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4. NERVOUS SYSTEM4.1 Neurotransmitters (2)2005-1What are the effects of nitric oxide?Smooth muscle relaxant (vasodilator)Platelet inhibitor Immune regulator NeurotransmitterWhat are potential therapeutic applications of nitric oxide?Vascular effects -On vascular smooth muscle tone and B.P. -May play a role in normal regulation of vascular tone -Vasodilator action -Inhibits neutrophil adhesion to vascular endothelium -Artherosclerotic risks (smoking, lipids, HTN, DM) reduce endothelial NO productionHypertension associated with pregnancy - Resemble deficiency of NO and PG - Possible role of enhancing NO levels via nutritional supp. w/L-arginineRespiratory disorders -Used via inhalation to newborns w/pulmonary hypertension and ARDS -Decreases pulmonary arterial pressure and improves blood oxygenation -Also used in open trials in adults with ARDS -May act also act as bronchodilator by relaxing airway smooth muscleSeptic shock –Endotoxin (cell wall), TNF and other cytokines induce iNOS synthesis in macrophages, neutrophils, T-cells, SMC, endothelial cells (and more) -> exaggerated hypotension and shock –Potential for NOS inhibitors, but currently doesn’t improve survival ?if other beneficial effects of NOS counterbalance benefitsAtherosclerosis -May act as antioxidant, blocking oxidation of LDL, preventing foam cell formation in the vascular wallPlatelets -NO = potent inhibitor of platelet adhesion and aggregation -As per vascular sm.muscle, cGMP mediates protective effect of NO in platelets -May have additional effect on blood coagulation by enhancing fibrinolysis via effect on plasminogenOrgan transplantation -NO reduces free radical toxicity, inhibits platelet and neutrophil aggregation and adhesion to vascular wall -Too high concentration of NO may be detrimental - so need to inhibit synthesis to prolong graft survivalCNS -Modifies neurotransmitter release in different areas of the brain -Also may have role in epileptic seizures -Also has negative effects - causes destruction of photoreceptor cells in retina - prolonged increase in cGMP formationPeripheral nervous system - NO promotes relaxation of sm.muscle in corpora cavernosa - impotence trials with NTG ointment and NTG patchAdditional: Nitric Oxide DonorsOrganic NitratesGlycerin via mitochrondrial aldehyde reductase: dilates veins and coronary arteriesISMN via unknown enzymes pathwayLess effects on platelets (?platelets don’t have enzymes needed)Tolerance ?b/c/ NO mediated inhibition of aldehyde reductaseOrganic NitritesArterial dilatorsNo rapid toleranceSodium nitroprussideRapid BP reduction in hypertensive emergenciesNO Gass inhalationReduced pulmonary artery pressure, improved perfusion in ventilated lung areasAlternative strategies - Type 5 phosphodiesterase inhibitorsProlongation of NO-induced cGMP elevations (e.g. sildenafil)4.2 Drugs acting on autonomic nervous system4.2.1 Sympathetic (1) 2009-2What is the mechanism of action of amphetamines?Indirectly cause increased release of catecholamines at synapsesCompetitively inhibits dopamine transport/re-uptake at pre-synaptic neurone (DAT), and intracellularly inhibits VMAT displacing DA from the vesicles -> causing non-vesicular release (reversal of DAT direction) of dopamine into synapse (& similarly for other catecholamines)Describe the effects of amphetamines?Catecholamines: (increased arousal & decreased sleep) elevated HR (dysrhythmias) and BPDopamine release: addiction, euphoria, potentially abnormal movements & psychosisSerotonin: Appetite suppression, hallucinogenic & hyperthermia2005-2Describe the effects of an intravenous adrenaline infusion on the CARDIOVASCULAR system.Adrenaline is an (endogenous) agonist at both and receptors1: Increased cardiac output (chronotropy + inotropy)2: vasodilation with widened pulse pressure (2 – relaxation of skeletal SMC, also resp and uterine)Higher doses: > 1: vasoconstriction with narrowing of pulse pressure and increase in TPRWhat are the potential side-effects or complications of an adrenaline infusionGENERAL: Anxiety, tremor, nausea, vomiting, pallorHEART & CIRCULATION: Palpitations and/or arrhythmias, myocardial ischaemia, hypertensionMETABOLIC ( effect): hyperglycaemia, metabolic (lactic) acidosis, hypokalemiaHow does the effect of adrenaline differ from noradrenaline?Noradrenaline peripheral alpha effect- vasoconstriction, but 1>>2Adrenaline mixed peripheral alpha and beta as aboveNoradrenaline lesser cardiac effectSlightly different side-effect profile (metabolic effects due predominantly to beta receptor activation)2011-2What is the adrenoreceptor selectivity of noradrenalinealpha1 = alpha2 alpha 1: post-synaptic effector cells, especially smooth muscle alpha 2: presynaptic nerve terminals, platelets, lipocytes, smooth muscle beta1 >> beta2beta 1: post synaptic effector cells, especially heart, lipocytes, brainDescribe the cardiovascular effects of infused noradrenaline1. Increases peripheral vascular resistance 2. Increases SBP and DBP 3. Little chronotropy 4. Positive inotropy2009-1What are the effects of adrenaline on the blood vessels in different tissueWhat receptors mediate these effectsTissueReceptor(s)ToneCutaneous, mucous membranes++Venous , +Renal, D1+Splanchnic, -/+*Skeletal muscle2,-/+*Total peripheral resistance-/+**Low doses decrease (physiologic e.g. in exercise), high doses increase (e.g. in infusion)Describe the effects of adrenaline on other organs besides the heartSystemReceptorEffectRespiratory2BronchodilationEyesPupillary dilation, IOP, aqueous humorGIRelaxation of gastric smooth muscleGenitourinaryUterine smooth muscle relaxation, Bladder relaxation, Bladder sphincter contraction, Ejaculation Apocrine Sweat glands - palm of handsSalivaryLeading to dry mouthLipocytes3Lipolysis - increased fatty acids and glycerol in circulationMetabolismLiver: Enhanced glycogenolysisMetabolic acidosis 2Potassium uptake into cells, decreased extracellular potassium Hormones (2)Insulin, glucagon1 (2)ReninLeucocytosisDemargination of white cells2003-2Regarding-agonists, by what cellular mechanism do they exert their effects?Bind to specific receptorG-protein activationStimulate adenyl cyclaseIncreased cyclic AMPIncreased free intracellular CaActivate protein kinaseNote: 1 receptors (phenylephrine) -> IP3 and DAG2 receptors (clonidine)-> cAMPCompare the cardiovascular of adrenaline and dobutamine.DrugReceptorNotes agonistsPhenylephrine1>2>>>Not a catechol derivative (nil COMT) so long duration of actionMydriatic, decongestant, increases BPClonidine2>1>>>Reduce BP via CNS (vasomotor area)Mixed and Noradrenaline1=2, 1>>2Vasoconstricts, positive inotrope (minimal chronotropy)Adrenaline1=2, 1=2Vasoconstricts except skeletal m, positive inotrope/chronotrope agonistsDobutamine*1>2>>>Positive inotrope > chronotrope (vasoconstricts) COIsoproterenol1=2>>>Positive chronotrope and inotrope, vasodilates (CO, MAP)Albuterol2>>1>>>Asthma treatment (ritodrine – uterine relaxatn in prem labour)Dopamine agonistsDopamineD1=D2>>>>Vasodilation of renal, coronary, cerebral (via D1) and D2 suppresses noradrenaline release. High doses mimick adrenalineFenoldopamD1>>D2*Dobutamine is a selective 1 agonist.Increases cardiac output with less reflex tachycardia as it has fewer 2 effects. Comes as racemic mixture of +ve and –ve isomers. One isomer has B agonist and alpha antagonist effects; the other has alpha agonist effects.Additional: Receptor regulation/DesensitisationRepsonses mediated are not fixed and static but modulated by:Catecholamines themselvesHormones and drugsAge and diseaseAdrenoceptors display desensitization after exposure to agonistsMechanisms may occur slowly (hours-days) involving transcription at receptor protein level or migration to the cell surfaceMay occur quickly (minutes) involving covalent modification (phosphorylation, protein association, change to subcellular location)Homologous desensitization: Due to repeated/sustained stimulation by agonist (G-protein coupled receptor kinase (GRK) -> higher affinity for arrestins -> reduced G protein activation upon receptor stimulation)Heterologous desensitization: Desensitisation of one receptor results in desensitization of another receptor not directly activated by the agonist in question Second messenger feedback (cAMP or receptor activation -> increased protein kinase -> structurally similar receptor phosphorylation)4.2.2 Parasympathetic (1)2008-1, 2007-1, 2003-2What is the mechanism of action of atropine? (2010-1)Reversible block of cholinergic muscarinic receptors, non-selective between the M1, M2 and M3 sub-types. Very selective for muscarinic (vs nicotinic or histamine c.f. synthetic antimuscarinics)What are the toxic effects of atropine? (2006-2 – benztropine)Dry as a bone: Dry mucous membranes, urinary retention, ileusBlind as a bat: Mydriasis (pupilary dilation), acute angle glaucomaRed as a beet: Hyperthermia, flushing, tachycardiaMad as a hatter: Central anticholinergic syndrome – delirium w/ visual hallucinationsWhat are the therapeutic uses for atropine?CNS disordersDecrease tremor and rigidity in Parkinson’s disease Scopolamine for motion sicknessOpthalmologicMydriasis and cycloplegia (but caution b/c toxicity, and agonists shorter acting)RespiratoryAtropine was used to dry secretions pre-op with older irritant inhalantsQuaternary amine ipatropium (synthetic analogue of atropine) used in COPDCardiovasularSymptomatic bradycardias, especially when vagally mediatedSA node: blocks vagal slowing -> reflex tachycardiaAV node: increases conduction -> shorten PRGastrointestinalRarely now, but low dose with opioid for diarrhoea (e.g. traveler’s)Urinary Was used for urinary urgency, but replaced by M3 selective oxybutininCholinergic poisoningOGP poisoningInocybe Mushroom poisoningOthersAdjunct to reversal of non depolarising muscle relaxants and suxamethonium administration in young infantsWhat is benztropine? (2006-2)Centrally acting anti-muscarinic. As a tertiary amine it is widely distributed in the body including the CNS (quaternary amines such as ipatropium poorly taken up by CNS). Used as an adjunct in the treatment of the tremor in Parkinson’s.Describe the pharmacokinetics of atropine (2010-1)Well absorbed (even transdermal with suitable vehicle e.g. scopolamine patches)Natural and tertiary forms widely distuburted incl CNS, vs quaternary low CNS uptake and effectsQuaternary (e.g. ipatropium) only 10-30% absorbed b/c decreased lipid solubility of charged moleculet? has 2 phases, rapid 2h and slow is 13h50% excreted unchanged (the rest hydrolysis and conjugates)Effects on eye last longer >72 hours (rapid decline in other tissues)What are the effects of atropine on heart rateLower doses often an initial bradycardia (Blocks prejunctional M1 receptors)Tachycardia2003-2What is the mechanism of action of indirectly acting cholinomimetics?Inhibition of the enzyme acetylcholinesterase thereby increasing the concentration of endogenous acetylcholine in the vicinity of cholinoreceptorsWhat types of indirectly acting cholinomimetics are there? Please give examples.TypeNameUsesDurationAlcoholEdrophoniumMyaesthenia gravis, arrythmias, ileusMinutesCarbamatesNeostigmineMyaesthenia gravis, ileus0.5 – 2hPhysostigmine3 – 6hPyridostigmineGlaucoma0.5 – 2hOrganophosphatesEchothiophateGlaucoma100hoursWhat are the cardiovascular effects of these groups of drugs?CardiovascularAction on both nicotinic and muscarinic receptorsAction on the neuromuscular end plate and autonomic ganglion cellsBoth sympathetic and parasympathetic ganglia can be activated Parasympathetic effects generally predominate Bradycardia, decreased CO, decreases contractility, no change or modest decrease in BPOD may cause tachycardia and hypotensionCNSHigh conc -> convlusions, coma and respiratory arrestEye – miosis (pupilary contraction) and ciliary muscle contractionLung – bronchial contraction and secretions stimulationGI – increased motility, sphincter relaxation and secretionsUrinary bladder – detrusor contraction and trigone and sphincter relaxationGlands – sweat, saliva, lacrimal and nasopharyngeal secretionsSLUDGE (OGP poisoning): salivation, lacrimation, urination, defecation, GI distress and emesis4.3 Local anaesthetics (1) 2011-2, 2006-1, 2004-2What classes of local anaesthetics are used in the ED? (Prompt for examples)Amides: lignocaine, prilocaine, bupivacaine, ropivicaine Esters: cocaine, procaine, benzocaine, tetracaineWhat factors affect the systemic absorption of lignocaine after local infiltration?Systemic absorption is an important cause of toxicity from local anaesthetics. DoseSite of injection - for blocks absorption intercostal > caudal > epidural > brachial plexus > sciaticDrug-tissue bindingTissue blood-flow - absorption will be higher from highly vascular tissues e..g tracheal mucosa vs tendons, or dermis. Blood flow can be altered e.g. an ischaemic arm block or vasoconstrictorsVasoconstrictors – Reduce absorption by 30%, increased concentration at sire increases effect and decreases toxicityWhat are the toxic effects of lignocaine? 2007-1 (prilocaine), CNSInitially: Sleepiness, light-headed, visual, auditory disturbance, restlessness Early toxicity: Circumoral/tongue numbness, metallic taste Serious/higher: Twitching, nystagmus, seizures Direct neurotoxicity Radicular irritation with spinals CVS Direct: Na channel (depress abnormal pacemaker, excitability, conduction) v Ca channel effects at high doses – decrease myocardial contractilityIndirect: via autonomic nervous system cause arteriolar dilatation, hypotensionWith bupivicaine can get idioventricular rhythm, broad QRS, EMD HaematologicMethaemoglobinemia due to accumulation of o-toluidine which oxidizes haemaglobinIf high enough conc. then can cause cyanosis and “chocolate coloured” bloodImportant if pre-existing cardiac or pulmonary diseaseTreat with reducing agent e.g. methylene blue or ascorbic acidAllergyRare with amides as not metabolized to PABA2009-2, 2007-1 (prilocaine), 2006-1What is the mechanism of action of local anaesthetics?Blockade of voltage-gated Na channels in neurones which interferes with AP propagationProvide pain relief by blocking nociceptive fibers, although other fibers are affected as wellBlock is both voltage and time-dependant: i.e. higher affinity for channels in open or inactivated state at more +ve membrane potentials (vs. resting) -> preferentially block rapidly firing neuronsChannels recover 10-1000 slower from inactivated state due to LA -> increased refractory periodIncreasing doses lead to higher excitation threshold, slower impulse conduction, lower APBlocks conduction if 2-3 nodes of Ranvier in a myelinated nerve are affectedWhich local anaesthetics are used topically? EMLA (Eutectic Mixture of Local Anaesthetics): mixture of lignocaine and prilocaine Cocaine: ENT procedures (combines vasoconstriction)Eye Drops: Proxymetacaine, amethocaine, oxybuprocaineBenzalkonium: Oral gels2007-1How is prilocaine metabolized?Amide link hydrolysed by P 450 in liver and then renal excretionSignificant variation is rates between amides, prilocaine is the fastest (lidnocaine intermediate, bupivicaine is slow)Hepatic disease, reduced flow, competing P450 agents will reduce metabolismNote: Ester local anaesthetics are hydolysed rapidly in the blood by circulating pseudocholinesterase (very short t? < 1min for procaine)2006-1Describe the ideal local anaesthetic for topical application?Ease of application (Not messy, No dressing)Well tolerated by kids (Not painful)Rapid Onset of action Low (nil) systemic toxicity eg MetHb with EMLA in neonatesHigh analgesic efficacyReasonable duration of actionNot allergenicMay be applied to the skin, the eye, the ear, the nose and the mouth as well as other mucous membranesEMLA (Eutectic Mixture of Local Anaesthetics) - mixture of lignocaine and prilocaine Eutectic mixture means solidifies at lower temp, both lidnocaine and prilocaine are solids at room temperature, but together form an oil Provides surface anaesthesia of the skin (partic paeds)Cutaneous contact (usually under an occlusive dressing) should be maintained for at least 60 min prior to venipunctureOther LA agents may be absorbed in significant amounts particularly after topical application to the more vascular areas, fatalities have occurred after application of these agents to mucosal surfaces2004-2Explain tachyphylaxis associated with LA useMost local anesthetics are weak bases, pKa 7.5-9.0Often marketed at hydrochoride salts (pH 4.0 – 6.0) to maximize aqueous solubilitylog[cationic form/uncharged form] = pKa – pH (thus more cationic form at acidic pH)Receptor site is intracellular, and the uncharged form is thus needed to obtain access through the lipid cell membrane -> the cationic form (“ion trapping”) -> then binds With repeat injections the LA can deplete the buffering capacity of the tissue -> low pH -> more extracellular LA in cationic form that cannot diffuse though cell membraneCommon in tissues with poor buffering e.g. CSFExtra:Sensitivity depends on: Fiber diameter/typeSmaller > larger b/c distance over which passive AP propagation can occur is smaller Myelination – 2-3 nodes of Ranvier needed to block propagation (myelinated blocked before unmyelinated nerves of the same size, Type B preganglionic > Type C pain)Firing frequencySensory (pain) fibres have a high firing rate and long AP duration, so more sensitiveSensory modalities are affected in the following order: pain, cold, warmth, touch, then pressure4.4 General anaesthesia4.4.1 Induction agents (1) Describe the distribution of thiopentone following an IV bolus 2011-1Rapidly crosses the BBB, may induce LoC in one circulation timeThe plasma:brain equilibrium occurs <1min because high lipid solubilityThen rapidly redistributed to muscle and body fatBecause of this rapid removal from brain tissue it only causes brief LoCMetabolised at about 15% per hour with <1% excreted unchanged by kidneysWhat are the potential adverse effects of thiopentone?Disadvantages: Hypotension, respiratory depression/transient apnoea, venous irritant, myocardial depression, minimal muscle relaxation and analgesia, hepatic metabolism (vs inhalational agents), reduces hepatic blood flow, can cause porphyric crisis in susceptible patientsAdvantages: Rapid, Controllable, Amnesic, Reduction of ICP (head trauma, brain tumours), anticonvulsantDescribe the pharmacokinetics of propofol? 2009-2, 2003-1Intravenous administration (of emulsion)Distribution t1/2 2-8 min, redistribution t1/2 30-60 minMetabolised rapidly in liver (10x c.f. barbituates), and total body clearance is greater than hepatic blood flow, suggesting extrahepatic mechanisms also – advantageous in hepatic diseaseExcretion in urine as glucuronides and sulphates w/ <1% unchangedWhat are the side effects of propofol?Pain on injection is the most common (admixture with lidocaine may minimise)Respiratory: dose-related depression of central ventilatory drive, apnoea,Cardiac: Marked decrease in blood pressure through decreased peripheral arterial resistance and venodilatation, and direct negative inotropic effectSoy/egg allergyProlonged administration: severe acidosis in critically ill children, elevated serum lipids, delayed arousalWhat type of anaesthesia does ketamine produce? 2006-2Dissociative anaesthetic state: analgesia, amnesia, catatonia +/- LoC (hypnosis)Which receptor action produces the anaesthesia?Blockade of glutamic acid (excitatory neurotransmitter) at NMDA receptor subtypeHow does ketamine affect the cardiorespiratory system? 2009-2, 2006-2CaridiovascularHR, BP and cardiac output increasePeak 2-4 minutes and last 10-20 minutesStimulates central sympathetic nervous system, and inhibits re-uptake of noradrenaline at sympathetic nerve terminalsRespiratory: Decreased rate, airway reflexes remain intact, bronchodilatorWhat are the side effects of ketamine?Decreased RR HypersalivationPostoperative disorientationSensory and perceptual illusionsEmergence phenomenonVomitingRaised ICP (cerebral blood flow, O2 consumption)Rash4.4.2 Muscle relaxants (1) 2010-2What is pancuroniumNon-depolarising neuromuscular blocking drugQuaternary ammonium compound, structure like 2 acetylcholine fragments on a steroid nucleusPotent competitive antagonist of acetylcholine at nicotinic receptors of skeletal muscle motor end-plates Interruption of transmission requires > 70% occupancyBlockade requires > 95% occupancyDescribe the pharmacokinetics of pancuronium?Poorly absorbed after oral adminRapidly and widely distributed after iv Highly ionized, does not readily cross cell membranes and not bound in tissues – Vd is small (~blood volume, 80-140ml/kg)Rapid elimination (t? 30min) by urinary excretion (80%) unchanged drug (highly water soluble)Some hepatic metabolism with biliary excretionDuration of action >35minWhat are the adverse effects of pancuronium?Uncommon Cardiac (slight block of cardiac muscarinic receptors): Minor tachycardia, hypertension, ↑ CO Life-threatening anaphylaxis < 1:10,0002009-2, 2006-1, 2003-1Describe the mechanism of action of suxamethonium?Depolarizing neuromuscular blocking drug2 molecules of acetylcholine linked via the acetate methyl groupsActs like acetylcholine except not metabolised effectively at the synapse so much longer effectAction is terminated by diffusion away from the end plate into the extracellular fluid, where it is hydrolysed by plasma cholinesterase to succinic acid and choline (in fact it is so rapidly metabolised that little of the injected drug reaches the motor end plate)Very short half life, duration of action 4-8minPhase I (depolarising)Reacts with nicotinic receptor and opens the channel -> depolarisation of the motor end plateNot metabolised at the synapse so membranes remain unresponsive to subsequent impulsesLack of “repriming” leads to flaccid paralysisThis phase I block is augmented by cholinesterase inhibitors (c.f. reversed with non-repol drugs)Phase II (desensitising)Prolonged exposure -> repolarized but desensitized end-plateUnclear, but channel block may be more important than agonist actionBehaves more like non-depolarizing blockIs reversed by cholinesterase inhibitors like with non-repol (i.e. neostigmine)What are the side effects of suxamethonium?Bradycardia- negative inotropic and chronotropic effects (inc. second dose bradycardia)Hyperkalaemia (esp burns, nerve damage, NM disease, closed head injury)Increased intra-ocular pressureIncreased intragastric pressure (inc. aspiration)Muscle pain (in up to 20%)Malignant hyperthermia (when combined with volatiles)Sux apnoea in susceptible patients4.4.3 Volatile anaesthetics(3) 4.4.4 Nitrous oxide (1)2006-1What are the organ effects of nitrous oxide?CNS: Analgesic, amnesic, increased cerebral blood flowRenal: Decreased GFR, increased filtration fraction & increased renal vascular resistanceCVS: Dose dependant myocardial depressionResp: Reduced respiratory response to CO2 & hypoxiaHaematologic: Inactivates B12 -> B12 deficiency and pernicious/megaloblastic anaemia (prolonged exposure)What is the mechanism of action of nitrous oxide?Directly activate GABA A receptorsGABA A receptor-chloride channel is a major mediator of inhibitory synaptic transmissionAlso facilitates GABA mediated inhibition at GABA receptor sitesLeads to:Membrane hyperpolarisationDecreased duration of opening of nicotinic receptor activated channelsDecreased excitatory effect of acetylcholine4.5 Antipsychotic agents (2)2009-1What are the clinical uses of chlorpromazineTypical phenothiazine antipsychotic especially for schizophrenia, also deleriumSedative for agitation AntiemeticMigraine (and hiccups)What are the pharmacodynamic properties responsible for these effectsAntipsychotic: D2 blockade in mesolimbic & mesofrontal systems Sedation 5-HT blockadeAntiemetic: dopamine receptor blockade in medullary chemoreceptor trigger zone & peripherally on receptors on stomach 2011-1, 2005-1, 2009-1What are the major side effects of phenothiazine antipsychotics? (e.g. chlorpromazine)Anti-cholinergic: Dry mouth, dry eyes, urinary retention, constipationExtra-pyramidal: Dystonia, Parkinson-like effects, akinesia (can’t start), akathisia (can’t stop), tardive dyskinesiaSedationWeight gainHypotensionHyperprolactinaemia - ammenorrheaOccular corneal depositsNeuroleptic malignant syndromeF – FeverA – Autonomic instability (labile BP and diaphoresis – “sweat shock”)L – LeukocytosisT – TremorE – Elevated enzymes (elevated CK)R – Rigidity of musclesWhat mechanisms of drug action are responsible for these side effects?Prompt: What receptors are involved?Muscurinic cholinoceptor blockade -> anticholinergic Dopamine receptor blockade -> Extra-pyramidal and NMS-Adrenoceptor blockade -> hypotension5-HT2A receptor blockade -> weight gain, sedation and hypotensionH1 antihistamine blockade -> weight gain, sedation and hypotensionHow could the extra-pyramidal side effects be managed?Prompt: What about acute EP side effects? What about chronic EP side effects?Switch to an atypical drug (lower incidence of extra-pyramidal effects)Administer benztropine or diazepamNo effective treatment for tardive dyskinesia: prevention vital; monitor for early signs and reduce or cease anti-psychotic asapNote: Tardive dyskinesia is characterized by repetitive, involuntary, purposeless movements Likely results primarily from neuroleptic-induced dopamine supersensitivity in the nigrostriatal pathway, with the D2 dopamine receptor being most affected2010-2Describe the general pharmacokinetic characteristics of antipsychotic drugsMost are readily but incompletely absorbedMany undergo significant first pass metabolism – less systemic availabilityMost are lipid soluble (lipophilic)Most have high PPB (92-99%)Most are completely metabolised by hepatic enzymes (oxidation; demethylation) These are catalysed by liver enzymes.Define the term “atypical” antipsychotic and provide an example.Newer antipsychotic agents with less propensity to cause extra- pyramidal side-effectsBetter at treating negative features of schizophreniaGreater ability to alter 5-HT2A receptor activity than to interfere with D2-receptor actionExamples: olanzapine, clozapine, quetiapine, risperidone, loxapineDescribe the adverse drug reactions to olanzapine.Weight gain (increased lipis, risk of diabetes mellitus) Sedation (but less than typical antipsychotics) Minor orthostatic hypotension Minor anticholinergic effects (dry mouth, urine retention etc)Extrapyramidal effects less prominent than with typical antipsychotics2007-1, 2006-1What the pharmacological characteristics of olanzepine?Atypical antipsychoticThienobenzodiazepineMost 5-HT2A and D4 receptor effects, also alpha-1 and H1 effectHigh potencyVery low extrapyramidal effectsMedium sedativeLow hypotensive effectsCauses weight gain long term (may precipitate diabetes)How does it differ from haloperidol?Typical antipsychoticButyrophenoneMost D2 receptor effectsHigh potencyVery high extrapyramidal effectsLow sedativeLow hypotensive effectsCheapWhat are the clinical conditions Olanzapine is prescribed for? 2006-1Wide Spectrum of use:SchizophreniaAcute treatment of maniaBehavioural emergenciesAutism spectrum disordersDelirium: mood and behavioural disturbances, palliative care, AIDSDementia: General, Sleep disorder in patients with dementia (palliative care)4.6 Antidepressives2008-1How do anti-depressants exert their action?Thought to enhance amine-dependent synaptic transmission (serotonin and noradrenalin) by:Inhibition of metabolism within nerve terminal (MAOIs)Inhibition of reuptake from synapse (TCAs, SSRIs)Increased release due to antagonism of specific serotonin and 2 NA receptors (Mirtazapine)What are the relative advantages of different classes of antidepressants? (Adverse effects?)DrugAdverse effectsOverdose riskInteractionsSSRIGI, libido, insomnia, headachesLowCYP2D6 inhibition -> TCASerotonin syndrome w/ MAOIsSNRISame as SSRIs + noradrenergic:BP, HR, insomnia, agitationLow butVenlafaxine –> cardiotoxicFewer interactions c.f. SSRIsTCAAnticholinergic (antimuscurinic)-blocking -> BPH1 block -> weight and sedationClass 1A -> arrhythmogenicLethal arrhythmias, hypotension, seizuresIncreased TCA levels w/ CYP2D6 inhibition and slow metabolisers, interactions w/ BP meds -> hypotensionMAOIOrthostatic hypotensionWeight gainSexual dysfunctionAutonomic instability, hyperadrenergic, psychosis, seizuresSerotonin syndromeDietary tyramine, SNS drugs -> BP, CVA, MI (via NA effects)Sample viva, 2006-2What are the medical uses for St Johns Wort?St John's wort is widely known as an herbal treatment for depression Cochrane review states:Superior to placebo in patients with major depressionSimilarly effective as standard antidepressantsFewer side-effects than standard antidepressantsHowever poor repeatability and effects greater in German trialsWhat are its important drug interactions?Kinetic as a CYP inducer (decrease drug effect)Subtherapeutic digoxinBirth control pill -> pregnancyWarfarinAnticonvulsantsDynamic b/c inhibits catecholamine reuptake (potentiates some drug effects)Serotonin syndrome or MAO crisisAdditional: Serotonin syndromeLife-threatening serotonin poisoningClassically a clinical triadCognitive effects: headache, agitation, hypomania, confusion, hallucinations, comaAutonomic effects: shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhoeaSomatic effect: myoclonus, hypereflexia, tremor4.6.1 Tricyclics (1) 2011-2What are the pharmacokinetics of tricyclic anti-depressants?Oral, well-absorbedHigh first pass metabolism so bioavailability ~50%Long half-time (once daily dosing, usually nocte b/c sedating)High tissue protein bindingHigh lipid solubilityLarge VdMetabolised in liver by CYP2D6, active metabolitesOnly 5% unchanged in urineWhat are the toxic effects of tricyclics in overdose? 2011-2, 2008-2Anticholinergic (antimuscurinic) -> Dry mouth, blurred vision, constipation, urinary retention, confusion, tachycardia-blocking -> HypotensionH1 block -> SedationClass 1A -> Arrhythmogenic sodium channel blockade w/ QT prolongation, reduced contractilitySeizures, psychosis, agitationSympathomemetic -> tremor, insomniaWhat drugs could be used in the treatment of tricyclic toxicity in overdose?Supportive: dopamine/NA for hypotensionCardiac toxicity: sodium bicarbonate 50-100 mEq IV (unblocking drug from Na channels)Intralipid: binding of drug due to lipophilic profile, decreased available drug2008-2What is the mechanism of action of the tricyclic antidepressants? Prompt: Name one amine? Block amine (noradrenaline and serotonin) reuptake pumps at presynaptic nerve endingsProlongs duration of action of neurotransmitters at postsynaptic receptorsMost non selective4.6.2 Serotonin re-uptake inhibitors (2) 2008-2What is the mechanism of action of the SSRI drugsMonoamine hypothesis of depression: that depression is caused by deficiency or imbalances in the monoamine neurotransmitters (5-HT, NE and DA)Selective binding to serotonin transporter (SERT) leading to 80% reduction in activity and reuptake inhibitionHigh synaptic serotonin levels leads to downregulation of autoreceptors (presynaptic), downregulation of postsynaptic 5-HT2A receptorsDepressed and suicidal patients have shown higher levels of 5-HT2A, suggesting overactivityThese (slowly proceeding) neurophysiological adaptations of the brain tissue are the reason why usually several weeks of continuous SSRI use is necessary for the antidepressant effect to become fully manifested and why increased anxiety is a common side effect in the first few days or weeks of useWhat receptor/channel effects lead to the SSRI side effect profile. Prompt why are SSRIs safer than TCAs?SSRIs very SERT specificSerotonin syndrome/ restlessness/ GI upsetMinimal autonomic effects ( adrenoceptors, noradrenaline reuptake transporter/NET)Only mild muscarinic / Na channel, H1 block effects Well tolerated and low risk in overdose4.6.3 Newer agents(2) 4.6.4 Lithium (1)2010-2, 2005-2Describe the pharmacokinetics of lithiumAbsorption: Complete in 6-8 hours, peak concentration 0.5-2h, 100% bioavailabilityMetabolism: noneProtein binding: noneVd: In total body water w/ slow entry to intracellular compartment and some into bone – 55L/70kgExcretion: 95% in urine w/ clearance 20% of Crt? about 20 hoursSteady state plasma concentration takes 5-7 daysWhat are the adverse effects of Lithium at therapeutic levels?May be associated with therapy or toxicity:Neurologic: Tremor (common), motor hyperactivity, ataxia, dysarthria, aphasiaPsychiatric: Confusion, withdrawalThyroid: HypothyroidismRenal: Polydipsia and Polyuria (common), nephrogenic diabetes insipidus (inhibits the effect of ADH on the DT cells)Oedema (Na retention) and weight gainAcne and psoriasisLeukocytosis (may be beneficial)What are the signs/symptoms of lithium toxicity?CNS: Tremors, confusion, slurred speech, ataxia, drowsiness, blurred vision, seizuresGIT: Vomiting Note: Therapeutic overdoses are more common than intentional, often caused by a change in the patient’s status e.g. diuretic use, decreased serum sodium, fluctuating renal function2005-2What factors may influence lithium excretion?Renal function (Glomerular filtration rate)Water and sodium status (increased lithium reabsorption in proximal tubule in sodium or water depleted states)Drugs: thiazide diuretics and NSAIDs reduce clearanceLithium serum concentrationAdditional: Pharmacodynamics of lithiumUsed as a mood stabiliser in bipolar affective disorder, and sometimes as an adjunct in depression and schizophreniaPoorly understood mechanismClosely related to sodium, inhibiting it’s transport across cell membranesEffects on second messengers, notably inhibiting inositol monophosphatase (IMPase) and other enzymes, reducing IP2 -> IP1 -> inositol and ultimately PIP2 (the precursor of IP3 and DAG)4.7 Anticonvulsants4.7.1 Phenytoin (1) 2010-2, 2008-2Describe the pharmacokinetics of phenytoin.Weak acid pKa 8.3Oral absorption almost complete 90%, but slow and variable with peak serum conc. 3- 12hrs IMI: unpredictable and incomplete absorption with drug precipitation in the muscleHighly plasma protein boundVd 45L/70kgSaturable hepatic metabolism leading to dose dependant (zero order) kinetics (metabolised to inactive metabolities)Variable t? of 7-42hrs (average 24 hours)Takes 5-7 days to reach steady state with low dosage, 4-6weeks with highUrinary excretion, < 2% unchanged in urineDrug interactions via plasma protein binding or via enzyme induction (CYP2C19 & CYP2C9)Therapeutic level 10-20mg/LDescribe the pharmacodynamics of phenytoin? 2008-2Blocks sodium channelsInhibits the generation of repetitive APsPreferential binding to & prolongation of the inactivated state of the Na channel (use-dependant effect on Na conductance)Other electrolyte effectsAlters K+ conductanceAlters Ca2+ conductance and decreases Ca2+ permeability, inhibits Ca2+ influx therefore affecting neurotransmitter and hormone releaseInteracts with membrane lipids ?stabilising membranesParadoxical excitation in some neuronesAlters membrane potentials and the conc. of amino acidsAffects neurotransmitters NA, Ach & GABAHigh conc inhibits serotonin and NA release, promotes uptake of DA & inhibits MAO activityWhat are the adverse effects of phenytoin? 2010-2, 2010-1Dose related neurotoxic effects: Diplopia and ataxia (most common), nystagmus, drowsiness, hallucinations, slurred speech, confusionLong term: Hirsuitism, gingival hyperplasia & overgrowth with bleeding, acne, facial coarseningIdiosyncratic: Skin rash, SJ syndrome, lymphadenopathy, agranulocytosisRapid IV administration associated with CV collapse (hypotension and arrhythmias)Alters TFT results (binding to thyroid globulins, TSH is still useful test)Drug interactions (plasma binding), also reduced Cl and binding in neonatesTeratogenic -> foetal hydantoin syndrome (IUGR, microcephaly, developmental delay)Describe how phenytoin is administered in status epilepticus 2010-1IV load 13-20mg/kgGiven diluted in saline (precipitates in glucose)Max rate in adults of 50mg/minContinued 100mg Q6-8hrly4.7.2 Carbamazepine (1) 2009-1, 2005-1Describe the mechanism of action of carbamazepineTricyclic compound with structural similarities to phenytoin and anticonvulsant properties:Like phenytoin blocks Na+ channels -> inhibits high-frequency repetitive firing of neurones Also presynaptic blocker of synaptic transmissionInhibits uptake and release of noradrenaline from brain synapses Does not influence GABA uptakeAdditional: Pharmacokinetics of carbamazepineWell absorbedPeak levels 6-8 hours 70% protein bound (but does not displace other drugs)Vd 100L/70kg Half life 36hr after single dose, 15h on continuous therapyInduces liver enzymes and dose has to increase markedly over first few weeksHow is carbamazepine metabolised and what is the effect of the metabolism of other drugsMetabolised by microsomal enzymes -> active metabolites (clinical significance uncertain)Enzyme induction increases rate of metabolism of other drugs e.g. phenytoin, valproate, clonazepamSome of these drugs also can inhibit carbamazepine metabolism (valproate)Phenytoin and phenobarbital may induce the metabolism and decrease levels of carbamazepineWhat are the clinical indications for its use?Partial tonic-clonic seizuresWith phenytoin if difficult to control tonic-clonic seizuresTrigeminal neuralgia and other pain syndromesSome patients with bipolarWhat are its potential adverse effects?Commonly: diplopia, ataxia Dose-related: GIT upset, ataxia, drowsiness, hyponatraemiaIdiosyncratic: Blood dyscrasias - aplastic anaemia, agranulocytosis (needs monitoring)Skin rashAlters clearance of other drugs w/ drug reactions due to induction of liver enzymes4.7.3 Sodium valproate (1) 2011-2, 2005-1What are the proposed mechanisms of action of valproate?Blocks Na+ channels thereby blocking sustained high frequency firing of neuronesBlockade of NMDA receptor mediated excitationIncreases GABA levelsDescribe the toxic effects of valproate?Commonly: GI upset w/ nausea and vomiting (dose related, start gradually)Idiosyncratic hepatotoxicity: Mostly within 4 months of initiation of treatment, treat with intravenous L-carnitine, requires monitoring of LFTs Others: Tremor, weight gain, appetite, sedation, allergy Teratogenic: Increased malformations (spina bifida, cardiac) in pregnancyWhat interactions does valproate have with other anti-seizure drugs?Phenytoin: inhibits metabolism and displaces from plasma proteins Phenobarbitore & carbamazapine induce metabolismLamotrigine decreases clearance4.7.4 Newer agents(3)4.8 Hypnotics / sedatives4.8.1 Benzodiazepines (1) 2011-2What benzodiazepines are commonly used in the ED?Diazepam, lorazepam, midazolam, clonazepam, temazepam,2011-2, 2005-2, 2007-2 (clonazepam), 2007-1 & 2004-2 (midazolam) What is the mechanism of action of benzodiazepines? Facilitates GABA binding at GABAA receptor (ligand-gated chloride channel)Thus GABA inhibition enhanced through hyperpolarisationActs throughout brain but the distribution in CNS of the different GABAA receptor isoforms varies Binding between 1 & 2 subunit (modulatory BZ site) – more selective than barbituatesLow affinity for GABABWhat are the clinical effects of benzodiazepines?Sedation and anxiolysisHypnosis (sleep inducing)Reduced sleep latency (time to fall asleep)Increase stage 2 NREMDecrease REM and stage 4 NREMAnaesthesia (adjunct)Anticonvulsant (potentiates inhibitory interneurones)Muscle relaxationCardiorespiratory depressionEspecially if respiratory or cardiovascular diseaseDecreased contractility and vasomotor tone in toxic doses -> cardiovascular collapse2010-2What are the indications for benzodiazepine use?Anxiety disordersPreoperative medication Insomnia and sleep disturbances Seizure disordersPanic disorder Alcohol withdrawal Muscle spasm Induce amnesia during cardioversion/endoscopic procedures Explain the rationale for use of benzodiazepines in alcohol withdrawalDown-regulation of neuro-inhibitory GABA receptors in alcohol dependent individual leads to symptoms of GABA deficiency in withdrawal (anxiety -> seizures)BZD act at a modulatory site on the GABAA receptor to facilitate GABA binding to the GABAA receptors, enhance chloride channel opening, and overcome neuroexcitatory symptoms of GABA deficiency2007-2What properties make clonazepam an effective anticonvulsant?Lipid soluble so croses the blood brain barrierActs on alpha I GABA receptor isoform -> potentiates inhibitory interneurones2007-1What are the pharmacokinetics of Midazolam?Water soluble hence oral/IM/intranasal but crosses BB barrier easily at body pHShort elimination half-life 2-4 hours56% renal excretion2010-2What is the mechanism of action of flumazenil?Competitive antagonist at the BZD binding site on the GABAA receptorDecreases the binding of GABABlocks GABA-induced increase in Cl- permeability and influx of Cl- into the cell causing hyperpolarisation and decreased excitability of the neuronWhat are the indications for flumazenil useAvoid intubation or ICU admission in BZD overdoseReverse BZD sedation after procedures Diagnostic role2007-1 2005-2, 2004-2What potential problems should be anticipated when using flumazenil?Precipitate seizures in mixed overdoses with BZD and proconvulsants (TCAs)Precipitate seizures in patients taking BZD to control epilepsy Precipitate withdrawal symptoms and seizures in BDZ-dependence Duration of action is only 1-3hrs thus repeated administration may be necessaryReversal of BZD-induced respiratory depression has not been demonstrated, so respiratory and cardiovascular support may be requiredAdverse Effects: headache, visual disturbance, increased anxiety, nausea, light-headedness4.8.2 Barbiturates (1) 4.8.3 Newer agents (3)4.9 Ethanol (1)PharmacokineticsSmall water soluble molecule, rapidly absorbed from stomachPeak blood alcohol reached in 30minsVd approximates TBW (0.5-0.7L/kg)Higher levels reached in women b/c lower TBW and less GI ADH metabolism90% oxidized in the liver, the remainder excreted via lungs and kidneysZero order kinetics – i.e. fixed clearance amount (not related to time or concentration) of about 1drink/hour2 major pathways, 3rd final common pathway:Alcohol Dehydrogenase (ADH)EtOH –(ADH)-> AcetaldehydeRequires NAD+ -> NADH (lactic acidosis and hypoglycaemia in acute toxicity)Inhibited by fomepizoleMicrosomal Ethanol Oxidizing System (MEOS)Utilises NADPHActivates at higher levels (when ADH system saturated b/c depletion of NAD)Induced in chronic alcoholism (generation of toxic fee radicals)Acetaldehyde MetabolismAcetaldehde –(aldehyde dehydrogenase, ALDH)-> AcetateInhibited by disulfiriam (and metronidazole, trimethoprim) or may be genetic underactivityAccumulation of acetaldehyde -> facial flushing, nausea, vomiting, headachePharmacodynamicsCNSEffects many receptors in signaling pathways, esp: enhances action of GABA (inhibitory) at GABAA and inhibits glutamate (excitatiory) opening NMDA receptor (learning and memory)Sedation, anxiolytic -> impaired motor function, slurred speech, ataxia -> emesis, stupor -> coma -> respiratory depression and death (>500mg/dL)Cardiac – reduced contractilitySMC – vasodilator (via CNS and direct effects of acetaldehyde)Chronic consumptionLiver and GIFatty liver -> hepatitis -> cirrhosis -> failurePancreatitisSmall bowel damage – malabsorption of nutrients and vitaminsNervous systemTolerance and dependence (delirium tremens)Neurotoxicity (peripheral neuropathy, B12 deficiency -> Wernicke’s encephalopathy)CardiovascularCardiomyopathyArrythmiasHTNCVDHaematologicEndocrineFetal alcohol syndromeImmuneCancer risk2005-1Describe the metabolism of methanol.Oxidation via ADH to formaldyhyde, formic acid and CO2ADH inhibited by fomepizole, and EtOH has higher affinityToxicity due to the metabolites, especially formic acidFolic acid dependent pathwayLeads to metabolic acidosis w/ elevated anion and osmolar gapKey symptoms is visual “like being in a snowstorm”What specific modalities of treatment are available for the treatment of severe methanol poisoning?Common treatment: Support of respirationSuppression of metabolism (EtOH or formepizole)Removal w/ haemodialysisAlkalinisationAlso: Formic acid to prevent formic acid accumulation2010-2 Explain the rationale for use of benzodiazepines in alcohol withdrawalDown-regulation of neuro-inhibitory GABA receptors in alcohol dependent individual leads to symptoms of GABA deficiency in withdrawal (anxiety -> seizures)BZD act at a modulatory site on the GABAA receptor to facilitate GABA binding to the GABAA receptors, enhance chloride channel opening, and overcome neuroexcitatory symptoms of GABA deficiency4.10 Anti-parkinsonian agents (3)2007-2Why is levodopa used in combination with carbidopa?Carbidopa is a peripheral dopa decarboxylase inhibitorBecause it doesn't penetrate the blood brain barrier, it reduces the peripheral metabolism of levodopa => increased levodopa levels and increased half-life resulting in more dopa being available for entry into brain to exert its effects.What are the adverse affects of levodopa?GIT: Anorexia, nausea and vomiting in up to 80% of patients. Due to stimulation of emetic centre in brainstem Incidence I, to < 20% if a peripheral decarboxylase inhibitor is added.CVS: Arrhythmias-tachycardia, ventricular ectopics, AF. Due to increased catecholamine formation peripherally. Postural hypotensionDyskinesias: Up to 80% of those receiving levodopa for long periods.Behavioural effects: Depression, anxiety, agitation, insomnia, nightmares, euphoria and mood changes. More common if taking a levodopa with a decarboxylase inhibitor. Due to higher levels presenting to the brain.Fluctuations in clinical response occurs with increasing frequency as treatment continues.Miscellaneous: Mydriasis, acute glaucoma, Coombs positive haemolytic anaemia, gout, abnormalities of taste and smell, Brownish discolouration of saliva, urine or vaginal secretions, priapism, abn urea, LFTs.Drug Interactions: Pyridoxine enhances metabolism of levodopa. Hence effect drecreased.4.11Anti-migraine agents (2)2011-1What drugs can be used in the treatment of an acute attack of migraine?Simple analgesia (eg paracetamol, aspirin, codeine)MetoclopramideProchlorperazineErgot alkaloids eg ergotamine (+/- caffeine added)ChlorpromazineTriptans e.gg sumatriptanOpoids can be used but not treatment of choiceHow do triptans work? Structural analogue of 5-HTSelective agonists at 5-HT1 receptorsThese receptors are found on cerebral & meningeal vessels Causes vasoconstrictionChlorpromazine can be used to treat acute migraine. What are the major side effects of chlorpromazine?HypotensionSedationAnticholinergic (dry mouth, dry eyes, urinary retention, constipation)Extrapyramidal (eg acute dystonia)Pain with IM injections, risk of muscle necrosis2005-2Please describe the pharmacokinetics of SumatriptanBioavailability 15% (other agents in the group have availabilities of 40- 70%)t? 2-3 hoursGiven S/C, nasally, orallyPoor bio-availability given s/cWhat are the pros and cons in using Sumatriptan for migraine?Pros: Mild side effect eg tingling, dizziness, muscle weakness, neck pain, injection site reactionsEffectiveCons:Contraindicated in patients with IHD due to coronary spasmShort duration of action (several doses required for prolonged attack)Very expensive ................
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