on plasma lipids/glucoseo Safe in renal diseaseo Adverse effects – postural hypotension, dizziness, headaches and fatigue, oedema

Beta blockers e.g. atenolol, bisoprolol, nebivololo Developed for angina but found to lower BPo Reduce HR and COo Inhibit rennin releaseo Initially a TPR increase later falls to normal. o Indicated in concurrent angina, CHF or past MIo Adverse effects – lethargy, impaired concentration, ↓exercise tolerance,

bradycardia, cold hands, impaired glucose tolerance, contraindication - asthma Direct rennin inhibitors (new) – aliskirin

o Aliskiren binds to a pocket in the rennin molecule, blocking cleavage of angiotensinogen to angiotensin 1

o Aliskiren ↓plasma rennin activity by 50-80% vasodilatory properties leading to BP reduction

o Blockade of RAAS at any points leads to compensatory ↑in rennin release, as Ang II levels drop, or its effects at AT1 receptors on JGA cells in the kidney are blocked.

o PK – BA 2.6%, T1/2 – 40 hours, supports once-daily dosing. Steady state takes 5-8 day. Elimination – mainly as unchanged compound in faeces (78%), less than 1% is renal excreted, not metabolised via p450,

o Caution in patients at risk of hyperkalaemia, Na and volume depleted patients, patients with HF, severe renal impairment and renal stenosis

o No initial dosage adjustment required in elderly patientso Contraindicated in pregnancy, o Only significant drug interaction - Frusemide

Centrally acting agents – methyl dopa, clonidine, moxonidine,

o Methydopa – converted to alpha- methyl, BA – a potent a2- adrenoceptor agonist. Used in pregnancy

o Clonidine – direct pre-synaptic a2-adrenoceptor agonist Rebound HTN with withdrawal, causes NA release

Desensitisation of inhibitory a2 receptors Super-sensitivity of post synaptic a1 receptors

o Moxonidine – imidazoline I1 receptor agonist and some a2 agonist effect Reduced sympathetic outflow Side effects restrict use – tiredness/lethargy, depression

Vasodilators – hydralazine, minoxidil, sodium nitroprusside

Heart FailureAetiology of HF

IHD HTN Cardiomyopathies – e.g. alcohol, idiopathic, chemotherapy, iron overload etc. Valve disease Others

Prognosis after MI (or any cardiac injury) is inversely related to amount of LV damage

Prognosis can be influenced by drugs

Treatment of HF. Prognosis may be improved by: RAAS antagonism (ACEi/ARB, aldosterone blockage), Beta blockers

NB. Diuretics – loop +/- Thiazide useful for Rx but no evidence to suggest improves prognosis

In spite of ACEi/ARB therapy, aldosterone concentration returns to normal.

Spironolactone proven to ↑survival in HFβ-blockers – physiological effects

1. ↓heart rate (cardiac beta receptor)2. ↓BP (reduced CO)

1+ 2 ↓myocardial oxygen demand3. ↓mobilisation of glycogen4. Negate unwanted effects of catecholamines

CARE - failing myocardium dependent on HF. Initiate at low dose, and titrate slowly, may have to alter concomitant medication (e.g. diuretic)

Direct acting vasodilators - relax vascular SMC (arteries > veins) selective action on heart, peripheral vasculature, cerebral circulation, used in resistant/severe HTN

Minoxidil – open ATP-modulated K channels thus inhibits influx of Ca, usually given with by a diuretic and β-blocker to ↓effects of tachycardia and fluid retention. SE is hirsutism

Hydralazine – mechanism unclear, oral/IV, main ADRs, flushing, tachycardia, and mild fluid retention

Secondary causes of HTN

Endocrine – conn’s syndrome, bilateral adrenal hyperplasia, glucocorticoid-remediable aldosteronism, congenital adrenal hyperplasia, Cushing’s, pheochromocytoma, thyroid disease, acromegaly, hyperparathyroidism, carcinoid

Mogenic renal tubular defects – liddle’s syndrome, Gordon’s syndrome Renal causes – renovascular HTN, chronic pyelonephritis, diabetic renal disease, renal

parenchymal disease Miscellaneous – coarctation of the aorta, neurologic disorder, psychogenic, sleep apnoea,

drug-induced, oral contraceptive, HRT, pregnancy

Pheochromocytoma – adrenal catecholamine –secreting tumour. Adrenaline/NA/dopamine. Paroxysmal symptoms very sustained high BP. Diagnosed – urinary catecholamines/imagining

Treat with non-selective αblockers – direct effect on α-1 and α2 adrenoreceptors preventing the action of released NA. βB are given after a-blockage

Primary hyperaldosteronism – causes hypertension

Includes – conn’s syndrome and bilateral adrenal hyperplasia. Excess secretion of aldosterone, plasma rennin suppressed

Rx. with aldosterone antagonists, Spironolactone, eplerenone

Hypertensive emergencies

Very high BP (often over 220/120 mmHg), associated with acute complications, pulmonary oedema, renal failure, aortic dissection etc. Need to reduce BP by 20% or to 100 mmHg diastolic within 1-2 hrs

Sodium nitroprusside – mimics the action of endogenous NO on vascular SM, acting as a potent vasodilator. IV use with powerful rapid onset and offset. Breakdown to cyanide – caution in liver disease, but renal excretion. Avoid prolonged use (>72 hours)

Anti-coagulant and antiplatelet therapy

Disorders of haemostasis are common these are thrombosis and embolism

Arterial – white clot – CVA, MI: antiplatelets and thrombolysis

Venous – red clot – DVT, PE. Anti-coagulation

Other uses – pro thrombotic state and primary prevention

Basic pharmacology – ACAs – Warfarin – inhibits production of vitamin K dependent clotting factors

Stops conversation to vit K to active reduced form. II (prothrombin), VII, IX, X – extrinsic pathway. Onset – days due to turnover of clotting factors (t1/2)Heparins

Glycosaminoglycan – glucose backbone, one of 5 different groups on each glucose, some with sulphate, produced by mast cells. Unfractionated Vs low molecular weight, both activate anti-thrombin II via unique pentasaccharide sequence. Deactivates factor Xa, IIa, IXa

Process of clot

Role of coagulation

system

Anticoagulation - prevention and Rx of thromboembolism

Fibrinolysis -breakdown of existing clot

Role of platelets

Antiplatelet agents - Rx of

vascular disease

Warfarin

PK – GI absorption, dose-dependent reduction in vit K dependent factors, many drug interactions, hepatic metabolism and slow onset of action

Give orally Slow onset of action – heparin cover Slow offset – t1/2 48 hours but variable Need to stop 3 days before surgery to give time to synthesise new clotting factors Heavily protein bound – caution with drugs that displace it

PKs and clinical consequences:

Hepatic metabolism – MFO p450 system – caution with liver disease, caution if used with drugs that affect p450 system

Crosses placenta – do not give in 1st trimester – teratogenic, do not give in 3rd trimester either due to brain haemorrhage risk.

Monitoring Warfarin – extrinsic pathway factors, prothrombin time citrated plasma clotting time after adding calcium and Thromboplastins

INR – international normalised ration: Allows a standard value between labs Corrected for different lab Thromboplastins reagents

DRUG-DRUG INTERACTIONS WITH WARFARIN ARE HIGHLY SIGNIFICANT

Effects on anticoagulation – majority ↑anticoagulant effect, but some ↓effect

Drugs potentiating Warfarin3 ways are clinically significant

1. Inhibit hepatic metabolism (P450) – Amiodarone, Quinolones, metronidazole, cimetidine, ingesting alcohol

2. Inhibit platelet function – aspirin3. Reduce vitamin K from gut bacteria – cephalosporin antibiotics.

Albumin displacement (NSAIDS & drugs that ↓GI absorption of vit K has lesser effect)

INR will ↑if you start one de novo

Drugs inhibiting Warfarin

Antiepileptics, rifampicin, st. Johns wort all induce CYP450 thereby ↑metabolism of Warfarin ↓INR

Main uses of Warfarin

Indication (duration) INR rangeDVT (3-6 months) 2.0-3.0

AF (until risk > benefit)Mechanical prosthetic valves (high risk) 2.5 - 4.5Patients with recurrent thromboses on warfarin, thrombosis associated with inherited thrombophilia conditions

Other uses – cardiac thrombus, CVA esp. With AF, cardiomyopathy

Adverse effects – bleeding/bruising sites intracranial, epistaxis, injection, GI loss- Teratogenic- Reversal of therapy - parenteral vit K – slow takes 2-3 days- Fresh frozen plasma – fast

Practical informationInitiation

1. Indication2. PMH e.g. PUB, SAH, bleeding disorder3. Medication interactions4. Age, mobility (blood tests and clinics)5. Falls risk score6. Review blood tests (LFTs, Plt, INR)7. Consider loading dose and heparin cover8. Prescribe (when to start)

Discuss with patient the SE, and when to consult a doctor. Interactions with other medication and over the counter drugs, alcohol and cranberry/grapefruit juice, INR monitoring (1-4 weeks), give patient anticoagulant card

Warfarin reversal

- Common sense – stop Warfarin- Consider – bleeding, INR, indication, mechanical valve call cardiologist- Agents

o IV vit K – poor-coagulant affects re-warfarinisation for 6 weekso Prothrombin complex concentrateo Fresh frozen plasma

- Source of bleeding (OGD, surgery)

- Elective surgery -

Heparin molecules

Unfractionated heparin (IV, continuous, occasional, subcut for prophylaxis) 20 kDa

Mix of variable long length heparin chainsUnique pentasaccharide sequence which binds to anti-thrombin II, this causes conformational change and ↑AT II activity, AT III inactivation, thrombin (IIa), and factor Xa, but also V, VII, IX, XI

To catalyse inhibition of IIa b AT III, heparin needs to bind simultaneously to IIa and AT/ II. Unfractionated heparin is large enough for this, but not low MW heparin. Xa inhibition by AT II needs only heparin to bind to AT II, so both low and UH can act here.

LMWH (subcut) 3-4kda have smaller chains that are < 18 saccharide units, absorbed more uniformly, high bioavailability (>90%), long t1/2. More predictable dose response than UH (does not bind to macrophages, endothelial cells, plasma proteins). Like UH, have unique sequence to bind to AT III,

unlike UH, they do not inactivate thrombin. Affects factor Xa specifically. No monitoring required usually. Cleared by kidneys, care in renal failure, less likely to cause thrombocytopenia.

Pharmacokinetics given parenterally as poor GI absorption, rapid onset and offset of action

UFH LMWHDose- response Non-linearity PredictableBio-availability Variable PredictableAction Variable monitor with APTT test No monitoring – little affect on APTTAdministration IV SCInitiation Bolus then IVI OD/BD

CHEAP More expensive however, no monitoringUses of heparin

Prevention of thromboembolism- Peri-operative – LMWH low dose- Immobility – CCF, frail or unwell patient

Used to cover for risk of thrombosis around times of operation in those normally on Warfarin but who have stopped it for the surgery, as quick offset time allows its cessation if bleeding.

- DVT/PE and AF – administered prior to Warfarin – quick onset to cover patient whilst Warfarin loading is achievedo LMWH often used unless fine control required

- Acute coronary syndromes – ↓recurrence/extension of coronary artery thrombosis, and MI, unstable angina

- Pregnancy – can be used cautiously in pregnancy in place of Warfarin

Adverse effects- Bruising/bleeding sites

o Intracranial, injection sites, GI loss, epistaxis- Thrombocytopenia (HIT) (heparin induced t)

o Autoimmune phenomenon (usually 1-2 weeks of Rx)o May bleed or get serious thromboseso Heparin and PF4 on platelet surface are immunogenic – immune complexes activate

more platelets release more PF4, forms more IgG and complexes, leads to depletion of platelets and thrombosis

o Platelets < 100 (or 5% reduction)o Lab assay for these antibodieso Stop heparin, add hirudin

- Osteoporosis

Reversal of therapy – protamine sulphate, dissociates heparin for AT III, irreversible binding to heparin. Stop heparin, if actively bleeding give protamine, monitor APTT (activated partial thromboplastin time) if Unfractionated.

Anti-platelet drugs

Thromboxanes A2 inhibition- Aspirin – COX-1 inhibition irreversible

Covalent acetylation of serine – hit and run drug- Dipyridamole – phosphodiesterase inhibitors

PGI2 ↑cAMP ↓aggregation + inotrope and vasodilatory (flushes and headaches), secondary prevention

Thromboxane A2 liberated from activated platelets- causes platelet aggregation/vasoconstriction

Purpura is the appearance of red/purple discolorations on the skin due to small haemorrhage in the skin caused by various factors: blood disorders, vascular abnormalities, and trauma. It may be caused by aspirin as it infers with platelet adhesion and this factor potentiated by heparin as it ↑ the risk of haemorrhage.

Platelet ADP receptor antagonists

- Clopidogrel – ADP antagonists Blocks platelet activation blocks PY2Y12 receptor ↓cAMP via Gi Used with aspirin, more serious bleeds but same rate of life threatening, not

for long term use if possible

Glycoprotein IIb/IIIa inhibitors

Inhibit final common pathway of platelet aggregation - Abciximab, tirofibran, eptifibatide, ↓platelet cross linking by fibrinogen- Fibrinogen binds these receptors which cause platelet aggregation so good to block this

final pathway. - High risk ACS, post PCI (↑bleeding complications but ↓acute thrombosis and re-stenosis)

Session 10 – thrombolytic Drugs Fibrinolytic drugs make use of vascular intrinsic defence mechanism. Amplify the conversion of an inactive enzyme precursor plasminogen to active enzyme plasmin.

Plasminogen a single chain glycoprotein is 760 AA. Converted to plasmin by cleavage of ARG560-Val561 peptide band

Plasmin is a serine protease with trypsin like activity. Attacks lysyl & arginyl bands of fibrin

Clinical uses of thrombolytics MI, PE, And ACUTE ISCHAEMIC STROKE1st generation thrombolytics

Streptokinase – non enzymatic protein of beta- haemolytic streptococci. Activates fibrinolytic system by forming 1:1 stoichiometric complex with plasminogen converting to active enzyme plasmin.

o Antigenic so only used once per patient SE – pyrexia, hypotension (if this occurs infusion is slowed), allergic reaction, very short T1/2

Urokinase (not licensed for use in MI) – trypsin – like serine protease of 2 polypeptide chains activates plasminogen directly converting it to plasmin binding activates SK active site by conformational change.

2 nd generation thrombolytics

APSAC acetylation of plasminogen T1/2 90 mins. Permit bolus dosing. Less bradykinin produced than with streptokinase (therefore less hypotension)

3 rd generation thrombolytics

Alteplase found to be same efficacy in acute MI than SK, but better in stroke

Reteplase – recombinant plasminogen activator. T1/2 18 mins. 2 IV bolus injection 30 mins apart

Tenecteplase – multipoint mutation of parent tPA

Recombinant tPA’s (tissue plasminogen activators) – general points Expensive but acceptable costs 10x more than SK Lower risk of intracranial bleeds Works preferentially in the presence of fibrin therefore clot specific. SK causes systemic

fibrinolytic activity. Practical difference is uncertain. Possibly better efficacy Efficacy preserved on repeated exposure non-antigenic

PLASMIN Fibrin

FIBRINOGENFIBRINOGEN

DEGRADATIONPRODUCTS

PLASMINOGENExtrinsic activators

Lysis(Thrombus)

Thrombin activity

Intrinsic activators

Lysis

SK-plasminogen

complex

Conformational change leading

to activation

Streptokinase

More rapid restoration of TIMI (thrombolysis in MI it is a grading scheme) – grade 3 flow great perfusion

Mechanism of action

Angioplasty the outcome is slightly better

Administration of thrombolytic drugs. IV bolus/infusion No oral administration In acute MI:

o Aspirin ASAP prior to thrombolysiso IV heparin following administration of recombinant tPA’s

See if thrombolysis has worked check ECG if ST falls patient doesn’t need an angioplasty

Fibrinolytic therapy within the first 1-2 hours (up to 12) of onset of MI will prevent up to 60 deaths per 1000.

Other uses: Massive PE

o Haemodynamic compromiseo Good clinical evidence or positive CT pulmonary angiogramo Controversial benefito Needs a clear diagnosis, evidence of significant haemodynamic compromise and

absence of major contraindications are criteria for fibrinolytic therapy Acute ischaemia CVA

o Within 3 hours of symptomso Confirmed thrombotic CVA on CTo Specialised CVA units onlyo Contradictory evidence therefore not routine use

Less common uses include clearance of thromboses shunts and intraocular thromboses

Time is of the essence. Longer time = more ischaemic death also thrombi become more resistant to lysis. Therefore benefit of Rx declines but the risks of Rx remain constant.

MI: inclusion criteria

Acute ST elevation/bundle branch block MI confirmed on ECG: onset <12hours (<6 ideal), no exclusion criteria,

MI: absolute exclusion criteria

Active bleeding, previous CVA (any intracranial haemorrhage, ischaemic stroke within 3 months), if there is a high risk of bleeding e.g. (recent active or bleeding DU, recent surgery, intracranial SOL), acute aortic dissection, uncontrolled severe hypertension

MI: relative exclusion criteria

Pregnancy, peptic ulcer disease, poorly controlled BP, anticoagulant use (INR > 4), trauma or prolonged CPR (>1 mins), >12 hours since onset

Need to balance the risk of bleeding with the risk of leaving an MI untreated – can perform angioplasty if near appropriate centre, angioplasty also requires anticoagulants (though not thrombolytics)

Informed consent – patients should give (at least) verbal consent to thrombolytic therapy – there needs to be adequate explanation of risks/benefits, assessment of risk based on inclusion and exclusion criteria, but decisions should be reached as quickly as possible.

Haemorrhage: Rate per 10000 patients exposed to thrombolytics:

Fatal stroke 2 Disabling stroke 1 Minor stroke 1 Bleeding (non-cerebral) major 7

Caused by lysis of physiological thrombi, lytic state due to systemic plasmin activation

Acute side effects Hypotension (transient, more with SK) Allergic response (SK products only)

o Anaphylaxis/allergy (rarely severe)o Reduced efficacy on re-exposure after antibody response

Reperfusion arrhythmiaso Transient, sometimes need treatmento Sinus bradycardia, idioventricular rhythmo Occasionally more severe: VT, VF

Any cerebrovascular event occurring after fibrinolytic therapy requires a CT or MRI diagnosis to establish where the cause is haemorrhagic (i.e. treatment related) or ischaemia (emboli from hear). The two are equally likely.

Serious bleeding after fibrinolytic treatment may require transfusion of blood or volume expanders, inhibition of further fibrinolysis with tranexamic acid or aprotinin, specific recombinant or pooled clotting factors.

Cancer ChemotherapyCancer biology

By the time a patient presents with symptomatic cancer already large no’s of tumour cells.

An example:

A tumour 1cm diameter has approx/ 109 cells

A lethal tumour burden is 1012 cells

Cell kill of a drug (90-99.9%) depends on both sensitivity of the cells to the drug and dose. 99.9% cell kill (999 to 1000) reduces tumour population 1011 to 108.

The aim of several courses of chemo is to kill several logs of tumour cells

Technical inability to detect fewer than 103 to4 (minimal residual disease) explains recurrence after apparent complete remission.

Cell cycle: variation in cycle is 9-43 hours between cancer cells.

The growth fraction of a cancer represents the % of cells actively progressing through the cell cycle. Some drugs cause cytotoxicity when exposed to cancer cells at any stage of the cell cycle. Some drugs are phase-specific:

Chemo drugs interfere with some essential steps required for cell growth or division, often with synthesis and replication of DNA. The damaged cancer cell will either repair the damage or initiate apoptosis.

Apoptosis is initiated at G1s or G2M checkpoints, provided the mechanisms for apoptosis are in place – not the case in some cancers = e.g. p53 mutations or deletions

Mechanisms of action Anthracyclines – doxorubicin – topoisomerase – prevents the enzyme from religating

cleaved DNA Alkylating agents – cyclophosphamide – formation of DNA cross links – interferes with

cellular replication Antimetabolites – disrupt the synthesis of essential compounds required for cell synthesis

o Methotrexate inhibit the enzyme required to convert folate to its active formo Cytarabine inhibits DNA synthesis (S-specific)o Vinca Alkaloids – vincristine – bind to tubili – prevent formation of the mitotic

spindle (M specific) Synergism with some of these drug classes

The cancer cells may evade kill by the chemotherapy in many ways, such as: ↓drug uptake – alteration of folate receptor – Methotrexate ↑drug efflux – MDR – 1 gene p-glycoprotein – many drugs ↑DNA repair mechanisms Mutations leading to alteration of drug target – topoisomerase II mutations – Anthracyclines Upregulation of anti-apoptotic genes – proteins and pathways

Prescribing – need specialist to prescribe drugs because: they have narrow therapeutic indices, significant SE profile

Also dose needs to be altered for the individual based on their SA or BMI, their drug handling ability (eg. LFTs, renal function – dependent on the metabolism and excretion routes), general wellbeing

M - mitosis (<1hour)

G1 - gap number 1 (0-

30hrs)

S- DNA synthesis (6-8

hrs)

G2- gap number 2 (2-

4hours

Treatment phasing needs to take into account the balance between: growth fraction, the cell kill of each cycle of the chemo regimen, marrow and GIT recovery before next cycle, chose tolerable regimen – both short term organ toxicity and physical SE and long term damage causing late SE.

Hence each patient dose is different and always remembers the aim of the Rx

Clinical indication Cancer… but varies Predicted response is also different within the same cancer based on performance score,

clinical stage, prognostic factors or score, molecular or cytogenetic markers Side effects Vs anticipated or best outcome

Neoadjuvant – given before surgery or radiotherapy for the primary cancer

Adjuvant – given after surgery to excise the primary cancer, aiming to ↓relapse risk e.g. breast Ca

Palliative – to treat current or anticipated symptoms without curative intent

Primary – 1st line Rx of cancer in many haematological cancers this will be with curative intent initially aiming for remission

Salvage – chemotherapy for relapsed disease

For many types of cancer, chemotherapy regiment will consist of a number of different drugs – combination chemo – usually given an acronym. A drug may be given as a single agent. Routes of administration:

IV is the most common – bolus, infusional bag, continuous pump infusion, PO convenient, dependent on oral BA SC convenient in community setting Into a body cavity - bladder, pleural effusion Intralesional – directly into a cancerous area – consider pH Intrathecal – into the CSF – by lumbar puncture or ommaya reservoir Topical – medication will be applied onto the skin IM – rarely

Chemotherapy Adverse effects – toxicity

Need a balance between cancer cell kill and toxicity to normal cells undergoing cell division e.g. Myelosuppression ↓ Neutrophils (infection), anaemia and thrombocytopenia GI effects – mucositis, diarrhoea Temporary alopecia Skin and nail changes Cardiomyopathy or arrhythmia Gonadal failure – temporary or permanent Teratogenicity – must be advised to use contraception

#Neurotoxicity – peripheral and central

Hepatocellular damageAdverse effects – those due to Rx on the tumour

ARF – often multifactorial – hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules

GI perforation at site of tumour – reported in lymphoma Disseminated intravascular coagulopathy onset within a few hours of starting Rx for AML

Properties of drug Some IV chem. Drugs are vesicants – extravasation may lead to extensive skin and subcut

tissue necrosis Nausea – multifactorial but includes direct action of chemo drugs on the central

chemoreceptor trigger zone. Beau’s lines are transverse depression in the nail plate caused by temporary cession of cell division in the proximal nail matrix.

Drug interactions – other drugs may ↑plasma levels of the chemo drugs Vincristine and intraconazole (anti-fungal) leads to more neuropathy 6-mercaptopurine and allopurinol (commonly used to prevent gout and renal failure) the

latter inhibits the breakdown of 6-MP Methotrexate – caution with prescribing penicillin, NSAIDS

Monitoring during Rx Response of the cancer – reassessment of solid tumours by radiological imaging; leukaemias

by BM examination after a predetermined no of cycles to ensure response Drug levels e.g. Methotrexate drug assays taken on serial days to ensure CL from the blood

after folate rescue Checks for the organ damage – some regiments stipulate measurement of Creatinine

clearance, ECG or LFTsTreatment for non-Hodgkin’s lymphoma – R-CHOP which is Rituximab, Cyclophosphamide, doxorubicin hydrochloride, vincristine (AKA oncovin), prednisolone

Session 11- Drugs Treatment of Parkinson’s DiseaseClinical features of Parkinsonism – Tremor (low Hz high amp), rigidity (cog-wheel, clasp knife), bradykinesia, postural instability

Causes of Parkinsonism: Idiopathic PD Other degenerative diseases – manifest with akinetic degenerative syndrome, Drug induced – anti-psychotic drugs ↓dopamine Neurotoxins Metabolic Vascular (pseudoparkinsonism) Toxins CO, MN, MPTP

Pathophysiology of idiopathic Parkinson’s disease

Degeneration of neurones in Substantia nigra (pars compacta), depletion of dopamine, symptoms appear with 50% neuronal loss. DA receptors in corpus striatum intact. Other NT also involved

Pathology – neurodegenerative, Lewy body (at post mortem), loss of pigment on SN, ↓dopamine in that part of the brain.

Clinical – progressive disease, motor symptoms improve with levodopa, however non motor manifestations... mood changes, pain, cognitive change, urinary symptoms, sleep disorder, sweating

Prognosis in PD 15 year follow up: 80% somnolence (sleepiness) 50% swallowing difficulties 27% severe speech problems

94% dyskinesia 81% falls 84% cognitive decline (50% hallucinations)

Diagnosis of IPD – clinical features, exclusion of differentials, response to levodopa, structural neuro imaging is normal, functional neuro imaging – SPECT, PET

DAT scan (like SPECT) – labelled tracer, presynaptic uptake, abnormal in PD, not diagnostic,

Rx of Parkinson’s Disease

Drugs classes in IPD – Levodopa, DA receptor agonist, MAOI type B inhibitors, COMT, anticholinergics, Amantadine

Phenylalanine Levodopa dopamine then either MAO or COMT

LEVO DOPA used in combination with peripheral decarboxylase inhibitor: e.g. carbidopa

LEVO DOPA – tablet, standard dosages given with controlled release preparations.

L. Dopa is toxic to neurones in cell culture; ↑ DA turnover may enhance oxidative stress. L. Dopa is not toxic to non PD patients.

Long term usage – loss of efficacy, involuntary movements, motor fluctuations (on/off)

Motor complications – wearing off, dyskinesias, dystonia, freezing, on/off flux

LEVO dopa: +’ves – highly efficacious, low SE -‘ves – precursor (enzyme conversation), may be neurotoxic, long term failure of effect

DA agonists (ERGOT derivatives pergolide, cabergoline, non ERGOT ropinirole, PATCH – rotigotine subcut - apomorphine)

Advantages - direct acting, no dyskinesias, possible neuroprotection Disadvantages – SE, less efficacy than levo dopa, and expensive ERGOT cause fibrosis of: peritoneum, heart valve cavities and pleural cavity. Non-ERGOT

don’t

Impulse control disorders with DA receptor agonists – pathological gambling, hypersexuality, compulsive shopping, desire to ↑dosage, punding

Uses of DA agonists – de novo therapy, and add on therapy

Anticholinergics – Ach may have antagonist effects to dopamine drugs, trihexyphenidyl, orphenadrine, procyclidine

Advantages – treat tremor, not acting via DA systems

Disadvantages – no effect on akinesia, SE!

Mono amine oxidase inhibitors – non selective ‘cheese effect’ (e.g. selegiline, rasagiline)

Selective type B – enhance dopamine. No therapeutic effect alone, prolong action of levo dopa and may be neuroprotective

Catechol-o-methyl transferase inhibitors – ↓peripheral breakdown of levo dopa, have levo dopa ‘sparing’ effect. Smoothes out motor response

Surgery carried out stereotactically, of value in highly selected cases, controlled trails

o Lesion – thalamus for tremor, GPi for dyskinesiaso Deep brain stimulation – Subthalamic nucleus

Session 11- Anti-epileptic drugs

Epilepsy = episodic discharge of abnormal high frequency electrical activity in brain leading to seizure. Diagnosis requires evidence of ‘recurrent’ seizures unprovoked by other identifiable causes

Seizure – is the episodic discharge of high frequency impulses in the brain, or a part of it.

Medical overview epilepsies should be viewed as a symptom of underlying neurological disorder and not a single disease entity. Common condition- 0.5-1% prevalence therefore 450000 in UK with some form of the disease, chronic epilepsy – 500 sudden deaths/year in UK, therapeutics currently effective for about 75%. 10% will still have frequent seizures

Anti epileptic drugs – ADRs – common some serious DDIs – some positive combined with other AEDs often significant negative PK interactions

Medic-social consequences of misdiagnosis – inappropriate labelling of epilepsy has serious implications such as social financial and medical there is a certain degree of difficulty in diagnosis

Classification: Two main types: Partial seizures (simple conscious normal) complex (consciousness effected)

o Loss of local or local excitatory/inhibitory homeostasis, ↑ discharges in focal cortical area,

Symptoms reflect area affected e.g. involuntary motor disturbance, behavioural change, impending focal spread accompanied by ‘aura’ e.g. unusual smell or taste

May become secondarily generalised Generalised seizures

o Generated centrally spread through both hemispheres with loss of consciousness (reticular system affected)

o Tonic-clonic seizures (grand mal) – 60% Tonic phase = patient falls unconscious with muscles in spasm and lack of

respiratory movement leading to possible cyanosis Clonic phase – convulsive movements with possible biting of the tongue and

urinary incontinence. o Absence seizures (petit mal) – 5%o Many other types recognised

Complications

Status epilepticus – most seizures are short lived (<5mins) some seizures prolonged beyond this or experienced as series of seizures without recovery internal. This is referred to as status epilepticus. Can occur for any type of epilepsy, prolonged seizure treated as a medical emergency, untreated status epilepticus can lead to brain damage or death.

Dangers in severe epilepsy – uncontrolled epilepsy is not a benign condition

Physical injury relating to fall/crash; hypoxia (cytotoxic damage in brain); SUDEP – sudden death in epilepsy; varying degrees of brain dysfunction/damage; cognitive impairment; serious psychiatric disease; significant adverse reactions to medication. Stigma and loss of livelihood

Aetiology Primary – no identifiable cause – idiopathic (65-70%) Secondary – medical conditions affecting brain (30-35%), vascular disease and tumours both cause (inhibitory imbalance as a result)In elderly (60+) secondary responsible for 60% of seizures

Precipitants Sensory stimuli – flashing lights/strobes or other periodic stimuli Brain disease/trauma – brain injury, stroke/haemorrhage, drugs/alcohol, structural

abnormality/lesion Metabolic disturbances – hypoglycaemia/hypocalcaemia/hyponatraemia Infections – febrile convulsions in infants Therapeutics –some drugs can lower fit threshold AEDs + polypharmacy: PKs lower level

Therapeutic TARGETS

Voltage gated sodium channel blockers - bind to bottom of receptor to inactivated it – as they having higher affinity to depolarised neurones and binds when it is such they bind mainly to neurones which are excessively firing

Examples:

Carbamezepine (EXAM NOTE) pharmacology – prolongs VGSC inactivation state

PK – well absorbed – linear PK, initial t1/2 – 30 hours but strong inducer of CYP450

Affects its own phase 1 metabolism

Repeated use t1/2 = 15 hours

ADRs – wide ranging type As: CNS – dizziness drowsy ataxia, motor disturbance numbness tingling, GI upset – vomiting, CV – variation in BP, contraindicated with AV conduction problems, rashes hyponatraemia, RARE – severe bone marrow depression resulting in neutropenia

DDIs – because CYP450 inducer can affect many other drugs

Phenytoin (AED) ↓ (but CBZ plasma concentration ↑) Warfarin ↓ Systemic corticosteroids ↓ Oral contraceptives ↓

Antidepressants – SSRIs, MAOIs, TCAs– all interfere with action of Carbamezepine

Drug monitoring – dosing to effect and adjust dosing as t1/2 ↓

Treats – generalised tonic – clonic, all partial seizures but not absence seizures

VGSC blockers – PHENYTOIN

Pharmacology of phenytoin prolongs VGSC inactivation state

PK – well absorbed – but 90% bound in plasma competitive binding can ↑ levels also CYP450 inducer

Sub-therapeutic concentrations linear PK but non-linear PK at therapeutic concentrations – very variable t1/2 – 6-24 hours

ADRs – very wide ranging type A’s – CNS – dizziness ataxia headache nystagmus, nervousness, gingival hyperplasia (20%), rashes – hypersensitivity

DDIs – competitive binding e.g. with valporate salicylate ↑ plasma levels – exacerbates non-liner PKs

Very wide range of interactions including OCs ↓ CHECK BNF

Drug monitoring – close monitoring of free concentration plasma, can use salivary levels as indicator of free plasma

Epilepsy types treated with phenytoin – generalised - clonic; partial all; not absence seizures

VGSC blockers – Lamotrigine

Pharmacology – prolongs VGSC inactivation state perhaps CCB and ↓ glutamate release

PK – well absorbed – linear PK t1/2 = 24 hours (phase 2), no CYP450 induction fewer DDIs

ADRs less marked CNS dizziness ataxia somnolence nausea, still some mild (10%) and serious (0.5%) skin rashes.

DDIs – adjunct therapy with other AEDs, OCDs ↓LTG plasma level, valporate ↑ LTG in plasma (competitive binding)

Epilepsy types treated with LTG – partial seizures, generalised – tonic-clonic and absence seizures and other types

LTG ↑first line AED for epilepsy, however not first line in children, and appears safer in pregnancy

Enhancing GABA mediated inhibition – major role in post synaptic inhibition – 40% synapse in brain are GABA-ergic –GABA ↑ is a natural anticonvulsant or excitatory brake.

Distinct pharmacological targets: Binding with GABAA receptor Direct GABA agonist Benzodiazepine site – enhance GABA action Barbiturate site – enhance GABA action Inhibition of GABA inactivation GABA ↑ Inhibition of GABA re-uptake GABA ↑ Increase rate of GABA synthesis GABA ↑ Targeting these sites enhance action of GABA

Valproate E’GABA’MI

Pharm – mixed sites of action Weak inhibition of GABA inactivation enzymes – GABA + Weak stimulus of GABA synthesising enzymes – GABA + VGSC blocker + weak CCB – discharge

PK – absorbed 100-90% plasma bound Linear PK t1/2 = 15 hours

ADRs – generally less severe than with other AEDs, CNS sedating ataxia tremor (weight gain), hepatic function transaminases ↑ in 40% patients – rarely hepatic failure

DDIs – adjunct therapy with other AEDs – care needed with adjunct therapy, both valproate and adjunct PKs affected – always check BNF. Antidepressants – SSRIs MAOIs TCAs & TCA inhibit action of valproate. Antipsychotics – antagonise valproate by lowering convulsive threshold. Aspirin competitive binding in plasma valproate ↑

Drug monitoring – close monitoring of free [plasma], can use salivary levels as an indicator

Plasma valproate not closely associated with efficacy monitor for blood, metabolic and hepatic disorder.

Epilepsy types treated with valproate – partial seizures, generalised – tonic-clonic + absence seizures

Benzodiazepines – E’GABA’MI

Pharm – BZDs act as distinct receptor site on GABA chloride channel. Binding of GABA or BZD enhance each others binding, act as positive allosteric effectors (like O2 and Hb), ↑Cl- current into neurone – ↑threshold for AP generation (makes it harder to achieve) (EXAM NOTE)

Pk: well absorbed 90-100% highly plasma bound 85-100% linear PK t1/2 vary 15-45 hours

ADRs – sedation, tolerance (chronic use), confusion impaired co-ordination, aggression, dependence/withdrawal (chronic use), abrupt withdrawal seizure trigger, resp and CNS depression

DDIs – some adjunctive use, OD reversed by IN flumazenil but use may precipitate seizure/arrhythmia

SE limit first line use

Lorazepam/diazepam - status epilepticus

Clonazepam– absence seizure short term use

AEDs basic prescribing rules

Drug choice based on individual patient and condition, dosing rationale – monotherapy is optimal aim. Systematic use of one drug replace if ineffective, ITU sedation is a Rx. Patients must remain under review. Significant variation in AEDs plasma levels – monitors and titrate to therapeutic level.

SE with AEDs are very common. Adjunctive drug use and polypharmacy with epilepsy is common. Always consult BNF in detail when managing patients on AEDs

AEDs and pregnancy – balance of risk

Epilepsy vs AED teratogenicity

Mild disease – stop treatment

Severe disease or status epilepticus – harm to both mother and baby if treatment is stopped

Failure of OCP with AEDs failure rate x 4 with carbamazepine/phenytoin

Dangers to foetus during pregnancy – congenital malformations, valproate (NTD↑), facial and digit hypoplasia, learning difficulties/mild neurological dysfunction. AED risk of birth defects = 8% vs 2% normally

With multiple AED teratogenic risk ↑

Use single AED if possible at lowest dose

Lamotrigine may be safest – birth defect rate 2%

AEDs and dietary supplements – folate supplement – ↓risk of NTD. AEDs associated with vit K deficiency in new born – coagulopathy and cerebral haemorrhage. Vit K supplement 10mg/day in last trimester

Status epilepticus – is a medical emergency. Can be convulsive and non-convulsive state. It is defined as either a single convulsion lasting > 30 mins or convulsions occurring back to back with no recovery between them.

NOTE any convulsion lasting >5mins or two convulsions without recovery should receive emergency Rx. Uncontrolled convulsions can lead to hypoxia and irreversible brain damage and death.

Adult mortality = 20% risk ↑with length of episode

Priorities are ABC, exclude hypoG, hypoventilation may result with high AED doses, ITU for paralysis and ventilation if failing

Rx – BZD e.g. Lorazepam (0.1 mg/kg) preferred as longer t1/2 than diazepam. IV route (rectal if difficult IV access) AND phenytoin (zero order kinetics (15-20mg/kg), rapidly reaches therapeutic levels IV cardiac monitoring – arrhythmias + hypotension

Other drugs – midazolam, pentobarbital propofol

VERY BASIC RULE OF THUMB Valproate sodium as 1st line for primary generalised seizures Carbamezepine for partial seizures (or generalised seizures) Lamotrigine can be used in either circumstances, and is probably the drug of choice for ♀of

child bearing age Benzodiazepines and phenytoin are 1st line for acute life threatening status epilepticus.

Drugs used in psychiatric DiseaseContemporary knowledge of CNS disorders is largely predicated on knowing how drugs act on disease systems and then inferring the pathophysiology of the disorder. Therefore pathophysiology is inferred rather than proved since we do not yet know the primary enzyme, receptor or genetic deficiency in any given psychiatric disorder

Virtually all effective psychopharmacological drugs discovered to date were found by good luck, or by empiricism, that is, by probing disease mechanisms with a drug of known action but no prior proof that such actions would necessarily be therapeutic.

Action of CNS Drugs As agonists/antagonists of NT receptors. Some drugs may compete with the NT for its own binding site attempting to mimic the NT or to block the NT. Less commonly act as inhibitors of regulatory enzymes – the enzymes most important in the NT processes are those that make or destroy NT. Key transmission and modulatory pathways in CNS

Noradrenergic pathways Dopaminergic pathways

Monamine oxidase inhibitors

With additonal actions(TCAs) Pure(SNRIs)

Non- selective noradrenalin and serotonin

Noradrenaline (NARIs) Serotonin( SSRIs)

Selective noradrenaline or serotonin

Monoamine uptake inhibiotrs Other drugs(e.g. mirtazepine)

Antidepressants

Serotonergic (5HT pathways) GABA-ergic pathways Cholinergic pathways Glutamate pathways

Formulation of psychiatric disorders

Genetic vulnerability to the expression of the disease. Life events that come the individual’s way. Individual’s personality, coping skills, social support. Other environmental influences e.g. viruses, toxins other disease. BIOPSYCHOSOCIAL MODEL

Depression Key Sx – low mood, guilt, loss of concentration, ↓energy, ↓↓appetite, sleep, pessimism disturbance, physical aches and pains, irritability, self harm, suicidal ideas/acts, psychotic Sx

Unipolar depression is where the mood swing is always in the same direction. The majority of cases are due to external triggers such as difficult life events (reactive depression). However about 25% of patients seems to have endogenous depression where no such relationship can be seen. This is often familial.

Pathophysiology: Theory 1

Monoamine hypothesis - depression due to a deficiency of monoamine NT – NA and serotonin – certain drugs that depleted these could induce depression - reserpine. E.g. monoamine oxidase inhibitors (MAOIs) – block enzyme from destroying NT

NT receptor hypothesis – an abnormality in the receptors for monoamine transmission leads to depression. Depletion of NT causes compensatory up regulation of post synaptic receptors, altered balance of various NT systems, long term adaptive responses e.g. altered gene expression – some post mortem evidence

HOWEVER = no clear and convincing evidence that monoamine deficiency accounts for depression or that receptor change accounts for depression. Growing evidence that despite apparently normal levels of monoamines and receptors that these systems do not respond normally

Theory 3 – the monoamine hypothesis of gene expression - deficiency in molecular functioning hypothesised problem within the molecular events distal to the receptor.

Theory 4 – “neurokinin hypothesis of emotional dysfunction”. Observation that substance P – an antagonist to neurokinins may have an antidepressant action

Selective serotonin reuptake inhibitors – First line nowadays due to improved safety profile

First line treatment for moderate to severe depression

Fluoxetine, citalopram, paroxetine

Citalopram most selective, paroxetine most potent may interact with extrapyramidal dopaminergic system.

PK - almost completely absorbed from gut. Long elimination T1/2 metabolised in liver.

Side effects and toxicity -

Common – anorexia, nausea, diarrhoea

Rare – precipitation mania, ↑ suicidal ideation and neurological SE such as tremor, extrapyramidal syndromes

NB – safe in overdose if taken on own

Tricyclic antidepressants

First generation antidepressants. Still used amitryptiline, imipramine, clomipramine

Block re-uptake of serotonin, NA

Other effects1. Inhibition of NA uptake, enhancing NA Neurotransmission (sympathomimetic effect)2. Muscarinic cholinoceptor blockade – ↓cholinergic neurotransmission (anticholinergic effect)3. Alpha 1- adrenoceptor blockade – suppression of NA neurotransmission (sympatholytic

effect)PK – lipid soluble, absorbed from gut, long half lives, metabolised in liver

SE and toxicity = CNS – sedation and impairment of psychomotor performance, lowering of seizure threshold. ANS, reduction in glandular secretions, eye accommodation block.

CVS – tachycardia, postural hypotension, impaired myocardial contractility

GI – constipation

Overdose

‘PURE’ non-selective monoamine uptake inhibitors

Developed as SSRIS with property of NA uptake inhibition grafted on. E.g. venlafaxine a second line drug. Dose dependent – lower doses serotonin action, higher doses NA

SE and toxicity- as with SSRIs, also sleep disturbance, ↑BP, dry mouth, hyponatraemia, relatively short T1/2 therefore may be a withdrawal syndrome on discontinuation

Schizophrenia – Psychosis

Schizophrenia is an example of a mental illness with psychotic symptoms. 1% of UK population

Other illnesses are mania, psychotic depression, and organic syndromes

Symptoms of schizophrenia Positive symptoms: hallucinations, delusions, thought disorders, abnormal behaviour Negative symptoms – blunted affect, social withdrawal, poverty of thought and speech Cognitive symptoms – selective attention, poor memory reduced abstract thought Affective symptoms – anxiety and depression

Schizophrenia – its symptoms are numerous, its presentations are diverse, its cause is unknown and its response to treatment is unsatisfactory

Genetic (strong familial component) + biological (e.g. maternal gestational hypertension) + upbringing schizophrenia

Dopamine theory of schizophreniaAmphetamine causes symptoms very similar to positive symptoms of schizophrenia. Dopamine antagonists are the best treatment for schizophrenia. Some evidence of ↑ dopamine function in schizophrenicsBut amphetamine does not cause negative symptoms. Dopamine antagonists do not treat negative symptoms; changes in dopamine function may be a response to long term drug treatment

Main dopamine pathways Mesolimbic – important in emotional response and behaviour, and connect to the

hippocampal and amygdala areas. Meso-cortical – important in arousal and mood Nigrostriatal – 75% of brain dopaminergic pathways. Neurones span from the substantia

nigra to the corpus striatum and is the key pathway damaged in Parkinson’s disease. Dopamine antagonism can thus induce ‘extra-pyramidal’ movement disorders and are relevant to SE of anti-psychotic drugs key pathway damaged in Parkinson’s disease

Tuber-hypophyseal in hypothalamus and pituitary gland

Is schizophrenia associated with ↑ 5HT FUNCTION?

5HT has been implicated in a number of behaviours which are disturbed in schizophrenia (e.g. perception, attention, mood, aggression, sexual drive, appetite, motor behaviour, sleep)

Many of the most effective antipsychotic drugs are antagonists at 5HT-2A receptors

Lysergic acid diethylamine (LSD), a 5HT-2A agonist is psychotogenic. Precursors of 5HT exacerbate schizophrenia. Chronic Fluoxetine (Prozac) ↑ 5HT activity and ↑ both +ve & –ve symptoms

BUT LSD produces mainly visual hallucinations: other psychotic symptoms (conceptual disorganisation and cognitive impairments) are generally absent

No strong evidence for changes in 5HT function

Is schizophrenia associated with ↓ cortical glutamate function?

Glutamate is the predominant excitatory NT in the brain

Phencyclidine (PCP: non-competitive antagonist at NMDA-type glutamate receptors) induces symptoms very similar to schizophrenia

Post mortem studies have shown:

D2ANTAGONIST

Mesolimbic pathway dramatic

therapeutic action on positive

psychotic symptoms

Tuberoinfundibular pathway

hyperprolactinemia (lactation,

infertility, sexual dysfunction)

Nigrostriatal pathway

extrapyramidal side effects (EPS) and

tardive dyskinesia

Mesocortical pathway

enhanced negative and

cognitive psychotic symptoms

↑ cortical glutamate receptors ↑ binding of glutamate receptor ligands in cortex, basal ganglia and hippocampal formation BUT both ↑ and ↓ in glutamate binding in temporal lobe have been reported Glutamate systems are important, mechanism unclear

DRUGS

First generation typical antipsychotics haloperidol, chlorpromazine (increased dopamine antagonism)

Atypical antipsychotics olanzapine, risperidone, quetiapine, Clozapine (most effective but serious ADRs)

Action of all antipsychotics

Sedation – within hours Tranquilisation – within hours Antipsychotic – several days or weeks Activating effect within weeks – negative symptoms Production of extrapyramidal side effects – hours or days advantage of atypical

Atypical advantagesLess SE so more acceptable to patient, different preparations e.g. dissolvable some once daily dosage. Differing SE profiles can be matched to patient characteristics, 1st line treatment in schizophreniaTypical antipsychoticsHaloperidol safe in emergencies, more sedating, well known SEWide range of pharmacological action, DA receptor blockade, anticholinergic effects, α-adrenergic blockade, antihistamine effect, allergic reactions

SE – extrapyramidal SE – Parkinsonism, acute dystonia, akathisia (inner restlessness), tardive dyskinesia

Neuroleptic malignant syndrome - severe rigidity, hyperthermia, ↑ CPK, autonomic lability

Postural hypotension, weight gain, endocrine changes e.g prolactinaemia, pigmentation

Toxicity – CNS depression, cardiac toxicity, risk of sudden death with high dose

Anxiety

Fears out of proportion to situation avoidance fear of dying, going crazy

Physical symptoms – light headedness, SOB, hot and cold flushes, palpitations, numbness

Treatment – non-pharmacological approaches first line. Treat any coexistent disorder

Drugs – antidepressants, anxiolytics, occasionally antipsychotics

Principle NT systems – GABA, 5-HT, NA, many of drugs prescribed however have very specific pharmacological effects

Benzodiazepines e.g. diazepam, lorazepam

Exerts effects through structure known as GABA-BDZ receptor complex. BDZ only bind to BDZ receptor of which there are 2 main groups – high and low affinity

High affinity group – important in anxiolytic, hypnotic and anticonvulsant effects of BDZ. Inhibitory effects in brain

They act as full agonist at these receptor sites, lead to enhancement of GABA. BA following oral admin – almost complete-maximum concentration 30-90 mins, highly lipid soluble – CNS diffusion rapid. Renal excretion, long t1/2

Tolerance can occur; dependence-on discontinuation of Rx can get withdrawal effects such as insomnia, agitation, anxiety

SE – Common – drowsiness, dizziness, psychomotor impairment Occasional – dry mouth, blurred vision, GI upset, ataxia, headache, ↓BP Rare – amnesia, restlessness, skin rash

Toxicity – cleft lip and palate if used in pregnancy. If taken late in pregnancy may cause resp depression and feeding difficulties in baby

Treatment of overdose – deaths are rare – support

Flumazenil and antagonist/partial inverse agonist at BDZ receptors may be useful in reversing effects

Bipolar disorder

Depression and hypomania/mania

Feeling unusually excited, happy, optimistic or feeling irritable

Overactive – poor concentration and short attention span, poor sleep, rapid speech, jump from one idea to another, poor judgement, ↑interest in sex

Psychotic symptoms – hallucinations, grandiose delusions

Mood stabilisers – Lithium, sodium valproate, carbamazepine, olanzapine

Lithium

Theories1. Electrolytes and channels – may compete with Mg and Ca ions2. NT – acute Li ↑5HT, chronic Li may ↓5-HT receptor sites3. Second messenger systems – Li attenuates the effects of certain NT on their receptors

without altering receptor densityClinical pharmacology – renal excretion, slow release preparations can be given once daily. Li levels need to be monitored (at least 3 monthly) and taken 12 hours after last oral dose. Need to check renal function and thyroid function before starting

Side effects: Memory problems – 52% Thirst – 42%

Polyuria – 38% Tremor – 34% Drowsiness – 24% Weight gain – 18%

Other effects – kidneys, hypothyroidism, hair loss, rashes

Toxic effects – need to monitor V&D, coarse tremor, Dysarthria, cognitive impairment, restlessness, agitation

Rx of toxicity – supportive measure, anticonvulsants, ↑fluid intake, haemodialysis may be necessary

Session 13: Drugs Affecting Acid SecretionThe parietal cell: mechanism of acid secretion

When stimulated, parietal cells secrete HCl at a concentration of roughly 160mM (pH 0.8). The acid is secreted into large cannaliculi which are continuous with the lumen of the stomach. Cytoplasmic tubulovesicular membranes are abundant in the resting cell and virtually disappear in concert with a large increase in the cannalicular membrane. It appears that the proton pump as well as the K and Cl conductance channels initially reside on intracellular membranes and are transported to and fused into the cannalicular membrane just prior to acid secretion.

Mechanism of acid secretion

The [H+] in parietal cell secretions is roughly 3 million fold higher than in blood, and chloride is secreted against both a conc grad and electric grad. This, the ability of the parietal cell to secrete acid is dependent on active transport. H+/K+ ATPase or the proton pump located in the cannalicular membrane. Current model:

H+ are generated within the parietal cell from dissociation of water. The OH- in this process rapidly combine with CO2 HCO3

- by a carbonic anhydrase. The HCO3- is transported out of the

Basolateral membrane in exchange for chloride. The HCO3- into the blood is known as the alkaline tide. This process serves to maintain intracellular pH in the parietal cell.

Cl and K are transported into the lumen of the canaliculus by conductance channels, and such is necessary for secretion of H+. H+ pumped out of the cell by the proton pump; K is thus effectively recycled.

Accumulation of osmotically-active H+ in the canaliculus generates an osmotic gradient across the membrane that results in outward diffusion of water – the resulting gastric jucice is 155mM HCl and 15 mM KCl with some NaCl

Control of Acid secretion

Parietal cells bear receptors for three stimulators of acid secretion: Ach Gastrin Histamine (H2 type receptor)

Extracellular Ca is also necessary for acid secretion. Binding of Ach and gastrin result in elevation of [Ca]i while histamine’s effect is to activated adenylate thus ↑[cAMP]. Histamine from enterochromafin-like cells may be the primary modulator, but the magnitude of the stimulus appears to result from a complex additive of multiplicative interaction of signals of each type. Pharmacologic antagonists of each of these molecules can block acid secretion

Drug therapy for suppressing secretions of Gastric acid1. Antacids – neutralise if given sufficiently large volumes can heal ulcers2. Promoting gastric emptying and so removing acid – metoclopramide efficacy limited3. H2 blockade

a. H1 receptor drugs have no effectb. H2 blocking drugs – cimetidine, ranitidine, famotidine, nizatidine

4. Proton pump inhibitorsa. Blocks H+ K+ ATPase, non-competitive bind and inactivate the ATPase.

i. Omeprazole, lanzoprazole, esomeprazole

H. pylori – Rx. Lanzoprazole, clarithromycin and amoxicillin. Bacteria causes ulcers, especially duodenal ulcers =. Urea breath test used for diagnosis

Drugs affecting gut MotilityMyogenic control of the gut. Rhythmic contraction creates slow waves of depolarisation throughout the smooth muscle. Passive current spread through gap junctions. Interstitial cells of cajal act as pacemaker to drive electrical activity.

Neural control – intrinsic and extrinsic control, stimulation of the post-ganglionic cholinergic enteric nerves ↑force of contraction of gut. Stimulation of non-adrenergic inhibitory nerves inhibits contractions.

Gastric motility – a complex neuronal network

Local nerves – enteric nervous system – autonomous collection of nerves within gut wall Auerbach’s plexus – between circular and longitudinal muscle layers Meissner’s plexus – submucosa Henle’s plexus in circular muscle adjacent to submucosa Cajal’s plexus in circular muscle adjacent to longitudinal muscle.

Extrinsic nerves

Intestino-intestinal inhibitory reflex – distension of one intestinal segment causes complete intestinal inhibition

Anointestinal inhibitory reflex – distension of the anus causes intestinal inhibition

Gastrocolic and duodenocolic reflexes – stimulates motility after material has entered the stomach or duodenum .

Neurotransmitters – all endocrine hormones in the GIT are peptides produced in the endocrine cells of mucosa

Gastrin promotes acid secretion Secretin – duodenum Cholecyskinin – small intestine Motilin – small intestine Paracrine transmitters – histamine, somatostatin, prostaglandins

Nausea and Vomiting

Emesis – the pyloric sphincter closes while the cardia and oesophagus relax. Gastric contents propelled by contraction of abdominal wall and diaphragm. Glottis closes with elevation of the soft palate preventing entry of vomitus into the trachea and nasopharynx.

Anti-emesis drugs

Dopamine D2 receptor antagonists –, metoclopramide, Domperidone (D 2 antagonist) (spiel below)

Acts – postrema on the floor of the 4th ventricle and to ↑rate of gastric emptying

Indicated in acute nausea/vomiting (esp. Induced by L-dopa or dopamine agonists

Route – oral or PR (extensive FPM) but does not cross blood-brain barrier. ADR – stimulates prolactin release (galactorrhoea) but rare dystonia

Ondansetron (5-HT3 receptor antagonist)

5-HT released into the gut causes vagal stimulation. Therefore Ondansetron is effective:

postrema on the floor of the 4th ventricle Against vagal afferent nerves in GI Indicated – in high doses in radiation sickness and chemo Rx/ post-operative Route – IV, IM or orally The anti-emetic effect can be enhanced by single dose of a corticosteroid ADRs; headaches; constipation; flushing (IV

Metoclopramide

In addition to D2 antagonism anti-cholinergic effects (GI) and blocks vagal afferent 5-HT3R (GI

Indications are GI cause for N&V; migraine; post-op

Routes – oral; IM; IV Short T1/2 – 4 hours

ADRs – extra-pyramidal reactions (dystonia) occur in 1% - therefore avoid in PD; galactorrhoea

Vestubular apparatus

Ach and H1

Medullary centre Ach, H1 and 5HT

Posterma on the floor of

the 4th ventricle -dopamine

Hyoscine (Ach antagonist) – direct antagonist of muscarinic receptors, it is used to treat motion sickness – oral or patch. Effects usually short lived

ADRs – systemic anti-cholinergic effects; bradycardia

Cyclizine (H1 antagonist) – has additional anti-muscarinic effects used in acute N&V. Can be given oral, IV or IM but can cause QT prolongation and therefore Cl in myocardial ischaemia etc. Crosses the BBB – sedative effect

Other H1 antagonists include promethazine; phenothiazine may suppress nausea following surgery or gastric irritation/opioid induced nausea and useful if sedation required.

Other agentso Cannabinoids – nabiloneo Benzodiazapines –lorazapam

Constipation

Laxatives treatments non-pharmacological

o Consider underlying medical cause – diabetes, PD, dehydration, pregnancy, mechanical obstruction, or cancer

o ↑fluid intakeo High fibre dieto Exercise

Bulk – fybogel Faecal softeners – glycerol (Also acts as a stimulant Osmotic – lactulose/macrogols/phosphate enemas Irritant/stimulants – castor oil, senna, sodium picosulfate

Drugs causing constipation – anti-cholinergics, aluminium antacids, antidepressants (TCA, SSRIs), antiepileptics (carbamazepine), antipsychotics (Clozapine, quetiapine), antispasmodics (dicycloverine, hyoscine), calcium supplements,

diuretics (inadapamide), iron supplemenets, opioids (codeine, Buprenorphine), verapamil.

Bulk laxatives

Vegetable fibre – resistant to digestive enzymes, take a few days to work, attempt to re-establish normal bowel habit (chronic or

simple constipation related to IBS, pregnancy etc.) normal fluid intake essential. ADR – flatulence. Cl – adhesions/ulceration – may cause intestinal obstruction. Ideally patients should ↑fibre in their diet.

Faecal softeners

Arachis oil (enema) and glycerol (supplement) act by lubricating and softening stool, safe but not always effective. Indicated as per bulk laxatives but also: adhesions etc. As no risk of obstruction and anal fissures and haemorrhoids

Osmotically active laxatives mg and Na salts. Mg and Na salts (saline purgatives = phosphate enema) cause water retention in small/large bowel to ↑peristalsis act quickly and are severe, usually PR, reserve for resistant constipation.

Lactulose – disaccharide (galactose/fructose) cannot be hydrolyzed by digestive enzymes. Fermentation of lactulose by colon bacteria leads to acetic and lactic acid (osmotic effect). Oral takes 48 hours to work thus used in Liver Failure – reduced production of ammonia.

Movicol (polyethylene glycol) – powder dissolved in fluid, may prevent dehydration, initial effects within hours, takes 2-4 to get full relief. Like all osmotic laxatives – caution required to prevent intestinal obstruction .

Irritant/stimulant laxative

Excitation of sensory nerve endings leads to water and electrolyte retention and

thus peristalsis. Used for rapid treatment e.g. faecal impaction or surgical prep. Can act 6-8 hours (orally) so bedtime Rx. Repeated use – colonic atony and hypokalaemia

Anthraquinones – Danthron, senna plant, rhubarb roots.

Most frequently used senna and codanthramer. Danthron plus faecal softener e.g. docusate sodium. Some derivatives are absorbed in small intestine and excreted into colon along with those that have escaped absorption. Similar to the other laxatives – can cause abdominal cramps – don’t use in intestinal obstruction

Abuse – melanosis coli.

If history and/or examination reveals soft faeces stimulant laxatives (e.g. senna, bisacondyl glycerol)

If history and DRE reveals hard faeces: osmotic laxatives (e.g. movicol), bulk-forming laxatives (e.g. ispaghula)

Constipation hypokalaemia feedback

Diarrhoea

Think cause – may represent overflow to constipation, anti-diarrhoeal drugs treat symptoms not the cause. Appropriate fluid/electrolyte management is important: anti-motility, bulk forming – fluid absorbents, and fluid absorbents.

Anti motility drugs –

Opiate analgesics (codeine),

Opiate analogue – loperamide – 40 times more potent than morphine as anti-diarrheal agent and penetrates CNS poorly.

Act via opioid receptors in bowel:

↓bowel motility - ↑ time for fluid to reabsorb ↑ anal tone and ↓ sensory defecation reflex

Good for chronic diarrhoea. Avoid in IBD as causes toxic megacolon

Bulk forming – a relatively small amount of faecal fluid (10-20ml) influences composition drugs such as ispaghula act via water absorption. Particularly useful for patients with ICS (constipation and diarrhoea) and those with ileostomy.

Fluid absorbents a relatively small amount of faecal fluid (10-20ml) influences composition. Kaelin acts as a fluid absorbent, therefore producing a more formed stool, very little use

Cholestyramine is a bile acid sequestrant and used for bile salt induced diarrhoea (crohn’s/post-vagotomy)

Pancreatic enzymes help with diarrhoea due to pancreatic malabsorption

Irritable Bowel Syndrome

A heterogenous group of abdominal symptoms for which no organic cause can be found – 3 common patient profiles

1. Diarrhoea predominant2. Constipation predominant3. Altering symptoms

Symptoms – diarrhoea occurring mainly in the morning, colicky lower abdominal pain, stability of weight. Abdominal pain/discomfort relieved by defecation or associated with altered bowel frequency” Others. Altered stool passage, abdominal bloating, distension or hardness, symptoms made worse by eating, passage of mucus

Mebeverine – reserpine derivative

IT has direct effects on colonic hypermotility. It relieves spasm of intestinal muscle. It does not have troublesome systemic anti-muscarininc SE. Useful when combined with bulk forming agent (fybogel meberverine) other smooth muscle relaxants include peppermint oil and alverine.