· web viewadipose tissue thought to contain components of the ras system thereby giving increased...

Giles Kisby GE Y1 Pharmacology II

Pharmacology II:

Spring / Summer Term:

LECTURES:09/01/14: Tutorial 1

Notes:

- BMI = H(m) / W^2(Kg)

- Hypertension:o Results in increased risk of

myocardial infarction stroke heart failure renal disease

- How changing the following can affect blood pressure: [the mechanisms are largely unclear but known to be strong risk factors] [note that with blood pressure are thinking MAP = CO * TPR]

o Weight: Adipose tissue thought to contain components of the RAS system thereby

giving increased BP Will likely have high cholesterol therefore atheroschlerosis which will

increase TPR inc BPo Exercise

Widens blood vessels; therefore dec TPR and dec BP More efficient use of the CO means that lowered CO sufficient for a given

amount of work therefore direct decrease in TPR and lower systolic blood pressure will give less endothelial damage and so avoid this source of inc TPR too

o Salt High blood Na will give high entry of water to blood at gut High blood Na will give high water reabsorbtion at the kidney to reduce

excretion; will also be high Na in tubules but this will be reabsorbed to blood leaving high grad for water to move

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o Smoking Gives proinflam background for atheroschlerosis to develop high TPR and

high BP Nicotine acts at the sympathetic nervous system to stimulate blood vessel

contraction and is also an ADH stimulant Nicotine also acts (via sympa mech) to give release of cholesterol to the

blood atheroschlerosis high TPR and high BP

- Bendrofluazide:o Can be used to lower blood pressure / vs hypertensiono Is a Thiazide diauretic:

Blocks Na/Cl cotransporter on the tubule lumen side Therefore reduced Na reuptake so reduced water following it out so

increased water loss from body However increased Na in tubules means that some Na is instead

exchanged further along; is exchanged for K instead giving K exit from body and hypokalemia

o Give K supplements but in the long term will likely have to use a K sparing drug which will be less potent but will avoid the hypokalemia

Importantly the decreased Na reuptake will signal via the JGA (via the ECF vol depletion) to give RAS activation; this is bad and is the reason that is often used in conjunction with ACEi [the Thiazide diuretic makes the ACEi give a bigger effect]

Also gives dilation at blood vessels

- ATII:o As well as its range of other effects:

Angiotensin II enhances noradrenaline release from sympathetic nerves Gives increased reabsorbtion at the proximal tubule [acts at the Na/H

exchanger]

- Bradykinino Gives vasodilation [ie ACEi will also give benefits via this mechanism through buildup

of bradykinin]o Dry cough via sensitisation of the lungs [ie ACEi will give dry cough]

- Mechanism of BP negative effects:o Arterial damage

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o Organ damageo Decreased coronary artery perfusiono Increased afterload (due to high artery pressure) and preload (due to high venous

pressure) giving high heart workloado Risk factor for a range of cardiovasc diseases (MI, etc)

- Warfarin inhibits the reduction of VitK to its active formo Active VitK is used in the production of a range of clotting factors: (especially 2, 7, 9,

10)

- Prinzmetal's = Prinzmetal = variant angina [the other types are stable / unstable]o angina (cardiac chest pain) at rest that occurs in cycles. o It is caused by vasospasm, a narrowing of the coronary arteries caused by

contraction of the smooth muscle tissue in the vessel walls rather than directly by atherosclerosis

- Some specific drugs for angina:o Simvastatin:

Statin; as would be able to tell from _statin suffix; lowers LDL levelso Bisoprolol:

BB; as would be able to tell from _olol suffix; decreases heart workload and increases diastolic filling

o Aspirin: To avoid MI

o GTN Acts mainly at veins but will have some effect on the arteries; decreases

preload, some decrease in afterload

- MI: MONA acronym: morphine, oxygen, nitrates, aspirin

- Some specific drugs for heart failure:o Frusemide:

Is a very potent loop diauretic: potency order for decreasing potency is: loop diauretics thiazide diuretics K sparing diuretics

Blocks the Na/2Cl/K carrier of the ascending part of the loop of Henle Would help with HF edema and heart workload

o Perindopril An ACEi as can tell from _pril suffix

o Beta blocker: For heart failure can decrease the heart’s oxygen demand by reducing its

work but must be introduced gradually to avoid dangerous drops to CO; the heart is already struggling and may be reliant on sympa activity

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09/01/14: Drugs and the Heart: Dr Chris John

Los (from Slides&booklet for first two lecs):- Explain the mechanisms regulating heart rate and contractility that are therapeutic targets in

the heart- Identify the determinants of myocardial oxygen supply and demand and explain how these

are favourably influenced by: Beta blockers, Organic nitrates and potassium channel openers, calcium antagonists.

- Recognise the major adverse effects of: Beta blockers, Organic nitrates and potassium channel openers, calcium antagonists.

- Demonstrate awareness of the Vaughan Williams classification and explain its limitations- Identify the mechanisms of action of: Adenosine, Verapamil, Amiodarone, Digoxin and

cardiac glycosides- Recognise the mechanisms of action of cardiac inotropes and their clinical- Identify the mechanisms regulating vascular tone and peripheral vascular resistance.- Explain how the various inhibitors of the renin angiotensin aldosterone system act (i.e.

angiotensin converting enzyme inhibitors, angiotensin (AT1) receptor antagonists, aldosterone antagonists) and identify the major indications for their use and their major adverse effects

- Explain how calcium channel antagonists cause vasodilation and list the major indications for their use and their major adverse effects

- Explain how inhibitors of the sympathetic nervous system act and list the major indications for their use and their major adverse effects

- Identify the mechanism of action of sumitriptan and explain why it is used in migraine.- List the major adverse effects of sumitriptan.- Explain the principles underlying the treatment of hypertension and heart failure.

Notes:

- Overview:o Renin-angiotensin system, o calcium antagonists, o beta blockers, o nitrates

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- AT II:o Classical effects: [Increased BP etc]

Vasoconstriction (AT1 receptors) Increased Na+/fluid retention (AT1 receptors) Cardiovascular remodelling SNS activation [inc NA release] thirst Aldosterone secretion (AT1 receptors) ADH secretion

o Non classical effects: Increased insulin resistance Activation cellular immunity Pro-fibrotic Pro-thrombotic

o The effects then lead to a range of diseases: [some of the links detailed on the above diagram but don’t worry too much about the detail]

Diabetes Kidney disease Hypertension Heart failure Athero-thrombotic disease

- Aldosterone:o Acting on the nuclear mineralocorticoid receptors (MR) within the principal cells of

the distal tubule and the collecting duct of the kidney nephron: Increases the number of Na channels on lumen side

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Increases number of, and activates, NA/K pumps on the blood side [a consequence of this is that increased K will be secreted (will then exit on lumen side: Aldosterone stimulates the secretion of K+ into the tubular lumen) potentially giving a risk of hypokalemia [nb also; hyperkalemia if ACEi etc used]]

[together the above effects give increased Na transport across to the blood; the water will follow inc blood volume]

o Other effects: Aldosterone stimulates Na+ and water reabsorption from the gut, salivary

and sweat glands in exchange for K+. Aldosterone stimulates secretion of H+ in exchange for Na+ in the

intercalated cells of the cortical collecting tubules, regulating plasma bicarbonate (HCO3−) levels and its acid/base balance

- ADH = vasopressin:o Increasing the water permeability of distal tubule and collecting duct cells in the

kidney, thus allowing increased water reabsorption and excretion of more concentrated urine

Via insertion of water channels (Aquaporin-2) on tubule sideo Increasing permeability of the inner medullary portion of the collecting duct to urea

by regulating the cell surface expression of urea transporters, which facilitates its reabsorption into the medullary interstitium

o At high concentrations, it also raises blood pressure by inducing moderate vasoconstriction.

From renal; notes:- ANTIDIURETIC HORMONE:- As described in the preceding section, ADH has three actions on the renal tubule [but note

that the hormone does have other effects; see endocrinology for full detail]:o (1) It increases the water permeability of the principal cells of the late distal tubule

and collecting ducts. o (2) It increases the activity of the Na-K-2Cl cotransporter of the thick ascending limb,

thereby enhancing countercurrent multiplication and the size of the osmotic gradients to aid water retention.

o (3) It increases urea permeability in the inner medullary collecting ducts, enhancing urea recycling and therefore giving greater urea concentration in urine and eventual excretion in a smaller volume of water

- ACEIo Uses:

• hypertension• heart failure and post-myocardial infarction

- reduced afterload and reduced preload to reduce the load on the heart/how hard it must work

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• diabetic nephropathy- When the level of blood glucose rises beyond the kidney's capacity to reabsorb glucose from the renal ultrafiltrate, glucose remains diluted in the filtered fluid- This raises its osmotic pressure and causes more water to be carried out from blood thereby increasing the excreted urine volume. [ie in fact would likely not want to lose so much fluid]- The increased volume dilutes the sodium chloride in the urine, signalling the macula densa to release more renin, causing vasoconstriction- Because the kidney is nurtured exclusively by the blood it filtrates, the vasoconstriction also reduces the nutrients supplied to it, causing infarct of kidney tissues and reduction of renal function- can solve these problems using ACEi which will increase kidney perfusion (to counter the ischaemia) and reduce the GFR (to counter the high fluid excretion); sufficient filtering should still occur

• progressive renal insufficiency• patients at high risk of cardiovascular disease

- Angiotensin receptor blockers: (ARB = ATIIA)o Example: Losartano Antagonists of type 1 (AT1) receptors for ATII

prevent the renal and vascular actions of ATIIo Uses: hypertension, heart failure

- Direct Renin Antagonistso Example: aliskiren (if binds renin will inactivate it)o Inhibit enzyme activity of renin preventing conversion of angiotensinogen into

angiotensin I and hence generation of ATIIo A new class of agents, probably similar to other RAS inhibitors but limited clinical

experience as yet.o Allows avoidance of some of the side effects associated with ACEi eg dry cough

- Unwanted effects of ACEI and ARB [Generally well tolerated – particularly ARBs]o Angioedema (ACEi)o Urticaria [a kind of skin frequently caused by allergic reactions] / Angioedema

[swelling of the deeper layers of the skin] (ACEI - v. rarely)o Cough (ACEI; due to bradykinin)

o Hypotension (both)

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o Hyperkalaemia (because of a decrease in aldosterone; therefore should be careful with K supplements or K sparing diuretics)

o Fetal injury (both; the fetus will also be targetted)o Renal failure in patients with renal artery stenosis (both) [have low kidney perfusion

therefore the ATII is playing an essential role in maintaining GFR; ACEi results in reduced filtration of the already small amount of blood passing through]

- *** L-type calcium channel is a type of voltage-dependent calcium channel. L-type calcium channels are responsible for excitation-contraction coupling of skeletal, smooth, and cardiac muscle

o ***Dihydropyridine receptors = L-type Ca2+ channels: this is explained by the fact that dyhydropyridine is a drug that acts via binding to the L-type Ca2+ channel (on its extracellular side)

o Smooth muscle: It is important to note that contraction of smooth muscle need not require

neural input—that is, it can function without an action potential: humoral/paracrine, metabolic or physical stimuli.

Unlike skeletal muscle, which requires depolarization of the cell membrane and t-tubules, smooth muscle uses second messenger systems to open the calcium channels on the S.R.

Receptors on the smooth muscle membrane for such ligands as endothelin, Adrenaline/noradrenaline (including the NA sympa vascular SM innervation), and Ach (released as a neurotransmitter: actually extremely little para innervation of vascular smooth muscle but SM elsewhere will be activated in this way)) connect to the Gq protein and lead to the production of inosital triphosphate (IP3).

The IP3 is then directly responsible for opening the calcium channels on the S.R. membrane (IP3 sensitive Ca2+ channel on SER gives Ca release that will via Ca induced Ca release activate the ryanodine receptors), allowing the calcium to enter the cytoplasm of the cell.

Increased intracellular calcium binds calmodulin, which activates myosin light chain kinase (MLCK). MLCK phosphorylates the regulatory light chains of the myosin heads. Phosphorylated myosin heads are able to cross bridge CONTRACTION.

- Calcium antagonists:o Arteries have muscle, very little on veins so CCBs have their effects an arteries; very

little effect at veins; therefore help afterload but not so much preloado May also give effects at heart if are “rate slowing”o TWO CLASSES:

Rate slowing: Cardiac (striated) and smooth muscle actions

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Are the best option for angina as decrease heart workload / O2 demand (dec contractility and rate (both depend on Ca entry), Dilate coronary vessels to increase myocardial oxygen supply, and decrease afterload) - ie despite some reflex tachy

Benzothiazepines (e.g. Diltiazem) Phenylalkylamines (e.g. Verapamil)

o [Verapamil especially likely to give constipation side effect due to disruption of Ca channels in the gut]

o Gives greater reduction in rate / ionotropy compared to Diltiazem

o Is a supraventricular antiarrhythmic Non-rate slowing

smooth muscle actions only; are more potent here than “rate slowing” drugs

o therefore are the best option for hypertensiono would not be useful for angina as would give severe reflex

tachy inc heart work / palpatations Dihydropyridines (e.g. amlodipine)

o Verapamil and Diltiazem act on intracellular side Therefore show use dependant actions

o Dihydropyridines act on extracellular side Therefore do not show use dependant actions

o Unwanted effects of calcium antagonists Verapamil

Bradycardia and AV block (Ca2+ channel block) Constipation (Gut Ca2+ channels)

Dihydropyridines Ankle Oedema Headache / Flushing Palpitations (prob is reflex tachy) Vasodilation/reflex adrenergic activation

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- Beta blockers (β-adrenoceptor antagonists):o Beta blockers no longer 1st line for hypertension in UK.o Mechanism of hypotensive action not fully understood but beta1 antagonists

preferred.o Beta blockers do not reduce peripheral resistance (PVR) (except partial agonists /

vasodilatory beta blockers). o Beta blockers

Reduce cardiac output reduce renin release by the kidney (ie a1 at JGA) may diminish noradrenaline release by sympathetic nerves

via block of β1 presynaptic receptors eg there will be some inhibition of the signalling at α1 synapses (for

constriction) because β1 presynaptic receptors exist which ordinarily encourage NA synth and release (but this effect to lower BP is relatively small)[nb this β1 presynaptic receptor mech will also be a further way that adrenaline will be able to yield inc a1 effects]

lipophilic agents (e.g. propranolol) exert central sympatho-inhibitory actions. o Uses:

Angina Post myocardial infarction & Chronic heart failure [ie trying to decrease

heart exertion] Cardiac dysrhythmias Hypertension Also thyrotoxicosis [Thyrotoxicosis means an excess of thyroid hormone in

the body; Many of the common symptoms of hyperthyroidism such as palpitations, trembling, and anxiety are mediated by increases in beta adrenergic receptors on cell surfaces. Beta blockers offset this effect] glaucoma, anxiety states, migraine, benign essential tremor

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o Unwanted effects can be due to actions on beta1 (and sometimes beta2 receptors due to only partial selectivity)

Worsening of cardiac failure Bradycardia (heart block) Bronchoconstriction Hypoglycaemia (in diabetics on insulin) Fatigue Cold extremities and worsening of peripheral arterial disease impotence CNS effects (lipophilic agents) e.g. nightmares

- Organic nitrates:o Example: Glyceryl trinitrate (GTN), nicorandilo Uses

Angina Acute and chronic heart failure BP control during anaesthesia

o Mechanism of action: Reduce preload (venous return) Venodilation Reduce afterload (peripheral resistance) Vasodilation [ie some reduction

here but smaller than at veins]o Minor effects:

Are antiplatelet agents Are coronary artery vasodilators

o pharmacokinetics & unwanted effects Nitrates undergo extensive ‘first pass’ metabolism by the liver; therefore do

not give orally: Glyceryl trinitrate is often given sublingually for rapid relief of

angina - has a short half life (~5 mins). Longer acting forms of nitrate (e.g. isosorbide mononitrate) (eg

glyceryl trinitrate via a transdermal patch) are available for sustained actions

Nitrates can cause hypotension, headaches and flushing as a result of vasodilation

Excessive/prolonged use of nitrates is associated with tolerance Use for flareups/symptomatic relief, not regularly

o molecular mechanisms: Sodium nitroprusside (SNP) can directly ie non enzymatically donate NO Other nitrates used typically undergo enzymatic processes to generate NO NO activates guanylyl cyclase to give inc cGMP Cyclic-GMP activates

protein kinase G K channel opening for hyperpolarisation and blocks PLC (so reduced Ca channel opening)

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Nicorandil directly stimulates guanylyl cyclase (ie not via NO)

[cGMP PKG activation Ca entry inhibited (via PLC inhib) and K+ efflux for hyperpolarisation]

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09/01/14: anti arrhythmic drugs: Ruth Tarzi

Los (from booklet): - Explain the mechanisms regulating heart rate and contractility that are therapeutic targets in

the heart- Identify the determinants of myocardial oxygen supply and demand and explain how these

are favourably influenced by: Beta blockers, Organic nitrates and potassium channel openers, calcium antagonists.

- Recognise the major adverse effects of: Beta blockers, Organic nitrates and potassium channel openers, calcium antagonists.

- Demonstrate awareness of the Vaughan Williams classification and explain its limitations- Identify the mechanisms of action of: Adenosine, Verapamil, Amiodarone, Digoxin and

cardiac glycosides- Recognise the mechanisms of action of cardiac inotropes and their clinical- Identify the mechanisms regulating vascular tone and peripheral vascular resistance.- Explain how the various inhibitors of the renin angiotensin aldosterone system act (i.e.

angiotensin converting enzyme inhibitors, angiotensin (AT1) receptor antagonists, aldosterone antagonists) and identify the major indications for their use and their major adverse effects

- Explain how calcium channel antagonists cause vasodilation and list the major indications for their use and their major adverse effects

- Explain how inhibitors of the sympathetic nervous system act and list the major indications for their use and their major adverse effects

- Identify the mechanism of action of sumitriptan and explain why it is used in migraine.- List the major adverse effects of sumitriptan.- Explain the principles underlying the treatment of hypertension and heart failure.

Notes:

- Overview:o Anti-dysrrhythmicso Alpha blockers and sympatholyticso Vasoconstrictorso Therapeutic applications

- Anti-dysrrhythmics:- Arrhythmias / disarrhymias:

o Aims of treatment are Reduce sudden death Prevent stroke Alleviate symptoms

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- May be associated with decreased heart rate (bradyarrhythmias) or increased heart rate (tachyarrhythmias).

- A simple classification of arrhythmias is based on site of origin:o Supraventricular arrhythmias (e.g. adenosine, amiodarone [/dronedarone],

verapamil)o Ventricular arrhythmias (e.g. amiodarone [/dronedarone], flecainide, lidocaine).o Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide).

- The Vaughan-Williams classification of anti arrhythmic drugs:o is of limited clinical significance and not all drugs fit the systemo Class

o I Sodium channel blockade

o II Beta adrenergic blockade : ie Beta Blockers!!o III Prolongation of repolarisation ('Membrane stabilisation',mainly due to

potassium channel blockade)o IV Calcium channel blockade

o Not all drugs fit the classification system: Adenosine (energy metabolite and therefore will be relaxing cells / counter

contractions) Uses

o Used intravenously to terminate supraventricular tachyarrhythmias (SVT).

o Its actions are short-lived (20-30s) and it is consequently safer than verapamil.

Mechanism of action:o An endogenous mediator produced by the metabolism of

adenosine triphosphate (ATP).

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o Acts on adenosine (A1) receptors to hyperpolarize cardiac tissue and therefore slow conduction through the AV node.

Adenosine via the A1 receptor, inhibiting adenylyl cyclase, reducing cAMP and so causing cell hyperpolarization by increasing outward K+ flux (ie cAMP would otherwise prob act to give some K influx [ie is the mech for b1 signalling at heart to shorten refractory period etc])

Adverse effectso Chest pain, o shortness of breath, o dizziness and nausea

Amiodarone & dronedarone Uses:

o superventricular and ventricular tachyarrhythmias Mechanism of action:

o Complex action probably involving multiple ion channel block

Adverse Effectso Amiodarone accumulates in the body (t½ 10 - 100days) and

has a number of important adverse effects including: photosensitive skin rashes corneal deposits

hypo- or hyper-thyroidism pulmonary fibrosis

neurological disturbances and gastrointestinal disturbances

o Dronedarone is non iodinated (ie hence avoids the thyroid side effects) and is less toxic than amiodarone but is also less effective

- Digoxin and cardiac glycosideso Action:

Digoxin has some positive ionotropic activity and slows ventricular rate Ionotropy:

Inhibition of Na-K-ATPase (Na/K pump). [ie Na leaves by Ca exchanger rather than NaK pump]

Results in higher sodium level in the cell as illustrated by the arrow next to the letters on the below diagram

Therefore increased Na / Ca cotransport occurs to bring more Ca into the cell and increase the ionotropy

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HR and AV conduction:

Central vagal stimulation (ie at brain) by Dijoxin causes increased refractory period and reduced rate of conduction through the AV node

o It can be used in atrial fibrillation and relieves symptoms in chronic heart failure

o Long t½ (~40 hours) o Narrow therapeutic windowo Is metabolised at KIDNEY so should consider / check kidney function, esp if want to

give high dose because if impaired metabolism the effects will be even more potent!o An immune Fab (Digibind) is available for digoxin toxicity. o Adverse Effects (common and severe)

Triggers dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)

Note: Hypokalaemia (usually a consequence of diuretic use) lowers the threshold for digoxin toxicity: this is because Dijoxin acts by competing with K for acess to the Na/K pump (ie binds the same area as K then if binds will inhib the pump ); therefore less K means greater Dijoxin action

Note: Hyperkalaemia gives bracycardia because K gradient will become less so phase 3 of action potential is prolonged (takes longer to repolarise to be ready for a new action potential) (impaired excitability if persistent partial depolarisation!)

- Ivabradineo Mechanism of action:

blocks If channel (f is for "funny“); a Na/K channel important in the sinoatrial node.

Therefore slows heart rateo Uses

Angina in patients in normal sinus rhythmo Contraindications

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severe bradycardia / sick sinus syndrome / 2-3rd degree heart block cardiogenic shock recent myocardial infarction

o Adverse Effects bradycardia first-degree heart block triggers ventricular and supraventricular dysrhythmias

- Cardiac Inotropeso Agents that increase the force of cardiac contraction are used to treat acute heart

failure in some situations (e.g. after cardiac surgery or in cardiogenic or septic shock).

o Dobutamine is a beta1 adrenoceptor agonist that stimulates cardiac contraction without a major effect on heart rate due to reflex tachy (is B1 selective)

o Inhibitors of phosphodiesterase, such as milrinone, have inotropic effects by inhibiting breakdown of cyclic AMP in cardiac myocytes. [ie B1 receptors

signal via cAMP so this same pathway for contractility will be mimicked] But despite increasing cardiac contractile function so far all inotropes have

reduced survival in chronic heart failure.

- Alpha blockers & sympatholytics [sympatholytic (or sympathoplegic) drug is a medication which inhibits the postganglionic functioning of the sympathetic nervous system: eg. alpha2-adrenoceptor agonists]

o Alpha blockers: 1-adrenoceptor antagonists: direct antihypertensive effect They can be competitive (e.g. doxazosin) or irreversible (phenoxybenzamine)

o Sympatholytics: Centrally acting antihypertensive agents e.g. clonidine (alpha2-adrenoceptor

agonists), moxonidine (imidazoline agonist; Imidazoline receptors are receptors for

clonidine and other imidazolines) antihypertensive:

a2 agonists in the brain act to decrease sympathetic outflow will also be effect of increased NA uptake at synapses so dec sympa

activityo Use of alpha blockers has declined since they were shown to be associated with

increased rates of chronic heart failure in the ALLHAT study. However Phenoxybenzamine (combined with a beta blocker) is still used:

used to provide long-lasting alpha-blockade in catecholamine secreting tumours (phaeochromocytoma = tumours that secrete mostly norepinephrine, plus epinephrine to a lesser extent; the drug helps counter the hypertensive effects)

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- Vasoconstrictorso Sumatriptan [“triptan” because is stimulating the 5-hydroxytryptophan receptors]

Agonist at 5-HT1D receptors (ie serotonin receptors) Constriction of some large arteries including vessels in brain inhibits trigeminal nerve transmission [which, it is presumed, accounts for

sumatriptan's efficacy in treating cluster headaches/migraine]

Therefore used to treat migraine attacks, but contraindicated in patients with coronary disease.

o Sympathomimetic agents Adrenaline

the endogenous catecholamine produced by the adrenal gland is used in cardiac arrest and anaphylactic shock

- Selected therapeutic applicationso Angina = myocardial ischaemia

how drugs act: [summary of the info given prev on below diagram:]

[nb nitrate vs preload; CCB vs afterload] Clinical usage:

Beta blocker [or CCB in beta-blocker intolerant patient] to provide background anti-anginal cover

Glyceryl trinitrate (for symptomatic relief) Therapy to prevent cardiovascular disease:

o statin (to lower LDL cholesterol) o and aspirin (to inhibit platelet activation)

o Hypertension

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Typically patients require at least 2 drugs of different classes to control BP Angiotensin converting enzyme inhibitor (ACEI) or Angiotensin

Receptor Blocker (ARB) Calcium antagonist (long acting dihydropyridine) Thiazide diuretic Other CVD prevention measures (e.g. statin to lower LDL

cholesterol) If the above drugs fail there are the many other antihypertensives that have

been mentioned that can be considered Beta blockers are no longer first line agents for hypertension in UK but may

have a role in younger patients Ie due to weak hearts in older patients not coping with block: may

be reliant on sympa stimulation Also BBs give some inc in load from skeletal muscle block of B2 if not

cardio selective

o Chronic heart failure (CHF) Impaired cardiac function due to ischaemic heart disease (ie MI),

hypertension or cardiomyopathy that results in: fluid retention oedema fatigue

Decreased blood flow due to HF can trigger ATII production (due to the mechanisms at kidney) in turn gives range of potentially negative consequences eg heart remodelling

Typically patients will receive Diuretic ACEI (/ARB) Beta blocker +/- spironolactone [an aldosterone receptor antagonist] +/- digoxin

Note – while beta-blockers can occasionally precipitate acute heart failure in at risk patients due to their negative inotropic effects they have been shown to benefit survival in chronic heart failure and are standard therapy.

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23/01/14: Haemostasis & thrombosis: Dr Sohag Saleh

Los (from Slides&booklet for first two lecs):• Define the terms haemostasis and thrombosis and differentiate between them• Explain the process of coagulation and the actions of drugs that affect production or

activation of clotting factors• Explain the process of platelet activation and the action of specific antiplatelet drugs• Explain the actions of fibrin and the role of thrombolytic drugs• Understand the major clinical conditions for which each class of drug (i.e: anti-platelet,

anticoagulants, thrombolytics) is indicated.

With his notes:- Define the terms haemostasis and thrombosis and differentiate between them

o Haemostasis is a physiological process preventing blood loss whereas thrombosis is a pathophysiological process

- Outline the process of coagulation and the actions of drugs that affect production or activation of clotting factors

o The cell based theory of coagulation consists of three stages. Anticoagulants inhibit stage 1 and affect the activity/ production of clotting factors

- Outline the process of platelet activation and the action of specific antiplatelet drugso Platelets are activated by thrombin, which causes Ca2+ rise, ADP release and

GPIIb/IIIa receptor expressiono Antiplatelet drugs fall into 4 categories

- Summarise the actions of fibrin and the role of thrombolytic drugso Fibrin is produced from fibrinogen and stabilises blood clotso Plasmin can degrade fibrin strands and thrombolytic drugs activate plasmin

- To understand which of these classes of drugs can be used in specific clinical situationso Anticoagulants: More effective in the treatment of venous red thrombi e.g. Deep

vein thrombosiso Antiplatelets: More effective at treating arterial white thrombi e.g. Acute coronary

syndromes, ischaemiao Thrombolytics: used in the treatment of MI, stroke & pulmonary embolism

Notes:

Overview:

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- Blood constituentso BLOOD CELLS

Plateletso PLASMA CLOTTING FACTORS

Procoagulants Prothrombin Factors V, VII-XIII Fibrinogen

Anticoagulants Plasminogen TFPI [tissue factor pathway inhibitor]

o Tissue factor pathway inhibitor (or TFPI) is a single-chain polypeptide which can reversibly inhibit Factor Xa (Xa)

Proteins C & S Antithrombin

- HAEMOSTASIS vs THROMBOSISo Haemostasis - an essential physiological process where blood coagulation prevents

excessive blood losso Thrombosis - pathophysiological process where blood coagulation occurs within an

intact blood vessel obstructs blood flow Emboli

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Clot becomes life-threatening if it dislodges from the vessel (embolises) becomes trapped in another vessel

red thrombi form on the surface of the vessel Venous thromboses (= red thrombi) high fibrin components; also contain RBCs which give the red

colour

white thrombi A thrombus can form within an atherosclerotic plaque within the

wall of the vessel If the plaque ruptures the thrombus is released into the lumen If the thrombus embolises myocardial infarction (coronary artery) Arterial thromboses (= white thrombi) high platelet components

VIRCHOW’S TRIAD Rate of blood flow

o Blood flow is slow/stagnating no replenishment of anticoagulant factors & balance adjusted in favour of coagulation

Consistency of bloodo Natural imbalance between procoagulation &

anticoagulation factors e.g. Factor V leiden Blood vessel wall integrity

o Damaged endothelia means blood exposed to procoagulation factors

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o Alternatively direct endothelial dysfunction can be the cause of the clotting

- Coagulation: cell based theoryo Initiation

Small scale production of thrombin ANTICOAGULANTS act here

o Amplification Large scale thrombin production on the surface of platelets ANTIPLATELETS act here

o Propagation Thrombin mediated generation of fibrin strands THROMBOLYTICS act here

- Coagulation: cell based theoryo Initiation

Small scale production of thrombin Tissue factor (TF)

o TF bearing cells [on leukocytes and on the endothelium] activate factors V & X forming prothrombinase complex [ie TF, Va and Xa where a=activated]

Prothrombinase complex [ie TF, Va and Xa] o This activates factor II (prothrombin) creating factor IIa (=

thrombin) ANTICOAGULANTS act here

Antithrombin (AT-III)o AT-III inactivates thrombin

Direct thrombin inhibitors (DTI) o Inhibit thrombin (e.g. Dabigatran [the only orally available

drug of this type], Bivalirudin)o Mainly used against VENOUS clotso Prophylaxis of:

venous thromboembolism (VTE) during surgery stroke in patients with atrial fibrillation

Heparin and derivativeso Heparin potentiates antithrombin activity; short half life

[sometimes good to be able to stop effects fast eg renal failure]

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o Low-molecular weight heparins, (LMWHs, e.g. Dalteparin) have same effect as Heparin except also inhibit factor Xa and have a longer half life

Largely replaced Heparin Mainly used against VENOUS clots prophylaxis & treatment of deep vein thrombosis

Factor Xa inhibitorso Inhibit factor X (e.g. Rivaroxaban [the only orally available

drug of this type], Fondaparinux)o Mainly used against VENOUS clotso prophylaxis & treatment of DVT

Vitamin K antagonistso Vitamin K - essential for production of factors II, VII, IX & Xo Eg Warfarin

Can be used orally (but not the only oral one of this type)

Long delay of onset (~ 5 days) Narrow therapeutic window Unpredictable pharmacokinetics Numerous drug interactions

o Amplification Large scale thrombin production on the surface of platelets

Amplification of thrombin:

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o Thrombin activates platelets, which produce a number of other clotting factors (eg vWF as below)

o von Willebrand factor (vWF) liberation: This indirectly will inc activation of factor II (prothrombin) creating factor IIa (thrombin) [ie amplification of effect]

Platelet activationo Thrombin - acts on protease-activated receptors (PAR)

located on the surface of platelets.o PAR activation rise in intracellular Ca2+

o Ca2+ rise change in platelet shape & exocytosis of adenosine diphosphate (ADP) from dense granules

ANTIPLATELETS act here At ADP receptors:

o ADP has both autocrine and paracrine effects activating P2Y12 receptors results in platelet aggregation

o P2Y12 receptors antagonists - Clopidogrel & Prasugrel

o Mainly used for atherothrombotic disorders [ie on the arterial side not veins]

Cyclo-oxygenase o PAR activation also liberates arachidonic acid (AA) [ie 2x

mechs for PAR signalling clotting]o Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2)

from AA [will then lead to clotting as detailed immediately below] [nb inhib of PG also occurs but this effect of pro-platelet is outweighted by TX effect]

o COX-1 irreversible inhibitor – Aspirin [irrev means has antiplatelet effect; eg ibuprophen

reversible so lacks antiplatelet effect] Secondary prevention of cardiovascular disease NB: High doses no more effective BUT more side-

effects Glycoprotein IIb/IIIa receptor (GPIIb/IIIa)

o TXA2 activation expression of GPIIb/IIIa integrin receptor [ie GPIIb/IIIa integrins of other platelets will bind to them] on platelet surface

o GPIIb/IIIa - involved in platelet aggregation ie clottingo GPIIb/IIIa receptor antagonists e.g. Abciximabo Limited use AND only by specialists

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o Propagation Thrombin mediated generation of fibrin strands

Generation of fibrin strands: Large-scale thrombin production converts fibrinogen to fibrin strands [ie clotting]

THROMBOLYTICS act here

Anticoagulants & antiplatelets - DO NOT remove pre-formed clots [they can only prevent an increase in the size of the clot]; thrombolytics DO!:o Thrombolytics convert plasminogen to

plasmin o Plasmin - natural protease that degrades fibrin strands

Pharmacologyo Alteplase: a tissue-type plasminogen activator. (tPA) [ie is a

serine protease activator]o Streptokinase - bacterial product that is cheap and effectiveo Thrombolytics used for myocardial infarction and

other thromboembolic disorders e.g. DVT (Deep vein thrombosis) [arterial or venous]

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27


23/01/14: ATHEROSCLEROSIS, LIPOPROTEINS AND LIPID- LOWERING DRUGS: Mike Schachter

Los (from Slides&booklet for first two lecs):

Explain the major theories concerning the pathogenesis of atherosclerosis. Explain the role of lipids, particularly cholesterol, in the development of atherosclerosis. Explain the use of lipid lowering therapies in the prevention and treatment of atherosclerotic vascular disease. Summarise the metabolism of lipoproteins.

Notes:

- Pathogenesis of atherosclerosiso Chylomicrons get their fats from the gut and release their fats to skeletal muscle and

adipose tissue to become “chylomicron remnants” which are then taken up by the liver or contribute to atherosclerosis:

The remnants, if in the vessel walls, will encourage macrophage recruitment to play a role in inc atheroschlerosis

o By contrast to chylomicrons the fats in HDLs (implies ApoA1), LDLs (implies ApoB), IDLs, VLDLs are derived from the liver where lipogenesis and cholesterol synthesis occur

Endothelial dysfunction gives leaky or broken vessel walls and Upregulation of endothelial adhesion molecules to allow lipids to pass from LDLs to the vessel walls [whole LDLs enter; HDLs leave] [HDLs can perform ‘reverse transport’ but thought to be only certain HDL subsets so not all HDL incs give benefits]

Migration of smooth muscle cells occurs and Inflam response attracts macrophages to help remove the fats: However macrophages and smooth muscle cells become laden with fat to become foam cells [ie prob now useless and just contributing to plaques structure]

The remnants, if in the vessel walls, will encourage macrophage recruitment to play a role in inc atheroschlerosis

Fibrous cap and necrotic core form Plaque rupture thrombus

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[pre liver]

[post liver]

- Angina proportional to lumen size- MI risk proportional to thickness of boundary between atheromatous plaque and the blood

lumen

- LDL Cholesterolo Strongly associated with atherosclerosis and CHD events

10% increase results in a 20% increasein CHD risk

o Level Modified by risk factors low HDL cholesterol smoking hypertension diabetes

- HDL Cholesterol

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o HDL cholesterol has a protective effect for risk of atherosclerosis and CHDo The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHDo HDL cholesterol tends to be low when triglycerides are higho HDL cholesterol is lowered by:

smoking, obesity physical inactivity

- Therapy- Bile acid sequestrants- Nicotinic acid - Fibrates - Gemfibrozil- Statins- Ezetimibe

- Therapy vs cholesterol level- Bile acid sequestrants

o These prevent bile acid reabsorbtion therefore liver must make more cholesterol; however liver is able to compensate effectively so these drugs are not very effective vs blood cholesterol level and the dec in BAs gives big digestive side effects

- Nicotinic acid = niacin o Dec LDL inc HDL (it stimulates higher reverse cholesterol transport) BUT:

Extensive side effects and actually also there is little benefit to patient in reality too

- Fibrates eg Gemfibrozilo Main mechanism of action is activation of PPAR alpha receptors

PPAR = peroxisome proliferator activated receptors Actions at liver and adipose tissue lead to reduced plasma FAs and TGs

but it is the inc in HDLs that they cause which is the main help vs atheroschlerosis

ALSO: reduce inflam, inc plaque stability

o PPAR gamma activators are used in diabetes Ie ligands for this receptor have emerged as potent insulin sensitizers

used in the treatment of type 2 diabetes- Statins

o HMG-CoA reductase is blocked but not just cholesterol further down the pathway; certain other components have key role in post transl mods so can give disfunction of a range of prots: (rho, ras, etc)

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o Response to HMG-CoA reductase block (at liver) is to Increase number of LDL receptors (LDLRs) on hepatocytes to gain cholesterol in this way instead

o Will lead to inc HDLs and dec LDLso Note “rule of 6” for alkl statins: double the dose but only 6% further reduction in

LDL [but bad for side effects if v high doses have to be used]

o Note that statins also have an anti-inflammatory effect which is a second means by which plaques are combatted

o As preventative medicines: vast majority of people will gain no help; must treat v many to save someone

o Example: Rosuvastatin [nb all end _statin so can easily tell what they are]- Ezetimibe

o Absorbed then activated by glucuronidation phase I reactiono Inhibits cholesterol absorption from dietary intake

Liver will inc its synth but OVR the drug does translate to a very significant dec in plasma LDL

o However: the LDL dec doesn’t translate well to patient benefits [‘how the LDL (or HDL) change is achieved matters’]; despite this is still used

- PCSK9 inhibitorso [Proprotein convertase subtilisin/kexin type 9]o PCSK9 is a LDLR inhibitor; ie bad effect: blocks the removal of LDLs from the

blood when statins stimulate this removal (as above)o Therefore use PCSK9 inhibitors eg mAbs (with statins)

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23/01/14: NSAIDS: Prof Sue Smith

Los (from Slides&booklet for first two lecs):NSAIDS; Cycloxygenase inhibitor e.g. aspirin & ibuprofen (non-selective), celecoxib (COX-2 selective)

Identify the underlying mechanism of action by which all NSAIDs have their therapeutic effects. 2. Explain how the underlying mechanism of action produces the analgesic, anti-inflammatory and antipyretic effects of NSAIDs. 3. List the most important side effects of NSAIDS, explain why these occur and what attempts have been made to minimise them. 4. Explain why selective COX-2 inhibitors have proved less successful than hoped. 5. Explain why paracetamol is not a NSAID. 6. Identify the key difference between the mechanism of action of aspirin and other NSAIDs and explain how this difference can be harnessed clinically

Notes:

- From cardio:

Prostacyclin [=PGI2] (is a prostaglandin): signals via inc IP & inc cAMP Smooth Muscle

o Relaxationo Inhibition of Growth

Myocyteso Increase Blood Flow

Plateletso Inhibit Aggregation

Thromboxane [=TXA2]: signals via inc TP and inc IP3 Smooth Muscle

o Contraction Myocytes

o Reduce Blood flow Platelets

o Stimulates Aggregation

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[+ = vasoconstriction; - = vasodilation]

- Non-Steroidal Anti-Inflammatory Drugs: inhibit COXo Major Clinical Uses

Relief of mild-to-moderate pain (Analgesic) Toothache, headache, backache Postoperative pain (opiate sparing) Dysmenorrhea (menstrual pain)

Reduction of fever (antipyretic) e.g. Influenza

Reduction of inflammation in many diseases e.g.: Rheumatoid arthritis Osteoarthritis Other forms of musculo-skeletal inflammation Soft tissue injuries (strains and sprains) Gout

o NSAIDS inhibit production of prostanoids Prostanoids: = Prostaglandins and thromboxanes

They are derived from arachidonic acid (lipids) Inflammatory mediators; Actions receptor mediated Widely distributed Not stored pre-formed; they are synthesised in response to stimuli

(makes sense – is lipid derived, not from prot) Prostaglandins: many types: if PGI2 = prostacyclin

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Mechanism: NSAIDs inhibit Cyclo-oxygenase [ie COX 1/2] COX 1/2 catalyses Arachidonic Acid Prostaglandin H2 [is the

parent molecule for all PGs and TXs]o Cox-1 [nb is the one at platelets]

Constitutive (made all the time) Ubiquitous (found in nearly all cell types) Physiological

o Cox-2 [nb is the one at endothelium] Mainly inducible (made in response to specific

stimuli) Very widespread Physiological and pro-inflammatory roles [ie

important physiological effects but it is the form involved in the inflam effects that want to counter]

Prostanoid receptors 10 known receptors:

o These known receptors are all G protein coupled, but the Prostanoids also definitely also have effects independent of G proteins

o PGE2 has 4 Receptors Prostanoid effects are extremely complex: Physiological and pro-

inflammatory

Ibuprofen and Indomethacin Typical non-selective NSAIDs: Inhibit both COX-1 and COX-2 Have anti-inflammatory, analgesic (ie anti-pain) and anti-pyretic

actions Inhibit cyclo-oxygenase REVERSIBLY

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- Inhibition of PGE2 synth by NSAIDs:o analgesic

1. Stimulation of PG receptors on nerve endings sensitizes nociceptors to chemical and thermal stimuli which cause pain; Therefore if we block production of PGE2, we will raise the pain threshold and thus, reduce the perception of pain

2. COX inhibitors may increase levels of endocannabinoids; these dull pain perception via central and peripheral mechanisms

[Analgesic NSAID use Usually occasional so Relatively low risk of side effects]o anti-pyretic

PGE2 stimulates hypothalamic neurones initiating a rise in body temperature

Therefore NSAIDS reduce raised temperatureo anti-inflammatory

PGE2 has complex effects on immune and inflammatory pathways: May contribute to converting acute to chronic inflammation; therefore the NSAID mech is complex and poorly understood

[Anti-inflammatory use Often sustained and Higher doses so Relatively high risk of side effects]

o Unwanted Effects of NSAIDS NSAIDS inhibit cytoprotective mechanisms in the stomach

PGE2 downregulates HCl secretion NSAID gives Increased HCl secretion

PGE2 stimulates mucus and bicarbonate secretion NSAID gives Reduction or loss of protective mucus and bicarbonate

This can lead to gastric ulceration Renal toxicity

Due to reduction in renal artery flow (PGE2/I2 give vasodilation) Cardiovascular effects

(hypertension, myocardial infarction, stroke) Mechanisms unclear In part due to a small raising of blood pressure

Disruption of Arachidonic acid pathways in the airways NSAIDs block the Cyclooxygenase branch [to PG and TX] so inc

production of leutotrienes via Lipoxygenase will occur bronchospasm

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- Aspirin (is an NSAID)

o Binds more avidly to COX-1 than COX-2 [COX1 selective]

o Unique among the NSAIDS Binds IRREVERSIBLY to COX enzymes

Irreversible so reduces platelet aggregation [unlike other NSAIDs]:o Platelets mainly give TXA2 [ie in response to FIIa; TXA2 is

pro clotting as in notes from CV] and can’t regenerate their COX as have no nucleus ASPIRIN anti clotting effect

o Endothelial cells mainly give PGI2 [anti-clotting; see notes pasted from CV] and can regenerate their COX as have a nucleus ASPIRIN no effect; PGI2 anti-clotting retained

o Also: Inhibition of PGI2 is proportional to inhibition of COX-2 ASPIRIN little effect at COX2 so anti-clotting retained

Irreversible so serious side-effects at therapeutic doseso Gastric irritation and ulceration [as prev is standard NSAID

side effect due to some dec in PGE2; “COX 1 is the most important for physiological roles so this side effect enhanced in aspirin”]

o Bronchospasm in sensitive asthmaticso Prolonged bleeding timeso Nephrotoxicity [inhibits the kidneys' ability to excrete uric

acid]

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- NSAID: Celecoxib o Reversibly, selectively inhibits COX-2o therefore reduced side effects associated with interrupting COX1: Fewer ulcers with

Celecoxibo HOWEVER COX2 is important in some physiological roles: inhib gives enhanced CVD

risk; mech unclear but as prev it is a classic NSAID side effect: Suggested that they selectively inhibit PGI2 production and spare TxA2

production leading to more aggregation

- Strategies for limiting side effectso Topical application: ie lower doses needed

o Administration with omeprazole or other proton pump inhibitor [ie esp good with aspirin use]

- Paracetamolo Is a good analgesic for mild-to-moderate pain o Has anti-pyretic actiono Does NOT have any anti-inflammatory effect: Therefore it is not a NSAIDo Nb its Mechanism of action Not understoodo Side-effects

In overdose it may cause irreversible liver failure Antidote = cysteine donor for glutathione synth = intravenous N-

acetylcysteine or Occasionally oral methionine

37


23/01/14: Anti-emetics: Professor Glenda Gillies

Los (from Slides&booklet for first two lecs):1. Explain the physiological control of vomiting (see Fig.)2. Identify the receptor specificity, the main sites of action and the specific antiemetic uses of

promethazine, metoclopramide, hyoscine and ondansetron.3. List the main pharmacokinetic features and unwanted actions of promethazine,

metoclopramide, hyoscine and ondansetron

Notes:

- Overview:o Key pathways and events involved in nausea and vomiting (emesis)o Major classes of antiemetic drugs, clinical uses, proposed mechanisms of action:-

Mixed receptor antagonists Dopamine type 2 receptor antagonists Muscarininc receptor antagonists Serotonin (5HT3) receptor antagonists

N.B. ANTIEMETIC/ANTINAUSEANT DRUGS are used ONLY when the cause of the nausea/vomiting is known, otherwise they could mask the diagnosis of potentially serious conditions, e.g. digoxin excess, diabetic ketoacidosis.

- Vomiting:o Effect of Severe Vomiting:

Dehydration Loss of gastric hydrogen and chloride ions may lead to

hypochloraemic metabolic alkylosis (raise blood pH) hypokalaemia (renal K+ excretion in response to proton loss)

o Physiological control of vomiting: [receptors are as on diagram below] Stimuli from peripheral organs [eg if punched there]

[pharynx, stomach, duodenum, heart, bladder, uterus, viscera, testicles]

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5-HT (=serotonin) released on stimulation of mechanoreceptors/chemoreceptors or from gut enterochromaffin cells

o A) Activation of glossopharyngeal nerve IX and vagus nerve X [visceral afferents] Nucleus of the solitary tract Stimulation of vomiting centre (medulla)

o B) CTZ [CHEMORECEPTOR TRIGGER ZONE] of brain at area postrema (improper BBB allows sampling) Stimulation of vomiting centre (medulla)

Endogenous toxins, drugs Release of emetogenic agents eg. 5HT, prostanoids, free radicals

A) Activation of glossopharyngeal nerve IX and vagus nerve X

[visceral afferents] Nucleus of the solitary tract Stimulation of vomiting centre (medulla)

B) CTZ [CHEMORECEPTOR TRIGGER ZONE] of brain at area postrema (improper BBB allows sampling) Stimulation of vomiting centre (medulla)

C) Direct CTZ activation by the drug/toxin vomiting center Motion sickness

Labyrinth of ear Vestibular nuclei [ie of vestibular nerve] CHEMORECEPTOR TRIGGER ZONE VOMITING CENTRE

Pain, repulsive sights & smells, emotional factors. SENSORY AFFERENTS & CNS PATHWAYS HIGHER CENTRES

VOMITING CENTRE

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NB the locations of these receptors as above: [AChM = muscarinic receptors; H1R = Histamine 1 receptors; D2 = dopamine 2 receptors; 5HT3 = 5HT receptors = serotonin receptors]

- Hyoscineo Muscarininc receptor antagonisto MODE OF ACTION

Order of antagonistic potency: Muscarinic (>>>D2 = H1 receptors) Therefore acts centrally, especially in the vestibular nuclei, NTS, vomiting

centre to block activation of vomiting centre.o USE AS AN ANTI-EMETIC

Prevention of motion sickness Has little effects once nausea/emesis is established In operative pre-medication NOTE: Atropine is less effective than hyosine as an anti-emetic

o UNWANTED EFFECTS Typical anti-muscarinic side-effects: Drowsiness / CNS effects

40


dry mouth, no sweating cycloplegia [paralysis of the ciliary muscle of the eye, resulting in a loss of

accommodation] mydriasis constipation (not usually at anti-emetic doses)

- Promethazine (a phenothiazine derivative) [the only one classed as an actual Mixed receptor antagonist!!]

o MODE OF ACTION competitive antagonist at histaminergic (type H1), cholinergic (muscarinic,

M) and dopaminergic (type D2) receptors. Order of potency of antagonistic activity: H1> M > D2 receptors

Therefore acts centrally (vestibular nucleus, NTS, vomiting centre) to block activation of vomiting centre.

o c.f. other phenothiazines, which are used as neuroleptic drugs, have a different

order of potency with greater antagonistic effects at D2 receptors.o USE AS AN ANTI-EMETIC

Motion sickness – normally used prophylactically, but some benefit may be gained if it is taken after the onset of nausea and vomiting

Disorders of the labyrinth eg, Meniere’s disease Hyperemesis gravidarium [a complication of pregnancy characterized by

intractable nausea, vomiting, and dehydration] Pre- and post-operatively (sedative and anti-muscarinic action are also

useful).o For other uses see relevant parts of course for further details

Relief of allergic symptoms Anaphylactic emergency Night sedation; insomnia

o UNWANTED EFFECTS Dizziness Tinnitus Fatigue Sedation (‘do not drive or operate machinery') Excitation in excess Convulsions (children more susceptible) Antimuscarinc side-effects

- Metoclopramide; Domperidone o Dopamine (D2) receptor antagonistso MODE OF ACTION

Order of antagonistic potency: D2 (>> H1 >>> Muscarinic receptors)

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Therefore acts centrally, especially at CTZ Prokinetic effects in the gastrointestinal tract [encourages craniocaudal

movement (think of as countering vomiting effect)] increases smooth muscle motility (from oesophagus to small

intestine) accelerated gastric emptying accelerates transit of intestinal contents (from duodenum to ileo-

coecal valve) Therefore possible dangers:

o absorption and hence effectiveness of digoxin may be reduced

o nutrient supply may be compromised; especially important in conditions such as diabetes mellitus

o USE: To treat nausea and vomiting associated with: uraemia (the illness accompanying severe renal failure) radiation sickness gastrointestinal disorders cancer chemotherapy (high doses) eg. cisplatin (intractable vomiting) Parkinson’s disease treatments which stimulate dopaminergic transmission [NB is Not effective against motion sickness]

o UNWANTED EFFECTS In CNS (metoclopramide only; domperidone does not cross BBB so NOTE:

No anti-psychotic actions) dizziness drowsiness anxiety extrapyramidal reactions; children more susceptible than adults

(convulsions: Parkinsonian-like syndrome: rigidity, tremor, motor restlessness)

In the endocrine system hyperprolactinaemia galactorrhoea [ie inc milk production due to the inc prolactin] disorders of menstruation [prob due to the inc prolactin]

o PHARMACOKINETIC CONSIDERATIONS may be administered orally; rapidly absorbed; extensive first pass

metabolism may also be given i.v.

- Ondansetrono Serotonin (5-hydroxytryptophan) receptor antagonist (ie acts at 5-HT3R)o MODE OF ACTION

Acts to block transmission in visceral afferents and CTZ.o USE AS AN ANTI-EMETIC

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main use in preventing anticancer drug-induced vomiting, especially cisplatin

radiotherapy-induced sickness post-operative nausea and vomiting

o UNWANTED EFFECTS headache sensation of flushing and warmth increased large bowel transit time (constipation)

o USE IN COMBINATION WITH CORTICOSTEROIDS Eg in chemotherapy for inc anti-emetic effects: [nb chemotherapy gives

extensive vomiting]: 5-HT3 receptor antagonists may be used for low emetogenic

chemotherapy Corticosteroids, such as dexamethasone, may be used in

combination with 5-HT3 receptor antagonists for high or moderately high emetogenic chemotherapy

Improved efficacy of combined therapy may be due to anti-inflammatory properties of corticosteroids [imm system suppression]

Tutorial notes:

- Adrenal neurones are not really presynaptic neurones- Airway resistance is measured in cmH2OL-1s- Liver endothelium is fenestrated / discontinuous to allow for drug removal from circulation- Lung has M4 receptors- Drugs that are only wanted to have a local effect are often made hydrophilic: large

hydrophilic group addedo Firstly helps hold them at the tissue by slowing transfer through to bloodo Secondly may help metabolism as may already be activated for phase ii metabolismo Note that may also have inc direct excretion ability at kidney compared to a lipid

soluble drug but the main driver of excretion is the adding of large groups to the drug as these can then be recognised by active transport mechanisms at the kidney for excretion

- Local application may improve speed / magnitude of benefits but the main reason for local use is to allow for a reduced dose to be used and thereby avoid side effects

- Ipratropium bromide is used for COPD and asthma- Asthma patients have to thoroughly warm up to adapt to the exercise - Arachidonic acid product effects in lungs [ie are in addition to their blood vessel effects

which are detailed elsewhere]o PGs: mainly positive effects in lung vs bronchoconstriction

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o TX: prob little effect either wayo Bradykinin: negative effects in lung vs bronchoconstriction [ie hence ACEi dry cough]o Leukotrienes: negative effects in lung vs bronchoconstriction

- Asthma: dilator [Ipratropium bromide, Salbutamol, LABA], anti-disease med; ie vs the production of material, mucus etc in lungs [leukotriene receptor antagonists], anti-disease AND dilator [lipogenase inhibitor; give shift in Arachidonic acid pathway to PG/TX AND dec leukotriene level; but rarely used as not necessary], Not used: [not histamine antagonists: because there are many other mast cell products that will just give bronchoconstriction anyway]

- Vs glaucoma:o A1 agonisto BBo Musc agonist [major mech for this is via circular muscle contraction; cilary muscle

contraction plays only minor role]o CA inhibitor: but extensive side effects due to CA elsewhere: gut, pancreas, liver, etc

- Adrenaline has a net positive effect vs glaucoma because a1 agonism as a mechanism is so excellent vs glaucoma

44


03/02/14: Diuretics: Chris John

Los (from booklet):

Learning objectives1. Recall the physiology of the kidney, focusing on the mechanisms which regulate the ionic composition (particularly Na+, Cl- and K+), volume and osmolarity of the urine.2. Explain how the following groups of diuretic drugs alter the ionic composition, volume and osmolarity of the urine: osmotic diuretics, e.g. mannitol; carbonic anhydrase inhibitors, e.g. acetazolamide; loop diuretics, e.g. furosemide (frusemide); thiazides, e.g. bendroflumethiaze (bendrofluazide); potassium sparing diuretics. e.g. amiloride, spironolactone.3. Recognise that loop diuretics, thiazides and K+ sparing diuretics are clinically the most important groups of diuretics.4. Identify the principal conditions for which frusemide, bendrofluazide, amiloride and Spironolactone are used clinically, and identify their principal adverse effects.

Notes:

- Basic physiology at different parts of the kidney:

o 65-70% of the filtered Na+ is reabsorbed here

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o Note that therefore the events at the proximal tubule will contribute to urine acidityo Note that both the H+ and the HCO3- from CA act to move Na across (then water

follows; hence CA inhibitors used as diuretics – cf)o Note that both the H+ and the HCO3- from CA act to counter an acidaemia;

therefore high levels of this process in acidosis and low levels in alkylosis [prob means there is dec Na reabsorbtion in alkylosis]

o [nb COUNTERCURRENT EFFECT as described in renal lecs]: is the reason for the hyperosmolarity of the interstitium as is labelled; lumen is isotonic as both Na and H2O exited at proximal tubule: THEREFORE OSMOTIC GRADIENT FOR WATER EXIT

o Descending limb – permeable to watero More concentrated medullary interstitium draws water from the permeable

descending limb o Fluid in descending limb increases in osmolarity

o [nb COUNTERCURRENT EFFECT as described in renal lecs]o Ascending limb – impermeable to watero Na+ leaves the ascending limb and enters medullary Interstitiumo Fluid in ascending limb decreases in osmolarity

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o 15-30% of filtered Na is reabsorbed here

o Note that Na/Cl transport is cotransport into the cello Note that the events of the ascending tubule also contribute to the osmotic gradient

that exists here for water to move downo Note the actions of Aldosterone and ADH are both needed for water reabsorbtion to

occur: aldosterone to help establish the osmotic gradient and ADH to allow water to move down that gradient.

o 5-10% of filtered Na is reabsorbed here

o Note that the events of the ascending tubule also contribute to the osmotic gradient that exists here for water to move down

47


o Note that the pathway of Na movement across cell is coupled to inc intracellular K+ [eg Aldosterone directly increases the Na/K pump activity] which then exits on apical side as shown [this prob is not possible at the distal tubule]

o Note aldosterone: increases the basolateral/basal Na/K pump activity; increases apical Na channel activity

- Five main classes of DIURETIC DRUGS:o 1. Osmotic diuretics

e.g. mannitolo 2. Carbonic anhydrase inhibitors

e.g. acetazolamideo 3. Loop diuretics

e.g. frusemide (furosemide)o 4. Thiazides

e.g. bendrofluazide (= bendroflumethiazide)o 5. Potassium sparing diuretics

e.g. amiloride, spironolactone.

- Five main classes of DIURETIC DRUGS:o 1. Osmotic diuretics

e.g. mannitol Pharmacologically inert Filtered by the glomerulus but NOT reabsorbed Increase the osmolarity of tubular fluid H2O reabsorption where the

nephron is freely permeable to water, i.e. proximal tubule, descending loop of Henle, collecting duct (presumably distal tubule too)

NB will also increase the osmolarity of the blood plasma giving unwanted effects:

48


ECF volume (pseudo)Hyponatraemia; (nausea, vomiting, pulmonary oedema due to expanded blood volume)

Clinical Uses: Prevent acute renal failure: H2O excretion helps maintain urine

production which helps with renal failure intra-cranial pressure / intra-ocular pressure (ie glaucoma):

plasma osmolarity due to the water loss means fluid will move out of brain / eyes

NB Small in Na+/Cl- loss occurs [prob don’t worry about mech; “water pulling the NaCl with it”]

o 2. Carbonic anhydrase inhibitors e.g. acetazolamide Act mainly on the proximal tubule Prevent the reabsorption of Na+ and

HCO3- subsequent H2O reabsorption is therefore reduced

(if CA not present: HCO3- transiently becomes CO2 in lumen transported to cells with water CA action HCO3- transport with Na to interstitum / blood while the H+ from CA aids Na transport through the apical side)

Also indirect effects at the collecting duct: proximal tubule effects tubular fluid osmolarity H2O reabsorption in the collecting duct.

OVR effect is in Na+/ K+/ HCO3- loss (alkaline urine) coupled to water loss However:

Metabolic acidosis will result from low HCO3- reuptake (BAD) Are only weak diuretics / their effects quickly lost with time: prob

because because the low HCO3- reuptake to serum will soon give low lumen HCO3- and therefore will lose the diuretic component of inc tubular fluid osmolarity due to the drug (tubular osmolarity could even fall)

delivery of HCO3- to distal tubule K+ loss

Clinical Uses: Renal stones: uric acid loss: Uric Acid in urine coming out of

solution gives renal stones; the acid will stay in solution if HCO3- is present as is the case with CA inhibitors

Metabolic Alkalosis: due to inc HCO3- loss intra-ocular pressure (ie glaucoma): as in prev notes CA inhib gives

drop in eye HCO3- level which is a key component of the intraocular fluid so helps vs glaucoma

o 3. Loop diuretics e.g. frusemide (furosemide) Inhibit Na+ and Cl- reabsorption in ascending limb [blocks the Na2ClK

pump] tubular fluid osmolarity AND osmolarity of medullary interstitium = H2O reabsorption in the collecting duct.

Large in urine volume and Na+, Cl- & K+ loss Clinical Uses:

Oedema: Heart failure, pulmonary, renal, hepatic, cerebral

49


Moderate Hypertension: Piretanide [actually rare to use in hypertension as v potent]

Vs Hypercalcaemia Vs Hyperkalaemia

Unwanted effects: Hypovolaemia & Hypotension: are very potent diuretics! Ca2+ & Mg2+ loss caused: The Na2ClK pump net effect is to make

the lumen more positive because the K+ is recycled back to lumen while the Cl- is not (see diagram). Therefore there is a charge gradient in diuretic absence for Ca2+ & Mg2+ absorbtion to body

K+ loss (not reabsorbed at ascending tubule and delivery of Na+ to distal tubule so K+ loss by Na+/K+ exchange

Metabolic Alkalosiso Hypokalemia causes metabolic alkalosis by several

mechanisms. transcellular shift occurs in body tissues in which K leaves and H+ enters the cells, thereby raising the extracellular pH. Also, in the presence of hypokalemia, hydrogen excretion and HCO3- reabsorbtion in proximal tubules increases.

o 4. Thiazides e.g. bendrofluazide (bendroflumethiazide) Inhibit Na+ and Cl- reabsorption in distal tubule so dec water re-uptake

there Also: tubular fluid osmolarity = H2O reabsorption in the collecting duct. OVR:

Moderate in urine volume and Na+, Cl- & K+ loss Also: Mg2+ loss and Ca2+ reabsorption (unknown mechanisms!;

nb ca explanation in renal notes) Clinical Uses:

50


Heart failure Severe resistant oedema Hypertension:

o initially blood volume is the benefit; this prob will be compensated for long term but the thiazides also have a vasodilation effect which is maintained

Idiopathic hypercalciuria [ie risk of stone formation] Nephrogenic diabetes insipidus (paradoxical; see note from renal

module) Unwanted effects:

K+ loss [ delivery of Na+ to distal tubule K+ loss ( Na+/K+

exchange)] Metabolic Alkalosis

o Hypokalemia causes metabolic alkalosis by several mechanisms. transcellular shift occurs in body tissues in which K leaves and H+ enters the cells, thereby raising the extracellular pH. Also, in the presence of hypokalemia, hydrogen excretion and HCO3- reabsorbtion in proximal tubules increases.

Diabetes Mellitus: Inhibits insulin secretion [ie help treat DI but give you DM!]

Mg2+ loss (see above)

o 5. Potassium sparing diuretics e.g. amiloride, spironolactone. Triamterene

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Inhibit Na+ reabsorption (and concomitant K+ secretion) in late distal tubule / collecting duct so reduced water re-uptake here.

Ie even for amiloride: just slowing Na entry will be enough to slow the action of the Na/K pump thereby reducing K+ exit to lumen: Hyperkalemia does occur!

Also: tubular fluid osmolarity = H2O reabsorption in the collecting duct. OVR:

reabsorption of Na+ and water [ie Small in urine volume and Na+

loss] Renal stones: uric acid loss [prob don’t worry about mech]

Clinical Uses: With K+ losing diuretics: Amiloride Primary/Secondary hyperaldosteronism: Spironolactone

Unwanted effects: Hyperkalaemia Metabolic Acidosis

o Hyperkalemia causes metabolic acidosis by several mechanisms. transcellular shift occurs in body tissues in which K enters and H+ leaves the cells, thereby lowering the extracellular pH. Also, in the presence of hyperkalemia, hydrogen excretion and HCO3- reabsorbtion in proximal tubules decreases.

Spironolactone: Gynaecomastia [boys' and men's breasts to become larger than normal], Menstrual Disorders, Testicular Atrophy

Types: Aldosterone receptor antagonists

o e.g. spironolactone Inhibitors of aldosterone-sensitive Na+ channels

o e.g. amilorideo ie just slowing Na entry will be enough to slow the action

of the Na/K pump thereby reducing K+ exit to lumen: Hyperkalemia does occur!

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15/02/14: Tutorial: Variability in the human response to drugs

Learning objectives (from booklet):

Identify causes of variations in response to any specific drug between individuals or within an individual at different times in terms of: Differences in the concentrations of drug reaching the tissues (ie factors affecting absorption, distribution, metabolism and excretion of the drug)

Identify causes of variations in response to any specific drug between individuals or within an individual at different times in terms of: Differences in response of the target tissues to the same degree of stimulation (ie factors such as variation in receptor sensitivity, number and distribution).

Notes:

- Both the desired and unwanted responses to any given drug may vary between individuals. The reasons for this can be subdivided into:

- 1. Absolute differences in dose administered This may be deliberate or accidental eg due to:

a) error in prescription or dispensing b) patient non-compliance c) drug formulation

- 2. Relative overdose or underdose Because the patient varies from the text book standard. Some of the factors which may cause this variation include:

- a) Environmental exposure to chemicals, including other drugso i) enzyme inductiono ii) enzyme inhibition

- b) Food intake – drugs may interact chemically with components of food; this may reduce their absorption

o - foods delay gastric emptying and alter gastric pH.- c) Fluid intake

o – most drugs are better absorbed if taken with water eg may dissolve better

o - fluids may stimulate gastric emptying.- d) Age

Newborn infants haveo i) relatively more body water than adultso ii) poorer renal function, with immature tubular secretiono iii) an immature blood brain barrier

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o iv) lower capacity for drug metabolism.The elderly have an overall deterioration in many physiological functions that may affect

o i) drug absorption: decreased absorptive surface of small intestine

altered gastric and gut motility increased rate of gastric emptying

o ii) drug distribution: reduced lean body mass and reduced body water, relative increase in fat (ie all diffs are after having considered their OVR size)

lipid soluble drugs have increased Vd (volume of distribution) and decreased blood levels

water soluble drugs have decreased Vd and increased blood levels

reduced plasma albumin, so fewer plasma protein binding sites

o iii) drug metabolism - splanchnic and hepatic blood flow decrease by 0.3

– 1.5%/year - liver size and hepatocyte number decrease - hepatic enzyme activity and induction capacity

decreaseo iv) drug excretion – changes in renal function are probably

the most important factors affecting drug handling in the elderly. With age there is a steady decline in the following factors:

- reduced renal mass - reduced renal perfusion - reduced glomerular filtration rate - reduced tubular excretion These changes are normal – the situation may be

compounded if the patient has renal disease.o v) organ sensitivity – the elderly tend to be more sensitive to

CNS active drugs- e) Disease

o i) General nutritional status - unbalanced diets may lead to deficiency states and

enzyme abnormalities - starvation – decreased plasma protein binding and

metabolism - obesity – increased lipid fraction

o ii) Gastrointestinal disorders e.g. achlorhydria, coeliac disease, Crohn’s disease

altered drug absorption

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o iii) Congestive heart failure (especially in the elderly) may lead to

- reduced splanchnic blood flow - intestinal mucosal oedema - reduced hepatic clearance

o iv) Kidney failure (especially in the elderly) may lead to - decreased drug excretion leading to toxicity - water overload leading to changes in drug

concentrations in different body fluid compartments

o v) Liver failure may lead to - reduced metabolism - reduced first pass metabolism (hence increased

bioavailability) - decreased biliary secretion and hence decreased

removal - decreased albumin synthesis and hence reduced

plasma protein bindingo vi) Other acute or chronic disease states

- CYP3A4: a CytP450 enzyme in the liver responsible for the metabolism of a range of drugs including warfarin

- Digoxin: Is metabolised at KIDNEY so should consider / check kidney function, esp if want to give high dose because if impaired metabolism the effects will be even more potent!

- INR: o Normal: 0.9-1.2o International normalised rationo A measure of the prothrombin timeo Plasma isolated and TF (tissue factor added); time taken to clot measured

- Effect of what food is in the stomach:o Tetracycline: Food or dairy products reduce the absorption of tetracycline; works

best when taken on an empty stomach [tetracycline binds to calcium in stomach; When it is bound the body can't absorb it]

o Bisphosphonates: food may decrease and delay the absorption of the drug

- Effect of old age:o Benzodiazapines:

More sensitive CNS, reduced liver metabolism and kidney excretion means should consider using lower doses

Note that some Benzodiazapines actually need to be activated in the body by liver enzymes in which case a higher dose would be required!

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- Effect of weight:o Weight loss, other than being an important symptom also means that may need to

change the dosage of drug that a patient is on; as patient loses weight the drugs become more potent

o Mech: low protein uptake giving reduced plasma proteins so increased free drug relatively lower body water so reduced volume of distribution of the drug so

acts more potent

- Drugs increasing warfarin potency:o Clarithromycin:

Is an antibiotic but through mechanisms separate to its bac killing it can also irreversibly inhibit CYP3A4 that would otherwise metabolise warfarin

o Other drugs with the same effect on CYP3A4: Other antibiotics Fluconazole (anti-fungal) Omeprazole (PPI) Grapefruit juice Disulfiram (alcohol aversion therapy: inhibits aldehyde dehydrogenase) Cimetidine (histamine H2-receptor antagonist; inhibits stomach acid

production)

- Drugs decreasing warfarin potency:o St John’s Wort:

Used as antidepressant as it blocks 5HT reuptake transporter in brain Induces CYP3A4 which metabolises Warfarin

o Drugs which increase metabolism by liver by more general or alternative means: Alcohol (inc CYP2E1 and aldehyde dehydrogenase activity) Brussel sprouts (induces diff CYPs) Smoking (induces diff CYPs)

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17/02/14: ADVERSE DRUG REACTIONS AND INTERACTIONS: Mike Schachter

Los (from booklet): [these seem irrelevant to the lecture given]

1. Explain the physiological control of vomiting2. Identify the receptor specificity, the main sites of action and the specific antiemetic uses of promethazine, metoclopramide, hyoscine and ondansetreon.3. List the main pharmacokinetic features and unwanted actions of promethazine, metoclopramide, hyoscine and ondansetron

Los (from slides):- to appreciate clinical importance of adverse drug reactions (ADRs)- to outline how they might be classified- to introduce ways in which they can be detected- to outline how drugs interact, both intentionally and harmfully

Notes:

- Adverse Drug Eventso ME: Medication Errors (preventable)o ADR: preventable or unpredicted medication event

- Classification of ADRso Onset

Acute Within 1 hour

Sub-acute 1 to 24 hours

Latent > 2 days

o Severity

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Mild requires no change in therapy

Moderate requires change in therapy, additional treatment, hospitalisation

Severe disabling or life-threatening

o Type Overview of types/summary:

A Augmented pharmacological effect B Bizarre C Chronic D Delayed E End-of-treatment

Type A: “Augmented pharmacological effect” extension of pharmacologic effect of the drug therefore usually predictable and dose dependent commonest: responsible for at least two-thirds of ADRs May (paracetamol; non linear toxicity) or may not (dijoxin; linear

toxicity) demonstrate dramatic therapeutic window effect

Examples:o eg atenolol and heart block, o eg anticholinergics and dry mouth, o eg NSAIDS and peptic ulcer

Type B: “Bizarre” idiosyncratic or immunologic reactions; ie both mean that the effect

is individual to that person; some suffer ADR and some don’t includes allergy and “pseudoallergy” rare and unpredictable Examples:

o Eg chloramphenicol (an antibiotic) and aplastic anemia [= BM failure; is a blood disorder in which the body's bone marrow doesn't make enough new blood cells]

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o Eg ACE inhibitors and angioedema (is a pseudo anaphylaxis; similar traits to a proper anaphylaxis but is less severe) (not same as urticaria)

Type C: “Chronic” associated with long-term use involves dose accumulation [total drug taken in life is what counts] Examples:

o Eg methotrexate and liver fibrosis, o Eg antimalarials and ocular toxicity [includes Chloroquine

treatment of rheumatoid arthritis]

Type D: “Delayed” delayed effects; ie occur a long time after having taken the drug

(sometimes dose independent) Examples:

o (e.g. immunosuppressants) Eg carcinogenicity o (e.g. thalidomide [producing fetal malformation]) Eg

teratogenicity Type E: “End-of-treatment”

Withdrawal reactionso Eg Opiateso Eg benzodiazepines o Eg corticosteroids

Rebound reactions [relationship to withdrawal: is often an aspect of withdrawal; ie refers to the swinging back of the physiologic event being targeted that occurs when the drug is removed]

o Eg Clonidine, o Eg beta-blockers, o Eg corticosteroids

“Adaptive” reactionso Eg Neuroleptics (= Antipsychotics = “major tranquillisers”)

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Withdrawal-related psychosis from antipsychotics is attributed to increased number and sensitivity of brain dopamine receptors, due to blockade of dopaminergic receptors by the antipsychotics, which often leads to exacerbated symptoms in the absence of neuroleptic medication

- Allergies [these would all prob be classified as Type B]:o Types of allergic reactions

Type I - immediate, anaphylactic (IgE) e.g., penicillins giving anaphylaxis

Type II - cytotoxic antibody (IgG, IgM) e.g., methyldopa and hemolytic anemia

Type III - serum sickness (IgG, IgM) antigen-antibody complex e.g., procainamide-induced lupus [used for the medical treatment of

cardiac arrhythmias] Type IV - delayed hypersensitivity (T cell)

e.g., env substance giving contact dermatitiso “ allergies” [nb these reactions only occur in a fraction of the group of people on

these drugs] Aspirin/NSAIDs

Give bronchospasm [due to redirection of arachidonic acid from the neutral/dilator prostanoids to the constrictor leukotrienes]

ACE inhibitors Give cough (~20% of patients; due to bradykinin build-up) Give angioedema (~anaphylaxis response)

- ADR detection:o [note that rare ADRs are not picked up on until are in general use]o Genetic testing for known susceptibility genes (only used in a small number of

specific scenarios)o Yellow cards (esp for black triangle drugs; less than 2yrs old)

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- Drug Interactionso Pharmacodynamic

Ie acting via the drug’s effects in the body Ie Additive, synergistic, or antagonistic effects from co-administration of two

or more drugs Eg acting via receptor site occupancy Examples:

Synergistic actions: of antibiotics Overlapping toxicities: ethanol & benzodiazepines

o [alcohol increases the binding affinity of benzodiazepines to the benzodiazepine binding site, which results in a very significant potentiation of the CNS and respiratory depressant effects]

Antagonistic effects of two drugs: anticholinergic medications (eg amitriptyline) and acetylcholinesterase inhibitors

o Pharmacokinetic Ie acting via the body’s effects on the drug Eg

Alteration in absorptiono Chelation

Irreversible binding of drugs in the GI tract [ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2),

dairy products (Ca+2)] Tetracyclines quinolone antibiotics

Protein binding effectso Competition between drugs for protein or tissue binding

siteso Increase in free (unbound) concentration may lead to

enhanced pharmacological effecto Many interactions previously thought to be PB interactions

were found to be primarily metabolism interactionso Protein binding interactions are not usually clinically

significant but a few are (mostly with warfarin; warfarin is almost 100% bound to plasma proteins so any loss in plasma prot level will at least give temporary effects to inc warfarin level)

Changes in drug metabolismo Drug metabolism inhibited or enhanced by coadministration

of other drugso Phase 1 = CYP 450 system [more studied than phase 2]

Members: CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others

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A) Metabolism by multiple isozymes: Most drugs metabolized by more than one

isozyme Eg Imipramine: CYP2D6, CYP1A2, CYP3A4,

CYP2C19 Redundancy: If co-administered with

CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme

B) Metabolism by a single isozyme predominantly: Examples are drugs used primarily in

research on drug interactions There are few examples of clinically used

drugs though warfarin is mainly CYP2C9 or 3A4 and paracetamol/caffeine is mainly CYP1A2

CYP 450 Inhibitors [Nb Inhibition is very rapid] Cimetidine: histamine H2-receptor

antagonist that inhibits stomach acid production

Erythromycin and related antibiotics Ketoconazole etc [antifungal medication] Ciprofloxacin and related antibiotics Ritonavir and other HIV drugs Fluoxetine and other SSRIs Grapefruit juice

CYP 450 Inducers [Nb Induction takes hours/days] Rifampicin [antibiotic] Carbamazepine [anticonvulsant and mood-

stabilizing drug] St John’s wort (hypericin) (Phenobarbitone) [barbiturate] (Phenytoin) [antiepileptic drug]

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o Phase 2 metabolic interactions (glucuronidation, etc.) also can occur, is less studied but research in this area is increasing

Alteration in eliminationo Almost always in renal tubule

- probenecid and penicillin (good) probenecid [increases uric acid excretion in

treatment of gout] reduces paracetamol excretion

- lithium and thiazides (bad) Thiazides volume deplete you, so the prox

tubule wants to reabsorb greater quantities

of Na+ there, and Lithium is reabsorbed with the Na but lithium has narrow therapeutic window so inc level bad (eg can cause NEPHROGENIC DI) Nb [lithium = mood-stabilizing drug, primarily in the treatment of bipolar disorder]

o Pharmaceutical drugs interacting outside the body (mostly due to chemical/physical

interactions in IV infusions)

- Deliberate interactions:o levodopa + carbidopao ACE inhibitors + thiazideso penicillins + gentamicino salbutamol + ipratropium

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17/02/14: Tutorial: population studies and family studies

Los (from booklet):

- Explain how genetic differences influence individual response to drugs.- Identify differences between population studies and family studies in terms of assessing

genetic differences.

Notes:

- Pharmacogenetics: o Is regarding effects of genetic differences on reaction to drugs

- Pharmacogenomics:o Genome based techniques in drug development

- Polygenic controlo Several genes act together to give rise to a CONTINUOUS or UNIMODAL (GAUSSIAN)

distribution of the measured variable. o It is not possible to recognise or discern the influences of single genes.o there may be large quantitative differences between the extremes of this

distributiono Example: Salicylate rate of phase 2 metabolism: conjugation with glycine (as in prev

notes) or glucuronic acid

- Monogenic controlo Owing to the action of a single gene that has a large overriding effect. This gives rise

to a DISCONTINUOUS or MULTIMODAL distribution of the measured variable. o Example in Drug Metabolism:

(a) Rare trait succinylcholine hydrolysis by plasma cholinesterase

(b) Polymorphism debrisoquine (+ other drugs) hydroxylation by cytochrome P450 2D6 sulphadimidine (+other drugs) N-acetylation by N-acetyltransferase

o Simplest if just two alleles are governing the phenotype:

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Possibilities: If recessive or dominant inheritance this would give two peaks

(two phenotypes) If codominance there would be three peaks (three phenotypes)

Analysis: Ideally the two peaks would be separated ie with no overlap of the

peaks relating to the diff phenotypes If overlap occurs will have to assign a cutoff point to separate the

peaks into discrete groups Hardy-Weinberg

Hardy-Weinberg law: allele and genotype frequencies remain constant through time in the absence of a selection pressure

Hardy-Weinberg Equation: (p + q)2 = p2 + 2pq + q2 = 1 Nb p = dominant

Example: Sulphadimidine metabolism by acetylation Population study:

o Shows two peaks; both peaks almost same frequency: This does not give info on type of inheritance other

than is not codominant; ie the frequency is dependent on both the type of inheritance AND the frequencies of the alleles in the population

To establish the type of inheritance must do a family study: in this case parents are FAST metabolisers but one daughter is SLOW metabolizer so SLOW must be recessive [split between SLOW and FAST is at 0.51-0.60 so dividing the family members based on this categorises them]

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Then use equation: Use p2 + 2pq + q2 = 1: assign q2=SLOW (eg =

0.51) phenotype and p2 + 2pq (= 0.49) as FAST phenotype; know SLOW frequency so can learn q value

Then use (p + q)2 = 1 to find p value Then use p2 + 2pq + q2 to determine the

frequencies of each genotype (ie can distinguish the p2 and 2pq genotypes despite their same phenotype

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02/05/14: Drugs of Abuse1: General/ Cannabis: Chris John

Los (from booklet):- Drugs of Abuse 1&2 (Dr C. John)- General introduction/Cannabis & Nicotine and Cocaine- 1. Identify the ‘reward’ pathways in the brain activated by drugs of abuse, list the main

abused substances and explain how they specifically activate reward pathways. - 2. Explain the pharmacokinetics for the major drugs of abuse (e.g. routes of administration,

metabolism). - 3. Summarise the basic pharmacology for the main abused substances (cannabis, nicotine,

cocaine).

Notes:

- All drugs that give euphoria act by influencing the Mesolimbic dopamine system = the central reward pathway.

o Dopaminergic transmissiono As shown below this passes from the Ventral Tegmental Area [midbrain; see below

pic] to the Nucleus Accumbens in the Ventral Striatum [in front of hypothalamus] where dopamine is released to give the euphoria:

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[VTN]

[nucleus accumbens]

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- Routes o ‘Snort’ – Intra-nasal

‘Snort’ – Mucous membranes of nasal sinuses. Slow absorption

o ‘Eat’ - Oral ‘Eat’ – Gastrointestinal tract Very slow absorption

o ‘Smoke’ - Inhalational ‘Smoke’ – Small airways and alveoli Rapid absorption (slightly faster than IV)

o ‘Inject’ – Intra-venous ‘Inject’ – Veins Rapid absorption

- Smoking is the fastest route of action: alveoli v thin walled so straight to blood then straight to heart and up to the brain (IV has to go through full venous system then lungs and heart and finally brain)

o (ascending order for onset of euphoria): Oral < Intranasal < Intravenous < Inhalational

Classification [only certain ones will be covered in depth]

- Narcotics/Painkillers: opiate like drugs o e.g. heroin

- Depressants – ‘downers’ o e.g. alcohol, benzodiazepines (valium), barbiturates

- Stimulants – ‘uppers’o e.g. cocaine, amphetamine (‘speed’), caffeine, metamphetamine (‘crystal meth’)

- Miscellaneouso e.g. Cannabis, Ecstasy (MDMA)

Cannabis- Cannabis is from any part of the Cannabis Sativa plant esp yellow trichomes (glandular hairs)- 9-THC: Delta 9 THC is the most prevalent and active cannabinoid in the cannabis plant- Hashish oil can be used in combination to increase the cannabis dose further - Greater dose = greater effect; eg can be used to treat glaucoma better at higher dose- Smoked or eaten:

o Smoked 50% bioavailability (is typical for smoking route of most drugs)

o Eaten 10/15% bioavailability delayed onset/slow absorption first pass metabolism occurs

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Slow excretion of drug from the body:- 1. High fat solubility:

o fat soluble but fast has poor bloodflow so initially drug is mainly at brain and other highly perfused tissues

o However eventually will peak in fat and remain there for a long time due to the fat solubility

- 2. First metabolite is more potent than the parent compound! o so initially metabolism is not helping

- 3. main excretion is via liver to gut but then extensive enterohepatic cycling occurs due to its high lipid solubility

o 65% exits via liver to GIT but very little successfully excreted by this route so reliant on the 25% exiting in urine [10% must exit via another mech]

o Excreted as 11-hydroxy THC- Hence persists in body for 30 days after smoking a cannabis cigarette

Target- two types of cannabinoid receptor: are Gi linked hence inhibitory to adenylate cyclase (are

not GPCRs though): endogenously Anandamide is the NT acting at CB receptorso CB1 receptors

Central: Hippocampus/cerebellum/cerebral cortex/basal gangliao CB2 receptors

Peripheral: Immune cells

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- Euphoria: due to inhibition of GABA interneurone which otherwise gives inhibition of VTAo Ie disinhibition / ‘releasing the brake’ of dopamine release

- Schizophrenia and psychosiso Due to cannabinoid signalling at ACC [Anterior Cingulate

Cortex]: important in error detection and is an amplifier/filter to improve emotional processing (Insight/ response to emotional cues)

- Food intake: increases apetiteo Disinhibition of orexin increased appetite o Ie Positive effect on orexigenic neurones in lateral hypothalamus

- Memory loss: (Amnestic effects)o ↓ BDNF in limbic regions: BDNF important in the laying down of memory but levels

are reduced in cannabis use [low BDNF will prob contribute to increased hunger too]- Psychomotor decline

o Due to disruption at Cerebral cortex- Antiemetic- Pain inhibition:

o Is known to reduce pain levels (cf)- Infertility - Stroke

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- Peripheral effects;o Immunosuppressant

[expected due to effects at CB2 receptor]o Tachycardia/vasodilation [“is what the T and V stand for in TRPV1”]

Ie Conjunctivae: red eyes Effect mediated by TRPV1 rather than cannabinoid receptor

o Respiratory Only due to the side effects due to smoking anything (CO etc); possibly

hotter to lungs too- Upregulation of CB receptors occurs: Important info:

o 1. Multiple sclerosis to help cope with the pain: this is a regulatory response = good

Agonists therefore used to enhance such effects: Dronabinol Nabilone Sativex

CB agonists can be used in MS vs the pain and in other conditions to help with pain

CB agonists can be used in AIDS patients for weight gain CB agonists can be used in chemotherapy patients as antiemetic

o 2. Infertility/obesity/stroke: all can increase with cannabis use: this is a pathological response = bad

Antagonists therefore used to counter these effects: Rimonabant

CB antagonists can be used vs obesity for weight loss: “would also help avoid any CB mediated stroke or infertility problems”

- Cannabis – Summaryo Cannabis Sativa 9-THC ( potency)o Pharmacokinetics;o Onset = Seconds Minutes

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o Tissue t1/2 = 7 dayso Elimination 11-hydroxy THC: Gut (65%), Urine (25%)o Pharmacodynamics;o CB1 (brain), CB2 (periphery) – anadamideo Euphoria/Food intake/Memory Losso ‘Autoprotection’ – Dronabinol, Sativexo ‘Autoimpairment’ - Rimonabant

02/05/14: Psychoactive drugs 4: Cocaine & Nicotine: Chris JohnLos (from booklet):

- Drugs of Abuse 1&2 (Dr C. John)- General introduction/Cannabis & Nicotine and Cocaine- 1. Identify the ‘reward’ pathways in the brain activated by drugs of abuse, list the main

abused substances and explain how they specifically activate reward pathways. - 2. Explain the pharmacokinetics for the major drugs of abuse (e.g. routes of administration,

metabolism). - 3. Summarise the basic pharmacology for the main abused substances (cannabis, nicotine,

cocaine).

Notes:Cocaine

- From leaves of the coca part- Types:

o ‘Paste’ ~ 80% cocaine - dissolve in organic solvento ‘Cocaine HCl’ - dissolve in acidic solution

i.v., oral, intranasal cannot smoke it: heat labile Medicinal form

o ‘Crack’ - precipitate with alkaline solution (e.g. baking soda) Inhalation / smoking Most used form as a drug of abuse

o ‘Freebase’ - dissolve in non-polar solvent (e.g. ammonia + ether) Inhalation

- Quickly enters the blood system but also is quickly removedo Unless taken orally: pKa = 8.7: oral cocaine ionized in GIT hence slower absorption

and prolonged actiono Otherwise: T1/2 is short: 20-90mino Metabolism: Some breakdown in the blood, mainly in the liver: Plasma/liver

cholinesterases and non-specific esterases

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o Excretion: Extensively metabolised by the liver and then excreted in the urine as ecgonine methyl ester or benzoyl ecgonine ; little is excreted without having been metabolised

o Quick response allows strong association with euphoria hence high addictability; exacerbated by the rapid speed of loss of the effect: possibly the most addictive drug

Ritalin similar but taken orally so avoid the addictability

- Blocks uptake 1: inhibits monoamine transporterso Will increase levels of the following at that synapse:

NA/Ad 5-HT Dopamine

Targets:

- Local Anaesthetico Is an Na channel blocker hence pain blockero [“via hydrophilic pathway”]

- Euphoria: o Via uptake 1 block:

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o cocaine has no effect on dopamine affinity (effect of one molecule to bind at the receptor)/efficacy (ability of one molecule to act at the receptor) for the dopamine receptor

o Relatively harmless if not used in very high levels / chronically:

o Dangers peripherally: May be harmful peripherally due to its stimulant activity and binds receptors on platelets but need to have genetic predisposition:

sympathetic stimulation Vasoconstriction Increased heart rate platelet activation

o Some CNS effects but only harmful if underlying pathology that is exacerbated: CNS vasocontriction and Hyper-pyrexia [fever-mimic] can lead to Epilepsy in

some people

- Cocaine – Summaryo Erythroxylum coca Cocaineo Cocaine HCl – ‘Intranasal’o Crack/Freebase – ‘Inhalation’o Pharmacokinetics;o Onset = Secondso Tissue t1/2 = <90mino Elimination ecgonine methyl ester, benzoylecgonine : o Urine (75-90%)o Pharmacodynamics;o Blockade of Na+ channels – Local Anaesthesia

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o Transport Inhibitor – Euphoria (CNS effects), CVS problems

Cigarettes- Components:

o Volatile: (95%) Particulate: (5%)o Nitrogen Alkaloids [nicotine]o Carbon Monoxide/Dioxide Tar [alkaloids dissolve in the hot tar]o Benzeneo Hydrogen Cyanide

- Nicotine tends to be ionised in lung so poor transfer in upper airways though can still cross at alveoli [Absorption in alveoli independent of pH / charge]

o 20% bioavailability via inhalation/smoking compared to 50% for most smoked drugs o pKa 7.9 but cigarette smoke is acidic hence ionised and no buccal absorption. o All nicotine replacement therapies have a better bioavailability than smoking

- Not as addictive as cocaine but blood level change through time of nicotine is nearly as drastic [see pic below]

- Nicotine replacements do not achieve the same peaks of nicotine so may not be sufficient to quit; e-cigarettes may be able to get closer to level of cigarette

- Metabolism:o Hepatic CYP2A6

70-80% forms Cotinine [nicotine Cotinine] urine excretiono T1/2 = 1-4hrs

- Target:o nAChR

5 subunits

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Diff subunit compositions throughout the body: nicotine targets all nAChR types but drugs may in future be able to antagonist effects at certain nicotine receptor subtypes [DHTK]

o Not just peripheral effects as have looked at in prev parts of the course on nAChRs; also extensive CNS effects due to nAChRs in CNS

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http://jpet.aspetjournals.org/content/vol292/issue2/images/large/pt0200838002.jpeg


o Euphoria via nACHRs in CNS:

- Cardiovascular effects: o Extensive CV effects of nicotine lead to Cardiovascular Diseaseo Already parasympathetic tone so the effects seen are: sympathetic stimulation

(CNS & Adrenals) H.R. & S.V. Vasoconstriction

Coronary arterioleso Constriction (ie more NA like effects than Adrenaline like

effects) Skin arterioles

o Constriction: skin temperature drops by up to 5 degree Vasodilation

Skeletal muscle arterioles Negative lipid profile of change in serum:

lipolysis, FFA, VLDL, HDL

Clotting increased: TXA2, NO

- Weight o Increased metabolic rateo Sympathetic stimulation decreases appetiteo Hence if stop smoking will put on weight

- Potential for helping Parkinson’s or Alzheimer’s:

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o protective vs these diseases as removes toxins associated with these diseases; however only delays the onset of these diseases and only protective prior to onset of these diseases:

Parkinson’s Disease; brain CYPs → neurotoxins Alzheimer’s Disease: -amyloid toxicity; amyloid precursor protein (APP)

- Nicotine – Summaryo Nicotana tabacum Nicotineo Cigarettes – Nicotine 5% Particulateo Pharmacokinetics;o Onset = Secondso Tissue t1/2 = 2-3ho Elimination cotinine; liver (75-80%)o Pharmacodynamics;o Activation of nicotinic acetylcholine receptorso Euphoria, CVS disease, ↑ metabolic rate & ↓ appetiteo ++ - Alzheimer’s/Parkinson’s

- Dhtk:o Caffeine:

Adenosine positively signals presynaptically for an anti-dopaminergic effect; this brake is removed by caffeine’s opposition to adenosine signalling

o Chocolate: No effect of chocolate on reward pathway

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02/05/14: Psychoactive drugs 3:Alcohol: Chris JohnLos (from booklet):

- Alcohol - (Dr C. John)- Identify the dose-dependent effects of acute ethanol ingestion on: CNS function and put

forward theories to explain the underlying mechanism of action; Other body systems- Identify the consequences of long-term excessive ethanol consumption- Summarise the main pharmacokinetic features of ethanol.- Explain how tolerance to the effects of ethanol is produced and identify which symptoms are

associated with alcohol withdrawal in dependent subjects.

Notes:

- Absolute amount:o % ABV x 0.78 = g alcohol/100ml (ABV = alcohol by volume)o 80mg/ml = (Legal driving limit) but x 4 risk of driving accident at this dose

- Units:o [%ABV x volume (ml)] / 1000 1 unit = 10ml or 8g of absolute alcohol

- Safe level: o brackets = high risk level / percent of people in high risk bracketo non bracketed = is for low risk figures

Men <4 (8) units at least 1/7 42% (19%) Low dose consistently is potentially protective against cardiovasc

risk (and any kind of binge is harmful) Women < 3 (6) units at least 1/7 36% (8%)

- Absorption:o 20% = from stomacho 80% = from intestine

Hence a high rate of absorption is achieved when the stomach is empty and drinking on a full stomach keeps alcohol in stomach where absorption is less favourable: ie lower peak of blood alcohol

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- Metabolism [liver and stomach]o 10% not metabolised: some of this is via the lungs hence breath test workso 90% of the alcohol is metabolised: 85% by liver; 15% by stomach

Two major enzyme systems: Alcohol dehydrogenase (75%)

o This system is the method utilised by the stomach [the liver uses both enzyme systems]

Mixed function oxidase (25%)o This can be increased if person regularly drinks

Metabolised to acetaldehyde: toxic

o Alcohol passes via the liver first hence liver enzymes can quickly become saturated: means that repeated small doses far far lower blood alcohol than if take all at once.

o Why women more sensitive to alcohol: 1. More body water in an equivalent male vs women of same weight as

women made up more of fat; more body water in men to dilute out the alcohol

Body water: 50% in female Body water: 59% in male

2. Women have greatly reduced Alcohol dehydrogenase level compared to men

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o IMPORTANT DRUG INFO: Aldehyde dehydrogenase converts the acetaldehyde to acetic acid; this occurs in both the liver and the stomach:

Disulfiram = inhibitor of Aldehyde dehydrogenase hence used in alcohol eversion therapy by causing build-up of the toxic acetaldehyde in the blood giving unpleasant effects

Genetic polymorphism: Mutation prevalent in Asians to Aldehyde dehydrogenase hence less able to tolerate alcohol: natural alcohol eversion!

- Asian races possess genetic variations in the enzyme alcohol dehydrogenase associated with alcoholism

- Asian races possess genetic variations in the enzyme aldehyde dehydrogenase associated with alcohol intolerance

- IMPORTANT: LOW pharmacological potency, selectivity, affinity and efficacy; effects due to high doses and effects at many many targets:

o affinity and efficacy for its targets is lowo comparison:

Nicotine 20ng/ml Cocaine 200ng/ml Alcohol 200 microg/ml [ie high!]

- Acute CNS effects:o Both depression and excitation: Primarily a depressant in absence of social

stimulation or at high dose but CNS excitation at low dose in a social settingo Enhance: Promotes increase in GABAergic activity:

mech is via inc stim of Allopregnenolone release which then has the positive effect at GABA neurones

o Block: decreased signalling at Glutamate NMDA receptors [mech is Allosteric modulation]

o Block: decreased signalling at Ca2+ channels [mech is involving Neurotransmitters]

- Euphoria: arguably no euphoria as inc GABA inhibition and dec NMDA stimulation of dopamine release:

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ACUTE EFFECTS: Little known about what targets correspond to which effects- Cutaneous vasodilation:

o Mech: Ca2+ entry or ACETALDEHYDE prostaglandins vasodilation- Cardiovascular: increase to heart rate : [but BP will not inc due to the above

vasodilation]o Mech: Baroreceptors signal tonically for parasympathetic and inhib of sympa but

alcohol counters para baroreseptor signalling so dec para and inc sympa and increase in HR

- Diuresis (polyuria):o Mech: K+ entry or mediated by ACETALDEHYDE o Alcohol inhibits the pituitary secretion of anti-diuretic hormone ( ADH)

- Certain brain regions appear to be more sensitive;o CORTICAL region; here alcohol impairs both:

(a) Sensory function (b) Motor function

o Corpus Collosum Function: Passes info from the left brain (rules, logic) to the right brain

(impulse, feelings) and vice versa. o Hypothalamus

Function: Controls appetite, emotions, temperature, and pain sensation. o Reticular Activating System

Function: Consciousnesso Hippocampus

Function: Memoryo Cerebellum

Function: Movement and coordinationo Basal Ganglia

Function: Perception of time

CHRONIC EFFECTS: [long term high alcohol usage]- Dementia

o Cortical atrophy and dec volume cerebral white matter - Ataxia

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o Cerebellar cortex degeneration - Wernicke-Korsakoff syndrome

o Due to thiamine = vit B1 deficiency: alcoholic is getting calories from alcohol so not getting certain nutrients

o Wernicke’s encephalopathy Reversible

o Korsakoff’s psychosis Irreversible

- Liver:o Alcohol dehydrogenase uses up NAD+; leads to impaired metabolism of glycerol

and fatty acids hence lipid droplets build up (reversible but constantly present if chronic drinking)

o Acetaldehyde etc leads to inflammatory changes : increased ROS and Hepatic cytokine changes (e.g. IL-6 and TNF-) giving hepatitis

(reversible but constantly present if chronic drinking)o Cirrhosis: fibroblast infiltration and reduced hepatocyte regeneration leads to

impaired regeneration of the liver cirrhosis (relatively irreversible and may lead to liver failure)

- Cardiovascular System: BENEFICIAL EFFECTS o Mortality from coronary artery disease reduced in Men drinking 0-4 units/day due

to: Inc HDLs Inc t-PA levels / platelet aggregation Polyphenols of red wine may be particularly effective

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Other effects:- Gastrointestinal tract

o Alcohol dehydrogenase in stomach gives high acetaldehyde build-up in gut leading to:

Damage to gastric mucosa increased permeability Carcinogenic effect

- Endocrine Systemo Increased ACTH secretion [“stress response”]

Ethanol can induce a pseudo-Cushing’s syndromeo Decreased Testosterone secretiono Alcohol inhibits the pituitary secretion of anti-diuretic hormone ( ADH)

- HANGOVER o Symptoms peak as blood alcohol concentration reaches zeroo Nausea

Irritant Vagus Vomiting centero Headache

Due to Vasodilationo Fatigue

1. Sleep deprivation, 2. ‘Rebound sympa’

Restlessness and muscle tremors ‘Rebound’ excitation of the CNS (muscle cramps etc) hence poor quality of sleep

o Polyuria and polydipsia ↓ ADH secretion

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08/05/14: Dopaminergic pathways of the brain and drugs used to treat Parkinson’s Disease and schizophrenia: Professor David Dexter

Los (from booklet):

Identify the main symptoms displayed by patients with Parkinson’s disease (PD) and explain their underlying pathology List the 3 main drug classes used to treat PD and explain their mechanisms of action Summarise the problems with the current drug treatment for PD and the side-effects associated with levodopa in particular Identify the major symptoms displayed by schizophrenic patients and the associated neural pathways List the main first-generation antipsychotic drugs in clinical use and identify their side-effects List the main second-generation antipsychotic drugs in clinical use and identify their side-effects

Notes: [can use last years lec by sohag or booklet info if want clarification / detail]:

- Describe the main symptoms displayed by patients with Parkinson’s disease (PD) and their underlying pathology

o Motor deficits: bradykinesia, resting tremor, rigidity, postural instabilityo Due to degeneration of nigrostriatal dopaminergic neurones

- Name the 3 main drug classes used to treat PD and describe their mechanisms of actiono DA replacement: Levodopa acts as DA precursoro DA receptor stimulation: D2 agonists: bromocriptine, ropiniroleo Prevention of breakdown: MAOB inhibitors (selegiline), COMT inhibitors

(entacapone)

- Summarise the problems with the current drug treatment for PD and the side-effects associated with levodopa in particular

o Drug therapies not disease modifyingo Levodopa induces dyskinesias and eventually ‘off’ periodso D2 agonists associated with psychosis

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- Describe the major symptoms displayed by schizophrenic patients and the associated neural pathways

o Positive symptoms: mesolimbic pathway; hallucinations, delusions, thought disordero Negative symptoms: mesocortical pathway; affective flattening, reduced self-

awareness, lack of motivation

- Name the main typical antipsychotic drugs in clinical use and provide details of their side-effects

o Chlorpromazine: phenothiazine causing antimuscarinic side-effectso Haloperidol: potent D2 antagonist causing extrapyramidal side-effects

- Name the main atypical antipsychotic drugs in clinical use and provide details of their side-effects

o Clozapine: very effective but causes agranulocytosiso Risperidone: effective but associated with weight gain & EPSo Quetiapine: low incidence of EPSo Aripiprazole: partial agonist, low incidence of hyperprolactinaemia

- Dopaminergic pathways:o Nigrostriatal

substantia nigra zona compacta striatum Control of Movement: involved in motor actions Associated with parkinsons

o Mesolimbic ventral tegmental area nucleus accumbens, frontal cortex, limbic cortex

and olfactory tubercule Involved in emotion (and consciousness) Associated with schitophrenia

o Tuberoinfundibular system Short neurones running

arcuate nucleus of the hypothalamus median eminence & pituitary gland

Regulate hormone secretion: specifically prolactin inhibition

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- Dopamine synapse:o Tyrosine hydroxylase: Tyrosine DOPA

Is the RDS and hence slow therefore do not give Tyrosine as a dopamine replacement: is better to give DOPA

o DOPA decarboxylase: DOPA dopamineo VMAT: uptake of dopamine to vesicles for storage until release

In addition to the neuronal death, the storage capacity of neurons for dopamine is lost as disease progresses hence “on/off” response to DOPA treatment develops ; cf

o Dopamine transporters: Presynaptic dopamine transporters recycle dopamine once it has served its synaptic function

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PARKINSON’S

- How common is Parkinson’s diseaseo 1 in 1000 of the general population.o 1 in 100 of those aged over 60 years of age.o Mean age of onset 65 years but younger people can develop the disease.o Women are less likely to develop the disease than men (4:1 males:females)o Familial Parkinson’s Disease

accounts for ~8% of all cases 6 main gene mutations are observed in these cases

o Idiopathic Parkinson’s Disease 92% of cases possibly due to a combination of environmental and oxidative stress giving

altered protein metabolism

- Relative prevalence to other conditions:o Increasing prevalence:

Parkinson’s Alzheimer’s schizophrenia = epilepsy stroke

[note that schizophrenia is common: 1% of general population]

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[Symptoms: see neuro notes for better / comprehensive coverage]

- Cardinal signs of Parkinson’s Disease [diagnosis is purely clinical and requires at least 2/4]:o Rest tremor

Shaking of the limb when relaxedo Rigidity

Stiffness, limbs feel heavy/weako Bradykinesia

slowness of movement: problems in initiating movemento Postural abnormality

flexion of the neck and trunk- Presenting symptoms of PD

o Difficulty with fine movements o Lack of blinking.o Impassive face.o Speech problems:

Monotony of speech & loss of volume of voice. Because is a motor task and the excess secretion will not help

o Lack of arm swingo Loss of balance

lack of righting reflexo Short steps, shuffling gait

- Presenting symptoms of PDo Symptoms appear on one side of the body first (unilateral onset).o Symptoms then spread to both sides of the body.o Generally symptoms worsen with some patients becoming severely disabled.

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- Non-Motor symptoms of PDo Depressiono Pain

Due to the disruption of motor movements eg the constant tremor o Taste/smell-disturbanceso Cognitive decline / Dementia / Memory impairmento Autonomic dysfunction

Constipation: loss of dopaminergic neurons in the ENS; is treated separately Postural hypotension Urinary frequency/urgency Impotence Increased sweating

- Neuropathology of Parkinson’s diseaseo Principal area: Substantia nigra

a-syneuclein deposits Lewy bodies:

Develop as part of a defence mechanism: attempt to clear the a-syneuclein

However when become full of a-synuclein toxic products begin to escape hence become pathological

o Other brain areas are affected [these involve other neurotransmitters; is not just dopaminergic neuron loss]

e.g. Locus coruleus (NA), Dorsal motor nucleus of Meynert (ACh), Raphe nuclei (5HT)

o Aetiology of PD is not known!

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- Parkinson’s Disease Stagingo Corresponds to progression upward in the brain (see below): disease starts in

brainstem then midbrain then cortexo Only beyond stage 3 does it become symptomatic in terms of motor dysfunction:

Corresponds to death of SNc dopaminergic neurons giving motor dysfunction

[note the grouping of stages]

- BIOCHEMICAL CHANGESo Marked reduction in caudate nucleus/putamen dopamine contento Necessary to lose 80% of the dopaminergic neurons and deplete 70% of the striatal

dopamine before symptoms appear!o Compensatory mechanisms prevent the appearance of clinical symptoms

Upregulation of dopamine receptors Increased exocytosis from neurons that have been spared

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Dopamine Replacement Therapy

- Dopamine o NOT SUITABLE: can’t cross blood-brain barrier; just crosses where BBB is incomplete

such as at CTZ where it will give vomiting!- L-DOPA - D2R agonists: but side effects- Inhibitors to the dopamine breakdown pathways

- L-DOPA [is the gold standard treatment for early parkinsons]:o DOPA is the precursor to dopamine, converted to dopamine in the brain by enzyme

DOPA decarboxylase (DD).o L-DOPA = short half lifeo However, DD also present in peripheral tissues.

If administered alone 95% of L-DOPA is metabolised to dopamine in the periphery CTZ major side effects of nausea & vomiting.

SOLUTION: Use peripheral DOPA decarboxylase inhibitor + L-DOPA. DOPA decarboxylase inhibitor:

o Carbidopao Benserazide

Eg Sinemet (Carbidopa + L-DOPA) Eg Madopar (Benserazide + L-DOPA)

o TREATS

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Hypokinesia, rigidity & tremor Start with low dose of the drug and increase dose until maximum benefit

without side effects Effectiveness of L-DOPA declines with time!: have to keep increasing the

dose until eventually side effects too severe: see belowo Side effects: [nb Impulse control disorders that include gambling, eating and hypersexuality

seem to occur more commonly with dopamine receptor agonists than L-DOPA]o ACUTE

Nausea/vomiting - prevented by Domperidone (peripheral acting D2 antagonist acting at CTZ)

Some of the DOPA is being converted to dopamine in the periphery then passing to CTZ giving the nausea; solution is to use peripheral inhibitors

Hypotension The most likely hypothesis is that L-DOPA forms dopamine which

acts as a false transmitter in the peripheral sympathetic nervous system.

Psychological effects Schizophrenia like syndrome with:

o Delusions, hallucinations, confusion, disorientation & nightmares

Ie due to also increasing dopamine in the mesolimbic systemo CHRONIC o After 6 years of therapy:

Dyskinesias (54%): uncontrollable muscle movements of limbs and face are due to the drug not the parkinsons, if taken off drug parkinsons symptoms reappear, patient will just

freeze; need to try the other drugs that are not acting via the neurons

On-off oscilations (64%) Eg periods of being locked-in due to period of extreme motor

dysfunction Rapid fluctuations in clinical state. Off periods may last from minutes

to hours. Occurs more with L-DOPA use than without In addition to the neuronal death, the storage capacity of neurons

for dopamine is lost as disease progresses hence “on/off” response to DOPA treatment develops ; need to try the other drugs that are not acting via the neurons

- DOPAMINE AGONISTS

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o ACTIONS Act on D2 receptors Ergot derivatives:

Bromocriptine/Cabergoline & Pergolide problems with heart valves: dangerous cardiopulmonary fibrotic

reactions. Any drug with ergot ring can target the heart valves to cause

damage Non-ergot derivatives:

Ropinirole & Rotigotineo Ropinirole also available as extended-release formulationo Rotigotine also available as a patch

o Vs L-DOPA: longer half-lives

Longer duration of action than L-DOPA: Smoother & more sustained response: Incidence of dyskinesias is

less Actions independent of dopaminergic neurons Can be used in conjunction with L-DOPA

o ADVERSE EFFECTS Common

nausea/vomiting Schizophrenia like syndrome with:

o Delusions, hallucinations, confusion, disorientation & nightmares

Rare Hypersexuality [high libido] Addictive behaviours eg gambling

Preserving dopamine that is present:

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- MAO B INHIBITORS

o Selegiline = Deprenyl Selective for MAO-B which predominates in dopaminergic areas of CNS

hence avoid peripheral side effects of non-selective MAO-I’s Eg avoid non-selective giving the ‘cheese reaction’ etc

Can be given alone in the early stages of the disease. Or in combination with L-DOPA, allows you to reduce the dose of L-DOPA

by 30-50%; hence less side effects of the L-DOPA Side effects are rare: [relatively safe drug]

hypotension, nausea/vomiting, confusion and agitation.

o Resagiline Inhibits MAO-B AND inhibits apoptosis Shown to have neuroprotective properties by inhibiting apoptosis; promotes

anti-apoptosis genes. Early clinical trials suggest that this drug may slow the disease down but subsequent studies not so positive: no disease modifying qualities

- Catechol-O-methyl transferase (COMT) inhibitors

1. Tolcapone (= CNS & peripheral)2. Entacapone (= peripheral only)

o Mechanism: CNS

Prevents breakdown of dopamine in the brain Peripheral

COMT in the periphery not only degrades catecholamines but also converts L-DOPA to 3-O-methylDOPA (3-0MD).

3-OMD and L-DOPA compete for same transport system across the blood brain barrier (BBB).

COMT inhibitors stop 3-OMD formation thus increasing the penetration of L-DOPA across the BBB thus increasing brain concentrations, where it is converted to dopamine.

In this way allows reduction of L-DOPA dosage!o Side Effects

Cardiovascular (esp entacapone) and liver (esp Tolcapone) complications

- Anticholinergic drugs: helps to relieve tremor in mild to moderate disease [vs M4R’s]- Deep brain stimulation:

o Like a brain pacemaker; elec stimulation to specific areas the lead may be placed in either the globus pallidus or the subthalamic nuc

o Purpose is to stimulate nerve signals to prevent tremor and other parkinsons symptoms

o Linked to causing depression thoughSCHIZOPHRENIA

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- Symptoms:o Positive symptoms:

Delusions, hallucinations, confusion, disorientation & nightmareso Negative symptoms:

emotion, speech, ability to experience pleasure, desire to form relationships, motivation

- Genetics:o Genetic component exists as shown but details are poorly characterised

- Once Schizophrenia has been diagnosed there are four main outcomes:

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o The illness resolves completely, with or without treatment and never returns (10-20% subjects).

o The illness recurs repeatedly with full recovery after each episode (30-35% subjects)o The illness recurs repeatedly, but recovery is incomplete and a persistent defective

state develops, becoming more pronounced with each successive relapse (30-35% subjects)

o The illness pursues a downhill course from the beginning (10-20% subjects)

NEUROCHEMICAL INVOLVEMENT- Dopamine theory

o Positive: Excessive dopamine transmission in the mesolimbic and striatal (see below) region leading to positive symptoms

mediated through D2 receptors. o Negative: Whilst dopamine deficit in pre-frontal region, leads to negative symptoms.

mediated by D1 receptors No drugs to help vs negative symptoms Ie dopamine can be excitatory but is inhibitory in other scenarios

o Evidence Dopamine agonists e.g bromocriptine, and amphetamine can induce various

psychotic reactions. Typical anti-schizophrenic drugs are dopamine receptor antagonists and

there is a strong correlation between antipsychotic potency and activity in blocking D2 receptors.

- Glutamate theory: = Effects due to lack of glutamate o Evidence

NMDA receptor antagonists e.g. phencyclodine, ketamine etc. produce psychotic symptoms.

Reduced glutamate concentrations and glutamate receptor densities in post-mortem schizophrenic brains.

In mice where NMDA receptor expression is reduced, show stereotypical behaviours suggestive of schizophrenia which respond to antipsychotic therapy.

Glutamate (excitatory) and dopamine (inhibitory) exert effects on GABA-ergic striatal neurons:

These GABA striatal neurons inhibit sensory neurons en route to the cortex

Too little glutamate (or too much dopamine), disables the GABA gate, allowing uninhibited sensory input to reach the cortex.

- Aetiology & Pathogenesis of Schizophreniao Disease shows a strong but incomplete hereditary tendency.o Genetic linkage studies have identified a number of risk genes, but no single gene is

responsible.

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o There are significant polymorphisms in individual genes which may trigger schizophrenia but many are weak associations.

o Genetics: The first and most robust is the gene for neuregulin-1 synaptic development and plasticity has effects on NMDA receptor expression.

o 8 other susceptibility genes have also been discovered all associated with glutamate or dopamine mediated neurotransmission.

o No specific neurotransmitter abnormality so far identified

- Mechanism of action of Antipsychotics o ALL NEUROLEPTIC DRUGS ARE ANTAGONISTS AT DOPAMINE “D2 LIKE” RECEPTORS.o Most neuroleptics block other receptors too e.g. 5-HT, thus accounting for some of

their effects.o Drugs treat positive symptoms but not the negative ones!o Delayed effects, takes weeks to work. o Initially neuroleptics induce an increase in Dopamine synthesis and neuronal

activity. This declines with time. Ie body trying to compensate for the drug action, then after failing to do so

will stop attempting this, treatment then starts being more effectiveo Antipsychotics lack dopamine receptor selectivity as shown hence a range of side

effects occur:

[just to illustrate the diverse targets]

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- OTHER ACTIONS/SIDE EFFECTS OF NEUROLEPTICS o Anti-emetic effect

Most antiemetics were developed from antipsychotics Blocking dopamine receptors in the chemoreceptor trigger zone.

Neuroleptic Phenothiazine, effective at controlling vomiting and nausea induced by drugs (e.g. chemotherapy) , renal failure.

Many neuroleptics also have blocking action at histamine receptors. Effective at controlling motion sickness.

o Extrapyramidal side effects Blockade of dopamine receptors in the nigrostriatal system can induce

“Parkinson” like side effects . Atypical antipsychotics avoid or have reduced incidence of the

extrapyramidal effects: Acute dystonia

involuntary movements: muscle spasm, protruding tongue, fixed upward gaze, neck spasm etc.

often accompanied by Parkinson’s features. Occur in the first few weeks , often declining with ongoing therapy. Reversible on drug withdrawal or anti-cholinergics. More associated with typical antipsychotics.

Tardive dyskinesias Involuntary movements, often involving the face & tongue, but also

limb and trunk. Occur in about 20% of patients after several months or years of therapy (hence ‘tardive’ [Tardive means "delayed"]).

More associated with typical antipsychotics. Irreversible: Made worse by drug withdrawal or anti-cholinergics:

are permanent effects!. o May be related to proliferation in pre-synaptic DA D2

receptors or glutamate excitotoxic striatal neurodegeneration .

o Endocrine Effects Dopamine is involved in the Tuberoinfundibular system and acts to inhibit

prolactin secretion via the D2 receptors. Antipsychotics increase serum prolactin concentrations which can lead to

breast swelling (men & women) and sometimes lactation in women.o Blocking a-adrenoceptors

causes orthostatic hypotensiono Blocking 5-HT receptors

weight gain “serotonin signals from gut when are full”o Blockade of cholinergic muscarinic receptors

Typical peripheral anti-muscarinic side effects e.g blurring of vision, increased intra-ocular pressure, dry mouth, constipation, urinary retention.

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Drug detail: [is from sohags lec from last year but we prob have to know about them; is in Los]:

- Typical:

o Chlorpromazine: phenothiazine causing antimuscarinic side-effects

o Haloperidol: potent D2 antagonist causing extrapyramidal side-effects- Atypical:

o Clozapine: very effective but causes agranulocytosis

o Risperidone: effective but associated with weight gain & EPS

o Quetiapine: low incidence of EPS

o Aripiprazole: partial agonist, low incidence of hyperprolactinaemia

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- Typical:

- Chlorpromazineo Discovered whilst trying to develop new antihistamineso Primary mechanism of action is thought to be due to antagonism of dopamine D2

receptorso High incidence of anti-cholinergic side-effects especially sedationo Low incidence of extrapyramidal side-effects (despite being a typical antipsychotic!)

- Haloperidolo Very potent D2 antagonist (~ 50 times more potent than chlorpromazine) o High incidence of extrapyramidal side-effects (EPS)o Therapeutic effects develop over 6-8 weekso Has little impact on the negative symptoms of schizophrenia

- Atypical:

- Clozapineo The most effective antipsychotic but dangerous side-effects mean it is only used as a

last resorto Very potent antagonist of 5-HT2A receptors

potentially fatal neutropenia and agranulocytosis myocarditis and tachycardia weight gain

o Only drug to show efficacy in treatment resistant & PD psychosiso Has shown efficacy in treating the negative symptoms of schizophrenia

- Risperidoneo Indicated for the treatment of acute & chronic psychoses, mania and aggressive

behaviouro antagonist of 5-HT2A (as well as antag to D2 receptors)

Some weight gaino Causes more extrapyramidal side-effects & hyperprolactinaemia than other atypical

antipsychotics (ie despite being an atypical antipsychotic!)

- Quetiapineo Indicated for the treatment of schizophrenia, mania and PD psychosiso Very potent antagonist of H1 receptorso Lower incidence of extrapyramidal side-effects than other antipsychotics

- Aripiprazoleo Indicated for schizophrenia, mania & control of agitationo Partial agonist of D2 & 5-HT1A receptors!!o No more efficacious than typical antipsychoticso Significantly reduced incidences of hyperprolactinaemia and weight gain than other

antipsychotics

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TUTORIAL:

- Loss of SNc function leads to pathological rise in Ach signalingo Anti ACh medications can therefore be used in parkinsonso High ACh explains the autonomic dysfunction effects

- Tyramine is a breakdown product of tyrosine- Cocaine has local anaesthetic properties- Ethanol can induce a pseudo-Cushing’s syndrome

- Asian races possess genetic variations in the enzyme alcohol dehydrogenase associated with alcoholism

- Asian races possess genetic variations in the enzyme aldehyde dehydrogenase associated with alcohol intolerance

[easter egg]

I bet you think you are so big and clever using CTRL + F “easter egg” to find this. Well $*%& you! Or was it the squiggly red lines that gave away my hiding place?

[/easter egg]

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09/05/14: Opioids: Dr Chris JohnLos (from booklet):

Learning objectives1. Define the terms opiate and opioid; identify the importance of opiates and opioids in the clinical control of severe pain.2. List the principal subtypes of opioid receptor and identify their endogenous ligands3. Identify the signalling mechanisms used by opioid receptors.4. Identify the main central nervous pathways concerned with pain transmission/perception. Identify sites within these pathways where opiates/opioids modify transmission.5. Explain how opiates influence physiological function (e.g. respiration) and identify which of these actions may be advantageous clinically and which may cause unwanted effects.6. Explain how opiates/opioids may produce tolerance and dependence.7. Identify the main pharmacokinetic characteristics of morphine.8. Explain how the following drugs differ from morphine in their pharmacokinetic properties: Heroin (diamorphine), Codeine, Methadone, Fentanyl9. Identify the clinical use of opioid receptor antagonists.

Notes:

- opiate o narcotic analgesic derived from a opium poppy (natural)o Common opiates include morphine and codeine, both made directly from poppy

plants.- opioid

o narcotic analgesic that is at least part synthetic, not found in nature

- OPIATES / OPIOIDS: Tertiary nitrogen [with <3xC’s] = confers analgesia effectso Permits receptor anchoringo Extend side chain to 3+ carbons and you generate antagonist to agonists at all the

targets that an agonist would give an analgesic effect at Ie side chain off the nitrogen must be short for the analgesic effects

- OPIATES

o Morphine Tertiary nitrogen present and short side chain therefore analgesic agonist POOR lipid solubility

Short 30min half life (quick liver metabolism) Oral 40-50% bioavailability

High plasma protein binding

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Quickly metabolised at the liver However morphine-6 glucuronide is an active metabolite that will

continue to give an analgesic effect Urine excretion

(as with most opioids!) Due to ionisation at physiological pH: pKa of morphine is 8.2

Hydroxyl modifications give:

Heroin = “diacetyl-morphine” at carbon 3 and 6o More lipophilic as a result

hence access the brain faster high brain effects Hydroxyl group at position 6: Oxidise the OH group

and lipophilicity Increases 10-foldo Must be converted back to morphine before can have its

effect This is fast Hydroxyl group at position 3: Required for Binding

i.e. heroin is a prodrugo Is short acting: plasma esterases quickly metabolise the

drug

Codeine = “methyl-morphine” at carbon 3o NB 5-10% codeine → morphine:

CYP2D6 O-dealkylation to morphine (slow) CYP3A4 deactivation (fast: most codine is process in

this way instead and hence lost)o Must be converted back to morphine before can have its

effect: This is a slow conversion therefore codine is not as

powerful as morphine Hydroxyl group at position 3: Required for binding

i.e. codeine is a prodrug

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- Pharmacokinetics of Other Opiates

o Fentanyl: Benzene ring gives its potency highly lipid soluble Oral

50-100% bioavailability Alternatively buccal/Intra-nasal or -dermal

Metabolism: Very short acting! [much faster metabolism than morphine] Liver oxidation of Fentanyl

Urine excretion (as with most opioids!) Due to ionisation at physiological pH

o Methadone EXTREMELY Lipophilic

Long half life due to distribution to fat where it remains Urine excretion

(as with most opioids!) Due to ionisation at physiological pH

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- Opioidso They act via specific ‘opioid’ receptorso Endogenous opioid peptides exist; [it is the receptors to these that are targeted]:

Endorphins Enkephalins Dynorphins/neoendorphins

o OPIATE RECEPTORS Mu ()

Endorphins bind here Pain/Stress

Delta () Enkephalins bind here

Kappa () Dynorphins/neoendorphins bind here Appetite/Temp. regulation

o OPIATE RECEPTORS Cellular Mechanism of Action:

Have depressant inhibitory action at targets!!

o Hyperpolarisation ( K+)o Ca2+ inward currento Adenylate cyclase activity

o Pharmacodynamics [detail given below]: Analgesia Euphoria Depression of cough centre (anti-tussive) Depression of respiration (medulla) Stimulation of chemoreceptor trigger zone (nausea/vomiting) Pupillary Constriction G.I. Effects

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- ANALGESIA MECHANISMS: opioids can do both the mechs!o Decrease pain perceptiono Increase pain tolerance

o Signalling for pain from periphery is as illustrated on the below diagrams:

o Periphery thalamus Thalamus outputs: 1. Via cortex for processing: info from past experience is integrated before

signalling of pain info to PAG region 2. Direct signalling of pain info to PAG region

o PAG = Periaqueductal gray is beginning of the inhibitory signalling; this is where the extent of the

descending inhibition is determined Signals to NRM: nucleus raphe magnus, which passes on the descending

inhibitory signals sensations of pain o NRPG: Nucleus reticularis paragigantocellularis

Is an automatic feedback system bypassing brain to NRM to give initial weak diminishment of pain

Fast acting but weak inhibitiono Hypothalamus

sends info to PAG to give integration to PAG of general info regarding state of health of the body

o LC: locus coeruleus Stress response information is integrated at the level of the dorsal horn can directly inhibit the pain signalling Eg during exercise do not feel pain at time, only after / the next day

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o Specifically, all the inhibitory signals act at dorsal horn Substantia gelatinosa [where first order neurons of the spinothalamic tract synapse]

o Opiod receptors are in: dorsal horn: to dec pain sensation peripherally: to dec pain sensation NRPG: to inc inhib signalling PAG: to inc inhib signalling

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- Euphoria:o Via a standard disinhibition mech as below:

- Antitussive:o Sensory neurons activate vagal afferents; these project to the cough center from

which cough is stimulatedo 1. Opioids give decreased Ach and NK [neurokinin] release from sensory neurons so

reduced activation of vagal afferentso 2. Centrally act in (dorsal) Raphe nucleus to inhibit 5HT1A R receptors

Ie act at dorsal part of the raphe nucleus [“blocking disinhibition”: in opioid absence the receptor supresses serotonin which would otherwise supress cough]

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- Respiratory depression:o 1. Opioids decrease firing of the central chemoreceptors by acting at Mu receptorso 2. Disrupt resp rhythm at central higher centers [not shown on diagram]

- Nausea/Vomiting: o 1. Opioids OVR increase signalling to CTZ by acting at Mu receptorso 2. Disrupt signalling from the vestibular system: increase firing to give nausea [not

shown on diagram]

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- Miosis:o Opioids OVR stimulate parasympathetic nerves to eye: Opioid inhibition of GABA

inhibition at Edinger-Westphal nucleus = the oculomotor nucleus

- GI tract: o Opioids dec gut activity via inhibitory actions on the ENS Constipation by acting at

Mu and kappa receptors: Dec gastric emptying Dec GI motility Inc water absorption

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- Opioid side effects:o Histamine mediated; take antihistamines to treat

Itching (pruritis) hives (urticaria) Hypotension

- Tolerance:o 1. Opioid receptor internalisation

Occurs at a physiological level for recycling but opioids increase arrestin level which leads to increased capacity for internalisation

o 2. Cells also will upregulate adenylate cyclase levels (cf)o Hence cells become less responsive to opioids

- Withdrawl:o Withdrawal associated with:

1. Psychological craving 2. Physical withdrawal (resembling flu)

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o Body will increase adenylate cyclase in response to opioids to try to reinstate normal positive signalling; hence if opioid removed there will be increased positive cellular signalling from the cell

“compensation unmasking”

- Prolonged Treatmento Comao Respiratory depressiono Pin-point pupilso Hypotension

- Treatment of overdose:

o Naloxone (opioid antagonist) i.v. Works due to long sidechain on the tertiary nitrogen Will precipitate a withdrawl reaction in addicts

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09/05/14: Anxiolytics, sedatives and hypnotics:Dr Martin Croucher

Los (from booklet):

1. List the principal clinical uses (with routes of administration) of the benzodiazepines and the barbiturates.2. Identify the main undesirable effects of the benzodiazepines. Explain how these compare with the unwanted effects of the barbiturates.3. Compare the mechanisms, profiles and durations of action of individual benzodiazepines.4. Explain, providing examples, how differences in durations of action influence the therapeutic usefulness of these compounds.5. Define the term ‘anxiolytic drug’. Identify three classes of drug which have useful anxiolytic properties.6. Identify three drugs widely used for their hypnotic effects. Explain why diazepam is not used in this capacity.

Notes: - Outline:

o Gaba A receptor complexo Benzodiazepines (bzs) & barbiturates (barbs)o Basic and clinical pharmacologyo Other drugs

GABA receptors:

- 1. GABA B = presynaptic = GPCRs = regulate GABA release

- 2. GABA A receptors = postsynaptic = inhibitory action in brain when GABA bindso Focus of leco Is a Cl- channel; Cl ions will enter the cell

Hyperpolarises the postsynaptic cell Ie inhibitory action

o 4 main proteins: 1. GABA receptor protein 2. Benzodiazapine receptor protein

o Increases the affinity of binding for GABA effect is reciprocated back to give increased

benzodiazepine affinity at the BZ Ro Increased Cl- influx results

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3. Barbiturate receptor proteino 1. Increases the affinity of binding for GABA

effect is NOT reciprocated back to the benzodiazepine

o 2. At higher concentrations can directly act on Cl channel to open it [NOT done by benzodiazapines]

This is due to the low selectivity demonstrated by barbiturates

o Increased Cl- influx results 4. [one other protein]: GABA modulin polypeptide

Gaba A receptor complex (fig. 1)

- Bzs & barbs :o I) no activity alone

Ie just enhance action of gaba; no effect by self Is allosteric action

o II) different binding sites and different mechanisms bzs frequency of openings barbs duration of openings

o III) barbiturates are less selective than bzs other membrane effects

eg can act directly at the chloride channels at high doses May explain

induction of surgical general anaesthesia low margin of safety

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Clinical pharmacology of bzs & barbs:

- Clinical uses:o General Anaesthetics

barbs only : Thiopentoneo Anticonvulsants

used in the treatment of epileptic seizures

BZ: Diazepam; Clonazepam Barb: Phenobarbital But give sedation; hence alternatives are used in reality

o Anti-spastics

Diazepamo Anxiolytics

Diazepam Oxazepam Other:

Propranolol Buspirone

o Sedatives / Hypnotics: ie Often are same drugs just at different doses

Oxazepam Temazepam Amobarbital Other:

Zopiclone Chloral hydrate

- Definitions: [spectrum of activity:]o Anxiolytics:

Remove anxiety without impairing mental or physical activity May be called “minor tranquillisers”

o Sedatives: Reduce mental and physical activity without producing loss of consciousness

o Hypnotics:

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Induce sleep Often are same drugs as the sedative just at higher doses

- Ideally: they should:o I) have wide margin of safetyo Ii) not depress respirationo Iii) produce natural sleep (hypnotics)o Iv) not interact with other drugso V) not produce ‘hangovers’o Vi) not produce dependence

- (i) barbiturates o Structures : have a 6 membered barbiturate ring which is modified to give the

different barbiturateso highly lipid soluble wide distributiono Metabolism

usually extensive metabolism by the liver glucuronide conjugateso Excretion

urine as glucuronide conjugateso Range of clinical uses (above) including:

Sedative / hypnotic

Amobarbital use vs severe intractable insomnia t½ 20-25h

o Unwanted effects (not drugs of 1st choice: “dirty drugs”) Low safety margins

depress respiration overdosing lethal

Alter natural sleep ( rem) hangovers/ irritability

Enzyme inducers Eg decreased warfarin potency

Potentiate effect of other cns depressants e.g. potentiates Alcohol

Tolerance Tissue tolerance: receptor donwnregulation Pharmatokinetic tolerance: liver enz upregulation

Withdrawal syndrome: gives dependance Insomnia Anxiety Tremor Convulsions Death

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- (ii) benzodiazepines o Key examples:

Diazepam Temazepam Oxazepam

o Antagonists:

Flumazenil competitively inhibits ie antagonizes benzodiazepines at the

benzodiazepine receptor protein on GABA Ao All act at GABAA receptorso Pharmacodynamics: All similar potencies & profileso Pharmacokinetics largely determine use:o Admin.

well absorbed p.o. (per os) = orally peak [plasma] 1h i.v. Vs Status Epilepticus:

= prolonged / repeated seizures without patient regaining conciousness

o Distribution: bind plasma proteins strongly

Hence risk of problems with aspirin / heparin giving displacement highly lipid soluble wide distribution

o Metabolism usually extensive metabolism by the liver glucuronide conjugates

o Excretion urine as glucuronide conjugates

o Duration of action Duration of action vary greatly

o I) short-acting

o Temazepamo Oxazepam

o Ii) long-acting

o Diazepam 1. Slow metabolism

And / or 2. Generate active metabolites which will be able to

continue to act [see diagram below for illustration of this for diazepam]

Diazepam Temazepam & Oxazepam!!

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- Anxiolytics :

o Diazepam (= valium) ‘long-acting’

o Oxazepam Gives hepatic impairment

- Sedative / hypnotics :

o Temazepam (‘short-acting’)

o Oxazepam (‘short-acting’)

o Nb. Zopiclone: not a benzodiazepine- Bz advantages:

o Wide margin of safety: Milder effect on REM sleep Do not induce liver enzymes Overdose prolonged sleep (but rousable) but not death

Flumazenil: antidote: antagonises bz at the gaba a receptor- Unwanted effects

o Sedationo Confusiono Ataxia (impaired manual skills)o Potentiate other CNS depressants

Eg alcohol Eg barbs

o Tolerance occurs

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But less marked than barbs: only causes tissue tolerance (receptor downreg), unlike Barbituates, which cause both pharmacokinetic and tissue tolerance.

o Withdrawl (dependence): withdrawal syndrome similar to barbs (but less intense) therefore must

withdraw slowlyo Free [plasma] can be triggered by other drugs

e.g. Aspirin, heparin

- Other anxiolytics

o Propranolol Improves physical symptoms:

Tachycardia (1) Tremor (2)

o Buspirone 5HT-1A agonist Few side-effects BUT: Slow onset of action (days / weeks)

- Other sedative/hypnotics

o Zopiclone o Chloral hydrate

ccl3ch(oh)2 ccl3ch2ohchloral hydrate trichlorethanol

Is a prodrug Method of action unknown Wide margin of safety (children ) (elderly )

- Bicuculline

o competitive antagonist of GABAA receptors at GABA binding siteo hence reduces action of all of GABA/Bzs/Barbso Since it blocks the inhibitory action of GABA receptors, the action of bicuculline

mimics epilepsy

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15/05/14: Principles of General Anaesthesia: Dr Chris John

Los (from booklet):1 Explain the clinical objectives of general anaesthesia 2 Explain using examples the pharmacology of inhalational anaesthetics. 3 Explain using examples the pharmacology of intravenous anaesthetic drugs. 4 Identify the potential neuroanatomical sites of general anaesthetic action. 5 Recognise that other drugs are used clinically to facilitate anaesthesia and explain why they are used.

Notes:

- Clinically desirable effects of GA: [ALL GA’s only share the first two traits!! Though some have some of the others too]

o Loss of consciousness at low concns

o Suppression of reflex responses at high concns

o Amnesia o Relief of pain (analgesia)o Muscle relaxation

- Types of General Anaesthetics [very structurally dissimilar!]o Gaseous/Inhalation

Nitrous Oxide Diethyl Ether Halothane Enflurane [the most utilised inhaled form]

o Intravenous

Propofol Etomidate

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- Meyer/Overton Correlation:o GA’s more effective the more lipid soluble they are

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- Mechanism of Action: o [NOT due to disruption of the lipid membrane]o Either: Reduced neuronal excitability

TREK K+ channels (background leak): Increase in background leak K+ activity thus giving hyperpolarisation and decrease in activity of the nerve

Main result is suppression of reflex responses All the GAs prob do this

o OR Altered synaptic function Intravenous agents:

GABAA receptors: Bind to GABA-A receptor to modulate it and make it more responsive to GABA

o GABAA receptors with high numbers of 3 subunits are associated with suppression of reflex responses

Act at Synapses o GABAA receptors with high numbers of 5 subunits are

associated with causing amnesia Extra-synaptic

Inhalation agents: Target GABAA receptors to make them more sensitive but not as

powerful in this action as the IV agents Target Glycine receptors receptors to make them more sensitive to

Glycine but not very powerful Nitrous oxide: Blocks NMDA-type glutamate receptors

BOTH target Neuronal nicotinic ACh receptors to give: Amnesia Relief of pain [effect on consciousness / reflex responses is via a diff mech!!]

o Inhalated agents tend to hit many more targets:

[Dark green or pink spot indicates significant potentiation or inhibition, respectively. A light green or light pink spot indicates little potentiation or inhibition, respectively.]

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How specific effects are mediated:- Loss of consciousness

o Thalamocortical area: Depress excitability of thalamocortical neurons

o Reticular activating system: Influences reticular activating neurons

- Suppression of reflex responseso Depression of reflex pathways in the spinal cord

Eg beta-3 containing GABAR enhancement by IV agents at synapses- Amnesia

o ↓ synaptic transmission in hippocampus/amygdala Eg alpha-5 containing GABAR enhancement by IV agents near synapses Eg via ACh block by both IV and inhalational agents

- Pain relief:o ACh block by both IV and inhalational agents

- Muscle relaxation:o None discussed

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IV to induce, inhalation to maintain anaesthesia:

- Eg Induction: Propofol; Maintenance: Enflurane

- Iv o Good for fast actiono Bad for careful modulationo Less coughing/excitatory phenomena

- Inhaledo Bad for fast action

Excitatory phenomena: patient thrashes around (hence use IV to induce)o Good for careful modulationo Choose one of low solubility: Low blood:gas partition coefficient:

Is no barrier to alveoli transfer but will quickly exit at brain

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Also quick recovery as if stop applying at lungs the drug leaving brain will quickly be lost at the alveoli

This allows careful controlo High solubility gives slower blood brain steps and recovery pathway of brain

blood is also slowed Only use if has a better side effect profile for that patient and the type of

surgery being performedo Rapidly eliminatedo Rapid control of the depth of anaesthesia

- Loss of consciousness and suppression of reflex responses

o Induction: Propofolo Maintenance:Enflurane

- Relief of pain (analgesia) = Opioid

o (e.g. i.v. fentanyl)- Muscle relaxation = Neuromuscular blocking drugs

o (e.g. suxamethonium)- Amnesia = Benzodiazepines

o (e.g. i.v. midazolam)

- Chloroform gives hepatotoxicity

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15/01/14: LOCAL ANAESTHETICS: Dr M.J. Croucher

Los (from booklet):1 Recall the properties of electrically excitable cells that underlie the generation of neuronal action potentials. 2 Identify the general chemical structures of local anaesthetics (LAs) and the two main classes into which they can be divided. 3 Explain the principal cellular mechanism of action of LAs and explain how this gives rise to the property of ‘use-dependency’ of these agents. 4 Identify the effects of LAs on i) AP generation and propagation and ii) resting membrane potential. Explain how and why these effects differ in infected tissue compared to healthy tissue? 5 Identify the six main routes of administration of LAs, including their clinical usefulness. Explain why vasoconstrictor substances are often co-administered with Las. 6 Identify the pharmacokinetic properties of i) lidocaine and ii) cocaine, indicating how their respective routes of metabolism influence their plasma half lives. 7 List and compare the major unwanted effects of lidocaine and cocaine on i) the CNS and ii) the CVS.

Notes:

LAs = Drugs which reversibly block neuronal conduction when applied locally

- Generation of neuronal APo Nb no calcium involvemento Refractory: AP possible but requires a greater stimuluso 1x cycle = ~12mseco APs are all or nothing: all that occur are the same size [by contrast endplate

potentials are graded potentials]

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- Structure of LAso 1. Aromatic regiono 2. Ester / amide bondo 3. Basic tertiary amide side chain

Are tertiary amines All LAs are weak bases

o [ie greater consistency than is observed with GAs]o RE structures: Only HTK:

Lidocaine = amide linkage

Cocaine = ester linkage

Benzocaine = no tertiary amine

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- Mech:o Hydrophillic pathway:

Is the primary mechanism of action of most LAs Only unionised unprotonated form can pass through connective tissue

sheath and the neuronal wall Once inside the ionised protonated structure must form: this binds the

voltage gated sodium channel Sterically hinders access of Na into the cell

Show use dependency: greater block with greater ion channel usage ie high neuronal firing [LA can only bind when the channel is open]

Allows selectivity of pain conducting fibres because of their high firing rate

o Hydrophobic pathway: Some highly lipid soluble LAs can access channels from within the bilayer in

the unionised unprotonated form (as opposed to fully traversing the memb as above)

This is a non use dependant mechanism

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- Effectso EFFECTS OF LAs: They:

Prevent generation and conduction of APs Do NOT influence resting membrane potential May also influence

Slowed resetting of channel gating [some LAs can hold channels in their inactivated state during the cycle for a longer duration than would occur naturally]

Decreased surface tension [can lodge in bilayer and give drop in surface tension for a non-specific disruption of proteins in the membrane (including the Na channels) this is different to the hydrophobic pathway specific targeting of the channels

Selectively block Small diameter fibres are more greatly affected Non-myelinated fibres are more greatly affected Ie vs the c fibres: small diameter non mylinated fibres!! carry pain

LAs are weak bases (pKa 8-9) Only a small proportion are unionised Infected tissue is more acidic so is harder to anaesthetise

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- ROA [route of action]o Surface anaesthesia

Mucosal surface (mouth, bronchial tree) Spray (or powder) But via this mech will require high concentrations of LA → systemic toxicity

o Infiltration anaesthesia Directly into tissues → acts on sensory nerve terminals rather than the axons Minor surgery Adrenaline co-injection (but adrenaline NEVER given at extremities because

would give risk of ischemia): vasoconstriction gives reduction of diffusion of the LA away from the

area o lowered systemic effects o lower dose necessaryo reduced bleeding

o Nerve block anaesthesia Close to nerve trunks to give block at axon e.g. dental nerves Widely used – low doses required – slow onset Adenaline co-injection

o Intravenous regional anaesthesia i.v. distal to pressure cuff [to keep the LA in that area] used vs Limb surgery Systemic toxicity of premature cuff release

Risk of bolus release to systemic circulation o Spinal anaesthesia

Injected to sub-arachnoid space at L3 level: will act on the spinal roots Ie inject more to give effects at higher level

Use vs Abdominal, pelvic, lower limb surgery Side effects:

↓ b.p. [presynaptic sympathetic neurons are also blocked] prolonged headache [if the anaesthetic diffuses up to the brain]

o Epidural anaesthesia Fatty tissue of epidural space: is acting on the spinal roots but prior to their

entry to the meninges Between the spinal dura and the walls of the canal is the epidural

space Uses as for Spinal anaesthesia: vs Abdominal, pelvic, lower limb surgery and

painless childbirth too Slower onset and need to use higher doses More localised action: less effect on b.p. and brain

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- Pharmacokineticso Both well absorbed so both suitable as surface anaesthetics [cocaine use is

restricted to surface LA use]

o Lidocaine Liver by Hepatic N-dealkylation Longer half life Plasma protein binding = 70%

o Cocaine Liver and plasma by Non-specific esterases and cholinesterases Shorter half life Plasma protein binding = 90%

- Unwanted effectso Lidocaine is representative of most LAs

o Lidocaine CNS [GABA most sensitive so initially is stimulation; at higher doses will be

depression]: stimulation restlessness, confusion tremor

CVS [Na+ channel blockade] ↓ HR: myocardial depression ↓ b.p. vasodilatation

o Cocaine [Sympathetic actions due to block of uptake 1; not due to its block of Na channels which it does do as well (for the LA effects)]

CNS Euphoria excitation

CVS [are opposite to lidocaine] ↑ HR ↑ b.p. vasoconstriction

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15/01/14: Antiepilepsy Drugs (AEDs): Dr Michael Johnson

Los (from booklet):

• Explain what an epilepsy seizure is • Explain what epilepsy is and identify its causes • Recognise that anticonvulsant treatment decisions are based on a balance of risk and benefit. • Identify the pharmacokinetic principles of prescribing, with reference to at least one important, commonly used anti-epileptic drug. • Identify the genetic associations with anti-epileptic drug-related hypersensitivity, and explain how and why these are used in clinical practice.

Notes: [he isn’t setting the questions; see the Los above; despite Los some drug names are on the essential drug list but seems likely that this lec will not be heavily examined as he avoids exam role etc]

Epilepsy:

- Definitions [is an LO]o Epilepsy is a physical condition defined as a tendency to recurrent, unprovoked

seizureso An epileptic seizure is the manifestation of an abnormal and excessive synchronised

discharge of a set of cerebral neurones- Causes:

o Seizures and epilepsy may occur as a result of: A primary epileptic process

(idiopathic epilepsy = genetic basis) Secondary to underlying disease processes

(symptomatic epilepsy = pathological cause) brain injury, stroke, brain cancer, drug and alcohol misuse

- Epilepsy seizure types:o Generalised seizures

impairs consciousness and distorts the electrical activity of the whole or a larger portion of the brain

o Focal = partial seizures seizures which affect initially only one hemisphere of the brain

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- Diagnosis of Epilepsyo Can be difficult o Up to 20% receiving AEDs misdiagnosed o Diagnosis of epilepsy should be made by an epilepsy-competent specialist service

- When to institute long-term treatment of epilepsy:o Personal decision - involves careful consideration of potential harm from further

Seizures versus benefits and harms of antiepileptic drugs (AEDs)o In general, do not treat after single unprovoked seizure unless:

Seizure associated with appropriate structural lesion of the brain Seizure associated with clearly epileptiform EEG (focal or generalized spike

and sharp waves) Seizure is in the context of a progressive neurological disorder (e.g.,

Alzheimer)o In general, do treat after 2 unprovoked seizures unless:

diagnostic uncertainty (possible psycogenic basis or recurrent syncope) widely separated seizures (>1 year) the presence of clearly identifiable and avoidable provoking factors (e.g.,

alcohol intoxication/withdrawal) certain benign childhood epilepsy syndromes

- Principals of AED therapyo Be clear about indication for AED therapy [see above]

Discuss risks and benefits with patiento Always consider potential for drug interactions

Effect of AED on other drugs (including other co-prescribed AEDs and OCP) Effect of other drugs on AED

o Never withdraw drugs suddenly Suddenly stopping these drugs can provoke a seizure or seizures Make one change at a time. If replacing, add-in before withdrawing other

- OCP / Pregnancy:o contraception is an issue with antiepileptics as can reduce OCP efficacyo antiepileptics negatively impact on IQ of foetus and increase foetal malformation

risko however can’t stop medication without risk of death to mother!!

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- Genetics: [is an LO]: HLA B – 1502 genotype:o gives 15x greater risk of skin problem in response to Carbamazepine and phenytoin

[gives Stevens–Johnson syndrome and toxic epidermal necrolysis] o [is common in Han Chinese population]

- Mech: Most existing antiepileptic drugs act by one or more of these mechanisms: o Enhancing GABA mediated inhibitiono Reduce glutamate-mediated Excitation o Inhibiting neuronal action potentials by blocking voltage-gated sodium channels. o Blocking Neuronal Ca channels; ie by binding and blocking presynaptic Ca channels

- Newer drugs are not more effective but are safer with fewer drug interactions

- Some drug examples: [not in Los but are in essential drugs list so surely HTK!!]]o Voltage-gated sodium channel inhibitors

Phenytoin Carbamazepine Lamotrigine

o GABA transaminase inhibitor [would otherwise inactivate GABA]

Vigabatrino Voltage-gated sodium channel inhibitor/GABA transaminase inhibitor

Sodium valproateo GABA analogue

Gabapentin

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Prob DHTK great detail on the below, just need to cover “know the pharmacokinetic principles of prescribing”; however is useful info!

- PHENYTOINo Complex pharmacokinetics

Hepatic metabolism: oxidation, followed by hydroxylation then conjugation Potent P450 enzyme inducer - hence large number of important

drug interactions Saturatable kinetics:

o I.e., non-linear kinetics (rising quickly after point of enzyme saturation)

o Blood drug levels increase suddenly once the enzymes are saturated (also occurs in alcohol)

o Start low dose and incrementally increase Renal excretion metabolites If urgent, can load IV Highly (70-90%) protein bound (displacement by some drugs, low albumin

states)o Indications:

Partial seizures Secondary generalized seizures Status epilepticus

o Mechanism of action: Blockade of v-gated Na channels

o ADRs: Acute side effects:

hypersensitive rash, fever, hepatitis, vasculitis Toxic side effects:[on target effects]:

ataxia, dizziness, sedation, diplopia, Chronic side effects: [from chronic enzyme induction]: gingival hypertrophy,

folate deficiency, megaloblastic anaemia, vit K deficiency, depression, hirsutism, peripheral neuropathy, osteomalacia (vit D) hypocalcaemia,, myopathy, coagulation defects, bone marrow hypoplasia

o Effect of other drugs on PHENYTOIN: all increase PHT level!! Amiodarone, Isoniazid [TB medication]

Potent inhibitors of PHT metabolism, lead to increased PHT levels Aspirin

displaces PHT from protein binding - only a prob near satn Sodium Valproate

displaces PHT from protein binding AND inhibits PHT metabolism. Can result in PHT toxicity with normal total PHT levels (measure free

141


PHT levels with this drug combination). Avoid combination where possible.

o Effect of PHT on other drugs Increases metabolism of Carbamazepine, Lamotrigine, (Sodium) Valproate WARFARIN

Complex pharmacokinetics, increases clearance of warfarin with chronic use. Monitor INRs closely after any change in PHT dose.

Estrogen containing OCP [oral contraceptive pill] efficacy reduced (min 50ug eostradiol req)

- Carbamazepine o Indications:

Partial seizures Secondary generalized seizures


o Metabolism: Hepatic oxidation then conjugation. CBZ is a potent hepatic enzyme inducer

o Active metabolites: carbamazepine epoxide

o ADRs: Acute:

Hypersensitive rash, hepatitis, nephritis, bone marrow suppression Toxic:

ataxia, dizziness, sedation, diplopia Chronic: vit K & D deficiency, depression, impotence,

osteomalacia, hyponatraemia, bone marrow dyscrasias,o Drug interactions

Susceptible to its own induction (auto-induction) Steady state reached at about 1 month

Effect of other drugs on CBZ PHENYTOIN, Phenobarbital

o induce CBZ metabolism reduced CBZ Ca2+ channel blockers (diltiazem/verapamil)

o Massively elevate CBZ levels Valproate:

o 4-fold increase in CBZ-epoxide levels - inhibition of epoxide hydrolase.

Macrolide antibiotics (e.g., erythromycin)o inhibit CBZ metabolism: can increase CBZ levels

Effect of CBZ on other drugs Reduces levels of Lamotrigine, (Sodium) Valproate [not Phenytoin]

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OCP reduced efficacy Inc clearance / Reduced levels of Warfarin

- Lamotrigineo Indications:



o Metabolism: Hepatic glucuronidation No phase 1 metabolism No hepatic enzyme induction.

so does not alter metabolism of warfarin o ADRs:

usually well tolerated, but high incidence of rash o Drug interactions

Effect of other drugs on LTG Enzyme inducing drugs (e.g., CBZ, PB, PHT)

o reduce half-life and lower LTG levels Valproate

o increases LTG levels OCP

o can lower LTG levels Effect of LTG on other drugs

OCP o reduced efficacy

- (Sodium) Valproate o Indications:


o Mechanism of action: Unclear, enhance GABA by a variety of mechanisms

o Metabolism: Hepatic oxidation and then conjugation. Potent inhibitor of hepatic enzymes

o ADRs: hepatic toxicity pancreatitis

o Effect of VPA on other drugs

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VPA is a potent inhibitor of both oxidation and glucuronidation PHT, PB, LTG levels all increased CBZ-epoxide levels increased

Effect of other drugs on VPA Levels reduced by hepatic enzyme inducers (e.g., PHT, PB, CBZ) Antacids

o may impair absorption Aspirin

o displaces VPA from its albumin binding sites and may result in toxicity

144


15/01/14: Cytotoxic drugs: Dr Sohag Saleh

Los (from booklet):

• Summarise the epidemiological findings and main hallmarks of cancer • Explain the actions of drugs used for adjuvant chemotherapy of colorectal cancer • Explain the actions of drugs used for adjuvant chemotherapy of early non-small cell lung cancer • Explain the actions of drugs used for treatment of advanced non-small cell lung cancer • Explain the actions of the cytotoxic drugs used for adjuvant chemotherapy of breast cancer • Summarise the different categories of cytotoxic drugs

1. Summarise the epidemiological findings and main hallmarks of cancer Four most common cancers affect - Bowels, lungs, breasts & genitals Cancer cells - Grow independently & without limit. Generate their own blood supply

& can evade detection2. Describe the actions of drugs used for adjuvant chemotherapy of colorectal cancer FUFA (5-fluorouracil & folinic acid) - Given as adjuvant treatment. 5-FU inhibits

thymidylate synthase Bevacizumab - Antibody directed against the VEGF

3. Describe the actions of drugs used for adjuvant chemotherapy of early non-small cell lung cancer

Platinum compounds (cisplatin) - Form DNA adducts Etoposide - Inhibits type II isomerase enzyme Gemcitabine - Inhibits the DNA polymerase enzyme4. Describe the actions of drugs used for treatment of advanced non-small cell lung

cancer The taxanes (e.g. docetaxel) - Inhibit microtubule disassembly The vinca alkaloids (e.g. vinorelbine) - Inhibit microtubule assembly Erlotinib- Small molecule inhibitor of the epithelial growth factor receptor

Notes: 11 DRUGS!!; learn these NOT those on the essential drugs list; he will make sure that it is these that are tested

- Cancer background

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o Biology Cause - Uncontrolled proliferation & growth of abnormal cells Due to - Multiple genetic mutations Cancer cell characteristics:

Self sufficient growth Angiogenesis Evasion of apoptosis Avoiding immune detection Limitless replication potential

o Epidemiology 4 most common cancers affect:

Digestive system (colorectal) Respiratory system (lung cancer) Genitalia (prostate) Breast

Pancreatic cancer - Worst prognosis

- Comparison of cancer staging prognoses b(r)est to worst(!):o Breast colorectal lung

- Colorectal cancer (CRC)o Background

Presentation 60% due to colon cancer Mostly adenocarcinomas - from polyps Common symptoms - Rectal bleeding, change in bowel habits

Biology 25% due to genetic defects, e.g. familial adenomatous polyposis

(FAP) Risk factors - Inflammation, meat consumption & smoking Protective - High fibre diets, folic acid intake & NSAID use

Non-pharmacological treatment Surgical resection Cornerstone of treatment

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o Adjuvant chemotherapy [ie drug given before or after chemotherapy] Offered to all stage C patients who are able to tolerate drugs following

surgery Standard treatment

5-fluorouracil & folinic acid (FUFA) Bevacizumab - Licensed as secondary treatment for metastatic CRC

o In detail:

5-fluorouracil An antimetabolite pyrimidine analogue,

o Interferes with thymidylate synthase enzyme involved in dUMP dTMP

The folinic acid helps potentiate its effects: 5-fluorouracil + folinic acid = FUFA

Bevacizumab Monoclonal antibody inhibits vascular endothelial growth factor (VEGF) [ie binds the

actual ligand of the receptor]

147


148


- Non-small cell lung cancero Background

Presentation 80% of lung cancers cases = non-small cell lung cancer (NSCLC) Common symptoms - Haemoptysis, cough, shortness of breath

Biology 3 major NSCLC categories 90% of cases are due to cigarette smoking Epidermal growth factor receptor (EGFR) mutations in ~15% of lung

cancer patients Non-pharmacological treatment

Surgery - lobectomy or pneumonectomy Often combined with adjuvant chemotherapy and/or radiotherapy

Adjuvant chemotherapy Given post-surgery stage 2

Cisplatin (I-V)o Is a platinum-compound based therapy o Alkylating (-like) agent - covalently bonds with and

crosslinks DNA guanine residues forming adducts to prevent replication of the DNA

Etoposide (oral)o Topoisomerase type II inhibitor o In this way DNA replication is prevented

Gemcitabine (I-V)o Anti-metabolite:

Inhibits ribonucleotide reductase Inhibits DNA polymerase Incorporates into DNA causing chain termination

Advanced chemotherapy Add 3rd-generation drug :

o Docetaxel, paclitaxel, vinorelbine In EGFR mutants

o Erlotinib & gefitinib

Docetaxel (I-V)o All the Taxanes [also include paclitaxel] work by preventing

microtubule disassembly

Vinorelbine (I-V)o Vinca alkaloido inhibits microtubule assembly

Erlotinib (I-V)o Selective small molecule inhibitor of EGFR tyrosine kinase o Binds on intracellular side

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o Is NOT an antibody o Only effective in individuals with an EGFR mutation

5 year survival is the worst out of the cancers looked at in depth here (see table below)

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- Which is the mechanism of action of the antimetabolite, 5-fluorouracil? o It is a folate antagonisto It is a dioxyuridine monophosphate antagonisto It is methyl tetrahydrofolate antagonisto It inhibits the thymidylate synthase enzymeo It inhibits the dihydrofolate reductase enzyme

- Which receptor does the antibody bevacizumab bind to?o Platelet derived growth factor receptoro Epidermal growth factor receptoro Vascular endothelial growth factor receptoro CD220 receptoro None of the above [binds to the ligand not the receptor]

- Breast Cancero Background

Presentation Common symptoms - lumps, shape change, skin dimpling, discharge

Biology Gene expression patterns distinguish between four main types of

breast cancer Risk factors - Age, breast tissue density, alcohol & exposure to

oestrogen

Numerous gene mutations implicated - BRCA1, BRCA2 & TP53

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Non-pharmacological treatment Lumpectomy & radiotherapy or mastectomy & surgical

reconstruction Survival rates are good through the stages compared to the other cancers

that are looked at in this lecture (see table below)o Adjuvant chemotherapy

Eostrogen receptor positive

Hormone therapy (e.g. Tamoxifen)

o Antagonism at ER Early node-positive

TAC regimen (Docetaxel, Doxorubicin & Cyclophosphamide)

Cyclophosphamide (I-V)

“Nitrogen mustard” forms covalent bonds with DNA & RNA

Doxorubicin (I-V)

‘Poison’ topoisomerase II by intercalating DNA [can still cut the DNA but then remains attached due to the drug]

Trastuzumab (I-V) = Herceptin Use vs Her2 + cancers Monoclonal antibody acting at the HER-2/neu receptor [ie binds

the receptor!] [= Herceptin]

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Or to put another way:…

- Cytotoxic drugs- nucleic acidso Nucleic acid inhibitors

Antimetabolites

A) 5-fluorouracil inhibits nucleic acid synthesis

B) Gemcitabine inhibits DNA polymerase

o DNA replication inhibitors Topoisomerase inhibitors

C) Etoposide inhibits type II topoisomerases

DNA intercalators

D) Doxorubicin intercalates DNA & poisons type II topoisomerase

Alkylating agents

E) Nitrogen mustards (Cyclophosphamide) form covalent bonds with DNA

F) Platinum compounds (Cisplatin) form DNA adducts

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- Cytoskeleton & Receptorso Microtubule inhibitors

Vinca alkaloids

G) Vinorelbine inhibits microtubule assembly

Taxanes

H) Docetaxel inhibits microtubule disassembly

o TyR kinase receptor inhibitors Antibodies

I) Bevacizumab binds to VEGF

J) Trastuzumab binds to HER-2 receptor

Small molecules

K) Erlotinib inhibits epithelial growth factor receptor (EGFR)

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- Which three drugs constitute the TAC regimen used in the treatment of early node positive breast cancer ?

o 5-fluorouracil & folinic acid o Docetaxel, doxorubicin & cyclophosphamideo Cisplatin & etoposideo Carboplatin & gemcitabineo Trastuzumab, doxorubicin & cyclophosphamide

- What is meant by topoisomerase II ‘poisoning’?o The topoisomerase II can no longer bind to DNAo The topoisomerase II can no longer cleave DNAo The topoisomerase II is unable to unbind from DNAo The topoisomerase II loses its enzymatic activityo The topoisomerase II is only able to cleave one strand of DNA

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BONUS INFO:

Cycloplegia is paralysis of the ciliary muscle of the eye Nitrous oxide inhibits muscular nicotinic acetylcholine receptors Misoprostol (prostaglandin analogue) is commonly co-prescribed with

chronic use of NSAIDS Absence seizures: a type of generalised seizure, characterized by a brief

loss and return of consciousness, generally not followed by a period of lethargy

The action of the 5-HT3 receptor is to efflux K+ C Fibers carry dull burning pain in the lateral "neospinothalamic" tract A delta fibers carry sharp “fast” pain in the anterior,

"paleospinothalamic" tract. primary somatosensory cortex found at Postcentral gyrus

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· web viewadipose tissue thought to contain components of the ras system thereby giving increased...

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