handouts 2014
TRANSCRIPT
School of Life Sciences
2013 – 2014
ClinicalPharmacology
&Medical
PharmacologyModule
Handbook
Convenor: Dr Robertsemail: [email protected]
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Clinical Pharmacology/Medical Pharmacology Modules
Dr. Richard Roberts- Module Convenor
Aim of the Module:
To provide background information aboutcommon drugs that may come across inclinical situation
-Mechanism of action
-Use
-Side effects
What is pharmacology?
Study of drugs:
The effect of the drug on the body-pharmacodynamics.
The effect of the body on the drug-pharmacokinetics.
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Receptors
•Neurotransmitters and some hormones cannot crossthe plasma membrane.
•Receptors: proteins in plasma membrane which bindthese compounds.
•Binding causes activation of the receptoractivates intracellular signalling cascadesresponse in the cell.
Membrane
contraction
eg noradrenaline released from sympathetic nerve endings acting onvascular smooth muscle cells.
a adrenoceptor
•Some receptors are intracellular eg nuclearreceptors
•Steroids act at nuclear receptors to alter genetranscription.
•Can cross plasma membrane.
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Steroid responseelement
Target Gene
Steroid hormone
Steroid hormone receptor
Dimer formation
Nuclear membrane
Cytoplasm
ExtracellularMedium
Intracellular receptors
Receptor Nomenclature
Receptors are combined into families based on the agoniststhat activate them and function.
eg adrenoceptor family
Activated by noradrenaline and adrenaline
adrenoceptors b-adrenoceptors
1 a2 b1 b2 b3
Contraction ofsmooth muscle
Relaxation ofsmooth muscle
Get different responses depending on proportion of receptor subtypespresent
Different subtypes useful for therapy.
Can generate compounds selective for 1 subtype overthe other.
eg Noradrenaline & adrenaline- act at a & b-adrenoceptors
Isoprenaline- selective for b-adrenoceptors.BUT not b1 or b2-adrenoceptors
Salbutamol- selective for b2-adrenoceptors
NA
Therefore can create selective drugs- selective effects
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Adrenoceptors- role in fight or flight
Drugs can be agonists ie activate a receptor
eg b2-adrenoceptor agonist acting on airways
Or antagonists- block the receptor thereforepreventing the agonist from having an effect.
eg b1-adrenoceptor antagonist acting on the heart
Membrane
contraction
eg noradrenaline released from sympathetic nerve endings acting onvascular smooth muscle cells.
a adrenoceptor
Antagonist binds to receptor, preventing agonist from binding.
x
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Competitive antagonist competes for the binding site with the agonist.
If there is a high enough concentration of agonist, the agonist candisplace the antagonist and the response recovers.
contraction contraction
Non-competitive anatagonist
Binds to the receptor in such a way that the agonistcannot displace it, no matter how much agonist ispresent.
R
NT
Alteration of Neurotransmitter Function
Agonist
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R
NT
Antagonist
eg b-blockers
R
NT
egLoperamide,Domperidone
Pre-synapticreceptor
Agonist orantagonist
Increaseor
decrease
R
NT
NTNT
NTNT
Reuptakeinhibitor
eg SSRI, St John’sWort, Sibutramine,Bupropion
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R
NT
NT Metabolism
Synthesis
Pre-cursor
Hormone
eg MAOIs
eg ACEis
R
NT
Enzymes
Inhibitors
eg PDE inhibitors
Inhibitorsor
activators
eg calciumchannelblockers
Action through Chemical Properties(non-specific effect).
eg antacids- reduce acidity because they are alkaline.
Laxatives- irritation- stimulates bowel movements.
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Summary
•The majority of drugs act at receptors.
•There are different receptors.
•And different subtypes of these receptors.
•Drugs can be designed to act selectively at thesereceptors.
•Therefore have selective effects in the body,and reduce side effects.
Drugs can be designed to activate (agonist) or block(antagonist) receptors (or enzymes/ transporters)
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The Physiology and Pharmacology ofDrug Abuse.
•Which drugs are abused and why?
•Are common mechanisms involved?
•What are the costs to individuals and society?
•Can drug abuse be treated?
Famous Drug abusers
Cocaine: Stephen King, Sigmund Freud, Robert Louis Stevenson (wrote DrJekyll & Mr Hyde in six days and nights on a cocaine binge. "That an invalid inmy husband's condition of health should have been able to perform the manual
labour alone of putting 60,000 words on paper in six days, seems almostincredible," said his astonished wife, Fanny).
Amphetamines: Charlie Parker, Lenny Bruce, Judy Garland, Anthony Eden,Adolf Hitler (couldn't function without daily methylamphetamine injections into his
buttocks by his ever-diligent, physician, Doctor Morell).
LSD: Timothy Leary, Jonathan Aitken, Aldous Huxley, Dr Kary Mullis (NobelPrize Winner for Chemistry in 1993 and inventor of PCR, a method for
detecting even the smallest amount of DNA. "Would I have invented PCR if Ihadn't taken LSD? I seriously doubt it, I could sit on a DNA molecule and
watch the polymers go by. I learnt that partly on psychedelic drugs.“)
Ecstasy: Shaun Ryder, Sting Fat Boy Slim, Eminem (takes half an E beforeevery stage performance to "loosen up“)
Heroin: River Pheonix, Thomas De Quincey, King George V, Charlie Parker,William Borroughs (“….heroin, the ultimate merchandise. No sales talk
necessary. The client will crawl through a sewer and beg to buy“)
Other abused drugs: cannabis, ethanol, nicotine, solvents, benzodiazepines
“Addictive” behaviours; eating, sex, exercise, Everton FC.
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Definitions
Addiction; the compulsion to take a drug irrespective of any associatedadverse consequences.
Dependence; the need for continuing exposure to a drug (to avoidphysical and/or psychological disturbances associated with abstinence
(withdrawal syndromes)). Many abused drugs not associated withwithdrawal symptoms; many therapeutic drugs are!
Tolerance; the need to increase drug dose to maintain the sameeffect.
All compulsive drug taking now considered to have an element ofdrug-seeking behaviour.
Abused drugs have very different structures; can they have a common mechanismin promoting reward?
Nerves communicate by releasing neurotransmitters that arerecognised by receptors
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Brain Reward Pathways
•Many essential behaviours are pleasurable (rewarding).
•Activity in some neuronal pathways in the brain are associated withreward. For example; rats will self-administer some drugs and these drugs
activate reward pathways.
•Much attention on the meso-limbic dopamine pathway (cell bodies inventral tegmental area, VTA, terminate in the nucleus accumbens).
•Many drugs of abuse, opiates, nicotine, amphetamine, cocaine,ethanol, cannabis, ecstasy, PCP, barbiturates, caffeine increase
dopamine release in the nucleus accumbens.
Dopamine release in the nucleus accumbens is a commonresponse to drugs of abuse
Drugs of abuse enhance release of dopamine from VTAneurones. GABA inhibits neuronal activity.
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Functional Magnetic Resonance Imaging(FMRI) for measurement of human brain activity
•Can be used to measure regional blood flow in the brainby BOLD technique.
•Increases in neuronal activity increase oxygenrequirement, accompanied by changes in local blood flow.
•Changes ratio of haemoglobin to oxyhaemoglobin (havedifferent characteristics in magnetic field).
•Can, therefore, detect which areas of the brain areactivated by different drugs.
•Administration of opiates, amphetamine and cocaine tohumans enhances blood flow in dopamine-rich areas suchas the nucleus accumbens and the VTA.
Does taking drugs “recreationally” do you any harm?
Short-term effects appear soon after a single dose and disappear in a fewhours. After an injection, the user reports feeling a surge of euphoria ("rush")
accompanied by a warm flushing of the skin, a dry mouth, and heavyextremities. Following this initial euphoria, the user goes "on the nod," an
alternately wakeful and drowsy state. Mental functioning becomes cloudeddue to the depression of the central nervous system.
Unwanted effects; respiratory depression (fatal in overdose), constipation.
Chronic users may develop collapsed veins, infection of the heart lining andvalves, abscesses, cellulitis, and liver disease. Pulmonary complications,
including various types of pneumonia, may result from the poor health conditionof the abuser and respiratory depression. Nutritional status tends to be poor.
Danger of HIV and hepatitis from injecting.
Withdawal precipitates craving, restlessness, muscle and bone pain, insomnia,diarrhea and vomiting, cold flashes with goose bumps ("cold turkey"), kicking
movements ("kicking the habit"). Major withdrawal symptoms peak between 48 and72 hours after the last dose and subside after about a week. Sudden withdrawal by
heavily dependent users who are in poor health is occasionally fatal, although heroinwithdrawal is considered less dangerous than alcohol or barbiturate withdrawal.
Heroin
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The powdered, hydrochloride salt form of cocaine can be snorted or dissolved inwater and injected. Crack is cocaine that has not been neutralized by an acid to
make the hydrochloride salt. This form of cocaine comes in a rock crystal that canbe heated and its vapours smoked. “Crack" refers to the crackling sound when it
is heated.
Cocaine blocks the re-uptake of monoamine neurotransmitters in theperipheral and central nervous systems.
Physical effects include constricted blood vessels, dilated pupils, andincreased temperature, heart rate, and blood pressure. The duration of
cocaine's immediate euphoric effects, which include hyperstimulation, reducedfatigue, and mental alertness, depends on the route of administration. The
faster the absorption, the more intense the high. On the other hand, the fasterthe absorption, the shorter the duration of action. The high from snorting may
last 15 to 30 minutes, while that from smoking may last 5 to 10 minutes.Increased use can reduce the period of time a user feels high and increases the
risk of addiction.
Cocaine
Some tolerance, but sensitisation possible. Binges, during which the drug istaken repeatedly and at increasingly high doses, may lead to a state ofincreasing irritability, restlessness, and paranoia; can result in full-blownparanoid psychosis. Cardiovascular complications, arrhythmias, heart
attack, stroke.
Appetite reduction leading to malnourishment.
Cocaine cont.
releases monoamine neurotransmitters (5HT, noradrenaline, dopamine). Acts asboth a stimulant and psychedelic, producing an energizing effect, as well as
distortions in time and perception and enhanced enjoyment from tactileexperiences.
In high doses, MDMA can interfere with temperature regulation. On rare butunpredictable occasions, this can lead to severe hyperthermia, resulting in liver,
kidney, and cardiovascular system failure, and death. ( Leah Betts died fromdrinking too much water). Cardiovascular risks similar to cocaine.
In animal studies (adolescents more susceptible) MDMA is neurotoxic.
MDMA meets many of the accepted diagnostic criteria for addiction, asevidenced by continued use despite knowledge of physical or psychological
harm, withdrawal effects, tolerance and almost 60 percent of people who useMDMA report withdrawal symptoms, including fatigue, loss of appetite,
depressed feelings, and trouble concentrating.
Ecstasy (MDMA (3,4
methylenedioxymethamphetamine);
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Cannabis: (active agent THC) mimics effects of small endogenous
lipid messengers (e.g. anandamide) , inhibits wide range ofneurotransmitter release in the brain and periphery.
Mild euphoric effect in moderate doses; dysphoria in high dosesparticularly naïve users. Context dependent.
Very low acute toxicity but some concerns about precipitationof schizophrenia in chronic heavy users.
Stimulates appetite through actions on feeding centres in thethe hypothalamus and possibly gut.
CNS depressant (excitatory effects due to disinhibition). Large dosesirritate stomach (nausea, dyspepsia). Inhibits anti-diuretic hormone causingdehydration (hangover). Involved in many accidents; alcohol use a major
factor in 25% males admitted to UK hospitals
Long term drinking leads to: neuropathies (peripheral and central e.g.Wernicke’s encephalopathy (psychosis)); myopathies (most seriously primarycaridomyopathy); hepatotoxicities (cirrhosis most common), haematological
disorders.
Suicide very common in alcoholics: 80x higher than non-alcoholic. Up to 30%alcoholics die by suicide and up to 50% all suicide attempts in UK made by
alcoholics
Severe withdrawal syndrome associated with alcoholism; most severe formdelirium tremens. Confusion, delusions, tactile and visual hallucinations,
convulsions, cardiovascular collapse (15-50% mortality)
Alcoholics often obese (high calorific intake) but malnourished, particularlyvitamin deficient.
Alcohol
Drug abuse costs society up to £18.8bn a year - or more than £300per person - in England and Wales including the costs of crime, socialsecurity and bringing drugs offenders to justice, as well as the bill tothe NHS. Annual costs per user; young recreational and older regular
users: less than £20; Class A users, £2,030; Problem users, £11,000
For every £1 spent on treatment, at least £5 is saved on healthservice and criminal justice costs.
Self-reported drug use (ever in lifetime) in 17-18 year old USstudents, 2005: Heroin, 1.5%; Cannabis, 45%; Ecstasy, 5.4%;
LSD, 3.5%; Solvents 11.4%; Amphetamines, 4.5%; Steroids 3.4%;Cigarettes 23% (in last 30 days),
How common is the use of abused drugs?
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Pharmacological approaches to treatment ofdrug abuse
(Not effective without psycho-social support).
Substitution e.g. methadone treatment for opiate abuse.
Long-acting synthetic opiate agonist administered orally forsustained period at dose sufficient to prevent opiatewithdrawal, blocks effects of illicit opiate use, and decreasesopiate craving. Patients stabilised on adequate, sustaineddosages of methadone can hold jobs, avoid crime andviolence of the street culture, reduces exposure to HIV bystopping injecting.
Nicotine replacement
•Nicotine-containing gum and sub-lingual tabletsprovide slow buccal absorption avoiding bolusobtained by smoking, reduces withdrawalsyndrome.
•Clinical trials evidence mixed: little use inreducing cigarette consumption, cravingsignificantly reduced but one year quit ratesunaffected (around 20%).
•Nicotine patch results similar: little effect on quitrates irrespective of nicotine dose or patientpopulation.
•Nicotine nasal sprays also available.
Antagonist treatments
Naltrexone therapy for opiate addiction
Long-acting synthetic opiate antagonist; all the effects of self-administered opiates, including euphoria, are completelyblocked. Few side effects, taken orally either daily or threetimes a week for a sustained period of time. Individuals mustbe medically de-toxified and opiate-free for several daysbefore naltrexone can be taken to prevent precipitating opiateabstinence syndrome. Best used in outpatient settings aftermedical detoxification in a residential setting.
Theory is that the repeated lack of the desired opiate effects,as well as perceived futility of using the opiate, will break thehabit of opiate addiction.
Naltrexone itself has no subjective effects or potential forabuse. Patient non-compliance is major problem.
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Nicotine Antagonists
•Mecamylamine: nicotinic acetylcholine receptor antagonist.Blocks rewarding actions of nicotine and (apparently) cue-induced craving.
•Interestingly, mecamylamine also reduces craving andanxiety associated with handling paraphernalia in cocaineaddicts.
•Since smoking is more common amongst cocaine users andnicotine enhances cue-induced cocaine craving, some arguethat the link supports “gateway theory”.
Peripheral “antagonists”
•General approach to produce circulating antibodies thatbind drugs of abuse in the bloodstream. Extension of this isto use enzymes or engineered antibodies that bind to andmetabolise drugs. Can be overcome by increasing dose ofdrug.
•Cocaine fragments bound to a protein carrier have beenused to generate an antibody (Cantab Pharmaceuticals)now in clinical trial.
•A nicotine vaccine has also been developed.
Anti-craving medicines
•Acamprosate (Ca2+salt of N-acetyl-homotaurine);registered for use as adjunct in maintaining abstinence inalcohol-dependant patients (666mg tds). Reduces alcoholconsumption in alcohol-preferring rats!
•Reduces neuronal excitability that occurs during alcoholwithdrawal.
•Naltrexone in addition to role in opioid dependence alsoreduces alcohol craving by interfering with positivereinforcement and possibly alcohol-conditioned cues.
•Possibly acts by blocking endogenous opioid disinhibitionof GABA neurones in VTA thereby reducing firing ofdopamine releasing neurones.
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Afebutamone/buproprion (Zyban)
•Registered as adjunct to smoking cessation.
•Old antidepressant drug; mixed NA/5HT uptake inhibitor.
•Significantly reduces craving and extends quit rates.
•Mechanism of action unknown.
•Other antidepressants reported to have beneficial effects inalcohol craving but differences between individual SSRIsindicates complex mode of action.
•Contraindicated in seizure-prone patients.
Acomplia (rimonabant, SR141716A)
•Cannabinoid receptor antagonist; blocks the effects ofnatural cannabinoids (endocannabinoids) such asanandamide in the brain.
•Cannabis increases appetite; Acomplia reduces appetite& aids weight loss.
•Also (apparently) reduces craving in smoking cessation.
•Early days; might block other useful endocannabinoideffects (e.g. ability to forget, anxiolysis, anti-cancer etc).
“Curing” addiction
Ibogaine, an hallucinogenic alkaloid found in the root barkof the African shrub Tabernanthe iboga.
•Claimed to be a complete “cure” for heroin, cocaine,alcohol etc, addiction.
•Has a complex pharmacology; reduces reward inexperimental animals but also somewhat neurotoxic.
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Antibiotics, antifungals,& antivirals
Learning Objectives:
To understand the mechanisms of action ofcommonly-used antibiotics, anti-fungals and anti-virals.
Precursormolecules& ATP
Aminoacids &
nucleotides
Peptidoglycan
Proteins
RNA
DNA
Cell Wall Cell membrane
Inhibiting these processes will prevent bacteriagrowing and dividing
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Aim:
Selectivity for bacteria over mammalian processes.
Target processes only in bacteria
eg synthesis of cell wall.
Make pores in cell wall.
Inhibit DNA/RNA synthesis.
Antibiotics
Beta-lactam antibiotics
1.Penicillins2.Cephalosporins and cephamycins3.Carbapenems and monobactams
Interfere with synthesis of peptidoglycan whichmakes up bacterial cell wall- not present in humans
Inhibits formation of cross-linking between peptidechains.
Peptide crosslinks
TetrapeptideSide-chain
b-lactams
-
--
Peptidoglycan Formation
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Penicillins
-Oral or iv-Widely used-Can cause hypersensitivity reactions eg skin rashes-GIT disturbances
eg amoxicillin, ampicillin
Cephalosporins & Cephamycins
-can be given orally, but most given parenterally, IMor IV
-septicaemia, pneumonia, menigitis, UTI.
- Can cause hypersensitivity reactions.
Resistance
Penicillins and cephalosporins contain beta-lactamring.
Beta-lactamases produced by bacteria break this ring.
NC
O
R1
SH
ON
COOH
CH3
CH3
Penicillin
b-lactamase
Carbapenems and monobactams developed to deal withb-lactamase producing bacteria
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Flucloxacillin- b-lactamase resistant penicillin.
Tetracyclines
Antibiotics affecting Bacterial Protein Synthesis
-Protein synthesis occurs in ribosomes-Tetracyclines compete with tRNA (translational RNA)prevent binding to ribosome, prevents proteinsynthesis.-Selective for bacterial ribosome.
-Bacteriostatic
-Wide spectrum of activity-eg tetracycline, minocycline, doxycycline
-Resistance due to induction of proteins promotingefflux of drugs from bacterium.
Chloramphenicol
-Prevents peptide chain elongation
-Reserved for serious infections due to toxicity
-Resistance through production of chloramphenicolacetyltransferase
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Aminoglycosides
eg gentamycin, streptomycin, neomycin
-Given by IV eg septicaemia
-Cause misreading of message- bactericidal
-Resistance by inactivation by enzymes.
-Can cause ototoxicity
tRNAV
30S subunit
50S subunit
TetracyclinespreventtRNA bindingChloramphenicol
prevents chainelongation
Peptide chain
Aminoglycosides:misreading ofmessage
Macrolides
eg erythromycin, clarithromycin
-Prevent peptide chain extension.
-Used in penicillin-sensitive patients.
-Given orally
-Side effects- GIT disturbances
-eg H. pylorri, Legionnaire’s disease, diptheria
-Resistance due to an alteration of the binding site onthe bacterial ribosome.
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Antifungal Drugs
Amphotericin
•Macrolide antibiotic.•Binds to cell membranes- forms a pore in membrane•Selective for fungi.
•Given topically
•Can cause renal toxicity
Griseofulvin
•Fungistatic
•Interferes with division/ growth
•Given orally
Azoles
eg ketoconazole, fluconazole, itraconazole
Inhibit fungal cytochrome P450 3A enzyme.
Prevents formation of sterol used in fungal membrane.
Alters fluidity of membrane- net effect impairs replication.
Liver toxicity (rare) with ketoconazole.
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Antiviral Drugs
Viruses- essentially nucleic acid contained inprotein coat
DNA Viruses- eg smallpox, herpes virusesDNA translated into mRNA by host
RNA viruses- eg influenza, measles, mumps,rubellaRNA acts as mRNA
Retroviruses- DNA copy made of RNA by reversetransciptase. DNA then integrated intohost cell DNA
Transcription
ProteinsReversetranscriptase
HIV replication in host cell
Anti-HIV Drugs (anti-retroviral drugs)
-Reverse transcriptase inhibitors.
-Prevents copying of viral RNA into DNA. Henceprevents replication.
-Nucleoside Reverse Transcriptase Inhibitors
-eg zidovudine (azidothymidine, AZT)
-Analogues of nucleosides. eg AZT analogue ofthymidine.
-Competes with host nucleosides for reversetranscriptase- causes chain termination.
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Reverse
TranscriptaseRNA DNA
ACGTCCTGC
AZT
ACGTCCTGCT
AZ
Morenucleosidescan’t attach
Associated with a number of unwanted side effects-can effect DNA replication in host.
Therapeutic response of zidovudine wanes with timedue to mutation of the virus and hence resistance.
Non-Nucleoside Reverse TranscriptaseInhibitors
Bind to reverse transcriptase near catalytic site anddenature it.
eg Nevirapine & Efavirenz
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Protease Inhibitors
HIV mRNA- transcribed into 2 polyproteins
These are converted into structural proteins by avirus-specific protease.
Protease inhibitors prevent this
eg saquinavir (SQV)nelfinavir (NFV)indinavir (IDV)
Can cause GIT disturbances and metabolicabnormalities (eg insulin resistance).
Combination Therapy
Changed prognosis of HIV.
Highly Active Antiretroviral Therapy (HAART).
2 Reverse transcriptase inhibitors with one or moreprotease inhibitor.
HIV replication is inhibited. Patient survival isprolonged.
But many unwanted side effects.
Lifelong treatment as virus not eradicated.
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Other Antiviral Drugs
Acyclovir
Treatment of herpes simplex (cold sores, genitalinfections) and Varicella-Zoster viruses (shingles &chickenpox).
Guanosine derivative.
Inhibits DNA polymerase- inhibits chain formation.
30x more specific for virus DNA polymerase
Neuroaminidase Inhibitors
Neuroaminidase (or sialidase)
-surface glyocoprotein (enzyme)-required for replication of influenza virus-Allows release of virus from infected cells
-Zanamivir (Relenza)-Oseltamivir (Tamiflu)
Reduce duration of influenza if given within 36 (Z)or 48 (Os) hours of infection.
Summary
-Multiple ways of inhibiting bacteria.
-Bacterial resistance is a growing problem.
-Fewer antifungal and antiviral drugs.
-Increased knowledge of HIV has allowed newtargets to be identified and hence new drugs.
-Antiviral drugs inhibit replication, but do noteradicate.
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RESPIRATORYRESPIRATORYPHARMACOLOGYPHARMACOLOGY
Dr. Richard RobertsDr. Richard Roberts
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Objectives
• Understand the pathophysiology ofasthma and COPD
• Be familiar with the pharmacologicaltargets of the drugs used
• Be familiar with current treatmentrecommendations
• Have a knowledge of the adverseeffects of the drugs used
Lung Structure
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Trachea
Main Bronchi
Bronchi
Bronchioles
Increasedsurfacearea
2
Alveoli
4
5
Structure
Alveoli
Epithelial cells
cilia
Smooth musclecells
Mucous secretinggloblet cells
LUMEN
Mucous traps particles and cilia help to move these particles out of lungNB cystic fibrosis- thick mucous
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Epithelial Cells
3
Innervation of the airways
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Pathways involved:
Sympathetic: circulating adrenaline- act on β2-adrenoceptors on bronchial smooth
muscle to cause relaxation- - inhibition of mediator release from mast cells
• β2-adrenoceptors also on mucous glands to inhibitsecretion
• Increased clearance of mucous.
• b adrenoceptors: Subtypes• b1 adrenoceptors eg sino atrial node and
ventricles in heart- rate andforce of contraction
• b2 adrenoceptors eg airway smooth muscle-relaxation
• b3 adrenoceptors eg skeletal muscle, adiposetissue
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Adrenoceptors
Parasympathetic Innervation:
• Release Acetycholine (ACh)
• activates muscarinic M3 receptors
Bronchoconstriction
increase mucous secretion
Sensory nerves
• local reflexes, respond to irritants
• Cause coughing, bronchoconstriction and increasedmucous secretion
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Muscarinic Receptors
• Subtypes:
• M1 CNS, salivary glands, gastric glands
• M2 Heart- rate of contraction, GI smoothmuscle contraction, CNS
• M3 Salivary glands, smooth muscle (GI,airways)
• M4 CNS
• M5 CNS
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Role of Sensory Nerves in Local Control:Potential Role in Exercise-Induced Asthma
Water loss from airways in exercise thought to stimulate releaseof mediators and activates sensory nerves:
Annals of Allergy, Asthma & Immunology Volume 110, Issue 5 2013 311 - 315
Thanai Pongdee , James T. Li
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Sensory Nerves
Other local controleg Cold Receptors:
Detect changes in temperature
May be involved in cold-induced asthma
Refs:TRPM8 mediates cold and menthol allergies associated with mast cell activation Cho etal. (2010) Cell Calcium 48, 202-208TRPM8 mechanism of autonomic nerve response to cold in respiratory airway . Xing etal. (2008). Molecular Pain
Sensory nerves: up-regulated by inflammation-are sensory nerves hypersensitive in asthmatics?
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Normal
Obstructive
FEV1 (4.0L)
FEV1 (1.3L)
FVC(5.0L)
FVC(3.1L)
FEV1:FVC= 0.42FEV1 = 32% of Normal
Normal v Obstructiveeg COPD, asthma- cannot expel all airquickly
FEV1 is lower as air comes out slower.FVC may be normal if all air can be expelled.COPD- may drop if all air cannot be expelled
Way of patients keeping an eye ontheir lung function
Small, hand held device.
Measures flow of air out of lungs.
PEF- rises rapidly during forcedexpiration, then drops.
Constriction of airways reduces peakflow.
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Peak Flow Meter
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Asthma
• Affects 5-10% of population
• Reversible increases in airway resistance, involvingbroncho-constriction and inflammation
• Decreases in FEV1 and the FEV1:FVC ratio
• Value of < 70% suggests increased airwayresistance. If it is asthma this should be reversed bya b2-adrenoceptor agonist.
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Asthmatic attack
Genetic predisposition, provoked by: allergens cold air viral infections smoking exercise
•Genetic component – associated with atopy (hayfever, eczema)
Allergen
histamine
PGD2
LT C4
LTD4
Bronchoconstriction
MastCell
Chemokines eg ILsChemotaxins
Leukocytes
Phases of an Asthmatic Attack
Early Phase
Late Phase
eg T cellsneutrophilsbasophils
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Late Phase
Occurs at a variable time after initial stimulus.
Chemotaxins (Leukotriene B4, PAF) attract monocytes &eosinophils (leukocytes)
Cause airway inflammation & airway hypersensitivity
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Two main categories:
1 Relief of symptoms – bronchodilators
Block early phase of asthma attack caused bybronchoconstriction.
2 Prevention of attack - anti-inflammatoryagents
Prevents late phase caused by release of cytokines.
ASTHMA THERAPY
Reverse bronchospasm Rapid relief
2-adrenoceptor agonists eg. Salbutamol (ventolin)
Agents of 1st choice
Increase FEV1
Act on 2-adrenoceptors bronchodilation
Given by inhalation
Longer acting agents (e.g. salmeterol) given forlong term prevention.
BRONCHODILATORS
cAMP
Salbutamol
Gs
Adenylylcyclase
ATP
Relaxation of airway tone
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β-adrenoceptors also on mast cells
Increase in cAMP prevents release of eg histamine
Also effects on mucous secretion
2-adrenoceptor agonists
eg salmeterol, formoterol (2x daily)Indacaterol (1x daily)
Salbutamol (SABA) 4x daily
Reason why they are long acting not clear
Current theory- absorbed into lipid bilayer ofcells
Slowly released over time to activate receptor
Long Acting β-adrenoceptor agonist(LABA)
2 Adrenoceptor agonists
Tremor, palpitations, hypokalaemia (high dosese.g. nebulisers)
Adverse effects
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Regulation of cAMP by PDEs
cAMP
Salbutamol
Gs
Adenylylcyclase
ATP
Phosphodiesterase (PDE) 5’ AMP
PDE Isoform Metabolises
PDE1 cAMP & cGMP
PDE2 cAMP & cGMP
PDE3 cAMP
PDE4 cAMP
PDE5 cGMP
PDE6 cGMP
PDE7 cAMP
PDE8 cAMP
PDE9 cGMP
PDE10 cAMP & CGMP
PDE11 cAMP & cGMP
•Roflumilast (PDE4) inhibitor (Daxas)
•COPD
•Reduces inflammation
•Potential for enhancing β-AR effects
Phosphodiesterase Inhibitors
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Block parasympathetic bronchoconstriction
e.g. ipratropium (non-selective antagonist)
Given by inhalation- no systemic side effects
Also inhibits mucous secretion
Tiotropium- long-acting
Muscarinic M-receptor antagonists
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cAMP
Bronchodilation
Adrenaline
Ca2+
Contraction
ACh
Gq
Non-selective therefore block muscarinic receptorsaround the body:
•Dry mouth (salivation)•Nausea/ headache (CNS)•Atrial fibrillation & tachycardia & palpitation (cardiac)•Constipation (GI)•Urinary retension•Blurred vision (accommodation)
Side Effects
11
eg theophylline (doxofylline, enprofylline)
Bronchodilators, but not as good as b-adrenoceptoragonists (2nd line use)
Oral (or i.v. aminophylline in emergency)
Historically- phosphodiesterase inhibitors- increasecAMP, but not at clinically relevant concentrations
Adenosine receptor antagonist?
Anti-inflammatory effects
Xanthines
Mix of theophylline and ethylenediamine (2:1 ratio)
Improves solubility
Monitor plasma levels- toxicity
Aminophylline
Side effects:
Tremor, palpitations, nausea
CNS stimulation (sleep disturbance, “overactivity”)
Drug interactions:
inhibition of metabolism increases risk of toxicityeg cimetidine
induction of metabolism reduces plasma levelseg smoking (NB smoking cessation will lead toincrease in plasma levels!)
12
Preventative; do not reverse an attack
Corticosteroids:
Act at intracellular glucocorticoid receptor.
Inhaled: BeclometasoneBudesonideCiclesonideFluticasoneMometasone
ANTI-INFLAMMATORY AGENTS
Oral:
Prednisolone eg acute asthma attack
OR IV
Hydrocortisone eg life-threatening acute asthma
ANTI-INFLAMMATORY AGENTS
Steroid responseelement
Target Gene
Steroid hormone
Steroid hormone receptor
Dimer formation
Nuclear membrane
Cytoplasm
ExtracellularMedium
Intracelular receptors
13
Leads to altered gene transcription:
•results in decreased cytokine and chemokineproduction eg TNFα, IL-1β, IL-2, IL-3, IL-6
•Upregulation of anti-inflammatory genes egannexin A1 (also known as lipocortin).
•Annexin A1 appears to act through formyl peptidereceptors (FPR)
oInhibits release of histamine from mast cells
oInhibits cPLA2- PGs
Mechanism
38
AnnexinA1: inhibits synthesis of PGs and LTs:
Membrane
PLA2
Arachidonic acid
Leukotrienes Prostaglandins
Side effects of corticosteroids:throat infections (inhalation) and adrenal suppression (oral)
Annexin A1-
Corticosteroid
Side effects
Corticosteroids
• Throat infections or oral candidiasis with inhaled
• Osteoporosis (diet/risk factors, bisphosphonatesfor prevention)
• Adrenal suppression in children
– Use lowest effective dose of steroid and notexceed max.
– Monitor height
• Indigestion (oral)
• Chicken pox severe (avoid contact)- immuneresponse
• Withdrawal effect (reduce oral steroids graduallyif >3 weeks)
14
•COPD is a chronic inflammation
•BUT, steroids largely ineffective at reducing inflammation inCOPD
•Suggests: steroid resistance
•May be due to alteration of glucocorticoid receptor.
Steroid Resistance
CysteinylLeukotriene receptor antagonistse.g. montelukast, zafirlukast
Allergen
histamine
PGD2
LT C4
LTD4
BronchoconstrictionMastCell
ChemokinesChemotaxins
Leukocytes
Early Phase
Late Phase
Block LT receptors – block inflammatory actions ofcysteinylleukotrienes (cystLTs)
Leukotrienes also cause bronchoconstriction,therefore this also blocked
Leukotriene synthesis inhibitors-block synthesis ofleukotrienes and LTB4.
eg zileuton, ZD-2138, Bay X 1005, and MK-0591(not licensed)
CysteinylLeukotriene receptor antagonistse.g. montelukast, zafirlukast
15
Side effects
• Headache, rash
• Nausea, jaundice or other signs of liver toxicity
• Mood disorders/ suicidal thoughts reported withmontelukast
Severe, allergic asthma that cannot be controlledby steroids.
Monoclonal antibody against free IgE
Prevents IgE from binding to immune cells thuspreventing allergen-induced mediator release
s.c. injection every 2-4 weeks
Omalizumab (Xolair)
Sodium cromoglicate
Preventative (both early + late)
May be of benefit in exercise-induced asthma
Inhalation
Uncertain action: mast cell stabiliser?
Cromones
16
46
Treatment of Asthma
Initially identify and avoid the triggers for an asthmatic attack-Dust, animals, smoke, cold air etc
Lifestyle changes- weight reduction. Breast feeding of babiesmay prevent development of asthma
47
British Thoracic Society Guidelines for the managementof asthma in adults
Step 2 Add regular inhaled Steroid.
Step 3 Step 2 plus trial of:long acting b2 adrenoceptor agonistTheophyllineLeukotriene receptor antagonist
Step 4 As above, but consider increasing concentration ofsteroid or adding 4th drug eg leukotriene receptor antagonist
Step 5. Add oral steroid to existing therapy
Step 1 Occasional bronchodilator (eg short acting b2
adrenoceptor agonist).If this is required frequently (> twice/week)- move up to step2:
48
If inhaled therapy isn’t working, may need to check thepatient is using the inhaler properly!
17
49
Acute severe asthma
Treatment• Oxygen• Nebulised 2 adrenoceptor agonist• Oral prednisolone or i.v. hydrocortisone
Life-threatening:+ Nebulised Ipratropium
s.c. 2 adrenoceptor agonisti.v. aminophylline
~ 15% of Asthmatics
• NSAIDs - inhibit COXMore AA Leukotriene production
• β adrenoceptor antagonists- especially non-selective e.g. propranolol- ‘selective’ e.g. atenolol also contraindicated inasthma/COPD
except extreme circumstances (specialist only)
• Drug allergy e.g. penicillins, cephalosporins,dipyridamole, tramadol, excipients (tartrazine)
Bronchoconstriction as anadverse drug reaction
Non-steroidal Anti-Inflammatory Drugs (NSAIDs)May provoke asthma in a number of sensitive patientsIncreased production of leukotrienes
Membrane
PLA2
Arachidonic acid
Leukotrienes Prostaglandins
Lipoxygenase Cyclo-oxygenase
NSAIDS
X
Increased inflammation/ spasm
18
52
• Comprises both chronic bronchitis + emphysema
• Loss of lung function.
• 80-90% of deaths related to smoking.
• Typically disease of late onset.
• High energy demand and difficulty eating e.g.use inhalers before a meal
• By 2020, projected to be 3rd leading cause ofdeath worldwide.
• 5% of deaths in UK
Chronic obstructive pulmonary disease(COPD)
53
http://www.nhs.uk/Conditions/Chronic-obstructive-pulmonary-disease/Pages/Lynnsstory.aspx
54
COPD
“Airflow limitation that is not fully reversible”
FEV, % predictedMild 80% ‘Smokers’ cough’ - little/no breathlessness
Moderate 50-79% Breathless on moderate exertion
Severe 30-49% Breathless at rest/mild exertionUsually with wheeze and cough
Very severe <30%
Prognosis depends on severity.Generally poor with progressive deterioration.
(NICE 2010)
19
55
•Destruction of parenchyma- emphysema
•Remodelling and thickening of airways- small airways disease
•Mucus hypersecretion- chronic bronchitis
56
COPD- aim of treatmentImprove respiratory function
1) Stop smoking- reduces progressive decline in lung function
2) Tend to be less responsive to bronchodilators.A combination of bronchodilators is better than one on itsown.
Mild COPD may be helped by short-acting b2 adrenoceptoragonist
More severe- a regular inhaled antimuscarinic blockershould be added (eg ipratropium)
57
BTS Guidelines for treatment of COPD
Mild bronchodilator drugs (b2-adrenoceptoragonist or anti-muscarinic)
Moderate bronchodilator drugs (poss. in combination)plus trial of corticosteroids
Severe regular bronchodilators, a trial of steroidsconsider nebuliser at home.
Long-term oxygen therapy (24-28%, 15 hours/day) isonly treatment known to improve outlook in severeCOPD
20
58
3) Corticosteroids - relatively ineffective in most patients onown.
BUT some evidence that combinations of steroids withb2-AR agonists beneficial.
eg carbocysteineErdosteineMecysteine
Antioxidants“Break up” thick mucous
Used in COPD
Mucolytics
60
Contents of cigarrette smoke:Particulate matter and tar- effects on lungsTar- solid material inhaled. Forms sticky brown residue.Oxidative stressBenzenebenzo(a)pyrene- DNA damageArsenicAcrolein- mitochondrial damageCyanideCOHeavy metals eg Cadmium
Smoking
21
• About 120,000 people die becauseof smoking in the UK each year.
• Smoking causes one-third of allcancer deaths.
• Half of long-term smokers will dieprematurely as a result ofsmoking.
61
Smoking
62
Time
Decline in lung function with smoking
63
Cystic fibrosis
• Inherited disorder of ion transport in epithelialcells
• Respiratory, hepatobiliary, gastrointestinal andreproductive tracts and pancreas affected
• Defect in chloride transporter (CFTR) leading toreduced Na+ and H2O transport
– Thicker secretions with obstruction and destruction ofexocrine glandular ducts
– Recurrent infections
22
64
CF- disease characteristics
• Pancreatic exocrine insufficiency– Reduced or absent secretions
• PERT- pancreatin. Inactivated by gastric acidtherefore given with food.
• Patients living longer- developing othercomplications:– Diabetes (20%)
– Liver Disease
– Osteoporosis
65
Management of CFAim: to clear viscous mucous from airways, treat
respiratory infection, improve respiratory function
Lung disease
• Physiotherapy
• Antibiotics
• Corticosteroids
• Bronchodilators
• Dornase alfa administered using nebuliser– synthetic version of enzyme which cleaves extracellular DNA
– ‘Digests’ extracellular DNA released from dyingneutrophils in the airway which contributes to increasedmucus viscosity.
66
Further Reading
•Disease Management- Randall & Neil
•Pharmacology- Rang et al.
•BNF
•National Institute for Clinical Excellence (NICE) Website
•British Thoracic Society Website
1
Cardiovascular DrugsAnd Diseases
Richard Roberts
Contents
• Hypertension
• Hypercholesterolaemia
• Ischaemic Heart Disease & MIs
• Chronic Heart Failure
Hypertension“A blood pressure which is associated with significant
cardiovascular risk”
• Cause of essential hypertension is notknown but may be multifactorial
• 2o hypertension:Caused by disease: eg renal disease, Cushing’s
syndrome, hyperthyroidism
Or pregnancy
Or drugs
2
• Stage 1 hypertension
bp measurement >140/90 mmHg.
Patient given ambulatory blood pressure monitoring(ABPM) or home blood pressure monitoring (HBPM) inthe daytime over 1 week.
Hypertension if average ABPM or HBPM bp >135/85mmHg.
• Stage 2 hypertension
bp measurement >160/100 mmHg & ABPM average orHBPM average bp is >150/95 mmHg.
• Severe hypertension
bp measurement >180 mmHg or diastolic bp >110mmHg.
Who to Treat?
•Stage 1 hypertensive if evidence of organ damageor renal disease or diabetes.
•Otherwise- lifestyle interventions
•Anyone with Stage 2 hypertension.
Goals of treatment
• Reduce blood pressure
• The BHS target: SBP < 140mmHg and DBP <85mmHg (80mmHg in diabetics).
• Reducing bp will:– cardiovascular damage.
– prevent renal damage.
– prevent LVH.
– prevent CAD.
– reduction risk of stroke and MIs.
3
Treatment of Newly Diagnosed Hypertension (NICE 2011)
Ca2+ channel blocker
ACEI + Ca2+ channel blocker
ACEI + Ca2+ channel blocker + thiazide
ACEI (or AT1 antag)
Add further diuretic, alpha-blocker, or beta blocker
< 55 yrs > 55 yrs or black pt
STEP 1
STEP 2
STEP 3
STEP 4
ACE Inhibitors
Angiotensinogen AI AII
StimulatesAldosterone
secretion
Vasoconstriction
Renin ACE
ACE: Angiotensin converting enzyme- found mainly in lungs
Renin- proteolyticenzyme from kidneys
Plasma protein
ACEIs
e.g. captopril, enalapril, lisinopril, perindopril,ramipril
• Inhibition of ACE angiotensin II, whichleads to:– Reductions in arterial and venous vasoconstriction
– Reduced aldosterone production leads to reductionsin salt and water retention
– Also potentiate bradykinin – cough
• May increase potassium – interaction with saltsubstitutes
4
AT1 receptor antagonists
e.g. candesartan, irbesartan, losartan,valsartan
• Block the action of angiotensin II at theAT1 receptor.
• Have similar consequences as ACEIs butdo not give rise to a cough.
Calcium channel blockers
• e.g. diltiazem, verapamil & DHPs (felodipine,nifedipine)
• Verapamil- heart rate cardiac output
• Dihydropyridines inhibit VOC on VSM,vasodilatation and a reduction in BP.
RCalciumchannelblocker
Smoothmuscle cell
Contraction
Diuretics
• Thiazides (e.g. bendroflumethiazide)
• Inhibit Na+/Cl- reabsorption in distalconvoluted tubule
• Reduction in circulating volume- reduceworkload of heart
• Hypokalaemia (decrease K+)
• Vasodilatation
5
Na+ Cl-
Thiazides
Na+
LoopDiuretics
K+
Loop ofHenle
DCT
Aldosterone
Na+
-
-
+
Cl-
Beta-Blockers
e.g. atenolol, propranolol
• Block action of Noradrenaline (andadrenaline) on heart.
• 1 ARs in sino-atrial node- blockersdecrease rate of contraction
• 1 ARs in ventricles muscle and atria-blockers decrease force of contraction
• cardiac output
Vasodilators
Alpha-blockers• e.g. doxazosin, prazosin• Last choice• These are competitive receptor antagonists of
a1-adrenoceptors• Wide spread side effects, which makes them
poorly tolerated.
6
Adverse effects
Thiazides• Urination!• Diabetogenic• Alter lipid profile• Hypokalaemia
Beta-blockers• Bronchospasm• Reduce hypoglycaemic
awareness
ACEIs• Cough• Severe first dose
hypotension
Calcium channels blockers• Peripheral oedema• Postural hypotension• Constipation (some)Alpha-blockers• Widespread• Postural hypotension
Lifestyle changes:
• ALCOHOL
• Weight reduction
• Reducing fat and salt intake
• Increasing fruit and oily fish in the diet
• Increasing exercise
• Stopping smoking.
Hypercholesterolaemia andAtherosclerosis
• Hypercholesterolaemia: elevatedplasma cholesterol, leads to:
• Atherosclerosis: focal lesions (plaques)on the inner surface of an artery.
7
Risk factors for atherosclerosis
• Genetic• Hypercholesterolaemia (raised LDL-C or
lowered HDL-C)• Hypertension*• Smoking*• Obesity*• Hyperglycaemia*• Reduced physical activity*
* Can be altered by lifestyle changes
Hypercholesterolaemia• Major risk factor for atherosclerosis.
• Total plasma cholesterol > 6.5mmol/l
• Ideal cholesterol <5.2mmol/l
• 25-30% middle aged population havehypercholesterolaemia (TC>6.5mM)
• Especially important is high LDL-C componentor low HDL-C
Management
Modify risk factors– Stop smoking
– Treat HT/DM
– Exercise
Low cholesterol diet
– but only 25-30% of cholesterol comes fromdiet
8
The Statins
HMG-CoA Reductase Inhibitors• Hydroxymethylglutaryl coenzyme A reductase which
catalyses:Hydroxymethylglutaryl
HMG-CoA reductaseMevalonate
Cholesterol (ultimately)• HMG-CoA reductase is the 1st committed step in
cholesterol synthesis
Statins
Cholesterol synthesis greater at night therefore statins takenat night
e.g. simvastatin, pravastatin, atorvastatin, fluvastatin• Reduce plasma cholesterol• cholesterol synthesis hepatic LDL receptors,
promoting LDL-C uptake
• Statins are hepatoselective– the liver is the main site of cholesterol synthesis
– 1st pass metabolism: 5% reaches systemic circulation
Effects of statins
• 4S trial (Scandinavian Simvastatin Survival Study) :
– Over 5 years, 30% reduction in mortality, 42%reduction in death from CAD
• Some evidence that statins may lead to regression ofatherosclerosis
• Treatment for 2 years with 40 mg rosuvastatin perday caused a reduction in size of atheroma in 75% ofpatients (ASTEROID study, 2006)
9
Trials• Heart Protection Study (2002) – Lancet 360, 7-22
• 40 mg simvastatin to high risk patients (CHD, stroke,diabetes, hypertension)
• Substantially (25%) reduced MI / Stroke /revascularisation / in all patients – even with low /‘normal cholesterols’
• Consider statins for all high risk patients irrespective ofcholesterol?
• Statin + aspirin + b-blocker + ACEi : independently andadditively reduce risk in secondary prevention. Total of75% reduction in risk.
Adverse Effects of statins
• Cautions: use with care in liver disease, monitor liverfunction
• May cause rhabdomyolysis –– Risk : 1 in 1,000 to 10,000.
– Cerivastatin withdrawn Aug 2001 because of reportsof fatal rhabdomyolysis.
– No evidence of muscle pain in Heart Protection Studyactually being due to simvastatin.
OTC Statins• What are the implications?
• 10mg simvastatin withoutcholesterol test withoutprescription
• For pts at high risk– All males over 55
– Males 45-55 and females over55 with
• Family history of IHD
• Smokers
• Overweight
• S Asians Indian sub-continent) ethnicity
• But treatment might not bedocumented with GP
10
Bile acid binding resins
Colestyramine• Used in addition to statin• Binds bile salts in intestine and prevents reabsorption
and cycling of cholesterol• Leads to incorporation of endogenous cholesterol into
bile salts.• Also increases LDL receptors• 13% fall in plasma cholesterol• 20-25% fall in CAD• Reduce absorption of fat soluble vitamins
Fibrateseg Bezafibrate, clofibrate, gemofibrozil
• Activate: PPAR-a, alters lipoprotein metabolism throughgene transcription (increase lipoprotein lipase)
• Promote breakdown in VLDL (with small reductions inLDL-C and increase in HDL).
• Also reduce triglycerides – used with statins when TGs(+ cholesterol) raised
• Decrease glucose, use in DM
• Reduce incidence of IHD
Cholesterol Absorption Inhibitors• e.g. Ezetimibe
• Prevents cholesterol absorption
• May benefit patients with low synthesis buthigh absorption
• Vytorin- combination of simvastatin &ezetimibe
11
OthersSterols/Stanols• Present in Benecol margarine
• Prevents absorption of cholesterol
• Reduces LDL cholesterol by 10-15%
• Helpful add on to dietary restrictions and statintherapy
ISCHAEMIC HEARTDISEASE
IHD
• IHD: angina or MI
• Can lead to CHF.
• IHD associated with atherosclerosis withinthe coronary artery - impaired blood flowor thromboembolic occlusion.
• Coronary blood flow does not matchdemand, leading to ischaemia, whichprovokes the symptoms.
12
Risk Factors
• Male gender
• Family history
• Smoking*
• Diabetes mellitus*
• Hypercholesterolaemia*
• Hypertension*
• Sedentary lifestyle*
• Obesity *
• Lifestyle– Stop smoking
– Exercise
– Diet
– Weight
• Coronary Artery Bypass Grafting
• Percutaneous transluminal coronaryangioplasty & stenting (open up CA)
Angina pectorisManagement
Pharmacological ManagementNitrates
eg GTN
• Via release of NO
• Venodilatation, leading to a decrease in preloadand a reduction in cardiac work
• Coronary vasodilatation
SmoothMuscle
Cell
NO cGMP PKG dilation
PDE5 Viagra
Guanylatecyclase
13
b-blockers
• First choice drugs for prevention
• HR & force cardiac work andpreventing symptoms.
• Slowing HR increases diastolic period, as willthe time for coronary blood flow.
Calcium channel blockers
• Vasodilatation and improve coronary bloodflow, so preventing symptoms.
• Verapamil- effects on HR so reducingcardiac work.
ACEIs
• vasodilatation
• HOPE trial indicated that ramipril reducedmortality in patients with IHD
• reduction in MI & stroke
14
Potassium channel activators
• Nicorandil: combined NO donor andactivator of ATP-sensitive K-channels.
• The target is the ATP-sensitive K+-channel (KATP):
K
Hyperpolarization
Increased K+pumped out of cell
SmoothMuscle
Cell
Antiplatelet drugs
• Low dose Aspirin (75mg)
• Used to prevent MI in patients who havepreviously had an MI
• Prevents clot formation
• Reduces incidence of stroke
• Inhibits cyclo-oxygenase (irreversible):
Arachidonic Acid in membrane
Free AA
PLA2
Cyclo-oxygenase
Endoperoxides
ThromboxaneProstaglandinsPGI2
X
Aspirin
Endothelium Platelets
15
Favours PGI2 production over TXA2 because
AA PGI2
COX
AA TXA2
COX
-
Endothelialcell
Platelets
Favours PGI2 production over TXA2 because
AA PGI2
COX
AA TXA2
COX
-
X
XAspirin
Endothelialcell
Favours PGI2 production over TXA2 because
AA PGI2
COX
AA TXA2
COX
-
X
NucleusmRNA Endothelium
16
Favours PGI2 production overTXA2 because
• Platelets have no nuclei - can’t produceany more cyclo-oxygenase (COX) - nomore TXA2 - until new plateletssynthesised (7 days)
• Endothelial cells have nuclei - can producemore COX (2 hours) - get PGI2 produced!
Anti-platelet drugs
• Clopidogrel & Prasugrel
– ADP receptor antagonist
– Equally effective
– Used in pts who can not receive aspirin
– Or used with aspirin
Other Anti-Platelet Drugs
• Dipyridamole
– PDE inhibitor
– inhibition of adenosine uptake into plateletsleading to increased inhibition of plateletaggregation by adenosine
• Abciximab- antibody targettingglycoprotein receptor on platelets
17
Drug Choice
• Low dose aspirin and/or clopidogrel.
• Reduce BP to a target of < 140/85 mmHg (anti-hypertensive drug)
• Reduce Hypercholesterolaemia (statin).
• For symptomatic relief or occasional treatment, aGTN spray or sublingual tablets.
Drug Choice - prevention
• In terms of continuous, preventativetreatment:
• 1st choice: b-blockers. Oral long-actingnitrates might be added.
• 2nd choice: if a b-blocker is ineffective orcontra-indicated, then verapamil (ordiltiazem) would be used
Myocardial Infarction
• MI: thromoembolism or rupture of plaque
18
Thromboembolism leading to MI
INFARCTION
Thrombusformation
Immediate Treatment:Thrombolysis
• Dissolves the clot, with reperfusion, salvages the cardiacmuscle
• Fibrinolytics convert plasminogen to plasmin- degradesfibrin
• If indicated, the earlier the better – damage is irreversible6h post MI. Only really effective in 1st 12h.
Discharge
• Aspirin and/or clopidogrel
b-blocker (or Ca-channel blocker if b-blocker contraindicated)
• ACEI
• Statin
• All lower risk –additive
19
Chronic/ Congestive HeartFailure (CHF)
Heart Failure
Failure of the heart as a pump to meetthe circulatory needs
Heart Failure
• May be due to failure of the heartmuscle or failure of the heart valves
• May be chronic or acute (post MI)
• Often secondary:– Hypertension
– IHD
– Cardiomyopathies (alcohol, viral)
– Lead to adaptation of heart muscle ordamage of heart muscle
20
Also Precipitated by
• Pregnancy
• Anaemia
• Hyper & hypothyroidism
• Fluid retaining drugs:
– glucocorticoids
– NSAIDS
Neurohormonal adaptation
Reduced cardiac output:-Body attempts to compensate for reduced
circulation get activation of:– Sympathetic nervous system– Renin-angiotensin-aldosterone system
But this leads to:• A vicious circle develops which further impairs
the pump activity of the heart.• Neurohormonal activation leads to myocyte
dysfunction• Get maladaptation of heart. Fibrosis &
stiffening due to increased aldosterone
Pre-load &After load
CO
AII
aldosterone
Na+/waterretension
Circulatingvolume
oedemalungs
Work loadOn heart
Can’tcope
SympatheticNS
Renalbloodflow
HF
21
CHF
Left-sided Failure
• Most common
• Associated with pulmonary oedema
Right-sided failure
Both sides
Signs & Symptoms
• Fatigue, listless
• Poor exercise tolerance (determinesgrade)
• Cold peripheries
• Low blood pressure?
• Reduced urine flow
• Weight loss
• Breathlessness- pulmonary oedema
Diagnosis
• Symptoms
• Echocardiogram: Ejection fraction <45%
• Chest X-ray – cardiomegaly (enlargedheart), pulmonary oedema
22
Prognosis
• Poor
• Median survival in mild/moderatefailure of 5 years
Goals of treatment
• Identify / treat any cause (valvulardisease; IHD)
• Reduce cardiac workload
• Increase cardiac output
• Counteract maladaptation
• Relieve symptoms
• Prolong quality life – reducehospitalization
Pre-load &After load
CO
AII
aldosterone
Na+/waterretension
Circulatingvolume
oedemalungs
Work loadOn heart
Can’tcope
SympatheticNS
Renalbloodflow
HF
ACEIsSpironolactone
Diuretics
bblockers
23
Pharmacological Management:ACEIs
See earlier• Reduce arterial (after load) and venous (pre-
load) vasoconstriction• Reduce salt/water retention, hence reduce
circulating volume• Inhibits RAS, prevents cardiac remodelling?• Inhibition of aldosterone production• aldosterone causes fibrosis & stiffening of
heart
AT1 Receptor antagonists
e.g. Candesartan, losartan,valsartan,
• Oppose actions of AII at the AT1 receptor
• Equally effective as ACEIs
• But don’t cause the cough
• Dual blockade with ACEIs?
Diuretics
• Mainstay
• Prevent water retention
• Thiazides (bendroflumethiazide)– usedin mild failure or in elderly
• Loop diuretics (furosemide) esppulmonary oedema
24
Spironolactone
• Spironolactone – aldosterone receptorantagonist
• Now being used as an effective agentwhich reverses the LVH
• ? Inhibits effects of aldo on heart –fibrosis? (stiffens heart + arrhythmias)
b-blockers
• Used to be contraindicated in CHF…..
• Now a central role
• Now known to reduce disease progression,symptoms and mortality
• Use in stable or moderate failure
• Reduce sympathetic stimulation, heart rateand O2 consumption
• Antiarrhythmic activity reduces suddendeath
• Symptoms may get worse at 1st.
Digoxin• +ve inotrope by inhibiting Na+/K+ ATPase, Na+
accumulates in myocytes, promotes Ca2+ entryleading to increased contractility.
• Impairs atrioventricular conduction and increasesvagal activity (via CNS). Leads to-
• Heart block and bradycardia- beneficial in heartfailure with atrial fibrillation as it controls ventricularrate.
• Digoxin reserved for failure with atrial fibrillation
• Reduces rate at which contraction passes from atriato ventricles. Allows time for ventricles to fill withblood.
25
A-V node
Atrial Fibrillation (AF)
• Atrial fibrillation – Commonconsequence of CHF. Impaired ejectionof blood dilation of left atriumimpaired rhythm of contraction of atria
• AF: stasis of blood, leading to thrombiwhich may dislodge and move tocerebral circulation – need forprophylaxis, warfarin or aspirin.
WarfarinWarfarin: Wisconsin Alumni Research Foundation
arin• Warfarin: Vitamin K antagonist• Blocks unwanted coagulation• Vitamin K essential for production of prothrombin
and Factors VII, IX and X
26
• Factors are glycopoteins with glutamic acidresidues at N-terminal end of peptide chain
•Glutamic acids converted to carboxyglutamic acidsafter synthesis of the chain- dependent on vit K
•Warfarin blocks Vitamin K reductase, needed forVit K to act as a cofactor: vit K needs to be inreduced form
New factor
Post-translational modification
Vit K-dependent
Carboxylation of glutamicAcid residues
Warfarin inhibition
Vit K-dependentX
X
WARFARIN
27
Warfarin
• Also used to prevent thrombosis
– in patients with replaced heart valves
– atrial fibrillation
– Pulmonary Embolism
– DVT
– Several days to act- existing clotting factorsneed to be used up.
Warfarin- specific advicevitamin K antagonist
If increase amount of vit K in diet, then reduceeffectiveness of warfarin (large amount of greenveg, green tea).
Avocado & soya bean products may also reduceeffects
Cranberry products/juice should be avoided (CSMwarning)- possible increase in metabolism
1
Diabetes Mellitus
Dr Richard Roberts
Diabetes Mellitus
TYPE 1 Insulin dependent (IDDM)insulin production impaired
TYPE 2 Non-insulin dependent (NIDDM)body not as sensitive to insulin
Gestational DMConsequences of XS GHXS cortisolRare genetic disorders
Clinical features of DM
Direct consequences of high blood glucose levels• Polyuria, nocturia, polydipsia (osmotic diuresis)• Visual disturbance (osmotic changes to intra-ocular
pressure)• urinogenital infections
Metabolic consequences of impaired glucose utilization• Lethargy, weakness, weight loss (intracellular glucose
deficit)• Ketoacidosis (increased fat metabolism)
Long-term complications of hyperglycaemia andhyperlipidaemia
• Cardiovascular disease, nephropathy, neuropathy,retinopathy, infections, arthropathy (stiffness)
2
Diagnosis
• Consider risk factors e.g. family history, obese
• Vigilant for symptoms– Persistent thirst (polydipsia)
– Nocturia, polyuria
– Recurrent infections e.g. cystitis, thrush (glycosuria)
– Weight loss (type 1)
– Lethargy
• Test urine
• Blood glucose >7 mmol/L fasting or >11.1 mmol/L random
Treatment of diabetes
Aim:– Improve glycaemic control
-Reduce hyperglycaemia withouthypoglycaemia
– Reduce co-morbidities\complications
Trials (Diabetes Control & complications(Type I) & (UK Prospective DiabeticStudy (Type II) found:
– Improving glycaemic control prevented ordelayed complications of DM
– But in type I this is often at expense ofincreased incidence of hypoglycaemia
3
Managing Type 2 Diabetes
Blood GlucoseLoweringTherapy
ManagingCardiovascular
Risk
Managing long-term
complications
Nephropathy Retinopathy Neuropathy
Dietary Advice
Dietary aspects - treatment
• Fat– Low saturated fat and total fat
• CHO - 55-60% energy intake– Low simple sugars– High complex CHO (low G.I.)
• Weight control - especially - Overweight\ObeseType 2
• Recent onset type 2 - Dietary change may beenough
Pharmacological Treatment of Type 2:Oral antidiabetic drugs
• Biguanides: metformin
• Sulphonylureas: gliclazide, tolbutamide
• Meglitinide analogues: nateglinide, repaglinide
• Glucosidase inhibitor: acarbose
• Glitazones (thiazolidinediones): rosiglitazone,pioglitazone
• Newer therapies
4
Biguanides (metformin)
Action not clear. Proposed:
– Increased uptake of glucose into muscle
– Reduced uptake of glucose from GI tract
– Decreased gluconeogenesis
– Combine to decrease blood glucose and increaseutilisation
– Favoured as not associated with weight gain(reduces appetite)
– Avoided in renal impairment
– Initial problem with diarrhoea (transient)
Sulphonylureas (gliclazide, tolbutamide)
•Rely on the fact that b cells still produce insulin
•Inhibit ATP-sensitive potassium channels (KATP-channels), causing depolarisation
•Increase insulin secretion from b-cells
•Short acting: tolbutamide, gliclazide
•Long acting (glibenclamide, chlorpropamide) avoidedin elderly due to hypoglycaemic effects
Insulin
K+
KATP channel
Ca 2+
Glucose
Glut-2
ATP
Sulphonylureas
X
Meglitinides
Islet b cell
5
• Meglitinide analogues (nateglinide, repaglinide)– Act on b-cells to close KATP-channels- release insulin
– Shorter acting- given at mealtimes to stimulate insulinrelease
– Nateglinide only licensed for use with metformin
– Repaglinide licensed for monotherapy for patients notoverweight or metformin contraindicated or nottolerated
Glucosidase inhibitor (acarbose)-Inhibition of alpha-glucosidases in small intestine
- reduces production of glucose in GI tract
-Problem of flatulence and osmotic diarrhoea- maydecrease in time
-Used alone or in combination with sulphonylurea ormetformin
Glitazones (thiazolidinediones) e.g. pioglitazone
enhance glucose utilisation by tissues, reducing insulinresistance
- PPAR- agonists- gene expression- insulin-like effects.Slow effect- takes 1-2 months for max. effect.
- hepatic glucose output; glucose transporters in skeletalmuscle- increased glucose utilisation; promotion of fatty aciduptake into adipose cells
- Not first line due to risk of liver toxicity (troglitazonewithdrawn), monitoring
- ‘add on’ to sulphonylurea OR preferably metformin
- NICE recommend for patients unable to take sulphonylureawith metformin combination or failure of this combination
6
Cardiovascular safety:
• Rosiglitazone and pioglitazone should not beused in patients with heart failure. Increased riskof heart failure when combined with insulin.
• Rosiglitazone not recommended for use inpatients with ischaemic heart disease- increasedrisk, particularly with insulin.
• MHRA warning increased risk with rosiglitazonecompared to pioglitazone (July 2010).
PPARg
Adipose tissue, skel muscle, liver
GLUT-4
Protein
Glucose
Glitazones
Fatty acidTransporterprotein
FAs
Newer treatments:
Glucagon-Like Peptide Receptor Agonist
Exenatide -GLP-1 Receptor Agonist
-stimulates insulin release from b cells in aglucose-dependent mechanism.
-Lower risk of hypoglycaemia
Used in combination with metformin or a sulphonylurea.
S.C. Injection
Reports of acute pancreatitis.
7
Insulin
K+
KATP channel
Ca 2+
GLP-1 agonistX
Islet b cell
GLP1-R
Sitagliptin & Vildagliptin
GLP-1 broken down by dipeptidylpeptidase-4 (DPP4)
Dipeptidylpeptidase-4 inhibitors prevent metabolism
Increase insulin secretion.
Used in combination with metformin or sulphonylurea or aglitazone.
Lifestyle changes
1st Line- Metformin
2nd Line- Add sulphonylurea
3rd Line- Add insulinOR a-glucosidase inhibitorOR DPP4 inhibitorOR TZD
IDF Guidelines for Treatment of Diabetes
8
• Insulin may be required– Particularly during illness
– Added to oral treatment
Treatment of Type 1
Replacement of insulin– Polypeptide hormone with role in regulation of
CHO, fat and protein metabolism– inactivated by GI enzymes
• subcutaneous injection (can also be given iv or im formore rapid effect), Human, porcine or bovine insulin
• Insulin requirement increased by stress, infection,puberty (GH effect), accidental or surgical trauma, 2nd
and 3rd trimesters of pregnancy
• Risk of hypoglycaemia: sweating, tremor,tachycardia, confusion, drowsiness
Insulin
• Insulin has a short plasma half-life unlesscomplexed with protamine (isophane) and/orzinc to reduce absorption.
• Short acting– soluble insulin
– 6-8 hr effect
– Peak response 2-5 hr
– Given 15-30 min before meals
9
•Intermediate-isophane insulin and insulin zincsuspension
•Long-actingcrystalline insulin zinc suspensionNew product- insulin glargine- humaninsulin analogue given once a day
• Biphasic-Combination of short & long-acting insulin
•Insulin pumpscontinuous subcutaneous infusion,expensive, reserved for poorly controlleddiabetes
Insulin regimens• Regimens adapted to suit individual. Insulin
requirements may alter eg depending on level ofexercise
eg
• Short-acting mixed with intermediate twice a daybefore meals
• Short-acting mixed with intermediate beforebreakfast; short acting before evening meal;intermediate at bedtime
• Short-acting 3 times a day before each meal;intermediate at bedtime
Enhanced sympathetic activity• tremor, pallor• sweating, shivering, palpitations• anxiety
Neuroglycopenic - reduced CNS glucose delivery• drowsiness, disorientation, confusion• aggression, inappropriate behaviour• apparent drunkenness• convulsions, coma, brain damage, death
Other effects - multiple or indirect pathogenesis• hunger, salivation, weakness, blurred vision
Treatment of diabetes may result in hypoglycaemia:
10
HypoglycaemiaHypoglycaemia unawareness - risk factors:
• Alcohol- may mask effects
• Sleep- NB hypoglycaemia common at night
• Exercise- may require reduction of insulin dose beforeexercise
Treatment of hypoglycaemia
• Oral CHO (drink, food)
• i.m. glucagon
• i.v. glucose
Ketoacidosis
In the absence of insulin- increasedbreakdown of triglycerides
- form ketone bodies
Results in acidosis
- diuresis- also causes depletion of Na+,K+, PO4
Sweet smell of ketones on breath
Managing Type 2 Diabetes
Blood GlucoseLoweringTherapy
ManagingCardiovascular
Risk
Managing long-term
complications
Nephropathy Retinopathy Neuropathy
Dietary Advice
11
Management of cardiovascular riskfactors
• Statin
• Low dose aspirin
• BP control reduces risk of cardiovascular disease
• ACEi (benefit in nephropathy)
• Increased risk of new-onset diabetes with thiazideand β-blocker combination- use with caution
b-blockers (atenolol) can mask hypoglycaemicsymptoms
Summary of treatment
• Patient with type 2 could have:– 1-2 oral hypoglycaemic drugs
– 2 antihypertensives
– Statin
– Low dose aspirin
– Requirement for lifestyle changes
Other Drugs Used in Diabetic Patients
12
Treatment of neuropathy Diabetic neuropathy- common secondary
complication Reduced sensory (& motor) neurones Loss of sensation- ulceration
Painful neuropathy:
Optimal diabetic control to prevent neuropathy1st step: paracetamol/aspirin- mild to moderate pain
2nd step: low doseTricyclic antidepressants (shown to beof use in some patients)
3rd step: anticonvulsants eg phenytoin, carbamazepine-shooting or stabbing pains
Chronic pain- opiates
Adverse Drug Reactions
• Diarrhoea with metformin– reassurance according to severity and duration
– Should improve with time
• Liver toxicity with glitazones:– Urgent referral for nausea & vomiting, abdominal pain,
fatigue, dark urine, jaundice
• Hypoglycaemia– If recurrent and on insulin- alternative
regimen/diet/education
– Sulphonylureas (meglitinide analogues)- dose?
• Weight gain– Sulphonylurea, glitazones
13
References
• BNF
• Disease Management, Randall and Neil
• Stockley’s Drug Interactions
06/01/2014
1
PHARMACOLOGY OF THE GASTROINTESTINAL TRACT
Dr Richard Roberts
First Part
• Acid secretion, GORD, Peptic Ulcers
• Treatment options
• Warning symptoms
• COX-2 inhibitors
• Case study
Oesophagus
Liver Abdominal aorta
StomachGallbladder Spleen
PancreasDuodenum
Colon Small intestine
Rectum
Ileum
Appendix
UpperRespiratoryTract
Overview of the GI Tract
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Gastric Pharmacology
The stomach is a major site of disease and drug action.
Neuronal and Hormonal Control of the GIT
Neuronal Control
Autonomic NS:
Parasympathetic (ACh)
Sympathetic (NA)
Hormonal Control
Endocrine (secreted into blood) eg gastrin
Paracrine (local hormones) eg histamine
Involved in:
•Gastric secretion
•Vomiting
•Motility of the GIT
•Formulation and excretion of bile
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Gastric Secretion
•Hydrochloric Acid (HCl)
•Mucus
•Bicarbonate ions (trapped in mucosa)
Others:
•Intrinsic Factor (uptake of vit B12)
•Pepsinogen (protease)
Protectmucosa
Control of Acid Secretion.
• Parietal cells release gastric acid followingstimulation of:
– Histamine receptors (H2)
– Muscarinic receptors (acetylcholine)
– Gastrin receptors (secreted by mucosa)
• Contain a proton pump which exchangesintracellular H+ for extracellular K+- acidsecretion
ECF-likeM
M1
VagusNerve
ACh
ACh
Histamine
H2
Gastrin
GR
PP
H+ K+
PGs PGR
Inhibits
GR
ParietalCell
Enterochromaffin-like cell
06/01/2014
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Pharmacological Control of Acid Secretion
•H2 receptor antagonists
•Proton pump inhibitors
•Prostaglandin analogues
H2 histamine receptor antagonists
cimetidine (Tagamet)ranitidine (Zantac)famotidine (Pepcid).
Low dose OTC for short term reliefHigh doses POM.
Histamine H2 receptors : coupled via adenylyl cyclase toincrease cAMP which activates the proton pump
H2 Histamine receptor antagonists
competitive antagonists at the H2 histamine receptor
‘antihistamines’ are H1 receptor antagonists
reduce gastric acid secretion
provide symptomatic relief
in the long term promote ulcer healing(relapse on discontinuation).
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Proton pump inhibitors (PPIs)
e.g. omeprazole, lansoprazole
irreversible inhibition of the proton pump (H+/K+-ATPase):
PPIs activated by acid pH
Inhibit H+ secretion by >90%, may lead toachlorhydria. Increase risk of Campylobacterinfection (food poisoning).
Prostaglandin Analogues:
eg Misoprostol
Inhibits release of acid& stimulates mucus & bicarbonate secretion
ECF-likeM
M
VagusNerve
ACh
ACh
Histamine
H2
GR
PP
H+
PGR
Inhibits
GR
ParietalCell
K+
PPI
H2 receptorantagonist
Misoprostol
06/01/2014
6
Neutralising AcidAntacids :- anti-acid; widely available (OTC) and act to raise pH.Provide relief
Sodium bicarbonate : simplestHCO3
- + H+ CO2 + H20
Magnesium hydroxide and Aluminium hydroxide also used:
Al(OH)3 + 3HCl AlCl3 + 3H2OMg(OH)2 + 2HCl MgCl2 + 2H2O
Some types of antacids in common use
Simple antacids
Soluble (more than about 10% of the dose is absorbed)
e.g. calcium carbonate, chalk, sodium bicarbonate
Insoluble (less than 5% of the dose is absorbed)
e.g. Aluminium hydroxide, aluminium and magnesium mixtures(co-magaldrox in Maalox & Mucogel), magnesium trisilicate,
aluminium-magnesium complexese.g. hydrotalcite (Altacite), magnesium carbonate
Alginates :
•Antacids may be combined with Alginateseg Gaviscon Double Action
• Mucopolysaccharides. The alginic acid combineswith saliva to form a viscous foam.
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Dyspepsia (“indigestion”)
Symptoms:
Heart burnAcidityNauseaAcid reflux
Symptoms can often be confused with cardiacproblems- need to rule these out.
Also need to rule out carcinoma
•GORD: gastro-oesphageal reflux disease, leading tooesophagitis
Dyspepsia can occur as a result of:
• Peptic ulceration (gastric and duodenal) – erosion, damage,bleeding (anaemia?)
•Gastritis
• Drug (NSAID and oral steroids) - induced damage
GORD
Reflux of contents of stomach into the oesophagus
Causes pain- heartburn. Sometimes back/shoulder pain
Sometimes wheezing or cough
Caused by:
Increased abdominal pressure- pregnancy, obesity,overeating
Incompetence of gastro-oesophageal sphincter caused byhiatus hernia
Can lead to tightening of oesophagus- difficulty swallowing
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Hiatus hernias
Management of GORD
Lifestyle: Weight reduction, reduce fatty foods, stopsmoking, avoid tight clothes
Pharmacotherapy:Initially antacids or antacids + alginates
Sometimes H2 antagonists- but not as effective as:
Proton pump Inhibitors- most effective agents. Removesymptoms & allow healing.
Peptic Ulceration
Gastric & duodenal ulcers
Erosion of inner lining
Perforation of lining- serious problem
OR erosion of blood vessel- vomit blood
Symptoms:Gastric painHunger pain- relieved by eatingNight pain- relieved by milk or food or antacidsnausea
80-95% ulcers due to Helicobacter pylori infection
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9
Early 1980s Robert Warren & Barry Marshall found H. pyloriin cultures from peptic ulcer sufferers. Not believed bacteriacould live in stomach.
1984 Barry Marshall drank culture of H. pylori. Developedgastritis- cured by antibiotics.
H. Pylori & Peptic Ulcers
Treatment:
•Decrease acid (antacid)
•Decrease acid production (H2 antagonist or PPI)
•Kill H. pylori (antibiotics)
•Remove NSAIDs
Treatment of Peptic Ulceration: H. Pylori Infection
“Triple Therapy”
Proton pump inhibitor + 2 antibiotics for 1 week
Associated with 90% eradication
PPIs may be required for 4-8 weeks to promote healing
Infection identified by serology (antibodies to H. pylori) orurea breath test
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Treatment of peptic ulcers (cont.)
If eradication failure:
PPI + Bismuth Chelate + tetracycline + metronidazole
Bismuth chelate- kills H. pylori, coats the ulcer, & absorbspepsin.
prostaglandin secretion acid secretion & neutralisesacid by increasing bicarbonate secretion
ECF-likeM
M
VagusNerve
ACh
ACh
Histamine
H2
GR
PP
H+
PGs PGR
Inhibits
GR
ParietalCell
K+
PPI
H2 receptorantagonist
Bismuthchelate
NSAID-Induced Ulcers
Oral NSAIDS commonly associated with pepticdamage/ulceration (includes low dose aspirin).
Ibuprofen low incidence of GI side effects.
Paracetamol not ulcerogenic
06/01/2014
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Prostanoid pathway:
Arachidonic acid (membrane)
AA (free)
Leukotrienes Prostaglandins
COX-1 - gastric?COX-2 - inflammationCOX-2 selective inhibitors (celecoxib) may have lessGI-side effects, but only reserved for certain patientgroups.
COX
Inhibits H+ secretion
NSAIDs
NSAID-Induced Ulceration- Treatment
If possible switch to paracetamol or stop NSAID
For healing use PPI or H2 receptor antagonist
If NSAID required, then prophylaxis with PPI may be needed
Use COX-2 inhibitor eg rheumatoid arthritis???
NSAIDs
Used in treatment of inflammation, pain & increasedbody temperature.
eg aspirin, ibuprofen, naproxen, diclofenac
Inhibit cyclooxygenase and therefore production ofprostaglandins.
Non-selective inhibit COX-1 & COX-2
COX-2 responsible for production of prostaglandinmediators of inflammation.
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COX-2 inhibitors
• Anti-inflammatory drugs with lower GI side effectse.g. celecoxib
BUT:
• COX-2 inhibitors are associated with small increasedrisk of CV effects (MI or stroke)
• Rofecoxib (Merck) voluntarily withdrawn 2004(lawsuits)
Other Problems:
• Valdecoxib (Pfizer) withdrawn 2005 due to seriousskin reactions
• Lumiracoxib (Novartis) withdrawn Nov 2007 due tohepatotoxicity
CSM guidance:
- COX-2 inhibitors should be used inpreferance to standard NSAIDs only inpatients with high risk of GI problems ANDafter assessment of cardiovascular risk
Non-selective NSAIDs
Inhibit COX-1 & COX-2.
Concerns that they may also cause CV events
June 2006- paper indicating moderate increase incardiovascular risk with ibuprofen and diclofenac at highestdoses used on a daily basis
MHRA guidance (October 2006):
NSAIDS and COX-2 inhibitors should be used at lowestpossible dose and shortest duration
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13
Minimize GI irritation by
•Avoid NSAIDs e.g. try paracetamol first
•Giving NSAIDs with food
•Prescribe only 1 NSAID at a time (includes low dose aspirin)
•Use less toxic NSAID first-lineibuprofen<diclofenac<naproxen
•Use lowest effective dose
•Give in combination with PPI or misoprostol
•Encourage patients to report warning symptoms
Warning symptoms for Upper GIproblems
• Unexplained weight loss
• Dysphagia
• Anaemia
• Vomiting
• Upper abdominal pain
• Evidence of GI blood loss
• Patient on long-term/high dose NSAIDs and takingGaviscon OTC
Case study• Mr DU 67 year old smoker (>20 per day)Medical history:
– Hypertension– Osteoarthritis– COPDComplains of stomach pains & heart burn
Medication includes:• Celecoxib (osteoarthritis)• Low dose aspirin (anti-platelet)
AlsoH.Pylori negative
First step? Check medication-
06/01/2014
14
What could be the cause of stomach problems?
Celecoxib & aspirin- both NSAIDs
Change to paracetamol & clopidogrel
Or aspirin + PPI
Lifestyle effects?
Smoking can cause GORD- heartburn
Other comments on current medication?
COX-2 inhibitor & cardiovascular disease! COX-2inhibitors shouldn’t be given to patients at risk of CVD
NAUSEA & VOMITING
Nausea and Vomiting
Stimulated by:• Toxins: bacterial poisons, alcohol (15%)• Smells• Motion sickness• Migraine• Pregnancy
Drugs- many, particularly:- Chemotherapy– Opioids e.g morphine
06/01/2014
15
Physiology of vomiting
Highly co-ordinated physiological response:
1. Discomfort, dry mouth, salivary inhibition.2. Yawning – sympathetic distress3. Reappearance of saliva4. Pyloris closes5. Tone of stomach increases6. Deep breath7. Contraction of abdominal muscles to force food out8. Forced expiration to prevent inhalation
Under central control, where most anti-emetics act:
Reflex Mechanism of Vomiting
Central regulation of vomiting occurs in the vomiting centre &the chemoreceptor zone (CTZ).
CTZ sensitive to chemical stimuli- main site of anti-emetic drugs
Output from the CTZ stimulates the vomiting centre, leading tothe initiation of vomiting
Neuronal signals from GIT feed in to CTZ and vomiting centre
Neurotransmitters Involved in Nausea & Vomiting
•Histamine
•Acetylcholine
•Dopamine
•5-HT
Blocking these receptors in the brain preventsnausea & vomiting
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16
Chemotherapy-Induced Nausea & Vomiting
Some chemotherapy agents stimulate release of 5-HTfrom enterochromaffin cells.
Acts at vagal afferents.
Feeds into CTZ & vomiting centre.
CTZ
VomitingCentre
Nucleusof the
Solitary Tract
VisceralAfferents
StimulifromGIT
Drugs,toxins
5-HT3
antagonists
Dopamine & 5-HT3
antagonists
Muscarinicantagonists
H1
antagonists
Anti-emeticsH1- Histamine receptor antagonistse.g. promethazine.
– Effective in motion sickness. Also have anti-muscarinicactions. Produce drowsiness.
Anti-muscarinic agentse.g. hyoscine, prochlorperazine
– Effective in motion sickness.– Also reduce gastric motility (see later).– Anti-muscarinic side effects (eg dry mouth).– Produce drowsiness.
06/01/2014
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Anti-emetics 2Dopamine antagonistse.g. domperidone, metoclopramide.
– Act in CTZ but has unwanted CNS effects. Effective againstanticancer drug-induced emesis.
– Also stimulates gastric emptying reduce nausea
5-hydroxytryptamine antagonistse.g. ondansetron
– blocks 5-HT at 5-HT3-receptors in gut and CNS - particularlyeffective against anti-cancer drugs. Act in CTZ.
Cannabinoid receptor agonistnabilone licensed for chemotherapy- action unclear
Newer Agents:
Neurokinin Receptor Antagonists
• NK1 Receptor activated by Substance P
• NK1 receptor antagonists suppressnausea & vomiting.
• eg Aprepitant
used in chemotherapy-induced N&V incombination with 5-HT receptorantagonist.
• Steroids eg dexamethasone also haveanti-emetic action.
• Used in chemotherapy-induced N&V
• Mechanism unknown.
06/01/2014
18
Standard Prescription for chemotherapyN&V:
• 5-HT3 receptor antagonist
• + steroid
• + NK1 receptor antagonist
LOWER GI PHARMACOLOGY
Constipation
’Persistent, difficult, infrequent or seemingly incompletedefecation’
Causes:– Dietary changes (reduced NSP and fluid intake)– Stress– Immobility e.g. due to illness– ADR e.g. Opioids, calcium channel blockers,
muscarinic antagonists– Dehydration– Irritable Bowel Syndrome
• Common in elderly due to reduced mobility, poor diet/low fluid intake
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Diverticular disease
Diverticulitis- occurs when these become inflammed/infected or strangulated (cuts off blood supply)
Diverticula- small sacs/ pouches that can form in the wall ofthe large intestine
May cause abdominal pain or altered bowel habits
Pain results from muscle spasms
Occurs in ~ 80% of elderly
Caused by long-term constipation- straining
Weak area of gut.Pouches formFood can get stuck
Infection
Management of constipation
• Determine the causee.g diet, lifestyle, medication, underlyingcondition eg. intestinal obstruction
• Best approach is diet with NSPs and fluid
• Could add bulking agents eg ispaghula husks
• Laxatives
06/01/2014
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Treatment of constipation
Bulk-forming:
– Ispaghula husk (Fybogel), methylcellulose, sterculia,unprocessed wheat bran
– May take several days to work
– ADRs: flatulence, abdominal distension
– Increase faecal mass, retain water- stimulatesperistalsis.
Laxatives- Osmotic
• Lactulose (disaccharide of galactose and fructose)– Colonic bacteria convert it into lactic and acetic acid -
raise fluid volume osmotically– Delayed effect approx. 48 hours– Good fluid intake required– Flatulance, abdominal cramps, discomfort
• Macrogols (Movicol, Idrolax)– Sequester fluid in bowel– Insufficient evidence to recommend over well-
established, cheaper products
• Magnesium sulphate & magnesium hydroxide- Remain in lumen & retain water
Work by increasing water in faecal matter
Stimulant laxatives
For use when required rather than regular use. Usually taken at night toproduce effect next morning.
Senna extractsEnter the colon & metabolised to anthracene derivatives. Stimulate GIT
activity by irritation.
DantronAlso a GIT irritant. Limited for terminal care only due to potential
carcinogenicity
BisacodylUsually taken as suppository.Rapid effect (1-2 hours)Stimulate rectal mucosa- causes peristaltic action
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Faecal softeners/lubricants
• Docusate sodium
• Detergent-used to soften stools & ease defecation
• Docusate also has weak stimulant activity
Other drugs that increase GI Motility(prokinetic)
Domperidone & Metoclopramide
• Dopamine D2 receptor antagonists.
• Stimulation of dopamine receptors inhibits gastric motility.
• Leads to postprandial bloating & pain, nausea & vomiting.
• Dopamine antagonists block this.
Prucalopride: 5-HT4 agonist which increases GImotility (used when others have failed).
M
ACh
D2Inhibits
X
Dopamine
06/01/2014
22
M
ACh
D2Inhibits
X
Dopamine
Domperidone
X
X
5-HT4
Prucalopride
Stimulates
5-HT (Serotonin)
5-hydroxytryptamine
Tryptophan
5-hydroxytryptophan
5-hydroxytryptamine (5-HT)
5-HT Receptors- Numerous subtypes
5-HT3
5-HT2
5-HT4
5-HT5
5-HT6
5-HT7
5-HT1 1F1A
5A
2A
5B
2C
to
to
&
06/01/2014
23
Prucalopride
•selective serotonin 5-HT4-receptor agonist
•chronic constipation in women
NICE guidancePrucalopride for constipation in women (December2010)treatment of chronic constipation in women for whomtreatment with different laxatives has failed
Prucalopride should be prescribed only by cliniciansexperienced in the treatment of chronic constipation.
www.nice.org.uk/TA211
Dopamine Receptor Antagonists
- Anti-emetic action through effects on CTZ
- increase gut motility
– Closes gastro-oesophageal sphincter- benefit inGORD
– Increases gastric emptying and increasesduodenal peristalsis
– Can prevent bloating.
central side effects (metoclopramide only):
•drowsiness, restlessness, insomnia,fatigue.
•10-20% can experience Parkinson’ssyptoms
•Domperidone- doesn’t cross BBB (NB butcan act in CTZ)
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• Gastroparesis- delayed gastric emptying
• Symptoms- nausea, vomiting, bloating, pain.
• Due to post-viral syndrome, diabetes mellitus,post surgery or unknown.
• Dopamine receptor antagonists beneficial byincreasing gastric emptying and anti-emeticeffects.
Diarrhoea
Common, debilitating and can be life threatening (5million deaths world wide due to dehydration).
Causes:
Often bacterial or viral infection.
Rotaviruses cause damage to small bowel villi
Adhesive enterotoxigenic bacteria : adhere to brushborder and increase Cl- and Na+ secretion followed bywater.
amoebae & giardia also cause diarrhoea
“Travel broadens the mind and loosens the bowels” Gorbach, 1987
Often bacterial or viral infection.
Rotavirus: damages small bowel villi
Invasive bacteria: damage epithelium.Cytotoxins: damage muscosae.g.Campylobacter
Adhesive enterotoxigenic bacteria: adhere tobrush border, increase cAMP leading to Cl- andNa+ secretion followed by water:
06/01/2014
25
Diarrhoea can also be caused by drugs:
• antibiotics can alter gut flora leading to superinfectione.g. clostridium difficile which may lead to colitis
• Orlistat – pancreatic lipase inhibitor used in obesity
• Misoprostol – via cAMP causing secretory diarrhoea
• PPIs – suppress acid secretion too much allowinginfection
• Metformin (type 2 diabetes)
Treatment of diarrhoea
Oral rehydration therapy (ORT)Diarrhoea: dehydration with electrolyte disturbances.
Therefore rehydration is a must:
• Electrolytes e.g. Dioralyte.
• + Glucose- allows transport of Na via a specific co-transporter on epithelial cells (H2O follows)
• Young & old are particularly at risk of dehydration.
• Also patients on concurrent diuretic treatment
Many GIT infections are viral- can only treat symptomsAntibiotics may be of use in eg ingestion of contaminated food
Water
Water Absorption
Na+
Glucose
Na+
Symporter
H2O2
Osmosis
06/01/2014
26
Drugs that Reduce GIT Motility
Neurotransmitters & Receptors:
• Acetylcholine (ACh) stimulates muscarinic or nicotinicreceptors on cholinergic neurons
– Muscarinic ACh receptors involved in the contraction ofsmooth muscle of the GIT (and the control of vomiting)
• Enkephalins via opioid receptors involved in GI motility
Treatment of diarrhoea
Opiateseg loperamide
gut motility. Reduce motility of lower GITallowing reabsorption of water and reducing waterstools
Allows bowel control and normal daily activities
Symptomatic relief
M
Ca2+
ACh
mOpioidreceptor
XX
Loperamide
Inhibits
06/01/2014
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NB:
Codeine- a derivative of morphine.- Also used as an analgesic.- Anti-tussive agent (cough medicines).- Constipation is an ADR for reasons
outlined.- All opioids eg morphine can cause
constipation
Methylnaltrexone
•peripherally acting opioid-receptor antagonist•treatment of opioid-induced constipation in patients
receiving palliative care•used on top of existing laxative therapy.
•No central effect therefore no effect on analgesiceffect of opioids.
Antimotility agentsOpioids (e.g. loperamide, codeine) & antimuscarinic agents
Opioids reduce tone and peristaltic movement
Inhibit acetylcholine release act at muscarinic receptors
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Antimuscarinic agents
• Rarely employed as primary therapy for diarrhoea due toeffects at muscarinic receptors around body.
• Inhibits secretions- dry mouth, dry eyes & dry skin(reduced sweating)
• Causes tachycardia (increase heart rate)
• Mild restlessness at low doses- agitation at higher doses-CNS effects
Anti-muscarinic agents act directly at muscarinic receptorseg atropine, buscopan (hyoscine)
Anticholinergics and opioids ADR
– All patients prescribed long-term opioidsshould receive laxative- constipation
– Anticholinergic effects with TCAs,antipsychotics, sedating antihistamines
IRRITABLE BOWEL SYNDROME(IBS)
This is a common, long-standing disorder
Present for at least 12 weeks within 1 year
Pain, bloating - relieved by defecation
Episodes of diarrhoea and/or constipation.
Cause not understood. May have a psychologicalassociation- stress or depression
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Treatment of IBS
-Treat symptoms as appropriateeg constipation- NSPs to diet or laxative
Diarrhoea- opioid as required
-For bloating/ pain:-Anti-spasmodic agents such as anti-muscarinics eg buscopaneg dicycloverine- reduces smooth muscle tone in lower GIT
-OR Mebeverine-Causes direct relaxation of GIT smooth muscle-PDE inhibitor?
Treatment of IBS (2nd line)
Tricyclic Antidepressantseg amitriptyline-Used at low dose-Analgesic effect-Also constipating (antimuscarinic effects)
Linaclotide
•Peptide
•guanylate cyclase-C receptor agonist
•Acts on guanylyl cyclase C receptor on epithelial cells
•receptor for endogenous hormones guanylin and uroguanylin
•Increases intestinal fluid secretion and transit
•Reduces pain
•GI selective- not absorbed
•Used in irritable bowel syndrome with constipation
http://jpet.aspetjournals.org/content/344/1/196.full.pdf+html
Pharmacologic Properties, Metabolism, and Disposition of Linaclotide, a Novel Therapeutic Peptide Approved for the Treatment ofIrritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipations
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Lubiprostone
Cl- channel activator
Increases intestinal fluid secretion
Constipation
Inflammatory Bowel Disease
Ulcerative Colitis-•mucosal inflammation in the colon.
•Cause unknown- possible role of colonic bacteria.
•Causes bloody diarrhoea. Severe attack ispotentially life-threatening.
Less nutritional consequences than:
Crohn’s Disease•Transmural inflammation. Can effect anywherein GIT (mouth to anus)•Cause unknown•Pain, diarrhoea, weight loss due to impairedabsorption and increased losses.•Fatigue•Micronutrient deficiencies.•Protein-energy malnutrition in 20-80% ofpatients.•Strictures can cause GI obstruction.•70-80% of patients require surgery at somepoint.•Exacerbations and remission.
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Treatment of inflammatory bowel disease
5-aminosalicylates
• All these compounds are broken down to 5-aminosalicylic acid (5-ASA).
• 5-ASA inhibits leukotriene & prostanoid synthesis,scavenge free radicals, & decrease neutrophilchemotaxis
• eg Sulfasalazine- metabolised to 5-ASA.Mesalazine- pH changes yield 5-ASA
Questionable use in Crohn’s but some effect in Ulcerative collitis
Drugs used are intended to reduce the inflammatory response
Treatment of IBD (cont)
Corticosteroids
e.g oral prednisolone
– anti-inflammatory, immunosuppressive actions.
– eg budesonide - poorly absorbed so far lesssystemic side effects.
– Used to induce remission, particularly in moresevere disease
– Enemas used for more distal or rectalinflammation e.g. Predfoam
Treatment of IBD…..
Immunosuppressants
e.g. Azathioprine and methotrexate- Inhibit purine synthesisand hence DNA. Reduces inflammatory cell proliferation
Cyclosporin- inhibits IL-2 induced gene expression– Used in refactory disease or for steroid-sparing
Infliximab
- monoclonal antibody for severe, active Crohn’s
- Neutralises inflammatory cytokine TNF-a, implicated inCrohn’s
– Associated with risk of TB
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Summary• Peptic ulcers and GORD require reduction in acid
secretion.
• H.pylori is responsible for 80-90% of peptic ulcers
• NSAIDs are associated with gastrotoxicity and requireclose monitoring
• Drugs that alter gastric motility can be used to treatconstipation and diarrhoea.
• Nausea & vomiting are controlled by the CNS- CNS-acting drugs
Summary
• Irritable Bowel Syndrome- treatment of symptoms
• Ulcerative Collitis & Crohn’s- treatment withimmunosupressants.
References
BNF
Rang, Dale, Ritter & Moore. Pharmacology.
Randall & Neil, Disease Management. Chapter 8
• Clinical guidelines for treatment of disease:www.prodigy.nhs.uk/Clinical%20Guidance/ReleasedGuidance/
• British Society for Gastroenterology Guidelines:www.bsg.org.uk/pdf_word_docs/ibd.pdf
• National association for Colitis and Crohn’s diseasewww.nacc.org.uk
• www.npc.co.uk/MeReC_Bulletins/
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Summary• Drugs that alter gastric motility can be used to treat
constipation and diarrhoea.
• Can also be a side effect of drugs
• Ulcerative Collitis & Crohn’s- treatment withimmunosupressants.
References
BNF
Rang, Dale, Ritter & Moore. Pharmacology.
Randall & Neil, Disease Management. Chapter 8
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Psychopharmacology;
Diseases of the brain and their treatment
Neurodegenerative disorders
Parkinson’s, Huntingdon’s, Alzheimer’s, Motor Neurondiseases
Disordered thought and perception
Schizophrenia
Mood disorders
Depression, Bipolar disease, Anxiety
Neurodegenerative diseases of movement
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Parkinson’s Disease;
•Progressive disease of movement (mainly in elderly)
•Symptoms; tremor at rest (“pill rolling”), muscle rigidity,suppression of voluntary movement (hypokinesia) comprisinginertia in motor system.
•Patients walk with shuffling gate, finding starting, stopping,changing direction difficult.
•Cause not known; might follow cerebral ischemia, viralencephalitis or other brain damage. Can be drug-induced;reserpine (depletes dopamine), anti-psychotic drugs (blockdopamine receptors). Rarely genetic link (2 gene mutations;synuclein & parkin). Neurotoxin MPTP, contaminant in designerdrug, causes destruction of nigro-striatal dopaminergic neuronesand Parkinsonian symptoms.
Organisation of extrapyramidal motor system
Dopamine-inhibitory; ACh (acetylcholine) excitatory;GABA (gamma amino butyric acid) inhibitory
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In Parkinson’s disease there is a progressive degeneration ofdopaminergic neurones in the substantia nigra. Symptoms notevident until very substantial loss has occurred.
Synthesis of catecholamine neurotransmitters;dopamine, noradrenaline and adrenaline
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Drug therapy:
•No drug reverses neurodegeneration.
•Aim to reverse effects of dopamine deficiency in basal ganglia orblock excitatory effect of acetylcholine (on muscarinic receptors).
•Most effective drug is levodopa (L-DOPA), brain permeabledopamine precursor. Co-administered with carbidopa (inhibitsDOPA-decarboxylase peripherally) and sometimes entacapone(inhibits catechol-o-methyl transferase) to prevent breakdown.
•Levodopa’s efficacy usually wanes after about 2 years. Sideeffects are involuntary movements and unpredictable “on-off”behaviour
• Other useful drugs include bromocriptine (DA agonist),amantadine (DA releaser) & benztropine (muscarinicantagonist).
Attempts to cure Parkinson’s disease include foetal stem celltransplantation, sub-thalamic lesions & deep brain stimulation.
DBS leaves electrodes in place in the brain to deliver continuousstimulation. The electrodes are powered by a programmablestimulator (like a pacemaker), which is implanted in the chestwall. Some positive effects on tremor reported.
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Huntington’s disease (Huntington's chorea)
•Inherited disorder resulting in progressive brain degeneration.
•Characterised by excessive, abnormal movements (dancing-like),also progressive dementia.
•Protein encoded by the HD gene (huntingtin) interacts with rangeof regulatory proteins causing excitotoxicity and neuronalapoptosis.
•75% reduction in GABA content in striatum; produceshyperactivity of dopaminergic
transmission (converse of PD).
•Drugs that alleviate the symptoms include
neuroleptics (e.g. chlorpromazine) and
the GABA receptor agonist baclofen.
Alzheimer’s disease (AD)
•Age-related dementia distinct from ischemia-related conditions.
•Can involve 75% loss of (particularly cholinergic) neurones inforebrain causing memory loss and language difficulties.
•Characteristic amyloid plaques and neurofibrillary tangles.
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•Amyloid plaques consist of excessive (neurotoxic) amounts ofAβ fragment of amyloid precursor protein (APP) a normal cellmembrane constituent.
•Neurofibrillary tangles are aggregates of highly phosphorylatedform of Tau (another normal neuronal protein); role inneurotoxicity not clear.
•Most AD of unknown cause (sporadic). Familial AD (rare) dueto mutations in genes for APP and unrelated presenilin; bothcause increased Aβ formation.
Treatment
•Anticholinesterases (preserve released ACh) e.g. tacrine are ofsome limited benefit.
•Anti-inflammatory drugs might retard neurodegeneration (someevidence that long term NSAID consumption associated withlowered risk of developing AD; not proven).
Motor neurone disease (MND);
•Also known as amyotrophic lateral sclerosis (ALS), affectsmovement due to progressive degeneration of the motor nervesconnecting the spinal cord to the skeletal muscles. Only 10%cases have a genetic component.
•Sufferers eventually lose allcontrol over voluntary movements,even processes like swallowing andeye movements, although it doesnot affect mental ability (StephenHawking !).
•No effective drug therapy althoughmodest success in slowingprogression claimed for riluzole;inhibits release and action ofglutamate.
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Nutrition and neurodegenerative disease;
•Alzheimer’s disease is often accompanied and worsened bymalnutrition.
•Weight loss can be progressive; loss of 4% body wt. in 1 y (aboutone third of patients) or severe loss of > 5 kg in 6 months (about10%).
•Disease severity a risk factor.
•Nutritional interventions indicated for severe groups.
•Up to 80% Parkinson’s patients suffer constipation.
•Related to reduced water intake (don’t feel thirst) throughout life.
•Complication in some with PD is oropharyngeal dysphagia, asymptom complex recognized by difficulty in transfer of a foodbolus from mouth to oesophagus.•Dysphagia is also major problem in motor neuron disease.•Gastrostomy feeding tubes are being inserted more frequently inMND patients but not associated with increased survival times.•Median survival from tube insertion 146 days; 1 month mortalityafter gastrostomy was 25%.•Body mass index should be used with caution for the evaluationof the nutritional status of patients with MND.•Experimental evidence that dietary restriction is neuroprotectivein PD and AD models.
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Schizophrenia; a disease of disordered thought & perception
Criteria for schizophrenia (DSM IV); 2 or more of eachpresent for significant time during 1 month period;
“Positive” symptoms:
•Delusions
•Hallucinations
•Disorganised speech (frequent derailment or incoherence)
•Grossly disorganised or catatonic behaviour
“Negative symptoms”:
•Flattening of mood and lack of volition
Only one of these required for diagnosis if delusions are bizarreor hallucinations consist of voice running a commentary onpatient’s behaviour or thoughts, or 2 or more voices conversingwith each other.
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•Typically equally affects men and women in late teens/early 20s
•Incidence about 0.2 per 1000 in UK (~12,000)
•Genetic component identified but concordance amongst identicaltwins only 50%.
Pathology; cause unknown but dopamine hypothesis partly basedon similar symptoms following some drugs that increase dopaminelevels or stimulate dopamine receptors (e.g. amphetamine, cocaine,apomorphine).
•Suggested hyperactivity in the mesolimbic system, dopaminergictract originating in the ventral tegmental area and projecting tonucleus accumbens, ventral striatum, amygdala, hippocampus andother parts of the limbic system (involved in emotion and memory).
• Supported by PET studies showing reduced mesolimbic bloodflow in schizophrenics.
Human dopaminergic pathways
movementcognition
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Treatment;
•Drug therapy can lead to remission and re-integration into society
•Drugs used referred to as neuroleptics or anti-psychotics
•“Typical” anti-psychotics (e.g. chlorpromazine, haloperidol)
•Antagonise dopamine D2 receptors reducing dopaminergicactivity in mesolimbic and mesocortical pathways.
•Major side effect; extra-pyramidal symptoms, Parkinsonian-like, due to blockade of D2 receptors in nigro-striatal pathway.
•As D2 receptors become supersensitive, Parkinsonian symptomsreduce. After months/years 20% patients develop tardivedyskinesia; repetitive, involuntary stereotyped movementsresembling Huntington’s chorea.
•“Atypical” antipsychotics; e.g. clozapine, olanzapine,risperidone. Fewer side effects, poor correlation between D2
antagonism and efficacy.
•Antagonists at D4 receptors; located in frontal cortex, medullaand midbrain i.e.areas not involved in movement control.
•However, atypicals have affinity at other receptors (5HT2, alpha1
and alpha2 adrenoceptors, histamine H1, muscarinic) and D4
blockade probably not complete explanation of activity.
clozapine
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Nutritional implications of schizophrenia:
•Schizophrenics make poor dietary choices,
•Likely to engage in less physical activity than normals.
•Atypical antipsychotic drugs produce weight gain; average ofbetween 4.5 and 7 kg in the 3 months following commencementof olanzapine.
•Good take up with free fruit and vegetable programmes.
•But, consumption fell to pre-intervention levels 12 months afterthe intervention stopped.
•No differences at any time in blood micronutrients, body massindex, physical activity or risk of heart disease compared withcontrols.
Depression
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Major Depression
•Lifetime prevalence of 9-15% (up to 20% in women).
•Reactive depression has link to stressful life events;endogenous, no clear trigger.
•Some evidence of genetic component (identical twin studies)but no gene defect identified.
•A major depressive episode is present if five or more of thefollowing nine symptoms are present during the same two-weekperiod. At least one of the five symptoms must be either adepressed mood or loss of interest or pleasure (anhedonia).
•Depressed mood for most of the day
•Disturbed appetite or change in weight
•Disturbed sleep
•Psychomotor retardation or agitation
•Loss of interest in previously pleasurable activities; inabilityto enjoy usual hobbies or activities (anhedonia)
•Fatigue or loss of energy
•Feelings of worthlessness; excessive and/or inappropriateguilt
•Difficulty concentrating or thinking clearly
•Morbid or suicidal thoughts or actions
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Raphe nuclei
Locus coeruleus
Noradrenaline and serotonin (5HT) pathways in the brain.
Synthesis of catecholamines
Metabolism via monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT)
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Synthesis of 5HT
Metabolisedby MAO
Reuptake and metabolism of noradrenaline
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Monoamine theory of depression:
•Reserpine (old anti-hypertensive drug) depletes nerves ofmonoamines and caused depressive symptoms.
•1st generation antidepressant drugs (ADs; tricyclics e.g.imipramine) block monoamine reuptake (increase synapticlevels).
•Suggested (1965) that depression due to deficiency of brain MA.
Problems
•Increased synaptic [MA] happens immediately but benefit fromADs takes weeks to appear.
•Some drugs that increase MA availability (e.g. cocaine) are notantidepressant.
Neurotrophic hypothesis
•Stress causes over-activity of hypothalamic-pituitary-adrenal(HPA) axis.
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•Increased hormones (glucocorticoid, ACTH, CRH) cause atrophyof stress-vulnerable neurones (e.g. hippocampus) and reduction inneurogenesis.
•Imaging studies demonstrate “shrinkage” of some brain areas indepressives.
•ADs increase the expression of protective neurotrophic factorssuch as brain-derived neurotrophic factor (BDNF) reversingstress-induced damage.
Treatment;
Despite problems with monoamine theory, most effective ADs dointeract with monoamine neurotransmission.
Antidepressant drugs:
•Tricyclics e.g. imipramine
Inhibit NA & 5HT re-uptake. Delayed effects, inhibit variety ofreceptors, dangerous in overdose (cardiac dysrhythmias), many druginteractions.
•Monoamine oxidase inhibitors (MAOI)
e.g. phenelzine
Reduce intracellular MA metabolism. Delayed efficacy; majorproblem of “cheese effect” (preserve dietary tyramine, asympathomimetic). Can cause fatal cerebral hypertension. Must notbe given with other ADs.
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Selective serotonin re-uptake inhibitors (SSRI)
e.g. fluoxetine
Currently most widely prescribed ADs. Safer in overdose; no moreeffective or rapid in action than older drugs. Side effects includenausea, anorexia, insomnia, reduced libido, ejaculation failure.
Other MA uptake inhibitors
Inhibit uptake by noradrenaline selective (e.g. reboxetine) or non-selective (e.g. venlafaxine). No more effective but less side effectsand safer in overdose that TCAs.
Electro-convulsive treatment
Patients anaesthetised and muscle relaxant given. Mechanismunknown but can be life saving in refractory depression. Someshort term memory loss.
Bipolar disorder (manic depression)
•Patients cycle between depression and mania
•Some famous manic depressives (mixed nuts);
•Buzz Aldrin, astronaut; Napoleon Bonaparte; Jim Carrey, actor;Dick Cavett, writer, media personality; Agatha Christie; Winston Churchill;Rosemary Clooney, singer; Francis Ford Coppola, director; Patricia Cornwell,writer; John Daly, athlete (golf), Ray Davies, musician;Emily Dickinson; PattyDuke, actor, writer; T S Eliot, poet; Robert Evans, film producer; Carrie Fisher,writer, actor; Edward FitzGerald, Robert Frost; F Scott Fitzgerald, author;Connie Francis, actor, musician; Sigmund Freud, physician;Cary Grant, actor; Victor Hugo, poet; Jack London, author; Robert Lowell, poet;Marilyn Monroe, actress; Mozart, composer; Spike Milligan, comic actor,writer; Ilie Nastase, athlete (tennis), politician; Isaac Newton, scientist; Plato,philosopher, (according to Aristotle); Edgar Allen Poe, author; Charley Pride,musician; Graham Greene, writer; Abbie Hoffman, writer, political activist;Gordon Sumner (Sting), musician, composer; St Francis; St John; St Theresa;Rod Steiger, film maker; Robert Louis Stevenson; Liz Taylor, actor;Mark Twain, author; Vincent Van Gogh.
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Treatment;
•Mood stabilising drugs used to control mood swings.
•Lithium is most common; recently, anti-epileptic drugs,(e.g.carbamazepine) proved useful and less toxic.
•Lithium is toxic in overdose (confusion, convulsions & cardiacdysrhythmias) and has narrow therapeutic window (plasma levelsmonitored and kept between 0.5 and 1.0 mmol/L).
•Given prophylactically, both phases reduced. Takes 3-4 weeks towork. Mechanism not clear.
•Neuroleptics used to manage acute mania.
•Some patients prefer to avoid treatment, preferring possibly creativemanic phase at expense of depression.
Anxiety
•Normal fear response to threat comprises
various components; defensive behaviour, autonomic reflexes,arousal, alertness, corticosteroid release, negative emotions. Inanxiety states, these occur in an anticipatory manner, independent ofimminent danger.
•Difficult to distinguish normal from pathological anxiety.
•More than 10% western populations regularly use anxiolytic drugs.
•Anxiety disorders include:
Generalised anxiety (excessive anxiety with no clear focus); panicdisorder (marked somatic symptoms); phobias; post-traumaticstress disorder (anxiety triggered by insistent memory of paststressful event).
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Anxiolytic and hypnotic drugs
•Main drugs used are benzodiazepines, e.g. diazepam
•Potentiate action of major inhibitory neurotransmitter, GABA.
•Benzodiazepines with short half-lives used mainly as hypnotics(e.g. midazolam) but problems with dependence. Longer actingdrugs (e.g. flurazepam) preferred as anxiolytics.
•Benzodiazepines obliterate memories of events experienced undertheir influence (use in minor surgery) and are anti-convulsant.
•Risk of dependence!
•Buspirone; 5HT1A receptor agonist is non-sedative anxiolytic.Takes weeks to work so ineffective in panic.
•Beta-adrenoceptor antagonists (e.g. propranolol) used to controlphysical symptoms of anxiety (palpitations, sweating etc). No effecton emotional component.
•Alcohol; short term effectiveness, side effects all too familiar.
•Anxiety commonly co-exists with depression. Can treat acutelywith benzodiazepine prior to ADs taking effect.
•Some disorders with anxiety component treated with other drugs;
e.g. GAD and obsessive compulsive disorder treated with SSRIsor TCAs.
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Nutrition and mood disorders:
•50% depressed patients overweight and 20% obese.
•Women with depression have more abdominal fat and are moreat risk of CVD than non-depressed.
•Depressed patients do not value modest weight loss; one studyreported that one third of patients thought that 10% loss in bodyweight required for benefit and were prepared to risk death toachieve this.
•SSRIs have common GI side effects (nausea, vomiting,dyspepsia, diarrhoea, constipation!), anorexia with weight loss(but increased appetite and weight gain also reported).
•Weight gain major reason for non-compliance.
Eating disorders
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Eating disorders:
•The main types of eating disorders are anorexia nervosa andbulimia nervosa. A third type, binge-eating disorder, has beensuggested but has not yet been approved as a formal psychiatricdiagnosis.
•Eating disorders frequently co-occur with other psychiatricdisorders such as depression, substance abuse, and anxiety.
•Females are much more likely than males to develop an eatingdisorder. 5 to 15 % of people with anorexia or bulimia and about35% with binge-eating disorder are male.
•Syndromes are complex and treatments require psycho-social aswell as medical intervention.
•SSRIs can contribute to treatment regime.
11
Obesity
MP3 L10 1 IAM
WHAT IS OBESITY?
Too much body fat
Too much fat in the ‘wrong’ place
Caused by chronic positive energy balance:Results from:
too much energy intake
or too little energy expenditure
or a combination of both??
Learning objectives- to:
define obesityDiscuss the treatment options for
patients with obesity
22
How do we assess obesity?
Body Mass Index
Risk ofco-morbidity
<18.5 underweight18.5-24.9 healthy average> 25 overweight25-29.9 pre-obese increased30-34.9 grade I moderate35-39.9 grade II severe40 and above grade III very severe
(WHO)
BMI= weight (kg)/height2 (m2)
Foresight model: by 2050 60% men, 40% women
Prevalence of obesity, adults aged 16-64, 1986/87 - 2004, England
0
5
10
15
20
25
30
1986/87 1991/92 1994 1996 1998 2000 2002 2004
Year
%B
MIo
ver
30
Men
Women
www.heartstats.org
Consequences of Obesity
Obesity is a major risk factor for CHD
Also:
Increases bp
Increases plasma cholesterol levels
Increases risk of type II diabetes
additional risk factors for CHD
Increase cost to NHS est. £45.5 billion by 2050
33
Cancer
WCRF Report 2007- systematic review of literature
Increased risk of certain cancers with increased body fat
Adult weight gain also associated with increased risk ofcancer- even within healthy range of BMI
Adult weight gain due to increase in fat
http://www.dietandcancerreport.org/
WCRF Report 2007- Systematic Review
Risk Risk
Convincing
Probable
Exposure Cancer Exposure Cancer
Body fatness OesophagusPancreasColorectalBreast (postmen)EndometriumKidney
Abdominal Fat Colorectal
Body fat Breast(premen)
Body fatness Gall bladder
Abdominal Fat PancreasBreast (postmen)Endometrium
Adult weightgain
Breast (postmen)
Waist Circumference
Risk of: high total cholesterol (> 6.5 mmol/l)low HDL cholesterol (< 0.9 mmol/l)High b.p.(>160 diastolic or
>95 mmHg systolic)
Han et al. BMJ, 311, 1995
MEN WOMEN
Waist circumference 94-102cm >102cm 80-88cm >88cm
Odds ratio for 1 ormore risk factors
2.2 4.6 1.6 2.6
Apples or pears- waist:hip ratioApples- greater risk of complications
44
Weight Loss Target:
An achievable target should be set-5-10% of original weightMax weekly weight loss of 0.5-1 kg
May still have BMI > 25 kg/m2
Dietetic Treatment
Based on energy balance equation
Energy input- energy consumption = energy balance
In order to lose weight energy balance must be negative
Current Prescription Only Medicines
Orlistat
Sibutramine- Suspended Jan 2010
Rimonabant- marketing authorisation suspendedOct. 23rd 2008.
Dexfenfluramine, fenfluramine and phentermineassociated with valvular heart disease andpulmonary hypertension.No longer recommended.
55
Orlistat
– Tetrahydrolipostatin.Synthesised derivative of lipostatin, (a metaolicproduct of Streptomyces toxytricini)
- Inhibits Gastric and Pancreatic lipase
- minimal absorption
- Needs to be taken before each main meal
- ~ 30% inhibition of lipases at normaltherapeutic doses (lose 200kcal per day)
-Needs to be combined with a low fat diet –reinforces the need to restrict fat intake
Side effects
Steatorrhea- fatty, foul smelling faeces- may actually help to reduce fat intake
Reduced absorption of fat therefore need tomonitor fat soluble vitamin status- supplements?
Meta Analysis of Clinical Trials(Rucker et al BMJ Online &Padwal et al Cochrane Database, 2003)
16 clinical trials (10,631 subjects)
Orlistat for 1 year reduced weight by 2.9kg more thanplacebo.
With calorie-reduced diet.
BUT – Controlled trials are not always mirrored inClinical Practice.
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Prescribing guidelines
To be combined with reduced calorie diet.
BMI > 30 kg/m2 orBMI > 28 kg/m2 if other risk factors eg type 2diabetes, hypercholesterolaemia, hypertension
Should only be continued after 12 weeks if weightloss exceeds 5%
Dose
120 mg taken immediately before, during or 1 hr aftereach main meal
Max. 360 mg daily
Miss dose if meal contains no fat
OTC Orlistat (Alli)
•Reduced dose- 60mg tds
•Max 6 months
•Combined with reduced fat diet
•BMI > 28
•Review after 12 weeks
•Dietary approaches and physical activity should betried before Orlisat
http://www.rpsgb.org/pdfs/otcorlistatguid.pdf
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Sibutramine (suspended)
•Combined NA and 5HT uptake inhibitor-CNS
•Appetite suppressant.
Side effects
Increases SNS activity, can raise BP
BUT offset by weight reduction
Increases heart rate slightly.
Rimonabant (Acomplia)
-CB1 receptor antagonist
-Licensed for use in EU July 2006
-NICE guidelines issued June 2008
-European Medicines Agency suspended marketingauthorisation Oct. 23rd 2008.
-Review found that benefits do not outweigh therisks.
•Blocks central and peripheral CB1 receptors
•Decreased motivation to eat palatable food
•Anorexigenic effects
•Stimulation of satiating signals in GIT
•Inhibition of lipogenesis (adipose and liver)
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Phentermine- US
Not licensed in UK.
Increases catecholamine levels in brain.
Also peripheral effects- increase hr, bp, palpitations.
Qnexa- phentermine + topiramate
42% > 10% weight loss
FDA rejected- Oct 2010- side effects
Qsymia- Licensed in US 2012
Bariatric Surgery
Roux-en-Y gastric bypass (RYGB)
results in 20–40% weight lossmaintained over at least 15 years.
99
Laparoscopic adjustable gastric banding(LAGB)results in 15–30% weight loss.
From O’Brien et al.Obes Surgery vol 16pp1032-1040
•Surgery can lead to major, sustained weight loss.
•Not possible with drugs
•Increases satiety and reduces appetite
•Therefore patients don’t want to eat as much.
1010
Bariatric Surgery reduces mortality and morbidity inmorbidly obese patients:
•Improves type 2 diabetes
•Reduces hyperlipidaemia
•Reduces hypertension
•Improves sleep apnoea
Buchwald, H. et al. JAMA 2004;292:1724-1737.
Risk?- risks associated with surgery~ 1% early mortality after RYGBP surgery~ 0.4% early mortality after banding
Cost?- cost effective as reduces impact on Healthservice of co-morbidities
Control of Appetite and Future Treatments
1111
Ghrelin
PYY
Pancreas
Insulin
Leptin
Vagus
ARC NPY/AgRP
POMC/CART
CCK
Adiposetissue GIT
Brain
Leptin (Greek: thin)
•Peptide hormone secreted from adipose tissue
•Mutations causing absence of leptin leads to severeobesity
•Many obese people have increased levels of leptin-Leptin resistance?
Ghrelin
•Produced from GIT.
•Secreted on anticipation of food
•Hunger at certain times of day- Ghrelin
1212
Ghrelin
Leptin
Insulin
B L D
Cummings et al., 2001
•Ghrelin levels peak before meal.
•Stimulates hunger in humans.
•Ghrelin antagonists/ synthesis inhibitors indevelopment for treatment of obesity.
•NPY orexigenic therefore blocking receptors-decrease appetite?
•Inhibition of NPY synthesis suppresses food intake.
•Energy homeostasis may be altered through NPY Y1,Y2 and Y5 receptors in the brain.
•Y1 antagonist- inhibits NPY-induced feeding in rats
NPY as a Drug Target
1313
Appetite linked to reward processes in the brain.
eg opioid receptors (endorphins)Cannabinoid receptorsDopamine
Reinforcement of motivation to find and consumefoods of high incentive/energy content?
Reward Centres also involved
Dopamine & Reward
•Feeding is associated with dopamine release in thedorsal striatum.
•Degree of pleasure correlates with the amount ofdopamine released.
Evidence from Other Drugs
Bupropion (Zyban)
•Anti-depressant and smoking cessation (cf rimonabant).
•Link to reward and dopaminergic system?
•NA and dopamine reuptake inhibitor
•Weight loss in obese patients being treated fordepression.
•Weight gain after smoking cessation less in patientstaking bupropion.
1414
Clinical Trial
Patients BMI>30
Placebo- 24 weeks, 600kcal/day deficit- ~5% weight loss
400mg/day bupropion- 24 wks, 600kcal/day deficit~10% weight loss
No increase in adverse effects compared to placebo.
(Anderson et al (2002) Obesity Research vol 10, pp633-641)
Empatic- bupropion + zonisamide
8.6 % weight loss after 24 weeks.
5-HT Receptor System (serotonergic)
5-HT (serotonin)- number of different receptorsubtypes.
5-HT1B, 5-HT2c, 5-HT6 all cause weight loss in rodents.
Serotonergic compounds alter expression ofneurotransmitters in hypothalamus:
POMC mRNA
NPY mRNA -
POMCCART
NPYAgRP
Food Intake
+ -
ARC
5-HT
5-HT1B5-HT2c
1515
Lorcaserin (APD356)
•5-HT2c receptor agonist
•Phase II clinical trials- greater weight loss than placebo.
•After 84 days- 3.5kg weight loss (moderate)
•(May not be as good as sibutramine)
•Phase III clinical trials
•Other compounds targeting these receptors in pipeline.
•FDA approved Oct 2012
Tesofensine
•Phase II clinical trials
•Triple reuptake inhibitor (5-HT, NA, dopamine)cf sibutramine
•15% weight loss over 22 weeks
Contains:
Fucus- kelpBoldoDandelion rootButternut
“A natural way to help speed up weight loss”
1
Drug Metabolism
Adverse Drug Reactions
Drug Interactions
Dr Richard Roberts
Objectives• To understand the basic principles of
pharmacokinetics including drug
– Absorption
– Distribution
– Elimination
• Understand how this relates to drug dosing
• Be aware of drugs commonly associated withadverse drug reactions and other risk factorsinvolved
• Understand the mechanisms of drug interactions
Involves:
AbsorptionDistribution
MetabolismExcretion
Contribute to:Interindividual variation in response to drug
Pharmacology- the study of what a drug does to thebody & what the body does to a drug
Pharmacodynamics- what the drug does to the body
Pharmacokinetics- what the body does to the drug
ADME
2
Absorption ADME
“The passage of a drug from its site of administrationinto the plasma”
Absorption is important for all routes ofadministration except i.v.
Main routes of administration are:
• oral• sublingual eg glycerol trinitrate• rectal• transdermal• inhalation• injection
• subcutaneous• intramuscular• intravenous• intrathecal (brain or s.c.)
...
. .
.. .
.
Circulation
1st passmetabolism
Oral Dose Drug is takenby mouth &swallowed
Tablet dissolves
Enters smallintestine-absorbed
Bioavailability:Proportion ofdrug thatreachessystemiccirculation
3
Rate of travel to small intestine- altered by:
• gut motility- some disorders decrease gut motility- Presence of food decreases gut motility
GIT Absorption dependent upon:
• Particle size- dependent on tablet formulation
eg. Capsules may be designed to stay intact forseveral hours to delay absorptionOr formulations designed to give gradual release overtime
GIT Absorption dependent upon:
Physicochemical Properties
eg -tetracycline (antibiotic) binds to Ca2+ .Milk inhibits absorption.
Drug interactions
• Altered Absorption
– Altered pH: antacids
– Binding: colestyramine with digoxin, warfarin(binds bile salts)
– Altered gut motility: anticholinergics or opioids
– Alcohol- inhibits absorption of erythromycin
4
• Antifungals:griseofulvin, itraconazole– Absorption of griseofulvin doubles if taken
with fatty meal- solubility– Itraconazole capsules- improved bioavailability
if taken after a meal– Itraconazole solution-bioavailability higher in
fasted state!
• Aspirin:Food decreases absorption rate. If rapid absorption
required, take without food. BUT food may alsoprotect gut mucosa from aspirin.
Food can Affect Drug Absorption
SINGLE ORAL DOSE – Availability over timeTime to peak plasma concentration determined by dissolution oftablet & rate of absorption
TimePla
sm
aconcentr
ation
Therapeuticlevel
Toxic level
Excretion
Half-life- time taken to reach half-max. concentration in plasma.Can be short (mins) or long eg mefloquine 30 days (1x week dose)
Distribution ADME
Defined as:Movement of drug from circulating blood to sitesof action, binding, and elimination
Rate and extent of distribution depends on:• relative arterial blood perfusion rate of different
organs• permeability characteristics of barrierseg Blood-brain barrier prevents some drugs reachingbrain• binding in blood (eg albumin) or tissues (eg fat)
5
METABOLISM AND EXCRETION ADME
Like any compound taken into the body, drugs areexcreted.
Most drugs are excreted in urine.Some through lungs (eg gaseous anaesthetics)
Lipophilic drugs require metabolism to polarmetabolites in order to be excreted.
General Features of Drug Metabolism
• Enzymes arose either to handle endogenouscompounds or eliminate toxic compounds
• Enzymes non-selective
• Enzymes exist in isozymic forms
• A single substrate may be metabolised thoughseveral different pathways
•Majority of metabolism occurs in liver.
METABOLISM AND EXCRETION 2
Routes of Drug Metabolism
2 phases of drug metabolism:
Phase I- Cytochrome P450 enzymes
Phase II – conjugation- attachment of a substituentgroup. Increased water solubility.
eg GlucuronidationSulphationGlycine conjugationAcetylation
6
Prodrugs
Some drugs require metabolism to form active drug
e.g. acetylsalicylic acid (aspirin) metabolised to salicylicacid
Codeine morphine
Toxic Metabolites
Metabolism can also produce active, but toxicmetabolites
eg paracetamol- see later
COOH
OCOCH3Aspirin
COOH
OH
COOH
O- glucuronide
SalicylicAcid
Phase 1
Phase 2
Interindividual Variation in Metabolism
Genetic variability in some P450 enzymes.-differences in metabolism of certain drugs.-reduced excretion & increased toxicity.-Or reduced concentrations of active drug
eg. Proguanil (antimalarial) metabolised tocycloguanil (active form). Genetic polymorphism-poor metabolisers- less of active form.
Also codeine morphine
CYP2D6.
Poor metabolisers- no pain relief
7
Alterations in drug metabolism is important site ofdrug-drug interactions.
Also, environmental factors can alter drugmetabolism eg nutrients
Alcohol and cigarette smoke can alter drugmetabolism
Drug-Drug Interactions
InductionInduction of drug metabolismeg phenytoin, ethanolDecrease plasma levels of drugs
eg Chronic heavy drinking reduces phenytoinconcs
Warfarin
Continuous heavy drinking stimulates hepaticenzymes leading to increased metabolism.
Inhibition
Inhibition of drug metabolismeg. erythromycin, cimetidine, fluconazoleIncreased plasma levels of drugs-toxic
8
Antibiotics & Antifungals with AlcoholMetronidazole & ketoconazole- flushing & gastric pain
Inhibition of alcohol dehydrogenase?
“Disulfiram-like reaction”
Most other antibiotics fine.
Smoked or barbacued food-Contain polycyclic aromatic hydrocarbons.Potent inducers of CYP1A1 & CYP1A2.Regular consumption of these foods can reduceplasma concentrations of drugs.
Brassicas- brussels sprouts, cabbage etcregular consumption decreases plasma levelsof some drugs by 50%
Broccoli every day induces CYP 450 enzyme activity.
Decrease plasma levels of drugs
Drug Metabolism
Grapefruit juice- phytochemicals increasebioavailability of certain drugs- inhibition ofCYP450 enzymes. Transient effect.
• Interactions with:– Simvastatin: Avoid concomitant use
– Dihydropyridine calcium channel blockers(nifedipine, nicardipine)
Effects of Nutrients on Drug Metabolism
9
Grapefruit and pills mix warningBy James Gallagher Health and science reporter,BBC NewsNov 2012
Cytochrome P450 induction
St John’s Wort (herbal medicine)
Stimulates CYP450 enzymeseg oral contraceptives
Increased metabolism and reducedlevels of drug
Effects of Herbal Medicines on Drug Metabolism
Effects of Vitamins on Drug Metabolism:
Folic Acid: Increases hepatic metabolism ofphenytoin.
NB As a result, phenytoin also decreases plasmalevels of folic acid
Vit B6: required for conversion of levodopa todopamine in brain.
However, if vit B6 levels are high (< 10mg od), getconversion to dopamine outside of brain.
10
Drug-Drug Interactions- Excretion
Competition for renal excretion e.g methotrexatewith NSAIDs
Consequence- increase methotrexate levels- toxic
Metabolism of paracetamol
Paracetamol is non-toxic at normal dosesOverdose- hepatotoxicity & death
Normal doses
GlucoronidationSulphation
Excretion
Toxic doses
NAPBQI
Saturated Oxidation
Glutathioneconjugate
Removal of toxiccompound
GSH becomesdepleted
NAPBQI
Cell damage
Death
Paracetamol Toxicity
•Serious liver damage at 150mg/kg (~10g for70kg)
•5g or more can cause liver damage in somepatients eg existing liver damage, gluthioninedepleted.
•Standard dose: 1g, 4 x per day.
•4th most common cause of death due to selfpoisoning in UK
•Treatment with acetylcysteine or methionineincrease GSH levels and reduces mortality
11
Plasma concentrations- relationshipto elimination
Plasma concentration of a drug determined by rateof absorption and rate of elimination.
Determines how often a drug needs to be given tomaintain plasma levels within therapeutic dose BUTbelow toxic dose
Single IV Injection
T im e
Injection
Injection- rapid rise inplasma concentration.
Gradual decline inconcentration due toelimination
Single Oral dose:
Pla
sm
aconcentr
ation
Time
Dose
Absorption Elimination
12
REPEATED ORAL DOSES
Pla
sm
aconcentr
ation
Dose every 12 hoursGradual increase in plasma conc. Until steady stateie absorption = excretion
Dosing rate depends on rate ofabsorption & elimination
Repeated oral doses
• drugs with long half lives (i.e. long time to beexcreted) take longer to reach steady state.
• Also longer for drug to be washed out of body,therefore side effects may persist for a while.
• Altered elimination: age, renal or hepaticimpairment or drug interactions result in reduceddose or dosage interval
IV INFUSION
Aim- to produce steady plasma concentration. Rate In = Rateout
May need to give bolus dose to start off with beforecontinuous infusion
Infusion
13
Individual Variation in Response to Drug
Individuals vary in their response to a drug due to:
• differences in absorption - genetic factors- presence of food/ drugs- age/ disease
• difference in distribution - other drugs- plasma binding proteins
• difference in metabolism - genetic- disease- environmental etc
• difference in excretion - genetic- disease- age
Factors influencing drug response:
• ethnicity• age• pregnancy• genetics• disease• drug interactions
Interindividual variation can determine whether adrug is effective at the concentration used, or istoxic.
Adverse Drug Reactions (ADRs)
ADRs or side effects?
Side effect - secondary effect of a medicine, oftenpredictable
sometimes desirable (e.g. sedation withantihistamines in OTC sleep medicine)
sometimes undesirable (e.g. sedation withantihistamines used in allergy relief)
ADR - side effect which is always undesirable
14
Time
Pla
sm
aconcentr
ation
Therapeuticlevel
Toxic level
TherapeuticIndex
Therapeutic Index- ratio of toxic dose: effective doseie benefit: risk ratioOTC medicine- high benefit: low risk of ADR/toxicity
However, anti-cancer/HIV treatment may be able to put up withnarrower therapeutic index (more risk of ADR)
Examples of ADRs:
• NSAIDS – ulcers
• Antibiotics (severe diarrhoea due to Clostridiumdifficile)
• Anticoagulants- bleeding/anaemia
• Digoxin- toxicity
• Diuretics- dehydration/electrolyte disturbances
• Anti-diabetic agents- hypoglycaemia
Adverse Drug Reactions
Some drugs can affect food intake:
Reduced appetite: digoxin, fluoxetine (SSRI)(nausea?)
Weight gain: corticosteroids, oral contraceptives,TCAs (increased appetite?)
Taste disturbance: terbinafine (anti-fungal),allopurinol (gout),metronidazole (anti-bacterial),metformin (anti-diabetic)
Dry mouth: anticholinergic effects e.g.antihistamines, TCAs
15
Adverse Drug Reactions
Nausea & Vomiting: Many, particularlychemotherapy, SSRIs
Dyslipidaemia: -blockers, thiazide diuretics
Hyperglycaemia: corticosteroids, thiazidediuretics
Malabsorption from the duodenum:
colestyramine, liquid paraffin
consider supplementing fat-soluble vitamins
No. of factors that may predispose a patient to an ADR:
• Polypharmacydrug interactions e.g cytochrome P450inducers or inhibitors
•Drugs with narrow therapeutic indexwarfarin, lithium, digoxin, theophylline
• Extremes of ageMildly impaired renal function in most elderlypatients
• Concurrent disease•Altered pharmacokinetics
e.g. renal, hepatic disease
Polypharmacy-Drug Interactions
• i.e. interactions of the effect of two or moredrugs on the body
• May result in an ADR but may be beneficial(e.g. atenolol + thiazide combine to reduceb.p. further)
• Can alter uptake/metabolism or oppose orenhance action of drug
16
Drug Interactions
Pharmacodynamic interactions
Similar pharmacological targets
– eg. b-adrenoceptor agonists for asthma & b-adrenoceptor antagonists (beta-blockers)for CVD (opposing actions)
Similar or opposing pharmacology• Warfarin and vitamin K
• Ca2+ channel blockers (verapamil) and Ca2+
(osteoporosis)– Possible interaction
• Alcohol and sedative agents (sedativeantihistamines, BDZ)- increased sedativeeffect
• Disturbances of the equilibrium of fluid andelectrolyteseg K+ sparing diuretics, ACEIs and K+
- hyperkalaemia
• Anticoagulants garlic (anti-coagulantproperties)
• Theophylline caffeine (same action)
17
Specific Information for Dieticians
Some of the components of enteral and parenteralfeeds may interfere with drugs. The next two slidescontain general points for use of enteral andparenteral feeds with drugs.
General points:
• Never put drugs into feed.
If nasogastric tube is to be used for drugadministration:
• Always stop feed and wash tube with waterbefore and after drug admin.
• If possible, separate feed and drug by 2 hours
• Consider drug-nutrient interactions
• Consider other routes of administration.
Drugs & Enteral Feeds
General points:
• Drugs should never be given down IV lines
• Drugs are not generally added to TPN– Stability– occasionally heparin, insulin, H2 antagonists,
corticosteroids
• Caution vitamin K and warfarin interaction
• Bioavailability of theophylline reduced by highprotein feeds
Drugs & Parenteral Feeds
18
Further reading
• British National Formulary!
• Pharmacology, Rang, Dale, Ritter & Moore
• Disease Management, Randall and Neil
• Stockley’s Drug Interactions
1
Herbal Medicines
Dr Richard Roberts
Objectives
Herbal Medicines• Licensing issues and health claims
• Herbal preparations and common uses
• Toxicity of herbal preparations and druginteractions
•UK study: people > 50 use 2.26 prescription drugs5.91 herbal & nutritional supplements2.66 herbal supplements
2
Licensing issues
• Most herbal medicines not controlled under theMedicines Act
• No sale restrictions
• Product Licence not required therefore rigorous clinicaltrials not required and controls re. dosage, labelling,purity, levels of ingredient not as strict as for medicines
Medicinal/Health claims
• Herbal Medicines cannot make medicinal claimse.g. cannot claim to cure, treat or prevent adisease
• However, can have health claims e.g. ‘for ahealthy nervous system’
Public perception-herbal medicines are safer thanconventional medicines because they are natural.
40% of people think herbal medicines are safebecause they are natural
However, conventional medicines need to gothrough rigorous trials to determine safety.
Herbal medicines- not required to go through safetytrials
3
Herbal Medicines can be:
1.Unlicensed- no specific standards of safety orquality
- don’t require product information- dose,ADRs etc
- internet
Herbal Medicines- Licensing Issues
2. Registered Traditional Herbal MedicineCompanies must supply evidence about thesafety and use of the product.
•Manufacturers must meet certain safety & qualitystandards.
• Registered products must be accompanied byinformation about the product and its safeusage.
Herbal practitioners
•manufacture herbal medicines on site thereforenot industrially produced.
ie unprocessed herbs classed as ingredients notproducts
•Anything manufactured elsewhere should becovered by THR or MA.
4
3. Licensed- hold product license just like any othermedicine.
Required to demonstrate safety, quality,efficacy and accompanied by product
information sheet
1. Ginkgo biloba
2. St. John’s Wort
3. Ginseng
4. Garlic
5. Echinacea
6. Saw palmetto
Not much is known about how they act, what theside effects are, or drug interactions
Herbal Medicines
Top selling herbal products:
Top selling herbal ingredients
1. Ginkgo biloba• Used for memory/ concentration problems• Dizziness, tinnitus, headaches• Stroke• Relax blood vessels- evidence?• Reduce blood viscosity- anti-platelet?• Anti-oxidant• Trials show inconsistent results• http://www.cochrane.org/reviews/en/ab003120.html
5
St John’s Wort (Hypericum)•Anti-depressant
•shown to be as effective as some conventionalantidepressants in mild to moderate depression
•Pure hyperforin has anti-depressant actions.
•Inhibits NA & 5-HT reuptake- similar to other anti-depressants.
5-HT-R
5-HT
5-HT
SSRI
SJW
5-HT
5-HT
5-HT
5-HT
•Hyperforin increases protein & activity of CYP2C9and CYP3A4 enzymes (see later).
•Wide number of drugs metabolised by CYP3A4.
•interactions with a number of drugs incl:oral contraceptives, warfarin, cyclosporin, digoxin,anticonvulsants, theophylline,( plasma concentrations )
•Decreased therapeutic effect
e.g. kidney transplant rejection in patient takingcyclosporin.
6
Also:increase in P-glycoprotein drug transporter. Decreasein drug levels (eg digoxin) through increased efflux.
Also interaction with other anti-depressants:
•similar mechanism of action. Increase 5-HT(serotonin) levels in brain
serotonin syndrome:
•neuromuscular hyperactivity – eg tremor
•autonomic hyperactivity - sweating, fever,tachycardia & rapid breathing
•altered mental status - agitation, excitement &confusion
Self-Prescribing.
SSRIs should be withdrawn gradually over a period ofat least 4 weeks. Involves a gradual dose reduction.
Rapid withdrawal may prescipitate a reaction egdepression, sensory and balance problems.
e.g. Report of woman taking SJW for 10 days thentook 20mg paroxetine.Complained of nausea, weakness, fatigue andbecame incoherent.
7
Side Effects:
Hypericin causes photosensitivity- skin irritation.
Refs:http://www.cochrane.org/reviews/en/ab000448.html
Wurglics & Schubert-Zsilavecz 2006 Clin Pharmacokinet vol 45 p449-468
List of drug interactions can be found at:http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/sjwfsh.pdf
Hypericalm- granted Traditional Herbal MedicinesLicense
Activity of Inhibited by Induced by
CYP1A2 Echinacea Wu-chu-yu-tang
CYP2C9 Cranberry juice SJWSiberian ginseng
CYP2C19 Ginkgo biloba
CYP3A4 Grapefruit juice SJWSeville orange juice Garlic
Echinacea root
P-glycoprotein Grapefruit juice SJW
Induction/Inhibition of metabolising enzymes
8
3. Ginseng• Short term: stamina, concentration, healing, stress
• Long term: well-being in debilitated/ degenerativeconditions- old age
ADRs: high doses may cause insomnia, nervous
excitement, hypertension, euphoria, nausea,diarrhoea, oedema, skin eruptions
Conventional doses: oestrogenic effects
Interactions include:- Oestrogenic activity may oppose tamoxifen
4. Garlic- anti-hypertensive, antithrombotic, anti-
microbial, cancer preventing, lipid-lowering
- Some evidence to support these
- Caution and ADRs: odour, indigestion, contactdermatitis, asthma, anti-platelet drugs(theory?)
5. Echinacea- now a Benylin product- Treatment of colds- no evidence- Immunostimulant
6. Saw palmetto-benign prostatic hyperplasia-Evidence that it improves urinary flow- may interact with diuretics or drugs used for
incontinence
Also claim to prevent hair loss
9
With all herbal medicines-What is the evidence?What is known about effective dose?What is the quality of the product like?Is it safe?
Reports of toxicityEphedra (Ma huang- ephedrine)
Used for: weight loss, coughs, bronchitis, nasalcongestion
• Supplements containing ephedra & caffeine causeincreased systolic BP and effects on heart rhythm
• Banned in US
Feb 2008: Danish Medicines Authority issuedwarning about Therma Power slimming drug after a36 yr old man died. Contains ephedrine andcaffeine.
Reports of toxicity
Chinese herbs: reports of:- renal failure and renal cancer (Aristolochia for the
treatment of eczema)
Women given Aristolochia for slimming.100 developed kidney failure.Some developed renal cancer.
In China, 12 out of 17 patients who took Aristolochia(Mu Tong) died of renal failure.
10
Traditional Chinese Medicines
MHRA-some TCM pose a health risk due to poorquality
Risk of heavy metal toxicity:
High levels of mercury &/or lead found in some TCMas well as traditional Indian medicines.
Ingredients unknown:Qianbai Biyan Pian- traditionally contains Senecio-
liver damage
Ingredients unknown:
TCM slimming drugs found to contain prescriptiononly medicineseg sibutramine, nitrosofenfluramine(1 case- patient required liver transplant)
Corticosteroids in skin creams
Illegal Ingredients:Nu Bao- contains human placenta, donkey skin, deerantler- potential sources of infection
Excite for Women and Ultimates for Men
From Malaysia- to increase libido
Found to contain sildenafil
OSAS Body Lotion
Sold in Asian and African beautyshops
Found to contain corticosteriodsand an antifungal
11
Reports of toxicity from HerbalMedicines
Hepatotoxicity• comfrey, coltsfoot, Scullcap• black cohosh
– increased use for menopausal symptoms– Reports of liver toxicity
Hypersensitivity- allergic reactionsChamomile, feverfew
Uteroactivity- avoid in pregnancy• blue cohosh, burdock, hawthorn, nettle,
raspberry, vervain, motherwort
Problems with Herbal Medicines
• Limited safety data
• Self-medication
• Cessation of medication without advice
• Exposure to toxic ingredients naturally present e.g.heavy metals, microbes, high levels of pesticides
• Quality may not have been assessed by a licensingauthority (ingredients found to differ with label)
• Herb-drug interactions: toxicity or reduced efficacy
Herbal medicines can be a source of new drugs:
Traditional Chinese Medicine- qinghao
Used to treat “bone steaming” and “heat vexation”but also malaria
From Artemisia annua. Contains artemisinin(qinghaosu).
•Artemether with lumefantrine licensed formalaria in UK.
12
Reference sources
• Stockley Drug Interactions
• Text books:– Herbal medicines, Barnes et al. (tables at the
end!)– MHRA Website– Cochrane Reviews
Summary
• Herbal Medicines may not be licensedand checked for safety
• Confusion may arise due to publicperception of safety
• Potential for interactions withconventional medicines
–serious clinical consequences possible
Abbreviations
OTC- over the counterPOM- prescription only medicine
a.c.- before food (ante cibum)b.d.- twice daily (bis die)o.d.- every day (omni die)o.m.- every morning (omni mane)o.n.- every night (omni nocte)p.c.- after food (post cibum)p.r.n. – when required (pro re nata)q.d.s.- to be taken 4 times daily (quarter die sumendus)q.q.h.- every 4 hours (quarta quaque hora)stat- immediatelyt.d.s- to be taken 3 times daily (ter die sumundus)t.i.d.- 3 times daily (ter in die)
Easy way to remember what drugs are:
Anything ending in:
“lol” likely to be a beta-blocker
“pril” likely to be an ACE inhibitor
“sartan” likely to be an angiotensin (AII) receptor antagonist
“pine” likely to be a calcium channel blocker
“statin” likely to be a statin
“prazole” likely to be a proton pump inhibitor
“one” likely to be a steroid
“coxib” likely to be a COX-2 inhibitor
“ol” (rather than “lol”) likely to be a beta2 agonist
“ine” could be an anti-histamine or an anti-depressant
“cillin” likely to be a penicillin antibiotic
“mycin” likely to be an antibiotic
There are exceptions to these rules, but this is a good starting point.
Below is a list of drug families, examples of drugs (with Brand names inbrackets) and common uses.
Respiratory Disease
Drug family examples Use
2-adrenoceptor agonists eg salbutamol (Ventolin) asthma.salmeterol (Serevent) COPD
Corticosteroids eg asthmaBeclometasone (AeroBec) Some effect in COPDBudesonide (Pulmicort, Preventative
Symbicort)
Xanthines eg theophylline (Nuelin) asthma(Slo-Phyllin)
(Uniphyllin Continus)
Muscarinic eg ipratropium (Atrovent) asthmaAntagonists COPD
Sodium (Cromogen Easi-Breathe) asthmaCromoglicate (Intal)
Leukotriene eg montelukast (Singulair) asthmaReceptor zafirlukast (Accolate) preventionAntagonists
Upper GIT
Drug family Examples Use
Antacids Sodium bicarbonateMagnesium hydroxide
Acid refluxExcess acid
Histamine H2 antagonists Ranitidine (Zantac)Cimetidine (Tagamet)
Peptic ulcerAcid reflux
Proton pump inhibitors Omeprazole (Losec)Lansoprazole (Zoton)Esomeprazole (Nexium)
Acid refluxPeptic ulcer
Prostaglandin analogues Misoprostol (Cytotec) Acid refluxPeptic ulcer
Dopamine D2 receptorantagonists
Domperidone (Motilium) Acid refluxBloatingAnti-emetic
H1- Histamine receptorantagonist
Promethazine(Phenergan)
Motion sickness (CNSeffects)
Anti-muscarinic receptoragents
hyoscine Motion sickness (CNSeffects)
Lower GIT
Drug Family Examples Use
Opioids Loperamide (Imodium)codeine
Anti GIT motility used indiarrhoea
Laxatives Lactulosemacrogels
constipation
Senna extracts constipation
Tricyclic antidepressants*
amitriptyline IBS
* cross reference with CNS
Cardiovascular
Drug Family Examples Use
Beta-blockers Propranolol (Inderal)atenolol (Tenormin)bisoprolol (Cardicor)
HypertensionHeart failureAnginaMyocardial Infarction
ACE Inhibitors Lisinopril (Carace)Ramipril (Tritace)captopril (Capoten)
HypertensionAngina?Myocardial InfarctionHeart Failure
statins Simvastatin (Zocor)Pravastatin (Lipostat)Atorvastatin (Lipitor)
HypercholesterolaemiaPossible use in:Hypertension? Angina?MI? stroke?
diuretics Furosemidebendroflumethiazide
HypertensionHeart failure
Ca 2+ channel blockers Nifedipine (Adalat)Nimodipine (Nimotop)Amlodipine (Istin)Verapamil (Cordilox)Diltiazem (Tildiem)
hypertensionAngina
Angiotensin II receptorantagonists
Losartan (Cozaar)Candesartan (Amias)
HypertensionHeart failure
nitrates Glyceryl trinitrateIsosorbide dinitrate(Angitak)
AnginaHeart failure
Warfarin Atrial fibrillationThromboembolicprophylaxis
Anti-platelet AspirinClopridogrel (Plavix)
Myocardial InfarctionStrokeAtrial fibrillation
Obesity
Drug Examples Use
Orlistat Orlistat (Xenical) Obesity
Sibutramine Sibutramine (Reductil) Obesity
Rimonabant Rimonabant (Accomplia) Obesity
Diabetes
Drug Family Examples Use
Insulin NovoRapidActrapidHumalogInsulatard
Type I Diabetes
Sulphonylureas ChlorpropamideGlibenclamideTolbutamide
Type II Diabetes
Biguanides Metformin (Glucophage) Type II Diabetes
Meglitinides Nateglinide (Starlix)Repaglinide (Prandin)
Type II Diabetes
Glitazones Pioglitazone (Competact)Rosiglitazone (Avandamet)
Type II Diabetes
Nutrition-specific Adverse Drug Reactions
Reduced appetite:digoxin, fluoxetine (SSRI)
Weight gain:corticosteroids, oral contraceptives, Tricyclic anti-depressants
Taste disturbance:terbinafine (anti-fungal), allopurinol (gout), metronidazole (anti-bacterial),metformin (anti-diabetic)
Dry mouth:antihistamines, Tricyclic anti-depressants
Nausea & Vomiting:Many, particularly chemotherapy, SSRIs
Dyslipidaemia:-blockers, thiazide diuretics
Hyperglycaemia:corticosteroids, thiazide diuretics
Malabsorption from the duodenum:colestyramine, liquid paraffin
Altered gastric mobility:Opioids (constipating)
Drug-Nutrient Interactions
Folic acidAnti-convulsants (epilepsy) such as phenytoin reduce plasma levels of folic acid.
Vitamin DLong-term use of Phenytoin can reduce plasma concs of vit D
Vitamin AOral contraceptives can increase levels of vit. A
IronChronic use of antacids can reduce uptake of ironTetracyclines (antibiotics) bind to iron, calcium, aluminium ions- reduce uptake
Fat-soluble vitaminsEg orlistat (obesity)- may impair absorption of fat soluble vitamins
Vitamin CAspirin reduces absorption of vit C by 1/3
Vit B6Reduces concentration of leva dopa in brain (Parkinson’s)
Vit KAntagonises effect of warfarin