Pharmacology and Therapeutics Flashcards

Question

Explain the actions of B-selective adrenoceptor agonists.

Answer 1

Isoprenaline b1=b2>a1/2 Chemically related to adrenaline - more resistant to MAO and uptake 1 Clinical Cardiogenic shock Acute heart failure Myocardial infarction B2-stimulation in vascular smooth muscle (vasodilation) in skeletal muscle results in fall in venous blood pressure which triggers a reflex tachycardia via the stimulation of baroreceptors ``` Dobutamine b1>b2>a1/2 Clinical use Cardiogenic shock Lacks isoprenaline’s reflex tachycardia Plasma half life 2 minutes (rapidly metabolised by COMT) ``` Salbutamol (ventolin) b2>b1>a1/2 Synthetic catecholamine derivative with relative resistance to MAO and COMT Blue inhaler Longer in system Clinical uses Treatment of asthma -b2-relaxation of bronchial smooth muscle inhibition of release of bronchoconstrictor substances from mast cells Treatment of threatened premature labour -b2-relaxation of uterine smooth muscle Side effects - reflex tachycardia, tremor, blood sugar dysregulation

Answer 2

Drugs need to be lipophilic so they can access tissues - therapeutic effect Drugs need to be water soluble to be retained in the blood and delivered to excretion sites. Body alters the drug to make it less lipid soluble and easier to excrete. The process of metabolism involves the conversion of drugs usually lipid soluble to metabolites (less lipid soluble and easier to excrete). Two biochemical reactions: Phase 1 - main aim is to introduce a reactive group to the drug (increase polarity) Phase 2 - main aim is to add a water soluble conjugate to the reactive group, make water soluble.

Answer 3

Mostly in liver - Most common =Oxidation (often start with hydroxylation - add hydroxyl group) - Hydrolysis - unmasks reactive group, functional group serves as a point of attachment for phase II reactions) - Reduction 3 outcomes of phase 1 metabolism: 1) active parent drug -> inert metabolite (no effect on body) 2) active parent drug -> active metabolite (prolongs effects) .e.g. cannabis 3) inactive parent drug -> active metabolite (prodrug) .e.g. codeine -> morphine

Answer 4

Most common: glucoronidation Glucoronidation is low affinity/high capacity (large amount metabolised)- more likely to occur at high drug dosages. Water soluble to be able to excrete Aspirin -> salicylic acid Sulfation: high affinity/low capacity (not a lot but very effective) - more likely to occur at low dosages Paracetamol Glutathione conjugation Drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate When there’s enough glutathione stores, conjugate formation not a problem. In overdose, we use up stores therefore in the case of paracetamol, NAPQI (Electrophile) can cause damage to liver tissue instead of forming glutathione conjugate. Problem: electrophilic are extremely reactive and glutathione stores overwhelmed. Less common metabolism pathways compared to previous 3: Acetylation - aromatic amine Methylation Amino acid conjugation - two reactions possible: 1) with carboxylate acid group of AA 2) with amino group of AA

Answer 5

The biological half-life of the chemical is decreased. The duration of exposure is reduced. Accumulation of the compound in the body is avoided. Potency/duration of the biological activity of the chemical can be altered. The pharmacology/toxicology of the drug can be governed by its metabolism.

Answer 6

A1 - vasoconstriction, relaxation of GI A2 - inhibition of transmitter (which inhibit sympathetic) release, contraction of vascular smooth muscle, CNS actions B1 - increased cardiac rate and force, relaxation of GIT, renin release from kidney B2 - bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis B3 - lipolysis

Answer 7

``` Non-selective: a1+b1 = carvedilol A1+a2: phentolamine A1: prazosin (selective) B1+b2: propranolol B1: atenolol ```

Answer 8

B-blockers decrease heart rate and force of contraction therefore decrease cardiac output, reduce b.p Renin and angiotensin II release decrease, angiotensin II is a potent vasoconstrictor and increase aldosterone production Therefore aldosterone and blood volume (Na+ and water) decrease Blockade of facilitatory effects of presynaptic B-adrenoceptors on noradrenaline release may also contribute to the antihypertensive effect (Not as effective as a2) 1) non-selective: equal affinity for B1 and B2 receptors (propranolol) 2) B1-selective: more selective for B1 (atenolol), MORE so may still activate B2 3) mixed blockers (B1, B2, a1): a1 blockade gives additional vasodilator properties (carvedilol) 4) Other: nebivolol = also potentiates NO (vasodilator), sotalol = inhibits K+ channels (interfere with cell hyperpolarisation) Atenolol may be advantageous over propranolol because only B1 so asthmatics and diabetes less likely to respond to drugs. Carvedilol advantageous over atenolol and propranolol because more powerful hypotensive effect on heart, kidney and block vasoconstriction decreasing TPR but does increase side effects. Unwanted side effects Bronchoconstriction - asthma/COPD Cardiac failure - need some sympathetic drive to the heart for blood tissue demand Hypoglycaemia - mask the symptoms of hypoglycaemia/ inhibit glycogen breakdown (B2 liberates blood glucose) Fatigue - decrease cardiac output and decrease muscle perfusion (B2 dilates) Cold extremities - loss of B-receptor mediated vasodilation in cutaneous vessels Bad dreams

Answer 9

A1-receptors are Gq linked (PLC and Ca2+ influx), postsynpatic on vascular smooth muscle A2-receptors are GI (inhibitory G protein) linked (decrease cAMP), presynaptic autoreceptors inhibiting NE release Non selective a-blocker: phentolamine used to treat phaechromocytoma-induced hypertension (tumour in adrenal medulla) Side effect is diarrhoea A2 receptors and baroreceptors reduce the effectiveness of phentolamine - a-blockers dilate blood vessels, decreasing pressure, 1) block a2 - negative feedback therefore increases NE, competitive reaction between phentolamine on a1 and NE in synapse baroceptor firing decreases -> sympathetic drive so CO and SV increases. A1-specific: prazosin inhibit the vasoconstrictor activity of NE Have modest b.p. Lowering effects Only used as adjunctive treatment because not as powerful

Answer 10

1) Methyldopa converted to false transmitter (produced instead of NA) 2) Less active at beta/alpha 1 receptor (more selective to a2) 3) Not metabolised by MAO (no conc. gradient, not broken down therefore uptake lower) 4) More likely to accumulate and displace noradrenaline in the vesicles ``` More powerful hypotensive with vasoconstriction but can cause very low hypotension. Improved blood flow Antihypertensive especially: Renal - kidney disease CNS - cerebrovascular disease ``` Side effects with saliva production and blood vessels to skin

Answer 11

Abnormal or irregular heart beat, main cause myocardial ischaemia Increased sympathetic drive to heart precipitates arrhythmias (b1) AV conductance dependent on sympathetic activity (b1) B-blockers such as propranolol used to rest - restore normal rhythm to improve blood flow therefore cardiac output

Answer 12

Stable: pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels .e.g. atheroma, still enough blood flow to meet demands at rest, not exercise Unstable: pain with less and less exertion, culminating with pain at rest. Platelet-fibrin thrombus associated with a ruptured atheromatous plaque but without complete occlusion of the vessel. Risk of infarction Variable: occurs at rest, caused by coronary artery spasm, associated with atheromatous disease At low doses, B1 selective agents such as metoprolol reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle. Decreases effort your heart makes, easing angina pain.

Answer 13

A-motor neurone found in ventral horn e.g. sciatic nerve. NAChR different to ganglionic nAChR so can develop drugs which have selectivity to neuromuscular function. The end-plate potential is a gradient potential. ACh binds onto a subunit, opening channel, influx of Na+

Answer 14

In order of transmission: 1) Central processes (a morose neurone generates a.p. In spinal cord) - spansmolytics (diazepam, baclofen) which cause relaxation of skeletal muscle, anti-spasticity 2) Conduction of nerve a.p. In motor neurone - local anaesthetics injected around terminals of sensory fibres, not effective near motor neurone. 3) ACh release - hemicholinium (prevents reuptake of choline), Ca2+ entry blockers, neurotoxins (decrease ACh release, bind to terminals and gains access inside nerve terminal and interact with intracellular proteins e.g. botox 4) depolarisation of motor end-plate, a.p. Initiation - tubocurarine, suxamethonium 5) propagation of a.p. Along muscle fibre and muscle contraction - spasmolytics (dantrolene) - acts inside skeletal muscle, decrease Ca2+ release from sarcoplasmic reticulum, relaxation of muscle.

Answer 15

Act post synaptically on skeletal muscle. Two types: 1) non-depolarising (competitive antagonists)e.g. tubocurarine, atracurium 2) depolarising (agonists) e.g. suxamethonium (succinylcholine) Similarities between ACh and drugs They do not affect consciousness (not anaesthetic) They do not affect pain sensation (no analgesics properties) ALWAYS assist respiration until drug inactive or antagonised 1) structure more rigid, little rotation, bind + block receptor 2) more free rotation, bind + activate - efficacy

Answer 16

Suxamethonium Mechanism of action: extended end plate depolarisation -> depolarisation block (phase 1) Overstimulation of nicotinic receptors therefore receptor shut down fasciculations -> flaccid paralysis, as drug diffuses into muscle, we see fasciculations (muscle twitching) then flaccid paralysis (shut down) Pharmacokinetics Route of administration: intravenous (highly charged) Duration of paralysis 5 mins Metabolised by pseudo-cholinesterase in live and plasma (short duration) Uses Endotracheal intubation - insertion of tube down trachea for general anaesthetics, investigating bronchoscope - suxamethonium allows relaxation of vocal cords to allow tube to be inserted Muscle relaxation for ECT(electroconvulsive therapy) used to treat severe clinical depression. Drug used to relax skeletal muscles Unwanted effects Post-operative muscle pains Bradycardia - direct muscarinic action on heart (atropine given as premed to prevent effect on heart) Hyperkalaemia - avoid use in soft tissue injury or burns (damage after EN6, fibres, response of skeletal muscle is putting more nicotinic receptors on surface of fibre on end-plate region to amplify reduced input) -> ventricular arrhythmias/cardiac arrest

Answer 17

Tubocurarine (prototype) Naturally occurring quaternary ammonium compound (alkaloid) Mechanism of action: competitive nAChR antagonist, 70-80% block necessary for end plate potential to be insufficient to cause firing ACh released but reduced binding to receptors Effects Flaccid paralysis Respiratory recovery in order of: 1) respiratory muscles e.g. respiratory arrest 2) small muscles of face, limbs and pharynx e.g. trouble swallowing 3) extrinsic eye muscles e.g. double vision Uses Relaxation of skeletal muscles during surgical operations (=less anaesthetic) Permit artificial ventilation Actions of non-depolarising blockers can be reversed by anticholinesterases - raise endogenous acetylcholine, cometitive overcome block Neostigmine (longer acting anticholinesterase) (+atropine - dampens down overstimulation of muscarinic receptors) Pharmacokinetics Route of administration - I.v. (Highly charged) Does not cross BBB or placenta Duration of paralysis: 1-2 hr (long) Not metabolised Excretion: 70% urine: 30% bile (if renal or hepatic function impaired - excreted more slowly, increased duration of action therefore increased duration of action) In case of these conditions, different drug like atracurium used which is chemically unusable, hydrolysed in plasma into 2 inactive fragments (15 mins) Unwanted effects (Ganglion block; histamine release) Hypotension Ganglion blockade, higher dose can block (decrease TPR therefor bp) Histamine release from mast cells (vasodilation, decrease bp) Tachycardia (may cause arrhythmias), reflex in response to low b.p., blockade of vagal ganglia (parasympathetic) Bronchospasm and excessive secretions (bronchial and salivary) due to histamine release Apnoea (ALWAYS assist respiration)

Answer 18

Heart rate Channels: if, ica (l), ica (t), ik in SAN If - hyperpolarization-activated cyclic nucleotide–gated (HCN) channels - switch on during hyperpolarisation, utilise cAMP and drive Na+ entry to initiate depolarisation Ica (T or L) – Transient T-type Ca++ channel -as current increases, open or Long Lasting L-type Ca++ channel - first T, then L IK – Potassium K+ channels - positive voltage, repolarisation Phase 4 is the spontaneous depolarization (pacemaker potential) that triggers the action potential Sympathetic - increase cAMP, increase If and Ica Parasympathetic - decrease cAMP, increase Ik Contractility 1) ap enters from adjacent cell 2) voltage-gated Ca2+ channeled open, Ca2+ enters cell 3) Ca2+ induces Ca2+ release through ryanodine receptor-channels (RyR), 25% Ca2+ from oudside, 75% from SR 4) local release causes Ca2+ spark 5) summed Ca2+ sparks create a Ca2+ signal 6) Ca2+ ions bind to troponin to initiate contraction 7) relaxation occurs when Ca2+ unbinds from troponin 8) Ca2+ is pumped back into the SR for storage 9) Ca2+ is exchanged with Na+ 10) Na+ gradient is maintained by the Na+-K+-ATPase Myocardial oxygen supply and demand Myocardial oxygen supply -Increase coronary blood flow -arterial O2 content Work —> myocardial oxygen demand - increase in heart rate - increase in preload - Starling’s law, more blood return, more SV - increase in afterload - pressure in system, acts as resistance —> work harder - increase in contractility

Answer 19

Heart rate - for angina to decrease HR - B-blockers - decrease If and Ica - SNS increase,B1 receptor, increase nodal activity, increase in If and Ca2+ influx - calcium antagonists - decrease Ica - ca2+ influx increases - ivabradine - decrease If - blocks If, decrease speed of depolarisation Contractility -B-blockers - decrease contractility - B1 receptor, less Ca2+ influx -Calcium antagonists - decrease Ica Two classes of calcium antagonists • Rate slowing (Cardiac and smooth muscle actions) - large effect on HR – Phenylalkylamines (e.g. Verapamil) – Benzothiazepines (e.g. Diltiazem) • Non-rate slowing (smooth muscle actions – more potent) - not much effect on heart but great impact on vasculature. Profound vasodilation can lead to reflex tachycardia - baroreceptors respond to vasodilation Myocardial oxygen supply and demand -organic nitrates and potassium channel openers = increase in coronary blood flow Vasodilation decreases afterload; dilate veins too (venodilation) - decrease preload because more blood can stay in venous system and doesn’t need to rent to heart – Dihydropyridines (e.g. amlodipine) Drugs for treating stable angina - heart doesn’t receive enough oxygen = pain, usually due to atherosclerosis Beta blocker/calcium channel blocker given as a first line treatment - reduce HR and contractility - decrease cardiac work but makes it harder to exercise Can combine If contradicted - long-acting nitrate, K+ openers

Answer 20

Beta blockers Worsening heart failure - inability to match CO to tissue need -CO reduction -increased vascular resistance Bradycardia -heart block - decreased conduction through AV node Non-selective e.g. pindolol Equal affinity for B1 and B2 receptors With intrinsic sympathetic activity - normal daily activities - some sympathetic activity, not in exercise Mixed B-a blockers A1 blockade gives additional vasodilator properties E.g. carvediol - b1, b2, a1 Trachea and bronchioles - constriction - asthmatics Liver - decreases glycogenolysis and gluconeogenesis - masks hyperglycameia - diabetics Cold extremities/ worsening peripheral artery disease because of loss of B2 receptor mediated cutaneous vasodilation in extremities - harder for blood to enter extremities Not tested in exam, not enough evidence Fatigue, Impotence (sexual dysfunction), Depression Calcium channel blockers - “safer drugs” Verapamil • Bradycardia and AV block (Ca2+ channel block) • Constipation (Gut Ca2+ channels) – 25 % patients Dihydropyridines – 10-20% patients • Ankle Oedema – vasodilation means more pressure on capillary vessels - gravity to feet • Headache / Flushing (blood flow peripherally to face) – vasodilation -in brain • Palpitations - reflex, barorecptors sympathetic response Vasodilation/reflex adrenergic activation (Above also in K+ channel openers, nitrates)

Answer 21

Rhythm disturbances • Abnormalities of cardiac rhythm (arrhythmias/dysrhythmias) affect around 700,000 people in UK. * Aims of treatment are * Reduce sudden death - cardiac arrest * Prevent stroke - heart bot beating rhythmically so increased likelihood of blood clotting - to Brian = stroke * Alleviate symptoms • Management is complex; usually undertaken by specialists ; and may involve cardioversion, pacemakers, catheter ablation therapy and implantable defibrillators as well as drug therapy • May be associated with decreased heart rate (bradyarrhythmias) or increased heart rate (tachyarrhythmias). • A simple classification of arrhythmias is based on site of origin: • Supraventricular arrhythmias (e.g. amiodarone, verapamil) • Ventricular arrhythmias (e.g. flecainide, lidocaine). • Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide). Use Vaughan-Williams classification of anti-arrhythmic drugs Class; mechanism of action I; sodium channel blockers (prevented/ reduced depolarisation) II, Beta adrenergic blockade (blocked B-receptors, generalised inhibitory affect on muscular contraction) III, prolongation of repolarisation (‘membrane stabilisation’, mainly due to potassium channel blockade) IV, calcium channel blockade Limited classification due to many drugs having different effects

Answer 22

Supraventricular arrhythmias Adenosine usually treatment of choice for terminating paroxysmal supraventricular tachycardia because a very short duration of action (half life 20-30 secs but prolonged in those taking dipyridamole), side effects short lived. Unlike verapamil hydrochloride, adenosine can be used after a beta-blocker. VH may be preferable in asthmatics. (III, IV) Used intravenously. Safer than verapamil Binds on adenosine receptor (A1) in SAN/AVN —> inhibitory effect on adenyl cyclase —> decrease cAMP —> decrease If —> decrease depolarisation —> decrease chronotropy. Less powerful in vascular smooth muscle - A2 receptor —> increase cAMP —> relaxation Verapamil Reduction of ventricular responsiveness to atrial arrhythmias Depresses SA automaticity and subsequent AV node conduction, block Ca2+ ion channels —> decrease ability to depolarise (increase time) Amiodarone (hydrochloride) Supraventricular and ventricular arrhythmias - often due to reentry (prevent reentry) Used when other drugs are ineffective or contraindicated. Used for paroxysmal supraventricular, nodal and ventricular tachycardias, atrial fibrillation and flutter. Intravenous or by mouth, advantage is cause little or no myocardial depression. Amiodarone accumulates in the body (t1/2 10-100 days) Has a number Of important adverse effects: -photosensitive skin rashes -hypo- or hyperthyroidism -pulmonary fibrosis MoA In normal cardiac tissue, a.p. Has 2 pathways which are equal and cancel out therefore propagation of signal across cardiac tissue When tissue is dead, there’s no cancelling out because 1 can travel, 2 can’t so uni-directional (depends on state of cardiac tissue e.g. hyperpolarised - not all cause contractility) , the pathway that can’t travel down, goes back up and reactivate tissue - jerky contractions- because tissue may have already gone into refractory period???, amiodarone prevents this by K+ channel blocker - prolongs repolarisation phase Digoxin (cardiac glycoside) e.g. prevent stroke risk Oral administration slows the ventricular response in cases of atrial fibrillation and atrial flutter but rarely effective for rapid control of ventricular rate. Inhibition of Na+-K+-ATPase. Results in increased intracellular Ca2+ via effects on Na+/Ca2+ exchange —> positive inotropic effect (prevent Na+ leaving cell so less involved in Na+/Ca2+ exchange, Ca2+ remains in cell, more powerful contraction) Central fatal stimulation causes increased refractory period and reduced rate of conduction through the AV node (slows heart down, so more rhythmical) • Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output. • Digoxin via vagal stimulation reduces the conduction of electrical impulses within the AV node. Fewer impulses reach the ventricles and ventricular rate falls. Hypokalaemia (usually a consequence of diuretic use) lowers the threshold for digoxin toxicity - digoxin binding site is K+ ion binding site, if K+ decreases, digoxin has more easier target access so greater effect • Adverse Effects • dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity )

Answer 23

Increase in sympathetic discharge to arteriolar (excluding brain and heart) —> increase in arteriolar constriction —> increase in peripheral resistance —> increase in arterial pressure Contraction: radius decreases, resistance increases, blood flow decreases - vasoconstriction (less space for blood to flow to arteriolar so remain in arteries —> b.p. Increase) Relaxation: increase in radius, decrease in resistance, increase in blood flow - vasodialtion Arteriolar smooth muscle normally displays a state of partial constriction - vascular tone

Answer 24

Physiology • Blood pressure (BP) = cardiac output (CO) x total peripheral resistance (TPR) Pathophysiology • Hypertension is defined as being consistently above 140/90 mmHg (for everyone) ; normal is 120/80 (average male) • Single most important risk factor for stroke, causing about 50% of ischaemic strokes • Accounts for ~25% of heart failure (HF) cases - work against hypertension, this increases to ~70% in the elderly • Major risk factor for myocardial infarction (MI) & chronic kidney disease (KD) • Ultimate goal of hypertension therapy —> reduce mortality from cardiovascular or renal events May be symptomless

Answer 25

``` STEP 1 • Angiotensin converting enzyme (ACE) inhibitor OR angiotensin receptor blocker (ACEi or ARB CCB or Thiazide- ARB) for under 55s type diuretic • Calcium channel blocker (CCB) or thiazide-like diuretic for over 55s or afro-Caribbean's STEP 3 • Combination of ACEi/ ARB with CCB and thiazide-like diuretic is recommended STEP 4: Resistant Hypertension • Consider low-dose spironolactone • Consider beta-blocker or alpha blocker ```

Answer 26

RAS = SNS activation/thirst, vasoconstriction, salt and water retention on kidneys, aldosterone secretion Decrease renal Na+ reabsorption, decreased renal perfusion pressure and increase in sympathetic NS activate RAS Angiotensin I to angiotensin II is inhibited along with breakdown of bradykinin to inactive metabolites being blocked, inhibit somatic form of angiotensin converting enzyme Uses: Hypertension - decrease TPR so decrease BP Herat failure - decrease vasoconstriction, decrease afterload, heart doesn’t have to work as hard. Also less fluid retained by kidneys, less volume return to heart, decreased preload, decreased cardiac work Post-myocardial infarction Diabetic nephropathy Progressive renal insufficiency Patients at high risk of cardiovascular disease Example: enalapril (end in pril = ACE inhibitor)

Answer 27

Example: Losartan Antagonists of type (AT1) receptors for Ang II, preventing the renal and vascular actions of Ang II Uses: hypertension, heart failure Decrease vasoconstriction, salt and water retention, heart failure Generally well tolerated Cough (ACEI) - bradykinin - stop break down bradykinin, exacerbate cough Hyperkalaemia (care with K supplements or K sparing diuretics) - interfere with Na+ uptake, less water followed by osmosis, blood volume decreases. In kidneys its a problem because decreased K+ exchange so not excreted in urine. Renal failure in patients with renal artery stenosis ( both) - if pressure falls in glomerulus - not efficient filtration, release Ang II, constrict efferent artery, blood cannot leaver glomerulus effectively, pressure in glomerulus increases and GFR restored. In renal failure, struggle to regulate glomerular filtration pressure Hypotension (both)

Answer 28

Smooth muscle contraction 1. Membrane depolarisation opens voltage-gated calcium (Ca2+) channels (VGCCs) 2. Ca2+ enters & binds to calmodulin (CaM) 3. Ca2+-CaM complex binds to & activates myosin light chain kinase (MLCK) 4. MLCK mediated phosphorylation —>smooth muscle contraction Calcium Channel Blockers (CCBs) Dihydropyridines (DHPs) • More selective for blood vessels • Amlodipine -does not cause any negative inotropy • Also licensed for prophylaxis of angina Non-DHPs (aka rate-limiting) • Verapamil - large negative inotropic effect For hypertension: Dihydropyridines inhibit Ca2+ entry into vascular smooth muscle cells ↓ T.P.R. = ↓ B.P. N.B. Powerful vasodilation can lead to reflex tachycardia and increased inotropy thus increased myocardial oxygen demand

Answer 29

ACEi or ARB given to younger than 55 as first line because more adherence 55 years older or Afro Caribbean given CCB or thiazide-type diuretic given. Afro - genetically have low plasma renin The older you get, the more hypertension comes down to atherosclerosis therefore some things that normally control vascular tone desensitises a bit e.g. RAS doesn’t work against atherosclerosis ``` RAS vs CCBs • CCBs decrease SBP more than RAS inhibitors • RAS inhibitors decrease heart failure • RAS inhibitors increase stroke • No difference for all-cause death RAS vs thiazides • Thiazides decrease SBP more than RAS inhibitors • RAS inhibitors increase heart failure • RAS inhibitors increase stroke • No difference for all-cause death RAS vs beta-blockers • No difference in SBP reduction • RAS inhibitors decrease CV events • RAS inhibitors decrease stroke • No difference for all-cause death ```

Answer 30

Alpha blockers - a1 adrenoceptor antagonists E.g. prazosin, phentolamine Used as antihypertensive because blocks vasoconstriction so TPR decreases, decreasing BP.

Answer 31

ventral tegmental area —> Nucleus accumbens (ventral striatum) part of central reward system - Mesolithic dopamine system Dopamine release in reward system, feeling of reward, induce euphoria

Answer 32

Snort - intranasal, mucous membranes of nasal sinuses - slow absorption Eat - oral, gastrointestinal tract, very slow absorption Smoke - inhalation, small airways and alveoli, already in pulmonary circulation so only needs to enter left side of heart - most rapid route Inject - intravenous - rapid absorption Oral < intranasal < intravenous < inhalation Classification Narcotics/ painfullers - opiate like drugs e.g. heroin, morphine Depressants - downers (slow things down), e.g. alcohol, benzodizepines (Valium), barbiturates Stimulates - uppers (speed things up), e.g. cocaine, amphetamine (speed), caffeine, nicotine metamphetamine (Crystal meth) Miscellaneous e.g. cannabis (depressant but also other properties), ecstasy (MDMA) “

Answer 33

Cannabis/marijuana Dose specific responses - as dose goes up, increase risk of negative vs positive THC and cannabidiol administered, now more THC so effects decrease Absorption Oral - 5-15% (bioavailability) - delayed onset/slow absorption, first pass metabolism -liver metabolises some before entering systemic circulation Inhalation (25-39%) - most exhaled out again, deeper you inhale, more likely to get into lungs to alveoli Bioavailability doesn’t really matter because drug titrated Distribution Really lipid soluble, can cross plasma membrane to tissues - slowly accumulate in poorly perfumed fatty tissues (chronic use) Fatty acid conjugated build up in fatty tissue, can slowly leak back into blood Metabolism Liver - 11-hydroxy-THC (phase 1 metabolite) More potent than THC only so much can be conjugated per unit time Excretion/ removal GIT - 65%, bile - enterohepatic recycling to faeces, problem if non polar - reabsorbs into gut Urine - 25% Poor correlation between plasma cannabinol concentration and degree of intoxication Effects of cannabis cigarette smoking can persist in body for 30 days - can sample hair

Answer 34

In brain: CB1 receptors, hippocampus/cerebellum/ cerebral cortex/ basal ganglia In periphery: CB2 receptors, immune cells Depressive drug because binds to CBR which is negatively coupled to adenyl cyclase. Inhibitory G protein suppresses adenyl cyclase - cellular activity decreases Same effect from endogenous anandamide (from cholesterol) Euphoria Cannabis bind to CB1 receptor on GABA interneurone - switch off so that reward system firing at a higher rate (GABA is natural suppressant on system). Therefore dopiminergic neurones from VTA to NAcc —> release dopamine Psychosis, schizophrenia The anterior cingulate cortex (ACC) Error detection e.g. word green in red - brain senses something wrong Involved with performance monitoring with behavioural adjustment in order to avoid losses E.g. driving car on wide road, then saddening dark, rainy, narrow road so have to redirect cognitive resource so more focussed Hypoactivity in cannabis users Food intake -hypothalamus Positive effect on orexigenic neurones in lateral hypothalamus (stimulates food intake) 1) presynaptic inhibition of GABA increases MCH neuronal activity 2) increased orexin production Immunosuppressant CB receptor expression, cannabinoid agonists B cells, T cells, NK, mast cells .etc. Memory loss - lambic regions (amnestied effects/ decrease BDNF - brain derived neurotrophic factor) Psychomotor performance - cerebral cortex Peripheral effects: Immunosuppressant Tachycardia/ vasodilation (conjunctivae - blood shot in eyes, TRPVI, Ca2+ entry) Medulla - low CB1 receptor expression, important because cardiorespiratory control will decrease (sometimes seen as more safer than alcohol)

Answer 35

High regulation of CB receptors: Multiple sclerosis/ pain/ stroke - regulatory (protective effect in these diseases) Fertility (decrease testosterone, inhibit PG gonadotrophins)/ obesity (CB1 in liver and adipose)- (pathological - high CB can cause these) Agonists: Dronabinol, nabilone Sativex - analgesia, MS Antagonist: Rimonabant - anti-obesity but no longer a viable because decrease reward so increase suicide rates

Answer 36

I.v., oral, intranasal, following can’t heat because will break down Paste -80% cocaine (organic solvent) Cocaine HCl - dissolve in acidic solution Inhalation Crack (crackles with heat) - precipitate with alkaline solution (e.g. baking soda) Freebase - dissolve in non-polar solvent (e.g. ammonia and ether) Smoking is low bioavailability because of pKa, smoke is acidic and drug has a high pKa Oral cocaine ionised in GIT - pKa is 8.7 so in alkaline more unionised, ionised in stomach, mouth, oesophagus .etc. (Poor absorbed) Slower absorbed, prolonged action Metabolism 75-90% - inactive T1/2 - 20-90 min (inactivated quickly) Plasma/liver cholinesterases - liver and blood quickly metabolised Pharmokinetics contribute to the addictive potential of the drug because: 1) speed on onset - quick onset 2) quick clearance

Answer 37

Local anaesthetic 8.7 pKa, 7.4 pH - pH closer therefore more unionised, outside cell so can enter cell more effectively 7 pH - more ionised and better at interacting with target (inside cell) and can’t leave cell Blocks sodium channel, sodium influx so disrupts a.p. Reuptake inhibition Cocaine blocks noradrenaline reuptake transporter so more NA in synapse, enhances NA Blocks dopamine transporter, dopamine builds up in synapse and can have an affect on D1R Other effects: Mild - sleep disturbance, anger, euphoria Severe - anxiety, incoherent speech, anorexia Cardiovascular: MI Increase catecholamines .... CNS: hyperthermia Cocaine inhibits cutaneous vasodilation and enhances sweat production Cocaine elevates threshold for sweating and cutaneous vasodilation

Answer 38

Administration Nicotine spray Nicotine gum - across mucous membranes in mouth Cigarettes - cigarette smoke is acidic, pKa 7.9 so no buccal absorption, breath out 50% Nicotine patch - diffuse across skin Absorption in alveoli independent of pH Bioavailability: nicotine patch > nicotine gum > nicotine spray > cigarettes (addictive) Metabolism Hepatic CYP2A6 to cotinine (t 1/2 1-4 hrs) Metabolised to inactive metabolite quickly, difference to cocaine (not metabolised in blood)

Answer 39

Nicotine acts on nicotinic receptor in ventral tegmental area to cause dopamine release from nucleus accumbens. Cardiovascular Free fatty acids - increase in VLDL, LDL —> atherosclerosis Metabolic Increase metabolic rate Neurodegenerative disorders - positive effect Parkinson’s disease: increase cytochrome proteins —> neurotoxins (increased metabolism of toxins) Alzheimer’s disease: decrease amyloid toxicity, decrease amyloid precursor protein (APP)

Answer 40

Causes euphoria Adenosine acts in A1 receptor and suppresses reward pathway Caffeine blocks adenosine (adenosine receptor antagonist)

Answer 41

Dosing Units: 1 unit = 10 ml/ 8g of absolute alcohol Administration Alcohol leaves stomach into small intestine Drinking on an empty stomach has a greater effect on you When drinking on a full stomach, alcohol remains in the stomach and stomach is busy churning up the contents Speed of onset is dependent on gastric emptying 20% in stomach, 80% in small intestines Metabolism (90%), 85% in liver Alcohol —> acetaldehyde Via alcohol dehydrogenase (75%) Mixed function oxidase (25%) - liver upregulates this enzyme —> tolerance to alcohol, better at metabolising and break down faster First pass hepatic metabolism Enzymes are saturable if not enough enzyme, alcohol leaks out to system Therefore, the faster you drink, the higher the blood alcohol levels 15% - GIT (stomach) Alcohol —> acetaldehyde (alcohol dehydrogenase) Females have 50% less AD Acetaldehyde —> acetic acid (aldehyde dehydrogenase) Distribution Alcohol is water soluble so distributes in water very effectively Blood levels are higher in a woman than a ,am because - more leaks out (enzyme) -more concentrated (less body water) Disulfiram Gentic polymorphism - Asian flush - don’t break down aldehyde dehydrogenase as well so acetaldehyde builds up = flush Disulfiram can be effective as alcohol aversion therapy because it blocks the enzyme so acetaldehyde builds up

Answer 42

Low pharmacological potency - small molecule so can bind to a lot of targets ‘lock and key’ but not so well so needs a lot more of it - high dose needed Acute effects CNS Has positive effect on GABA, promote Cl- influx (direct) - high pre vs post-synaptic allopregnenolone (binds to GABA receptor) (increased inhibition ) NMDA receptors - low allosteric modulation (reduced excitation) Ca2+ channels - low neurotransmitters (reduced excitation) Overall 1) CNS is functionally complex 2) ethanol has low potency therefore low selectivity Euphoria Opiates/ alcohol act as GABA receptor agonist on u-receptor so reduced GABA inhibition and more dopamine release. Also impair: - corpus callosum - passes info from left (logic) to right (feelings) - hypothalamus - controls appetite, emotions, temperature and pain sensation - reticular activating system - consciousness - hippocampus - memory - cerebellum - movement and coordination - basal ganglia - perception of time CVS Cutaneous vasodilation: flushing Decrease Ca2+ entry: precapillary can’t contract so increase blood flow Increase prostaglandins (vasodilation) Heart rate increases, tachycardia Alcohol depresses arterial baroreceptor so baroreceptor firing decreases so inhibition of sympathetic less Endocrine system Diuretics (polyuria) - AD suppresses vasopressin release Chronic effects CNS Thiamine —> enzymes in metabolism —> cerebral energy utilisation There are brain regions with high metabolic demand Thiamine not enough in alcoholics therefore impaired metabolism, NMDA excitotoxicity, ROS Dementia - cortical atrophy/ decreased volume of cerebral white matter - confusion (encephalopathy), oculomotor symptoms Ataxia - cerebellar cortex degeneration - gait Wernicke-Korsakoff syndrome (due to thiamine deficiency) Wernicke’s encephalopathy (hypothalamus/ thalamus) Korsakoff’s psychosis (deep brain e.g. hippocampus) Liver Use up NAD+ Decrease lipid metabolism Decrease oyruvate into citric acid cycle Decrease electron transport system therefore lipid increases, pyruvate —> lactic acid —> acidosis/ ketosis Healthy liver —> fatty liver (reversible) Glycerol and fatty acids deposited into hepatocytes as triacylglycerol (TAG) because of not enough NAD+ In hepatitis - mixed function oxidases are upregulated, generating free radicals so an inflammatory response, cytokine changes e.g. IL-6 ``` Cirrhosis Fibroblasts (connective tissue cells) - increased fibrin depositions Hepatocytes regeneration decrease Fibroblasts increase Active liver tissue decrease ``` CVS Beneficial effects Decrease in mortality from coronary artery disease Increase in HDLs Increase in tPA levels, decrease platelet aggregation Polyphenols in urine GIT Damage to gastric mucosa Carcinogenic due to acetaldehyde Endocrinology Increase in ACTH secretion Decrease in testosterone secretion Hangover Symptoms when blood alcohol concentration is 0, symptoms are worst Nausea - acetaldehyde is irritant —> vagus —> vomiting centre Headache - vasodilation Fatigue - 1) sleep deprivation 2) rebound Restlessness and muscle tremors - rebound Polyuria and polydipsia - decrease in ADH secretion Cure: sleep, drink water (clear our toxins - acetaldehyde?

Answer 43

Haemostasis: physiological formation of a blood clot Thrombosis: pathological formation of a blood clot

Answer 44

Immobility after surgery - susceptible to thrombosis Right calf swollen and collateral superficial veins present Palpation - localised tenderness and pitting oedema Investigation 2 level Well’s score - around 5 (high - higher the score the more likely) Blood taken for D-dimer testing (test for fibrin) Proximal leg vein scan Diagnosis and treatment Positive D-dimer test - diagnosis of deep-vein thrombosis Parenteral anticoagulant - Dalteparin (active antithrombin) Ultrasound scan confirms DVT Maintenance treatment with oral anticoagulant - rivaroxaban (FXa inhibitor)/ warfarin (VKA - vitamin K antagonist) Follow up Subsequent presentation: -chest pain -dyspnoea and tachypnoea Investigations Two level Wells score CTPA Diagnosis and treatment CTPA confirms pulmonary embolism —> dalteparin/ heparin (more effective than dalteparin) Ultrasound scan confirms DVT —> maintenance treatment - oral anticoagulant —> rivaroxaban/ warfarin

Answer 45

Virchow’s triad 1) rate of blood flow Blood flow slow/ stagnating —> no replenishment of anticoagulant factors and balance adjusted in favour of coagulation (When immobile - slow rate to leg) 2) consistency of blood Imbalance between pro-coagulation and anticoagulation factors (genetic) 3) blood vessel wall integrity Damaged endothelia —> blood exposed to pro-coagulation factors (surgery, hypertension)

Answer 46

Background - NSTEMI Non-ST elevated myocardial infarction (MI) White thrombin —> partially occluded coronary artery Treatment: antiplatelets Background - STEMI ST elevated myocardial infarction White thrombus —> fully occluded coronary artery Treatment: antiplatelets and thrombolytics Caused by: Damage to endothelium Atheroma formation Platelet aggregation

Answer 47

Initial stages Molecular level Small-scale thrombin production 1) Tissue factor (TF) TF bearing cells activate factors X and V forming prothrombinase complex 2) Prothrombinase complex This activates factor II (prothrombin) creating factor IIA (thrombin) 3) Antithrombin (AT-III) AT-III inactivated fIIa and fXa Amplification Cellular level Platelet activation and aggregation 1) thrombin Factor IIa —> activates platelets, high level of thrombin in artery —> activation of platelets 2) activated platelet Changes shape Becomes sticky and attaches to other platelets - aggregate, discoid —> skillet shape Molecular level Thrombin - binds to [rotease-activated receptor (PAR) on platelet surface PAR activation —> rise in intracellular Ca2+ (changes shape of platelet) Ca2+ rise —> exocytosis of adenosine diphosphate (ADP) from dense granules 1) ADP receptors ADP activates P2Y12 receptors —> platelet activation/ aggregation (autocfrine effect, paracrine effect - from other platelets) 2) Cyclo-oxygenate PAR activation —> liberates arachidonic acid (AA) Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2) from AA 3) glycoprotein IIb/IIIa receptor (GPIIb/ IIIa) TXA2 activation —> expression of GPIIb/IIIa integrity receptor on platelet surface GPIIb/IIIA - involved in platelet aggregation Initiation: anticoagulants 1) Inhibit factor IIa Dabiagatran (oral) - factor IIa inhibitor 2) Rivaroxaban (oral) - factor Xa inhibitor 3) increase activity of AT-III Heparin (IV, SC) - activates AT-III (decrease fIIa and fXa) Low-molecular weight heparina (LMWHs e.g. Dalteparin) - activate AT-III (decrease fXa) 4) Reduce levels of other factors Warfarin (oral) - vitamin K antagonist Vitamin K - required for generation of factors II, VII, IX and X Activation 1) prevent platelet activation/ aggregation Clopidogrel (oral) -ADP (P2Y12) receptor antagonist 2) inhibit production of TXA2 - low dose Aspirin (oral) - irreversible COX-1 inhibitor High doses no more effective but more side effects 3) Abciximab (IV, SC) - GpIIb/ IIIa targeted Limited use and only by specialists N.B. PAR receptor antagonists not used as much anymore ``` Propagation: thrombolytics Cellular level Generation of fibrin strands 1) activated platelets Large-scale thrombin production 2)thrombin Factor IIa —> binds to fibrinogen and converts to fibrin strands ``` Anticoagulants and Anti-platelets - do not remove pre-formed clots Thrombolytics: Convert plasminogen —> plasmin Plasmin - protease degrades fibrin Alteplase (IV) - recombinant tissue type plasminogen activator (rt-PA) - clotbluster Only in emergency because high risk of excess bleeding NB Antiplatelets used for prophylaxis, not specifically treatment of atherosclerosis Thrombolytics can be used to treat ruptured plaques but mainly indicated for ischaemic stroke

Answer 48

Exogenous Dietary triglycerides and cholesterol —> intestine —> chylomicron —> LP lipase —> free fatty acids and chylomicron remnants (remain after partial breakdown of chylomicrons) —> chylomicron remnants deposited into vessels - atheroma/ liver - remnant receptor FFA into skeletal muscle/ adipose tissue Endogenous Most LDL and HDL comes from this pathway. LPL (lipoprotein lipase) and HL (hepatic lipase) metabolise most IDL and LDL deposited into vessels - atheroma HDL - reverse transport of cholesterol from vessels to liver Remnant lipoproteins remain agter parietal breakdown of e.g. chylomicrons and high levels = prone to atherosclerosis. They can infiltrate through endothelium. Include VLDL, chylomicron remnant, IDL

Answer 49

Apoprotein A-1 - HDL Apoprotein B - LDL Can measure to see which one is higher - risk of heart disease. ``` LDL cholesterol Strongly associated with atherosclerosis and CHD events Modified by other risk factors: -low HDL cholesterol -smoking -hypertension -diabetes ``` ``` HDL cholesterol Protective effect for risk of atherosclerosis and CHD The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD HDL cholesterol tends to be low when triglycerides are high HDL cholesterol is lowered by smoking, obesity and physical inactivity ```

Answer 50

Atherosclerosis - an inflammatory fibroproliferative disorder 1) LDL moves into subendothelium 2) LDL oxidised by macrophages and smooth muscle cells 3) release of growth factors and cytokines attracts additional monocytes 4) foam cell accumulation and SMC proliferation result in growth of the plaque Endothelial dysfunction: 1) defective endothelium = leaky, increased endothelial permeability 2) upregulation of endothelial adhesion molecules 3) leukocyte adhesion 4) migration of leukocytes into the artery wall Fatty streak formation: 1) adherence and entry of leukocytes 2) migration of smooth muscle cells 3) activation of T cells 4) adherence and aggregation of platelets 5) formation of foam cells Complicated atherosclerotic plaque: 1) formation of fibrous cap 2) accumulation of macrophages 3) formation of necrotic core (macrophages and SMC’s die)

Answer 51

Type I - lesion-prone location - adaptive thickening Type II - macrophage foam cells Type III - preatheroma - small pools of extracellular lipid Type IV - atheroma - core of extracellular lipid Type V - fibroatheroma - fibrous thickening Type VI - complicated lesion - thrombus and fissure and haematoma

Answer 52

Vulnerable - thin fibrous cap, rich with lipids and macrophages Division between lipid core and lumen can break down Stable - thick fibrous cap - less likely to rupture even if thinner lumen

Answer 53

Statins HMG-CoA reductase inhibitors o This halts the cholesterol synthesis pathway. o Halts specifically the rate-limiting step. o Reduces the modification of proteins involved in modifying gene translation to create LDL. This has the effect of UP-REGULATING the LDL receptors expressed on hepatocytes in the liver which results in more LDL being removed from the blood. This also results in more HDL levels in the blood. Statin Properties Selectivity ratio – the higher the selectivity ratio, the greater the chance of it being concentrated in the hepatocyte. o I.E. Simvastatin gets into many cells as it’s very lipid soluble. Pravastatin is mainly hepatocytes. Potency – the lower the number, the more powerful the drug is as an inhibitor of the enzyme. Rule of 6: double the dose but only 6% reduction in LDL Statins can be described to have a pleiotropic effect – both good and bad effects. Statins have multiple effects not directly related to lowering cholesterol (e.g. anti-inflammatory action). Fibrates Main MoA is activation of PPAR alpha receptors (present in nucleus) o PPAR – Peroxisome Proliferator Activated Receptors. o Act on the liver. Decrease FFAs and TGs. Increases HDL very effectively but LDL doesn’t change a lot. NOTE: Thiazolidinediones – PPAR-gamma receptor agonists. o They are different! o Act on adipose tissue. Nicotinic acid Should be very good but turns out in clinical practice it isn’t so not used very much. Increase side effects and toxicity Ezetimibe Inhibits cholesterol absorption Absorbed into intestines then activated as glucoronide Can be co-administered with statins to avoid the “rule of 6” with statins to have a more dramatic effect at lowering LDL. CETP inhibitors E.g. torcetrapib CETP converts HDL into LDL and so inhibiting it increases HDL levels. Can lead to raised BP due to activation of aldosterone synthesis? PCSK9 inhibitors PCSK9 is an inhibitor of the LDL receptor. Monoclonal anti-PCSK9 antibodies have been made to inactivate PCSK9 and so more LDL can be absorbed by the liver. One such group of patients that benefits from PCSK9 inhibition greatly are the people with Familial Hypercholesterolemia. Vaccine?

Answer 54

Non-steroidal anti inflammatory drug • Relief of mild-to-moderate pain (analgesic) »Toothache, headache, backache »Postoperative pain (opiate sparing) »Dysmenorrhea (menstrual pain) • Reduction of fever (antipyretic) »Influenza • Reduction of inflammation (anti-inflammatory) »Rheumatoid arthritis »Osteoarthritis »Other forms of musculo-skeletal inflammation »Soft tissue injuries (strains and sprains) »Gout

Answer 55

• Inhibition of prostaglandin and thromboxane synthesis. These are: • Lipid mediators derived from arachidonic acid • Widely distributed • Not stored pre-formed • Receptor-mediated NSAIDs inhibit cyclo-oxygenases (COXs 1 and 2) - rate limiting step, preventing formation of prostanoids e.g. prostaglandin, prostacyclin and thromboxane formation COX-1 and COX-2 with different (but overlapping) cellular distributions, very similar structures Prostanoid receptors 10 known receptors e.g. DP1 and 2, EP 1,2,3,4 IP 1 and 2, TP Named based on agonist potency Prostanoids have both G protein-dependent and -independent effects Physiological (desirable) and pro-inflammatory (undesirable)

Answer 56

Can activate 4 receptors, cAMP-dependent and independent downstream mechanisms ``` Unwanted actions: • Increased pain perception - lower threshold for • Increased body temperature • Acute inflammatory response • Immune responses • Tumorigenesis • Inhibition of apoptosis ```

Answer 57

Increases Stimulation of PG receptors in the periphery sensitises the nociceptors which cause pain both acutely and chronically EP4 receptor antagonist blocks the effect of the PGE2 analogue. 1 possible mechanism: -cAMP mediated -activates P2X3 nociceptors -PGE2 only - PKA only -PGE2 + inflammation Epac pathway activated and additional more PGE2 produced Greater activation of P2X3 receptors = greater pain perception 2 possible mechanism: EP1 receptors and/ or EP4 receptors (in periphery and spine) Endocannabinoids (neuromodulators in thalamus, spine and periphery) NSAIDs increase beta-endorphin in spine Temperature PGE2 is pyrogenic - inducing fever Stimulates hypothalamic neurones initiating a rise in body temperature so NSAIDs reduce temperature.

Answer 58

• Bronchodilation (although there is evidence that PGE2 can desensitise β2adrenoceptors) • Gastroprotection • Renal salt and water homeostasis • Vasoregulation (dilation and constriction depending on receptor activated)

Answer 59

Inhibit cyclo-oxygenase so block formation of products Cyclooxygenase inhibition favours production of leukotrienes - bronchoconstrictors Gastric cytoprotection COX-1 PGE2 downrequlates HCl secretion PGE2 stimulates mucus and bicarbonate secretion so gastric pH increases NSAIDs can increase the risk of ulceration. Aspirin inhibits COX-1 so maybe inhibiting COX-2 can reduce these effects .e.g Coxib family - selectively reversible inhibit COX-2 (celecoxib)

Answer 60

``` Both COX-1 and COX-2 in glomerulus • PGE2 increases renal blood flow • NSAIDs can cause renal toxicity -Constriction of afferent renal arteriole -Reduction in renal artery flow -Reduced glomerular filtration rate ``` COX-1 and COX-2 in glomerulus COX-1 in collecting duct COX-2 in ascending limb So not like one enzyme is good and one is bad ``` CVS NSAIDS can have serious unwanted cardiovascular effects • Vasoconstriction • Salt and water retention • Reduced effect of antihypertensives 50% deaths from NSAIDs are cardiovascular • Hypertension • Myocardial infarction • Stroke ``` Evidence that selective COX-2 inhibitors pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear Coxibs MoA Suppression of prostaglandins, causes loss of control on mediators which act physiologically to instigate thrombosis, increased platelet aggregation, BP and atherogenesis

Answer 61

Analgesic use • Usually occasional • Relatively low risk of side effects Anti-inflammatory use • Often sustained • Higher doses • Relatively high risk of side effects (more likely in chronic conditions - usually elderly) Strategies other than COX-2 selective NSAIDs for limiting GI side effects • Topical application • Minimise NSAID use in patients with history of GI ulceration • Treat H pylori if present - predisposes to ulcers • If NSAID essential, administer with omeprazole or other proton pump inhibitor • Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g. • Alcohol consumption • Anticoagulant or glucocorticoid steroid use Development of newer NSAIDs which may be safer • Dual COX and LOX inhibitors For asthmatic patients No safe option on the market (liver injury) • Nitric oxide or Hydrogen sulphide releasing NSAIDS (protective in GI) NO and H2S protective to GI and CVS A number of options undergoing testing Late stage clinical trials Inhibit both prostaglandins and leukotrienes so May decrease risk in asthmatics

Answer 62

``` • Unique among the NSAIDS • Selective for COX-1 • Binds IRREVERSIBLY to COX enzymes • Has anti-inflammatory, analgesic and anti- pyretic actions • Reduces platelet aggregation ``` Effects of prostanoids on platelet aggregation Thromboxane A2 from platelets causes platelet aggregation Prostacyclin from endothelial cells inhibits platelet aggregation (PGI2). Effects of aspirin on platelet aggregation Irreversible blockage on thromboxane A2 made by COX-1, platelets - no nucleus so can’t make more platelets Some downregulation, not complete blockade on PGI2 synthesis by COX-2 and COX-2, endothelial cells have nucleus so can replenish stores of COX-1 and COX-2 therefore decrease in platelet aggregation Anti-platelet actions of aspirin due to: • Very high degree of COX-1 inhibition which effectively suppresses TxA2 production by platelets • Covalent binding which permanently inhibits platelet COX-1 • Relatively low capacity to inhibit COX-2 • Use low dose to allow endothelial resynthesis of COX-2

Answer 63

• Gastric irritation and ulceration • Bronchospasm in sensitive asthmatics • Prolonged bleeding times • Nephrotoxicity • Side effects likely with aspirin because it inhibits COX covalently, not because it is selective for COX-1

Answer 64

Patients under 20 Viral infection and aspirin Damage to mitochondria leading to ammonia production resulting in damage to astrocytes – oedema in brain

Answer 65

``` • Is a widely used effective analgesic for mild-to-moderate pain which is available over the counter • Has anti-pyretic action • Has minimal anti-inflammatory effect • Therefore it is not a NSAID ``` MoA • Not understood, probably central and peripheral • ? COX- 3 • ? Via Cannabinoid receptors • ? Interaction with endogenous opioids • ?interaction with 5HT and adenosine receptors Overdose May cause irreversible liver failure If glutathione is depleted the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death (Not enough glutathione to remove NAPQI) ``` Antidote for paracetamol • Add compound with –SH groups • Usually intravenous Acetylcysteine • Occasionally oral methionine • Could be added to the formulation but increased cost • Acetyl cysteine used in cases of attempted suicide and accidental poisoning • If not administered early enough, liver failure may be unpreventable – transplant only option ``` Now restriction how much you can buy No more than 2 packs per transaction

Answer 66

Derived from the poppy ``` Morphine - natural Codeine - natural (Methylmorphine) Thebaine Papaverine (Opioid - anything that has opiate like activity) ``` Structure-activity E.g. morphine 2 hydroxyl groups - position 3 and position 6, hydroxyl group at position 3 required for binding - codeine and heroin (diacetylmorphine) are pro drugs which need to be activated to reveal hydroxyl group so not as effective binding, hydroxyl at position 6 when oxidised increases lipophilicity of drug by 10 fold I.e. remove group (side note: heroin most lipid soluble because of acetyl groups) Receptor interactions: - hydrogen bonds - van Dee Wallace forces Tertiary nitrogen = analgesia and permits receptor anchoring, if quaternary decreases analgesia because can’t access brain as effectively Extend side chain to 3+ carbons and you generate antagonist ``` ‘Morphine rule’ Used to believe these were needed for activity -aromatic ring -spacer -quaternary carbon centre -basic nitrogen ``` Fentanyl most potent because it doesn’t have quaternary carbon

Answer 67

Route of administration/ bioavailability Oral vs intravenous Opioids are weak bases, pKa > 8 In blood and lymph least ionised so less access to tissues (pH low) Lipid solubility: methadone/fentanyl >> heroin > morphine More lipid soluble, more potent Methadone has slow metabolism so can accumulate in adipose tissue and is slowly released back into bloodstream (used for heroin treatment not anymore) The active metabolites of morphine, heroin and codeine are activity in the ability to cause euphoria but not restorative depression therefore positive Morphine - morphine 3-G glucuronide, morphine 6-G glucuronide Heroin - morphine Codeine - morphine Morphine has greater affinity to mu-receptors than M6G Metabolism 1: morphine - morphine-6-glucuronide (10% active metabolite), fentanyl (fast metabolism) vs methaodne (slow metabolism) Metabolism 2: 5-10% codeine —> morphine, CYP2D6 O-dealkylation - activates (slow); CYP3A4 - deactivates (fast)

Answer 68

Opioids act via specific opioid receptors Endogenous opioid peptides include: Endorphins (euphoria, analgesic) Enkephalins Dynorphins/ neoendorphins Endorphins bind to mu or delta receptors in cerebellum, caudate nucleus, nucleus accumbens, PAG It has a pain/sensorimotor function Enkephalins bind to delta receptors in nucleus accumbens, cerebral cortex, hippocampus, putamen Motor/cognitive function Dynorphins bind to Kappa receptors in hypothalamus, putamen and caudate Neuroendocrine function Cellular MoA at opiate receptors: Depressant - hyperpolarisation (increase potassium efflux), decrease Ca2+ inward current, decrease adenylate cyclase activity, decrease neurotransmitter release -analgesia -euphoria -depression of cough centre (anti-tussive) Other effects: -depression of respiration (medulla) -stimulation of chemoreceptors trigger zone (nausea/ vomiting) -pupillary constriction -GI effects

Answer 69

Decrease pain perception Increase pain tolerance Modulation of pain transmission Periacqueductal gray region receives stimuli from different parts of the brain and determines level of response, cortex can modify e.g. allergy to wasps - previous experience reminded so increase pain, decrease pain tolerance, think it’s more painful OR twist ankle in sports, previous experience not bad so increase pain tolerance Pathway: Information from thalamus (mu) + —> cortex (mu, delta) +/- —> PAG (mu, kappa)—> + NRM (delta) - —> dorsal horn (mu, kappa)—> periphery (or thalamus directly acts on PAG) Cortex, thalamus, dorsal horn and periphery, hypothalamus involved in pain perception PAG, NRM, NRPG involved in pain tolerance On top of the above, hypothalamus (kappa) can also modulate response to PAG e.g. state of health - if poor health - exacerbate pain; good health - reduce pain LC (sympathetic) suppresses painful stimulito dorsal horn e.g. for fight or flight Substantia gelatinosa within spinal cord in dorsal horn modifies signal from NRM to determine how much inhibition is needed on the sensory neurones Opioids act on dorsal horn and periphery to depress pain perception On PAG To enhance firing by surpressing GABA which has an inhibitory effect on pain tolerance centres On NRPG to enhance firing “

Answer 70

Opiates act on mu-receptor and decrease GABA exocytosis, reducing the inhibition on VTA so more dopamine is released from nucleus accumbens

Answer 71

Stimulation of mechano or chemo receptors (throat, respiratory passages or stretch receptors in lungs) —> afferent impulses to cough center (medulla) —> efferent impulses via parasympathetic and motor nerves to diaphragm, intercostal muscles and lung —> increased contraction of diaphragmatic, abdominal and intercostal (ribs) muscles = noisy expiration (cough) Peripherally: opioids act on Ach-NK-C fibres relaying to vagus (inhibit) (between stimulation of mechano... and afferent impulses) Centrally: act on 5HT1A receptors (between afferent and efferent impulses...) (inhibit) Centrally: act on

Answer 72

Opioids act on mu2 receptors. There central chemoreceptors which detect PaCO2. They depress receptors detecting PaCO2 therefore urge to breath also depressed because reduced firing of chemoreceptors to the medullary control centre (inspiratory and expiratory actions) Occurs at high dose

Answer 73

Opioids act on mu receptors which switches of GABA disinhibiting the chemoreceptor trigger zone This causes vomiting reflex from medullary vomiting centre

Answer 74

Opioids act on mu receptors within the Edinger-Westphalia nucleus which switches of GABA increasing parasympathetic nerve firing rate Unconsciousness and tightly constricted pupils = opioid/ heroin overdose ‘pin-prick eyes’ Normally when unconscious, pupils are dilated

Answer 75

There are lots of opioid receptors in the myenteric plexus (mu and kappa) Opioids cause decreased gastric motility, increase in water reabsorption, decrease in gastric emptying Urticaria Looks like allergic response but isn’t - non-IgE mediated Some opioids’ OH groups cause mast cell degranulation Massive histamine release from mast cells under the skin PKA mediated, not receptor mediated (mu receptor) Can switch opioids given

Answer 76

Tolerance Increased opioid use = high arresting which mediates receptor internalisation Therefore tissue less receptive to opioids Dependence Withdrawal associated with: -psychological craving -physical withdrawal - cells compensate, opioids cAMP decreases so cells upregulated cell activity increasing adenyl cyclase so muscular contractions and cramps Overdose - coma - respiratory depression - pin-point pupils - hypotension - treatment: naloxone (opioid antagonist) I.v. - resembling flu

Answer 77

There are two major forms: ulcerative colitis and Crohn’s disease Can’t distinguish in 10% of patients Affects children, adolescents and adults Genetic risk factors Genetic predisposition 201 loci identified People of White European origin most susceptible Environmental - diet - medication -antibiotics can upset the stomach and cause diarrhoea - smoking - microbiome - chicken and egg situation, change in microbiome caused by disease or caused the disease Autoimmune disease Defective interaction between mucosal immune system and gut flora - infection Complex interplay between host and microbes —> disrupted innate immunity and impaired clearance —> pro-inflammatory compensatory responses —> physical damage and chronic inflammation

Answer 78

``` Can be systemic as well as local • Abdominal pain and cramping • Diarrhoea, bloody faeces • Mouth ulcers • Anaemia • Fever • Arthritic pain • Skin rashes • Uveitis • Weight loss ```

Answer 79

Fluid/ electrolyte replacement (diarrhoea) Blood transfusion/ oral iron (anaemia) Nutritional support (malnutrition common when you can’t eat) ``` Classic symptomatic treatments For active disease and prevention of relapse -aminosalicylates e.g. mesalazine -glucocorticoids e.g. prednisolone -immunosuppressive e.g. Azathioprine ```

Answer 80

Mesalazine to 5-aminosalycylic acid (5-ASA) Olsalazine (2 linked 5-ASA molecules) Anti-inflammatory Pharmacokinetics: Mesalazine - no need to be metabolised, site of absorption is in small bowel and colon (absorbed throughout) Olsalazine - metabolised by colonic flora, absorbed in colon (active in colon where split) Aminosalicylates have anti-inflammatory actions by modulating transcription. Down regulate pro-inflammatory molecules such as TNF-alpha, IL-1beta, IL-6 Considered to be a safe drug Effective at induction and maintenance of remission Combined oral and rectal administration probably more effective than either alone for generalised disease Rectal delivery better for localised disease (proctitis) Probably better than glucocorticoids Usually first line treatment in UC CD Ineffective in inducing remission of CD Other therapies preferable

Answer 81

E.g. prednisolone, fluticasone, budesonide (not absorbed so fewer side effects for budesonide) - Powerful anti-inflammatory and immunosuppressive drugs. - Derived from the hormone cortisol - Activate intracellular glucocorticoid receptors which can then act as positive or negative transcription factors Potent anti-inflammatory and immunosuppressive actions of GCs due to downregulation of inflammation cascade caused by macrophages and T cells (works in CU When given systemically, chronic glucocorticoid administration causes many unwanted effects Budesonide is safe but standard oral glucocorticoids better at inducing remission in active CD UC: Strong evidence that aminosalicylates are superior and glucocorticoids are not recommended CD: GCs drugs of choice for inducing remission, budesonide preferred if mild, avoid as maintenance therapy due to side effects

Answer 82

A pro-drug activated by gut flora to 6-mercaptopurine. Now also give 6-mercaptoturine directly Purine antagonist Immunosuppressive Interferes with DNA synthesis and cell replication ``` Effects on immune responses It impairs: -cell and antibody-mediated immune responses -lymphocyte proliferation -mononuclear cell infiltration -synthesis of antibodies It enahnces: -T cell apoptosis ``` CD: Not recommended for active disease Azathioprine or other immunosuppressants recommended for maintaining remission - need to be given for few months before you see an effect Glucocorticoid sparing Slow onset - 3 to 4 months treatment for clinical benefit If ineffective move to biological therapies (antibodies) but more potent ``` Unwanted side effects: Pancreatitis Bone marrow suppression Hepatotoxicity Increased risk (around 4 fold) of lymphoma and skin cancer ``` Interferes with DNA synthesis and cell replication; metabolites cause side effects: 6-MeMP is hepatotoxic Allopurinol inhibits Xanthine oxidase - given for gout, wont form 6-TU so other pathways increased, increasing side effects 6-TGN (incorporation into DNA) - beneficial but also causes myelosuppression

Answer 83

Administer topically - fluid or foam enemas or suppositories - at site of action - not too much systemic Use a low dose in combination with another drug Use an oral or topically administered drug with high hepatic first pass metabolism .e.g budesonide so little escapes into the systematic circulation.

Answer 84

PH dependent polymer coating system - e.g. can’t degrade in stomach but can in gut Pressure/ osmotic controlled coating system - semi-permeable membrane; push layer pushing drug out Time-dependent polymer coating-system - gradual swelling of coating leading to drug release Prodrug based conjugates - enzymes in specific organs can degrade Now can combine time and pH - potential to give better targeting of frugs to areas of inflammation (higher conc. to site of damage and reduce side effects because reduce overall dose)

Answer 85

1) manipulation of the microbiome 2) biological therapies Manipulation of the microbiome: Exclusive enteral nutrition (EEN) -liquid diet -allows ‘resting’ of the mucosa and recovery of the gut flora because not a lot of work needed to be done -unpalatable and hard to maintain -only recommended for induction of remission if patient cannot take steroids Probiotic therapies - different organisms have different effects so difficult to generalise - no evidence for probiotics in CD - weak evidence for maintenance of remission in UC Faecal macrobiota replacement (FMT) therapies - faeces from healthy patient put into unhealthy patient, unhealthy bacteria outnumbered by healthy bacteria - unclear if help because cause or effect of microbiome Antibiotic treatment - rifaximin - interferes with bacterial transcription by binding to RNA polymerase - reduces inflammatory mediator mRNA - may be microbiome modulator - not absorbed from gut - some evidence for sustained remission in moderate CD - only recommended if complications relating to infection

Answer 86

-Anti-TNFalpha antibodies (anti-tumour necrosis factor alpha) E.g. infliximab (iv) -Other antibodies effective but some have more side-effects -New humanised antibodies coming on stream e.g. entanacept MoA Works on both TNF-alpha on cell membranes and and solubilised form Stops binding to receptors -Anti-TNFalpha reduces activation of TNF-alpha receptors in the gut -reduces downstream inflammatory events -binds to membrane associated TNF-alpha -induces cytolysis of cells expressing TNF-alpha -promotes apoptosis of activated T cells Pharmacokinetics - infliximab given intravenously - very long half-life (9.5 days) - most patients relapse after 8-12 weeks - therefore repeat infusion every 8 weeks Used successfully in treatment of CD Potentially curative, but many patients relapse Successful in some patients with refractory disease and fistulae (leakage can spread infection) Very good for maintaining fistula closure Problems and adverse effects: - responders lose response due to production of anti-drug antibodies and increased drug clearance - 4x-5x increase in incidence of tuberculosis - risk of reactivation dormant TB - increased risk of septicaemia - worsening of heart failure - increased risk of demyelinating disease - increased risk of malignancy - can be immunogenic - azathioprine reduces risk but raises TB/ malignancy risk Early use better than last resort Combined infliximab and azathioprine therapy recommended rather than monotherapy New targets: - integrins (needed for cells to migrate) - interleukins (IL12; IL17; IL23) - interleukin receptors - Janus kinase (JAK) cytoplasmic cell signalling

Answer 87

From inside to outside: Lumen, microvilli (maximise absorption), tubule cell, basal interdigitation, interstitium Capillaries surround There are aquaporins on apical side of proximal tubule cell. H2O flows through this, Na+ can enter the cell freely (transceullular) Glucose and amino acids can be reabsorbed into cell by being coupled with Na+ (cotransporter) There is also a Na+/H+ transporter CO2 and H2O enter freely and are converted to H+ and HCO3- by carbonic anhydrase within the cell On the basal side there is a Na+/K+ ATPase to maintain the concentration gradient; Na+ leaves the cell and K+ enters the cell There is also a Na+/HCO3- cotransporter which leave the cell to allow water absorption Within the tubule lumen (on apical side) there are no proteins, within the interstitium (basal side) there is oncotic pressure due to lots of protein drawing in water Paracellular pathway includes H2O, Na+, Cl-, HCO3- Exogenous agents -drugs e.g. glucoronide is excreted

Answer 88

Descending limb H2O enters transcellularly and paracellularly leading to a isotonic tubule lumen and hypertonic interstitium ; NO ions Ascending limb Impermeable to H2O Na+/Cl-/K+ cotransporter on apical side Na+/K+ ATPase and K+/Cl- cotransporter on basal side Countercurrent effect - Na+ leaves the ascending limb and enters medullary interstitium - concentrating it - Fluid in ascending limb decreases in osmolarity (H2O from ascending into descending within tubule -equilibrate) - More concentrated medullary interstitium draws water from the permeable descending limb - Fluid in descending limb increases in osmolarity (Na+ from descending into ascending to equilibrate) - More fluid enters and forces fluid from descending to ascending limb - this fluid has increased in osmolarity due to increased Na+ concentration in the medulla - Na+ leaves the ascending limb and enters medullary interstitium - Fluid in ascending limb decreases in osmolarity - Na+ leaves ascending limb again entering medullary interstitium and fluid in ascending limb decreases further in osmolarity

Answer 89

Early distal tubule On apical membrane there is a Na+/Cl- cotransporter On basal membrane there is a Na+/K+ ATPase and K+/Cl- cotransporter Impermeable to free water reabsorption Aldosterone acts on MR and increases Na+ channel and Na+/K+ ATPase Late distal tubule/ collecting duct On apical there is a Na+ transporter for free movement of Na+ Impermeable to free water reabsorption but there are aquaporins (AQP2)on apical membrane which can allow water to enter (mediated by vasopressin acting on V2 on basal membrane), H2O leaves through AQp 3/4 on basal membrane No free water movement because it would disturb the concentration gradient. Osmolarity increases down the medulla so water would just flow into the tubule.

Answer 90

1) inhibit the reabsorption of Na+ and Cl-; increase excretion 2) increase the osmolarity of tubular fluid I.e. decrease the osmotic gradient across the epithelia Classes 1) osmotic diuretics e.g. mannitol; proximal tubule, descending limb, collecting duct 2) carbonic anhydrase inhibitors e.g. acetazolamide; proximal tubule 3) loop diuretics e.g. frusemide (furosemide); ascending limb 4) thiazides e.g. bendrofluazide (bendroflumethiazide); distal tubule 5) potassium sparing diuretics e.g. a milo ride, spironolactone; late distal tubule First 2 not really used as diuretics

Answer 91

Block Na+/Cl- cotransporter on apical membrane, usually K+ enters lumen but LD reduces this Therefore ability to concentrate interstitium decreases, can’t absorb as much from CD, interferes with counter current mechanism Potassium recycling drives the positive lumen potential, a lack of this leads to a loss of Ca2+ and Mg2+ Action on Na+ reabsorption: inhibit Na+ and Cl- reabsorption in ascending limb - 30% Action on H2O reabsorption: increase tubular fluid osmolarity/ decrease osmolarity of medullary interstitium = decraesed H2O reabsorption in the collecting duct Other effects: increased delivery of Na+ to distal tubule because can’t reabsorb in ascending limb which increases K+ loss Ca2+ and Mg2+ - loss of K+ recycling

Answer 92

Block Na+/Cl- cotransporter on apical membrane. Lose NaCl because prevent reuptake Not affecting Loop of Henle so not affecting counter current so not too powerful Action on Na+ reabsorption: inhibit Na+ and Cl- reabsorption in early distal tubule Action on H20 reabsorption: increased tubular fluid osmolarity = decreased H20 reabsorption in the collecting duct Other effects: Increased delivery of Na+ to distal tubule, in tased K+ loss (increased Na+/K+ exchange) -in common with thiazides Increased Mg2+ loss and increased Ca2+ reabsorption (unknown)

Answer 93

One stimuli fro renin is low tubular Na+; diuretics cause more Na+ to distal tubule so sending more Na+ to macula dense. This inhibits renin but this is only short term (1-2 days) In the long term, it promotes Na+ and water loss; stimuli for renin secretion is reduced renal perfusion pressure and Na+ loss. Macula densa recognises this and causes renin production. Particular problem with loop diuretics because inhibits protein which puts Na+ in macula densa (triple transporter) Loop diuretics are most powerful because they cause most sodium retention in tubule Loop diuretic battling with RAAS to do opposite effect so give ACEi along with diuretics

Answer 94

Weakest diuretic because acts at end of kidney Spironolactone is a mineralocorticoid receptor antagonist and reduces effects of aldosterone on Na+ transporters, reduced Na+/K+ exchange so reduced K+ loss Action on Na+ reabsorption: inhibit Na+ reabsorption (and concomitant K+ secretion) in early distal tubule - 5% Action on H20 absorption: increased tubular fluid osmolarity = decreased H20 reabsorption in the collecting duct Other effects: decreased reabsorption of Na+ to distal tubule, increased H+ retention (decreased Na+/ H+ exchange)

Answer 95

Loop diuretics: hypovolaemia, metabolic alkalosis (Cl- loss), hyperuricemia, hypokalaemia, hyponatraemia Thiazides: metabolic alkalosis, hyperuricemia, hyponatraemia, hypokalaemia Potassium sparing diuretics: hyperkalaemia Hyperuricemia Uric acid uses same transporter as diuretic (organic anion transporter), excretes uric acid into lumen (too big through glomerulus), both uric acid and diuretic compete so reduced excretion of uric acid

Answer 96

Thiazides - 1st line treatment in most countries for hypertension Salt sensitive 55 or older of Afro Caribbean Second line in combination with ACEi in those younger than 55. Thiazides slightly more effective but people pee all the time More effective because: Initial response (4-6 weeks) - due to decreased plasma volume After 4-6 weeks: plasma volume restored because of RAS Chronic thiazides: decrease in TPR because activation of eNOS (endothelium)/ Ca2+ channel antagonism - prevent contraction of vascular smooth muscle / opening of KCa channel (smooth muscle) Short term - diuretic effect Long term: vasodilator effect

Answer 97

Loop diuretics can cause acute reduction in congestion - blood builds up in venous system because heart not effective —> exertion of pressure —> oedema (reduced) But can activate RAS increasing renin secretion Additional use of potassium sparing diuretics can be used to combat this Decreased Na+/K+ exchange later therefore greater effect of water and Na+ retention

Answer 98

Psychoses can be split into schizophrenia (disorder of thought process) or affective disorders (disorder of mood). Affective disorders can be further be split into mania and depression ``` Symptoms Emotional (psycho-logical): -misery, apathy, pessimism -low self-esteem -loss of motivation -anhedonia - loss of ability to enjoy activities ``` Biological (somatic) - slowing of thought and action (psychomotor retardation) - loss of libido - loss of appetite, sleep disturbance

Answer 99

1) Unipolar depression/ depressive disorder -mood swings in same direction -relatively late onset -reactive depression (response from external events) - stressful life events .e.g. death (Non-familial, not hereditary) -endogenous depression (response from inside body) - unrelated to external stresses - familial pattern (hereditary) -drug treatment similar for endogenous and reactive 2) Bipolar depression/ maniac depression - oscillating depression/ mania - opposite to depression e.g. aggression and increased activity - less common - early adult onset - strong hereditary tendency - drug treatment (lithium - mood stabiliser, affects intracellular secondary messenger systems e.g. decrease cAMP, narrow therapeutic window - dosage needs to be controlled)

Answer 100

Changes in transmission of NA and 5-HT: Depression = functional deficit of central MA transmission Mania = functional excess Based on pharmacological evidence Biochemical evidence inconsistent - chemicals depressed = decrease in monoamine metabolites in urine = reduction in turnover of monoamine in brain so supports but no pattern seen when seeing from mild to severe - we don’t see further decrease, no correlation Delayed onset of clinical effect of drugs - may be due to adaptive changes instead of MA theory: -down-regulation: a2, beta, 5HT receptors (may be what’s causing the anti-depressive activity) Other reasons: HPA axis (hypothalamic pituitary adrenal axis (increase in CRH (cortiocotrophin releasing hormone levels) - high in clinical depression Hippocampus neurodegeneration Pharmacological evidence supporting MA E.g. TCA’s, block NA and 5-HT reuptake, mood increases MAO inhibitors, increase stores of NA and 5-HTR, mood incraeses Reserpine, inhibits NA and 5-HT storage (inhibits loading of vesicles in pre-synaptic terminal), mood decreases

Answer 101

1) TCAs 2) MAOIs 3) SSRIs

Answer 102

Example: amitriptyline MOA: -3 ring structure -neuronal monoamine re-uptake inhibitors NA=5-HT Other receptor actions: - a2 - a2 antagonist = enhanced release - mAChRs - histamine - 5-HT Delayed down-regulation of B-adrenoceptors and 5-HT2 receptors - delayed action of anti-depressants Pharmacokinetics: - rapid oral absorption - highly PPB (90-5%) - plasma protein bound Unwanted effects: At therapeutic dosage -atropine-like effects (amitriptyline) - inhibits muscarinic receptors - dry mouth, dry skin, constipation, blurred vision -postural hypotension (vasomotor centre) -a2 receptors in vasomotor -sedation (H1 antagonism) - may be used for sleep disturbance Acute toxicity (overdose) - CNS: excitement, delirium, seizures (lowers seizure threshold) —> coma, respiratory depression - CVS: cardiac dysrhythmias —> ventricular fibrillation/ sudden death - care - attempted suicide Drug interactions: - PPB: highly plasma protein bound so other drugs can interact and displace from binding site so more circulation, TCA effects increased by aspirin, phenytoin, warfarin - hepatic microsomes enzymes: increase TCA effects - drugs that use same enzymes will compete therefore metabolised more slowly - potentiation of CNS depressants (alcohol) - antihypertensive drugs (monitor closely)

Answer 103

Example: Phenelzine MOA: MAO-A: NA and 5-HT MAO-B: DA -most are non-selective MAOIs - A and B -irreversible inhibition —> long d.o.a -structure consists of a highly reactive hydrazine -rapid effects: increase cytoplasmic NA and 5-HT (lipid soluble into brain and inhibits MAO in NA terminals, increase cytoplasmic NA, enhanced release of NA, increase synaptic, increase neuronal action -delayed effects: clinical response: down-regulation of B-adrenoceptors (B1 and B2) and 5-HT2 receptors -inhibition of other enzymes - not entirely specific Pharmacokinetics: - rapid oral absorption - short plasma t1/2 (few hours) but longer d.o.a. (Irreversible inhibition, hydrazine tightly covalently binds) - metabolised in liver, excreted in urine Unwanted effects: -atropine-like effects ( hypertensive crisis (throbbing headache, increase b.p., intracranial haemorrhage) Tyramine-containing foods can act on NA terminals and push NA out of vesicles; indirectly acting symptomimetic drug like amphetamine - tyrosine Tyramine broken down by MAO; dietery restriction: decrease marmite, mature cheese, red wine -MAOIs and TCAs —> hypertensive episodes (avoid) -MAOIs and pethidine (opioid analgesic, interact with MAOI) —> hyperpyrexia (increase body temperature), restlessness, coma and hypotension New: moclobemide: reversible MAO-A inhibitor (RIMA), decrease drug interactions, decrease doa

Answer 104

Example: fluoxetine MOA: - selective 5-HT re-uptake inhibition - less troublesome side-effects; safer in overdose (not prone to cheese reaction) - but less effective vs severe depression Pharmacokinetics: - p.o. Administration - plasma t1/2 (18-24 hours) - delayed onset of action (2-4 weeks) - fluoxetine competes with TCAs for hepatic enzymes (avoid co-administration) enhance each other;s effect = toxic Unwanted effects: -fewer than TCAs/MAOIs -nausea, diarrhoea, insomnia and loss of libido -interact with MAOIs (avoid co-administration) Fluoxetine (Prozac): currently most prescribed antidepressant drug

Answer 105

Venlafaxine: dose-dependent reuptake inhibitor 5HT > NA >> DA (SNRI) 2nd line treatment for severe depression Mirtazapine: a2 receptor antagonists Increased NA and 5-HT release Other R interactions (sedative) Useful in SSRI-intolerant patients

Answer 106

Onset Severity Type Onset of event: - acute: within 1 hour e.g. anaphylaxis - sub-acute: 1 to 24 hours - latent: > 2 days ``` Severity of reaction: -mild: requires no change in therapy -moderate: requires change in therapy, additional treatment hospitalisation -severe: disabling or life-threatening Results in death Life-threatening Requires or prolongs hospitalisation Causes disability Causes congenital anomalies Requires intervention to prevent permanent injury ``` Type A -extension of pharmacological effect -usually predictable and dose dependent -responsible for at least two-thirds of ADRs E.g. atenolol and heart block, anticholinergics and dry mouth, NSAIDs and peptic ulcer (Expect from the pharmacology of the drug:predictable) Side note: digoxin constant increase in ADR with dose, paracetamol rapid increase at high dose (diagram) Type B -idiosyncratic (in some people, not others) or immunologic reactions -includes allergy and “pseudoallergy” -rare (even very rare) and unpredictable -e.g. chloramphenicol and aplastic anaemia (total bone marrow failure) ACE inhibitors and angioedema Many serious ADRs are totally unexpected e.g. Herceptin and cardiac toxicity Type C - associated with long-term use - involves dose accumulation - e.g. methotrexate (immunosuppressant, cancer) and liver fibrosis, antimalarials and ocular toxicity Type D - delayed effects (sometimes dose independent) - carcinogenicity (e.g. immunosuppressants) - teratogenicity (e.g. thalidomide) Type E -withdrawal reactions: opiates, benzodiazepines, corticosteroids (lost ability to make steroids by themselves) -rebound reactions - when stop the drug; situation is worse than before giving frug Clonidine, beta-bookers, corticosteroids -adaptive reactions - anti-psychotics Neuroleptic (major tranquillisers) Augmented pharmacological effect Bizarre Chronic Delayed End-of-treatment

Answer 107

Type I - immediate, anaphylactic (IgE) E.g. anaphylaxis with penicillins Type II - cytotoxic antibody (IgG, IgM) E.g. methyldopa and haemolytic anaemia Type III - serum sickness (IgG, IgM) Antigen-antibody complex E.g. procainamide-induced lupus Type IV - delayed hypersensitivity (T cell) E.g. contact dermatitis Pseudoallergies: not associated with any immune response; just a pharmacological reaction Aspirin/ NSAIDs - bronchospasm (drugs stopping prostaglandins being made in lungs but still making leukotrienes - pro-inflammatory and bronchoconstrictors ACE inhibitors - cough/ angioedema (Afro-Carribean)

Answer 108

- antibiotics - antineoplastics - anticoagulants - cardiovascular drugs - hypoglycemics - antihypertensives - NSAID/ Analgesics - CNS drugs The more medications, the more adverse reactions. ``` ADR Detection: Subjective report -patient complaint Objective report -direct observation of event -abnormal findings: physical examination, laboratory test, diagnostic procedure ``` Yellow card scheme: introduced after thalidomide - for established drugs only report serious adverse reactions - for black triangle drugs (newly licensed, usually <2 years) - report any suspected adverse reaction

Answer 109

Pharmacodynamic: related to the drug’s effects in the body -receptor site occupancy Pharmacokinetic: related to the body’s effects on the drug -absorption, distribution, metabolism, elimination Pharmaceutical: drugs interacting outside the body (mostly IV infusions) Pharmacodynamic drug interactions: Additive, synergistic (one drug potentials another drug - more effective/ toxic) or antagonistic effects from co-administration of two or more drugs -synergistic actions of antibiotics -overlapping toxicities - ethanol and benzodiazepines -antagonistic effects - anticholinergic mediations (amitriptyline and acetylcholinesterase inhibitors) Asthma: anticholinergic and B-agonists both bronchodilator but different mechanisms

Answer 110

Pharmacokinetic drug interactions: - alteration in absorption - protein binding effects - albumin binding effects - changes in drug metabolism - alteration in elimination Alterations in absorption: Chelation -irreversible binding of drugs in the GI tract -tetracyclines, quinolone antibiotics - ferrous surface (Fe2+), antacids (Al3+, Ca2+, Mg2+), dairy products (Ca2+) - insoluble compound formed Protein binding interactions: -competition between drugs for protein or tissue binding sites - increase in free (unbound) concentration may lead to enhanced pharmacological effect -many interactions previously thought to be protein binding interactions were found to be primarily metabolism interactions -protein bound interactions are not usually clinically significant but a few are (mostly with warfarin) Displace —> free drug, short time as free drug can be metabolised and excreted ``` Drug metabolism and elimination 3 different pathways drug can take: 1) excreted, unchanged by kidney .e.g. diuretic 2) phase 1 —> liver/kidney 3) phase 1 —> phase 2 —> kidney ``` Phase 1 metabolism - oxidation (key pathway) - reduction - hydrolysis Phase II metabolism - conjugation - glucuronidation - sulphation - acetylation Drug metabolism interactions -drug metabolism inhibited or enhanced by coadministration of other drugs CYP450 substrates: - Metabolism by a single isozyme (predominantly) - Metabolism by multiple isozymes: most drugs metabolised by more than one isozyme; if co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme CYP450 inhibitors - climetidine - H2 antagonist in peptic ulcers - erythromycin and related antibiotics - ketoconazole - ciprofloxacin and related antibiotics - ritonavir and other HIV drugs - fluoxetine and other SSRIs - grapefruit juice CYP450 inducers - rifampicin - carbamazepine - (phenobarbitone) - (phenytoin) - St John’s wort (hypericin) - similar to SSRIs Inhibition is very rapid Induction takes hours/ days Drug elimination interactions: Almost always in renal tubule -probenecid and penicillin (good) - stop elimination of penicillin -lithium and thiazides (bad) - increased excretion of sodium in the expense of lithium; retain lithium Deliberate interactions - levodopa and carbidopa (infrareds efficacy of levodopa in CNS) - ACE inhibitors and thiazides (anti-hypertensive) - penicillins and gentamicin (staphylococcal infections) - salbutamol and ipratropium

Answer 111

ACUTE Presentation -epigastric pain, burning sensation that occurs after meals Investigations and diagnosis - carbon-urea breath test - positive (detect urea in breath positive likely to have H pylori positive ulcer) - stool antigen test - positive - H-pylori positive peptic ulcer Pathophysiology Helicobacter pylori (H Pylori) -dissolves mucus layer - protects epithelia from acidic environment -causes epithelial cell death -increased acidity —> peptic under; bleeding - blood loss in severe ulceration Treatment - amoxicillin and clarithromycin/metronidazole - antibiotics - proton pump inhibitor (PPI) - reduces acid production (Combination therapy used for peptic ulcers in general to eliminate bacterial infection and decrease H+ produced in stomach)

Answer 112

Helicobacter pylori - gram negative, motile (can form ulcers in other parts of stomach), microaerophilic bacterium - resides in human GI tract - exclusively colonising gastric-type epithelium (commensal) Ulcer formation - increased gastric acid formation - increase gastrin or decrease somatostatin - gastric metaplasia - cell transformation due to excessive acid exposure - downregualtion of defence factors - decrease epidermal factor and decrease bicarbonate production Virulence - urease - catalysed urea into ammonium chloride and monochloroamine —> damage epithelial cells - urease - antigenic (can be detected in stool)—> evokes immune response (can further damage epithelia) - certain virulent strains produce CagA (antigenic) - inflammatory response or VacA (cytotoxic - damages cells directly ) - more intense tissue inflammation

Answer 113

1st line not effective, CHRONIC - has had infection before and has been treated before Presentation -epigastric pain, burning sensation Investigations and diagnosis - carbon-urea breath test - positive - stool antigen test - positive - H pylori positive peptic ulcer ``` Pathophysiology Helicobacter pylori (H pylori) -dissolves mucus layer: urease enzyme -causes epithelial cell death: exotoxins and inflammation -increased acidity -> peptic ulcer ``` Treatment - antibiotics for H pylori (amoxicillin and clarithromycin/ metronidazole) - consider quinolone, tetracycline - bismuth, sucralfate (alkylating agents) - decreases acidity, harder for bacteria enter - proton pump inhibitor (omeprazole) - 4-12 weeks

Answer 114

H+-K+-ATPase (proton pump) - expressed ons excretory vesicles within parietal cells - increase Ca2+ —> increase cAMP —> translocation of secretory vesicles to parties like cell apical surface —> H+ secretion Ulcer formation -increased activity of proton pump - increased H+ secretion and reduction gastric pH 1) increase Ca2+ 2) increase cAMP cause incraese proton pumps, pump out H+ ions in exchange for K+ ions

Answer 115

Presentation -epigastric pain, burning sensation ``` Investigations and diagnosis -carbon-urea breath test - negative -stool antigen test - negative -NSAID use - positive (None of the above are not due to H-pylori) ``` ``` Pathophysiology NSAID -directly cytotoxic -reduces mucus production -increases likelihood of bleeding -increased acidity —> peptic ulcer ``` Treatment - removal of NSAID - if for heart, removing can cause heart problems - proton pump inhibitor or histamine H2 receptor antagonist (Ranitidine) - 4-8 weeks (PPI more cheap and effective) - H2 receptor increases acid secretion

Answer 116

gastric acid regulation 1) acetylcholine (ACh) released from neruones (vagus/enteric) acts on muscarinic (M3) receptors - increase Ca2+ 2) prostaglandins (PGs) released from local cells act on EP3 receptors - decrease cAMP (decrease expression, protective) 3) histamine released from enterochromaffin-like cells (ECL) act on H2 receptors - increase cAMP 4) gastrin released from G-cells, acts on cholecystokinin B receptors - increase Ca2+ Gastric acid secretion - increase Ca2+ and cAMP —> translocation of secretory vesicles to parietal cell apical surface —> H+ secretion - somatostain - peptide that inhibits G-cells, ECL cells and parietal cells

Answer 117

Epidemiology -main risk factor = age -huge economic cost but low research investment - lots of drug failures - low probability of success -genetics - APP, PSEN, ApoE (hereditary - early onset of Alzheimer’s) (2 types - age; genetics) Clinical symptoms - memory loss - especially recently acquired information - disorientation/ confusion - forgetting where they are - language problems - stopping in the middle of a conversation - personality changes - becoming confused, fearful, anxious - poor judgement - such as when dealing with money

Answer 118

Amyloid hypothesis - beta-amyloid plaques in brain Physiological processing: 1) amyloid precursor protein (APP) cleaved by alpha-secretase 2) sAPPalpha released - C83 fragment remains 3) C83 digested by gamma secretase 4) products removed Pathophysiological processing: 1) APP cleaved by beta-secretase - cleaves at different site, giving longer protein to be digested 2) sAPPbeta released - C99 fragment remains 3) C99 —> digested by gamma secretase released beta-amyloid (Abeta protein) 4) Abeta forms toxic aggregates - primarily form outside neurones but in Alzheimer’s primarily within May cause immune reaction, destruction of neurones, produce toxins and destroy Tau hypothesis Physiology: -soluble protein present in axons -important for assembly and stability of microtubules Pathophysiology: -hyperphosphorylated tau insoluble —> self-aggregates to form neurofibrillary tangles -these are neurotoxic -this also results in microtubule instability Primarily found intracellular you (in neurones) Usually first Tau, second Abeta Inflammation hypothesis Physiology - microglia -specialised CNS immune cells - similar to macrophages Pathophysiology - Microglia - increased release of inflammatory mediators and cytotoxic proteins - in tased phagocytosis - decreased levels of neuroprotective proteins Tau/ Abeta can activated these NSAIDs (ibuprofen) less likely getting Alzheimer’s

Answer 119

Anticholinesterases: 1) donepezil (used for severe form; most effective; only need to be administered once) - reversible acetyl cholinesterase inhibitor - (Bentyl-cholinesterase mostly in CNS, acetyl everywhere) - long plasma half-life 2) rivastigmine - pseudo-reversible AChE and BChE inhibitor - 8 hour half-life (don’t want BChE inhibition = side effects but counteracted when given as a patch - more selective to AChE) - reformulated as transdermal patch 3) Galantamine - reversible cholinesterase inhibitor - 7-8 hour half life - alpha7 nAChR agonist NMDA receptor blocker 4) Memantine - use dependent* non-competitive (different site of binding) NMDA receptor blocker with low channel affinity - only licensed for moderate-severe AD - long plasma half life * effective only if excessive NMDA activity, glutamate bind to NMDA (happens in severe neurodegeneration) 2 and 3 for mild - moderate disease Drugs don’t relate to pathophysiology (side note: 5 units in acetylcholine receptor arranged differently in NMJ and CNS)

Answer 120

1) gamma-secretase inhibitors Tarenflurbil (like Ibuprofen) and Semagacestat -Tarenflurbil binds to amyloid precursor protein (APP) molecule -Semagacestat is a small molecule gamma-secretase inhibitor, also inhibits enzyme notch - increase skin cancer Also involved in physiological processes 2) B-amyloid Bapineuzumab and Solanezumab -humanised monoclonal antibodies -developing Aducanumab - acts on aggregates and monomers different (vaccine in early stages of development) 3) Tau inhibitors Methylene blue -licensed for the treatment of methaemoglobinaemia - not much money to do clinical trials; make skin slightly blue

Answer 121

Synthesis -L-tyrosine —>(via tyrosine hydroxylase) L-DOPA —> (via DOPA decarboxylase) dopamine (DA) Tyrosine hydroxylase is rate-;limiting step, lots of tyrosine can be flooded by tyrosine hydroxylase needed Metabolism - DA removed from synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET) - transport back into neurone - Three enzymes metabolise DA: 1) monoamine oxidase A (MAO-A): metabolises DA, NE and 5-HT 2) MAO-B: metabolises DA (more selective) 3) Catecholamines-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines MAO A and B found in cell membranes of mitochondria COMT in glial cell; post synaptic membrane Major locations of dopaminergic pathways 1) Nigrostriatal pathway - substantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders 2) Mesolimbic pathway - ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc). Brain reward pathway 3) Mesocortical pathway - VTA to the cerebrum. Important in executive functions and complex behavioural patterns 4) Tuberoinfundibular pathway - arcuate nucleus to the median eminence. Inhibition results in hyperprolactinaemia (endocrine pathways; side effects in drugs)

Answer 122

Epidemiology - 1-2% of individuals over 60 years old - around 5% do cases are due to mutations in certain genes (e.g. SNCA, LRRK2) - early onset Pathophysiology - severe loss of dopaminergic projection cells in SNc - Lewy bodies and Lewy neurites —> found respectively within neuronal cell bodies and axons - consist of abnormally phosphorylated neurofilaments, ubiquitous and alpha-synuclein Clinical presentation - motor symptoms —> resting tremor (early onset), bradykinesia, rigidity (late onset), postural instability (cardinal symptoms) - autonomic nervous sue stem effects —> olfactory deficits, orthostatic hypotension, constipation - neuropsychiatric —> sleep disorders, memory deficits, depression, irritability Lewy bodies start at frontal so first neuropsychiatric —> motor symptoms

Answer 123

1) dopamine replacement L-tyrosine (TYR) (not given because need enzyme) —> dopamine (DA) Rate-limiting enzyme: tyrosine hydroxylase (TH) Dopamine not given because has effects in periphery so not enough enters CNS Levodopa (L-DOPA) - rapidly converted to DA by DOPA decarboxylase (DOPA-D) - can cross blood-brain barrier (BBB) - peripheral breakdown by DOPA-D —> leads to nausea and vomiting (give protector transport molecules - refer to adjuvants - long term side effects: dyskinesias and on-off effects*.NOT disease modifying; does not prolong life, just better QoL, target symptoms *on = L-DOPA pill give large dose in one go, dopamine doesn’t last long - wear off = off Counteracted by being given as intestinal gels -slow release Adjuncts DOPA decarboxylase inhibitors: Carbidopa and Benserazide -do not cross BBB —> prevent peripheral breakdown of levodopa -reduce required levodopa dosage because more goes to CNS COMT inhibitors: Entacapone and Tolcapone -increase amount of levodopa in brain; prevent breakdown of L-DOPA but not as effective as gels Receptor activation -dopamine (DA) can act on D1,5(Gs linked) or D2-4 9Gi linked) receptors -DA is re-uptaken by the dopamine transporter (DAT) and metabolised by monoamine oxidase (MAO) enzymes D2 receptors in post-synaptic do not disappear in neurodegeneration - don’t need intact presynaptic neurone 2) Dopamine receptor agonists Ergot derivatives: Bromocriptine and Pergolide -act as potent agonists of D2 receptors -associated with cardiac fibrosis - valve problems Non-ergot derivatives: Ropinirole and Rotigotine -Ropinirole also available as extended-release formulation -Rotigotine also available as a patch Can get hallucinations as side effect 3) Monoamine oxidase B (MAOB) inhibitors Selegiline (deprenyl) and Rasagiline -reduce the dosage of L-DOPA required -can increase the amount of time before levodopa treatment is required Cheese reaction

Answer 124

Epidemiology - affects 1% of population and has genetic influence - onset of symptoms between 15-35 years - higher incidence in ethnic minorities e.g, Afro-Caribbean immigrants - stick to their ethnicities - Patients’ life expectancy 20-30 years lower than average because lifestyle choices they make e.g. drugs, alcohol, suicide (not because of neurodegenration) ``` Symptoms Positive symptoms: -increased mesolimbic dopaminergic activity -hallucinations: auditory and visual -delusions: paranoia -thought disorder: denial about oneself ``` ``` Negative symptoms: -decreased mesocortical dopaminergic activity Affective flattening: lack of emotion -alogia: lack of speech -avolition/ apathy: loss of motivation ```

Answer 125

First generation antipsychotics Chlorpromazine: -discovered whist developing new antihistamines (histamine receptor antagonist) -primary mechanism of action - possibly D2 receptor antagonism Side effects -high incidence - anti-cholinergic, especially sedation -low incidence - extrapyramidal side effects (EPS) motor disorders like Parkinson’s Haloperidol -very potent D2 antagonist (around 50x more potent than chlorpromazine) -therapeutic effects develop over 6-8 weeks -little impact on negative symptoms Side effects -high incidence - EPS Second generation antipsychotics Clozapine -most effective antipsychotic -very potent antagonist of 5-HT2A receptors -only drug to show efficacy in treatment resistant schizophrenia and negative symptoms Side effects -can cause potentially fatal neutropenia, agranulocytosis, myocarditis and weight gain =metabolic side effects; black box warning Risperidone -very potent antagonist of 5-HT2A and D2 receptors Side effects -more EPS and hyperprolactinaemia than other atypical antipsychotics Quetiapine -very potent antagonist of H1 receptors Side effects -lower incidence of EPS than other antipsychotics Aripiprazole (third generation??) -partial agonist of D2 and 5-HT1A receptors (when too much activity , decrease DA, when to little increase DA) -no more efficacious than typical antipsychotics Side effects -reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics Microchip can be inserted in drug to monitor compliance

Answer 126

GABA neurotransmission - GABA neurones in brain are short axon interneurones in specific areas in the brain, can easily inhibit, e.g. reduce hyperactivity in hippocampus. 1) action potential arrives at presynaptic nerve terminal and 2) causes the ecocytosis of vesicles containing GABA 3) acts on postsynaptic Cl- ionophore receptor (GABA A) - type 1 receptor 4) uptake into presynaptic or into glial cells to inactivate 5) converted into SSA (succinct semialdehyde by GABA-T transaminase) - GABA is synthesised from glutamate (precursor) by GAD (glutamate decarboxylase) - autoreceptor in presynaptic membrane act like a2 receptors - regulate GABA release (GABA B) GABA metabolism GABA —>(via GABA-T) succinic semialdehyde —> (SSDH - succinic semialdehyde dehydrogenase) succinic acid - GABA-T and SSDH are mitochondrial enzymes - Succinic acid goes to TCA cycle (cycle because glutamate also from TCA “GABA shunt”) - GAD is a cytoplasmic enzyme - cytoplasm of presynaptic membrane, specific to GABA so can map GABA neurones -Inhibitors of GABA metabolism —> large increase in brain GABA Examples: -sodium valproate (epilim) - works by inhibiting voltage sensitive sodium channels; weak GABA-T inhibitor, inhibits SSDH as well -vigabatrin (sabril) - GABA-T inhibitor - binds covalently to GABA-T “suicide inhibitor” Above two can also be used as anti-convulsants in epilepsy -Vigabatrin (Sabril)

Answer 127

Consists of 4 main proteins: GABA receptor protein, GABA modulin, BDZ receptor protein, Barbiturate receptor protein GABA receptor protein: - GABA binds, links with BDZ by GABA modulin - this causes opening of chloride channel protein (transient) - Cl- flows through GABA receptor into postsynaptic cell (influx) - membrane potential drops, making it harder to excite the postsynaptic cell BDZ receptor protein: - Benzodiazepines binds to own receptor - enhances Cl- influx into PSC because of GABA - binding of GABA to GABA receptor increased because of better affinity - enhanced BDZ binding because of GABA binding Barbiturate receptor protein: - barbiturates enhance normal action of GABA (Cl- influx) - enhance binding of GABA - barbiturates bind here but doesn’t enhance barbiturate binding - also different to BDZ because higher conc. of barbiturates can directly act on Cl- channel Bicuculline - competitive GABAA antagonist, competes with GABA for GABA binding site -Flumazenil - benzodiazepine antagonist and competes with BDZ BZs and BARBs have no activity alone (allosteric action - not agonists, different sites to GABA; PAMs - positive allosteric modulation) They have different binding sites and different mechanisms: - BZs increase frequency of openings - BARBs increase duration of openings BARBs are less selective than BZs - decrease excitatory transmission: reduce glutamate mediated excitation - other membrane effects: direct effect on Cl- channel This may exploding its use in induction of surgical anaesthesia and its low margin of safety

Answer 128

- anaesthetics (BARBs only: thiopentone - inducing general anaesthesia) - anticonvulsants (diazepam; (BZ) clonazepam; (BZ) phenobarbital (BARB)) - anti-splastics (diazepam) - reduce muscle tone - anxiolytics - sedatives/ hypnotics Definitions - anxiolytics: remove anxiety without impairing mental or physical activity (used to be called minor tranquillisers) - sedatives: reduce mental and physical activity without producing loss of consciousness - hypnotics: induce sleep When increase anxiolytic, increase hypnotic effect When decrease hypnotic dose, increase anxiolytic effect Ideally they should: - hand wide margin of safety - not depress respiration - produce natural sleep (hypnotics) - not interact with other drugs - not produce ‘hangovers’ - not produce dependence

Answer 129

``` Ring structure, -tone, -tol, -tal Range of clinical uses (refer to previous flash card) including: - sedative/ hypnotic E.g. amobarbital Severe intractable insomnia T1/2 20-25 hrs ``` Unwanted effects (not drugs of 1st choice) - low safety margins - depress respiration - overdosing lethal After natural sleep (decrease REM —> hangovers/ irritability) - enzyme inducers: if another drug administered that is metabolised by same set of drugs - less effective e.g. warfarin - potentiate effect of other CNS depressants (e.g. alcohol) can increase risk of overdose - tolerance - dependence: withdrawal syndrome - insomnia, anxiety, tremor, convulsions, death

Answer 130

``` -Epam, -epate 3 ring structure -20 available, all act at GABA receptors -All similar potencies and profiles, MoA -Pharmacokinetics largely determine use ``` Pharmacokinetics - administration - well absorbed P.O (mainly administered orally) - peak plasma - 1hr - IV vs status epilepticus (severe prolong seizure activity) - distribution: bind plasma proteins strongly, highly lipid soluble, wide distribution - metabolism - usually extensive (liber) - excretion —> urine; glucuronide conjugates Duration of action vary greatly: 1) short acting 2) long-acting - slow metabolism and/ or generate active metabolites (which have BZ like activity) ``` Metabolism Long acting: Diazepam —> temazepam —> oxazepam —> glucuronide Short acting: Temazepam —> oxazepam —> glucuronide ``` ``` Uses: Anxiolytics: diazepam (valium) Chlordiazepoxide (Librium) Nitrazepam (Long acting) ``` Oxazepam - hepatic impairment (Shrina acting used in hepatic failure, longer because failure) Sedative/hypnotics: temazepam Oxazepam (Short acting) Nitrazepam - daytime anxiolytic effect (longer, early morning waking) BZ advantages: - wide margin of safety - overdose —> prolonged sleep (rousable), flumazenil given to decrease BZ - mild effect on REM sleep - do not induce liver enzymes Unwanted effects: - sedation, confusion, amnesia, ataxia (impaired manual skills) - potentiate other CNS depressants (alcohol, BARBs) - increase risk of overdose - tolerance (less than BARBs; ‘tissue’ only) - dependence —> withdrawal syndrome, similar to BARBs (less intense) - withdraw slowly - free plasma by aspirin, heparin - displace BZ from binding site

Answer 131

Other sedative hypnotics Zopiclone: -short acting (t1/2 5 hrs) -acts at BZ receptors (cyclopyrrolone) increase GABA, not BZ -similar efficacy to BZs -minimal hangover effects but dependency still a problem (used side by side with BZ) Other anxiolytics Some antidepressant drugs -SSRIs -less sedation and dependence/ delayed response/ long-term treatment - generalised anxiety disorder (can co-treat depression and anxiety) Some antiepileptic drugs -Valproate, tiagabine (both increase GABA inhibition) Some antipsychotic drugs -olanzapine, quetiapine (atypical antipsychotics) Propranolol -improves physical symptoms: tachycardia (B1), tremor 9B2) - damps down fast heart beats and shakes off anxiety Buspirone -5HT1A agonist -fewer side effects (< sedation) -slow onset of action (days/ weeks)

Answer 132

- Loss of consciousness (all anaesthetics at low conc) - Suppression of reflex responses (immobile) (all anaesthetics at high conc) - relief of pain (analgesia) - muscle relaxation - amnesia (forgetting experience)

Answer 133

Gaseous/ inhalation - nitrous oxide - diethyl ether - halothane - enflurane Intravenous - propofol (also has euphoric effects) - etomidate All anaesthetics structurally very different Mechanism of action -lipid theory: the more lipid soluble the anaesthetic, the more the potency -anaesthetic potency increases in direct proportion with oil/ water partition coefficient (Meyer/Overton correlation) Problems: 1) at relevant anaesthetic conc. change in bilateral was minute 2) how would this change impact membrane proteins? Mechanism of action cam either be due to reduced neuronal excitability or altered synaptic function ``` Altered synaptic function Intravenous agents: -increased activity of GABAA receptors -B3 subunit = suppression of reflex responses -A5 = amnesia ``` Inhalational agents: (halogenated agents) - GABA A (brain; 50% less effective)/ glycine receptors (SC) - a1 - suppression of reflex responses -Less specific - more places they act -Blocks NMDA-type glutamate receptors Probably compete with co-agonist glycine - Suppress receptor - neuronal nicotinic ACh receptors - Analgesic - as you increase conc. of anaesthetic, the activation of receptors decreases Reduced neuronal excitability Inhalational agents: -TREK (background leak) K+ channels - mediated hyperpolarisation of neurones; slowly leak K+ out -consciousness

Answer 134

Loss of consciousness -depress excitability of thalamocortical neruones “time to sleep” -influences reticular activating neurones (TREK switched on) Cortical neruones and reticular activating neurones are GABA A receptor rich. Suppression of reflex responses -depression of reflex pathways in the spinal cord - disconnect brain from SC GABA and glycine important in relaying painful stimuli from spinal cord to brain Amnesia -decrease synaptic transmission in hippocampus/ amygdala Impair memory - a5 subunit in GABA receptor

Answer 135

Inhalation vs intravenous anaesthetic If Anaesthetic has a low blood: gas partition coefficient = doesn’t dissolve well in blood, remains in gaseous state - allows transfer into brain When stop giving anaesthetic to remove it, low blood: gas partition coefficient means that anaesthetic can be quickly removed, diffuse into blood to lungs quickly (Can diffuse across because lipid soluble) If high blood:gas partition coefficient, not much transferred to brain, trapped in blood and slower removal ``` Inhalation anaesthetics -rapidly eliminated -rapid control of the depth of anaesthesia (Good control over excretion) Intravenous anaesthetics -fast induction (already in blood) -less coughing/ excitatory phenomena (Little control on removing it because rely on liver to metabolise) ``` Loss of consciousness and suppression of reflex responses Induction: propofol (induce with intravenous agent —> fast onset of anaesthesia) then remove Maintenance: enflurane (inhalational to maintain - control over anaesthesia) Relief of pain (analgesia) - opioid (e.g. i.v. Fentanyl) Muscle relaxation - neuromuscular blocking drugs (e.g. suxamethonium) Amnesia - benzodiazepines (e.g. i.v. Midazolam)

Answer 136

1) depolarisation - resting Na+ channels open (voltage sensitive), Na+ enters cells 2) repolarisation - Na+ channels close (inactivation) - flip, K+ channels open, K+ leaves cell 3) Na+ channels restored to resting state but K+ channels still open therefore cells refractory 4) Na+ and K+ channels restored to resting state therefore cell will respond normally to further depolarising stimulus Structures 3 main areas: aromatic region, ester or amide bonds, basic amine side-chain Cocaine is an ester, lidocaine is an amide Benzocaine is an exception, it has no amine side chain, only alkyl group - weak LA but good solubility therefore used as a surface anaesthetic

Answer 137

Most LA’s are basic Unionised form of anaesthetic allows it to cross membranes (both outer membrane - connective tissue sheath and axon is membrane) Ionised form binds inside of Na+ channels Ion channels need to be open (use dependent pathway - hydrophilic) - the more rapidly neurones fire, the more LA can have an effect In hydrophobic pathway, channels can be closed LA more effective on open sensory neurones Selectivity of pain - nociceptive neurones fire more rapidly than motor

Answer 138

1) percent generation and conduction of APs 2) do not influence resting membrane potential (unlike GABA) 3) may also influence channel gating - states of Na+ resting, inactivated and activated. LA may hold in inactivated state - refractory for longer 4) selectively block small diameter fibres and non-myelinated fibres (block more than myelinated as can enter more easily) LAs are weak bases (pKa 8-9) Infected tissue is acidic therefore higher proportion of LA imposed so not enough, need high concentration

Answer 139

1) surface anaesthesia - mucosal surface (mouth, bronchial tree) - spray (or powder) or ointment - high concentrations —> systemic toxicity 2) infiltration anaesthesia - directly into tissues —> sensory nerve terminals - minor surgery - can keep to minimal area - don’t want systemic toxicity - low in bloodstream - adrenaline co-injection (NOT extremities) - vasoconstrictor therefore confines LA and minimises amount in bloodstream (systemic toxicity) and can also help stop bleeding; don’t use in extremities (fingers) - ischaemia, shut blood supply 3) Intravenous regional anaesthesia (directly into bloodstream) - i.v. Distal to pressure cuff - restrict blood flow therefore regional - limb surgery eg reset bone - systemic toxicity of premature cuff release - when release early, can get bolts which can go straight to brain and heart (Atleast 20 mins) 4) Nerve block anaesthesia - close to nerve trunks e.g. dental nerves - widely used - low doses - slow onset - vasoconstrictor co-injection (need accurate injection) 5) spinal anaesthesia (intrathecal) - sub-arachnoid space (CSF found) - spinal roots - abdominal, pelvic, lower limb surgery - low does - limit systemic toxicity - low bp.( preganglionic neruones, blocked too - small diameter and close) prolonged headache - pass to brain - glucose (increase specific gravity) - restricting LA, bonus can move up or down, LA localise more L3/L4 6) Epidural anaesthesia - fatty tissue of epidural space - spinal roots - uses as for 5) and painless childbirth - slower onset - higher doses (systemic toxicity) - more restricted action - less effect on bp

Answer 140

Absorption (mucous membranes) Lidocaine (Amide) - good Cocaine (ester) - good Plasma protein binding 70% 90% Metabolism: Hepatic N-dealkylation Liver and plasma non-specific esterases Plasma t1/2 2hr (more stable) 1hr (Bupivacaine (doa 6 hrs; epidural anaesthesia) ``` Unwanted effects Lidocaine: CNS -central stimulation -restlessness -confusion -tremor (Above are paradoxical - higher conc. dampen down) CVS -myocardial depression -vasodilation -low bp (Above due to Na+ channel blockade) ``` ``` Cocaine: CNS -euphoria -excitation (dopamine re-uptake) CVS -high CO -vasoconstriction -high bp (Both CNS and CVS effects are sympathetic actions) ```

Answer 141

Physiological control: Chemoreceptor trigger zone (CTZ) - receives multiple inputs from areas including stomach and vestibular nuclei CTZ communicates with the vomiting centre —> nausea and vomiting Mechanistic triggers: cytotoxic drugs, motion sickness, gastrointestinal problems, pregnancy, other higher functions

Answer 142

Presentation - chemotherapy (cisplatin) for lung cancer - chemotherapy induced nausea and vomiting (CINV) Pathophysiology - cisplatin is toxic to enterochromaffin cells (ECs) - release of free radicals - free radicals - excessive 5-HT release - 5-HT activates 5-HT3A receptors on nerve fibres to chemoreceptor trigger zone (CTZ) - outside BB eventhough in midbrain, also called area postrema - CTZ activates nerves fibres to vomiting centre (VC) - VC —> nausea Treatment -Ondansetron - 5-HT3A receptor antagonist (early stage nausea) -glucocorticoids - reduce free radical production (anti-inflammatory - reduce nausea) -aprepitant - neurokinin-1 receptor antagonist (activate by substance P from higher centres) - later stage nausea (Triple therapy)

Answer 143

Presentation -motion sickness Pathophysiology - labyrinth (inside ear canals) - neural mismatch (seeing and moving mismatch) —> activates histamine receptors on vestibular nuclei - vestibular nuclei activate muscarinic receptors on CTZ - CTZ activates VC, which causes nausea Treatment - Promethazine - H1 receptor antagonist - Hyoscine (scopolomine) - non-selective muscarinic receptor antagonist (more serious)

Answer 144

Presentation - vomiting due to unknowingly cause - abdominal pain and bloating Pathophysiology -gastroparesis - delayed emptying of the stomach -reduced stomach contraction -5-HT activates 5-HT3A receptors on CTZ -CTZ activates nerve fibres to vomiting centre (VC) -VC —> nausea (D2 receptor activation on CTZ can —> nausea) ``` Treatment Metoclopramide -dopamine D2 receptor antagonist Pro kinetic - stimulates gastric emptying Inhibits D2 receptors in CTZ -5-HT3A receptor antagonist Inhibits activation of CTZ ```

Answer 145

5-HT3A receptor antagonists: headaches and constipation (because affects GI tract) Histamine H1 receptor antagonists: drowsiness (beneficial - long journey, want to be drowsy to go to sleep) Muscarinic receptor antagonists: dry mouth and drowsiness Dopamine D2 receptor antagonists: galactorrhoea and extrapyramidal side effects

Answer 146

- single-cell microorganisms - cell wall and cell membrane - an entire phylogenetic domain - around 1/3 are pathogenic Membrane properties Gram positive bacteria -prominent peptidoglycan cell wall E.g. Staphylococcus aureus Gram negative bacteria -outer membrane with lipopolysaccharide E.g. Escherichia coli Mycolic bacteria -outer mycolic acid layer -e.g. mycobacterium tuberculosis (Not differentiated by gram stain)

Answer 147

``` 1) Nucleic acid synthesis Dihydropteroate (DHOp) -produced from paraaminobenzoate (PABA) -converted into dihydrofolate (DHF) Tetrahydrofolate (THF) -produced from DHF by DHF reductase -THF —> important in DNA synthesis ``` 2) DNA replication DNA gyrase -topoisomerase —> releases tension (unplait hair) 3) RNA synthesis RNA polymerase -produces RNA from DNA template -differ from eukaryotic RNA polymerase 4) protein synthesis Ribosomes -produce protein from RNA templates -differ from eukaryotic ribosomes Protein synthesis inhibitors 1) DHOp - sulphonamides inhibit DHOp synthase THF - trimethoprim inhibits DHF reductase 2) DNA gyrase- fluoroquinolones e.g. Ciprofloxacin inhibit DNA gyrase and topoisomerase IV 3) RNA polymerase Rifamycins e.g. Rifampicin inhibits bacterial RNA polymerase - tuberculosis 4) RIbsomes inhibited by: - aminoglycosides e.g. Gentamicin - chloramphenicol - macrolides e.g. Erythromycin - tetracyclines

Answer 148

1) Peptidoglycan (PtG) synthesis (produced intracellularly to be incorporated into cell wall) - a pentapeptide is created on N-acetyl muramic acid (NAM) - N-acetyl glucosamine (NAG) associates with NAM forming PtG 2) PtG transportation - PtG is transporters across the membrane by bactoprenol 3) PtG incorporation - PtG is incorporated into the cell wall when trasnpeptidase enzyme cross-links PtG pentapeptides. Inhibitors 1) Glycopeptides e.g. Vancomycin bind to the pentapeptide preventing PtG synthesis 2) Bacitracin inhibits bactoprenol regeneration preventing PtG transportation ``` 3) B-lactams bind covalently to transpeptidase inhibiting PtG incorporation into cell wall. B-lactams include: -carbapenems -cephalosporins -penicillins (B-lactam ring in structures) ``` 4) Lipopeptide e.g. daptomycin disrupt gram +ve cell walls Polymyxins - bind to LPS and disrupts gram -ve cell membranes

Answer 149

Unnecessary prescription Lifestock farming Lack of regulation Lack of development - very few antibiotics in recent years Types of resistance 1) destruction enzymes 2) additional target 3) alteration of target 4) alteration in drug permeation 5) hyperproduction

Answer 150

B-lactamases hydrolyse C-N bond of the lactation ring. ``` Examples -Penicillins G and V —> gram +ve -flucloxacillin and temocillin —> B-lactamase resistant because steric hindrance -amoxicillin —> broad spectrum: Gram -ve activity Co-administered with Clavulanic acid ``` (Side note: gram -ve and +ve different antibiotics won’t work in each other)

Answer 151

Bacteria produce another target that is unaffected by the drug Example: E.coli produce different DHF reductase enzyme making them resistant to trimethoprim.

Answer 152

Alteration to the enzyme targeted by the drug. Enzyme still effective but drug now ineffective Example S Aureus - mutations in the ParC region of topoisomerase IV confers resistance to quinolones

Answer 153

Reductions in aquaporins and increased efflux systems. Examples Primarily of importance in gram -ve bacteria

Answer 154

Bacteria significantly increase levels of DHF reductase Example: E. coli produce additional DHF reductase enzymes making trimethoprim less effective Not very effective compared to others because bacteria have to work hard.

Answer 155

Fungal infections Can be classified in terms of tissues/organs: 1) superficial - outermost layers of skin 2) dermatophyte - skin, hair or nails 3) subcutaneous - innermost skin layers 4) systemic - primarily respiratory tract Drug details - 15 anti-fungal drugs licensed in the UK - two most common categories: 1) Azores: fluconazole 2) Polyenes: Amphotericin Azores - inhibit cytochrome p450 dependent enzymes involved in membrane sterol synthesis (sterol needed for cell membranes) - Fluconazole (oral) —> candidiasis and systemic infections Polyenes -interact with cell membrane sterols forming membrane channels -Amphotericin (I-V) —> systemic infections (Puncture holes in fungal membranes)

Answer 156

genetic material (RNA and DNA) present in every virus Capsid (protein shell surrounding the genetic material of the virus) in every virus Envelope proteins in some Lipid envelope in some

Answer 157

Tropism -liver hepatocytes Hepatitis (Hep) B and C -only chronic infection requires treatment Hep B treatment -Tenofovir —> nucleotide analogue (block replication), given sometimes with Peginterferon Alfa Contains disease, not cure, if stop drug, disease comes back ``` Hep C treatment -Ribavirin and Peginterferon Alfa Ribavirin —> nucleoside analogue prevents viral RNA synthesis -Boceprevir —> protease inhibitor Most effective against Hep C genotype 1 ``` The goal of HCV treatment is to cure virus The specific drugs and duration of treatment depend on: -HCV genotype (genetic structure of virus) -viral load -past treatment experience -degree of liver damage -ability to tolerate prescribe treatment -need for liver transplant

Answer 158

1) Attachment and entry - viral membrane proteins interact with leukocyte membrane receptors - Viral capsid endocytosis 2) replication and integration - within cytoplasm - reverse transcriptase enzymes converts viral RNA —> DNA - DNA transported into nucleus and integrated into host DNA 3) assembly and release - host cell’s machinery utilised to produce viral RNA and essential proteins - virus is assembled within cell —> mature virion is released HIV entry inhibitors 1) Attachment and entry - HIV glycoprotein (GP)120 attaches to CD4 receptor - GP120 also binds to either CCR5 (needs this) or CXCR4 - GP41 penetrates host cell membrane and viral capsid enters Enfuvirtide -binds to HIV GP41 transmembrane glycoprotein Maraviroc -blocks CCR5 chemokine receptor (Side note: bone marrow chemotherapy with delta 32 mutation, no CCR5) ``` HIV replication inhibitors 2) a) replication Reverse transcription • Viral single-stranded RNA —> double stranded DNA by reverse transcriptase Nucleoside RT inhibitors • Activated by 3 step phosphorylation process • E.g. Zidovudine Nucleotide RT inhibitors • Fewer phosphorylation steps required • E.g. Tenofovir Non-nucleoside RT inhibitors • No phosphorylation required • Not incorporated into viral DNA • E.g. Efavirenz ``` ``` HIV integrase inhibitors 2) b) integration DNA integration • Viral integrase inserts viral DNA into host DNA Integrase inhibitors • Raltegravir - first of 3 licensed integrase inhibitors ``` HIV protease inhibitors 3) Assembly and release • Gag precursor —> encodes all viral structural proteins • HIV protease cleaves Gag precursor protein Protease inhibitors (PI) • Saquinavir - 1st generation PI • Low dose Ritonavir reduces PI metabolism —> co-administered as ‘booster’

Answer 159

``` Virology • Double-stranded DNA • Surrounded by tegument & enclosed in a lipid bilayer Tropism • Herpes Simplex Virus (HSV)-1 —> cold-sores • HSV-2 —> genital herpes Treatment • Nucleoside analogues —> Aciclovir ``` Influenza Virology • Multipartite single stranded RNA virus • Envelope protein neuraminidase —>release Tropism • Nose, throat & bronchi Treatment • Neuraminidase inhibitor —> Oseltamivir (Tamiflu); need to take within 48 hours of symptoms

Answer 160

® Entry inhibitors - Enfuvirtide & Maraviroc ® RT inhibitors - Nucleoside analogues (Zidovudine), Non-nucleoside analogues ( Efavirenz) ® Integrase inhibitors - Raltegravir ® Protease inhibitors - Saquinavir Antiviral ® Nucleotide analogues - Ribavirin, Aciclovir ® Protease inhibitors - Boceprevir ® Neuraminidase inhibitors - Oseltamivir

Answer 161

Definition • A neurological condition causing frequent seizures • Seizures are “sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex” (overactivity of brain) Prevalence & Incidence • Prevalence between 2-7% of the population • Incidence increased over the last 30-40 years Diagnosis • Brain activity can be measured using: • Electroencephalography (EEG) - neurone activity • Magnetic resonance imaging (MRI) - brain damage

Answer 162

General Seizures Begins simultaneously in both hemispheres of brain Seizure types & Symptoms 1. Tonic-clonic seizures: loss of consciousness —>muscle stiffening—>jerking/twitching —>deep sleep —>wakes up 2. Absence seizures: brief staring episodes with behavioural arrest 3. Tonic/atonic seizures: sudden muscle stiffening/sudden loss of muscle control 4. Myoclonic seizures: sudden, brief muscle contractions 5. Status epilepticus: > 5 min of continuous seizure activity (any of above for >5 mins) Partial/ focal Seizures Begins within a particular area of brain and may spread out Seizure types & Symptoms 6. Simple: retained awareness/consciousness Complex: impaired awareness/consciousness

Answer 163

Neurotransmission 1. Voltage-gated Na+ channel (VGSC) opens —> membrane depolarisation 2. Voltage-gated K+ channel (VGKC) opens —> membrane repolarisation 3. Ca2+ influx through voltage-gated calcium channels (VGCCs) —> vesicle exocytosis a) Synaptic vesicle associated (SV2A) protein allows vesicle attachment to presynaptic membrane 4. Glutamate activates excitatory post-synaptic receptors (e.g. NMDA, AMPA & kainate receptors)

Answer 164

Voltage gated Na+ channel blockers/antagonists Carbamazepine Pharmacodynamics • Stabilises inactive state of Na+ channel —> reducing neuronal activity Pharmacokinetics • Enzyme inducer • Onset of activity within 1 hour • 16-30 hour half-life (long duration) Indications • Tonic-clonic seizures; partial seizures NB: potential severe side-effects (SJS & TEN) in individuals with HLA-B*1502 allele (skin conditions SJS, TEN) Lamotrigine Pharmacodynamics • Inactivates Na+ channels —> reducing glutamate neuronal activity Pharmacokinetics • Onset of activity within 1 hour • 24-34 hour half-life Indications • Tonic-clonic seizures; absence seizures (More safer in pregnancy than carbamazepine) Voltage gated calcium channel blocker/antagonist Ethosuximide Pharmacodynamics • T-type Ca2+ channel antagonist (CNS, cardiac pacemaker) —>reduces activity in relay thalamic neurones - prevent excitation Pharmacokinetics • Long half-life (50 hours) also fats onset Indications • Absence seizures Glutamate exocytosis and receptors Levetiracetam (SV2A inhibitor) Pharmacodynamics • Binds to synaptic vesicle associated protein (SV2A) —>preventing glutamate release Pharmacokinetics • Fast-onset (1 hour); half-life (10 hours) Indications • Myoclonic seizures Topiramate (glutamate receptor antagonist) Pharmacodynamics • Inhibits NMDA & kainate receptors • Also affects VGSCs & GABA receptors Pharmacokinetics • Fast-onset (1 hour); long half-life (20 hours) Indications • Myoclonic seizures

Answer 165

Neurotransmission 1. GABA can be released tonically & also following neuronal stimulation 2. GABA activates inhibitory post-synaptic GABAA receptors 3. GABAA receptors are chloride (Cl-) channels —> membrane hyperpolarisation 4. GABA is taken up by GAT & metabolised by GABA transaminase (GABA-T) to glutamate ``` Diazepam Pharmacodynamics • GABA receptor, PAM —> increases GABA- mediated inhibition Pharmacokinetics • Rectal gel - Fast-onset (within 15 min); half- life (2 hours) Indications • Status epilepticus ``` ``` Sodium Valproate Pharmacodynamics • Inhibits GABA transaminase —> increases GABA-mediated inhibition (also less glutamate) Pharmacokinetics • Fast onset (1h); half-life (12h) Indications • Indicated for ALL forms of epilepsy ```