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  • 8/7/2019 SAQ Pharmacology CVS

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    Q. Outline the difference between SNP and GTN

    Short answer question

    SNP

    Drug action

    y SNP react with oxyhb- heam guanylatecyclase

    y Oxyhb dissociate to formmetahaemoglobin , cyanide and NO

    y the NO then bind to guanylate cyclase toincrease intracellular cGMP

    y cGMP cause relaxation of smooth musclePharmacokineticabsorption

    y administered as a continuous IV infusionby a calibrated pump,y with continuous IABP monitoringy due to the rapid onset of action

    metabolism

    y The electron is transferred from the Fe++of HbO2 to nitroprusside

    y The reaction produced MetHb andunstable nitroprusside compound

    y unstable nitroprusside compoundproduced 5 cyanide molecules

    y cyanide then react with methaemoglobinto produced cyanmethaemoglobin

    y The other 4 cyanide molecules is thenundergo non-enzymatic reaction

    these CN-ions have 4 fates,SMHC

    1. Conversion to thiocyanide

    y 60-70% are enzymatically converted tothiocyanate

    y Reaction catalyzed by rhodanese in the liverand kidneys

    y requires thiosulphate and B12 as cofactorsy rate limiting factor is the availability of

    endogenous thiosulphate

    2. combination with MetHb to formcyanmethaemoglobin

    3. combination with hydroxocobalamin to form

    GTN

    Drug action

    y GTN---smooth muscle cell smooth musclecell release NO

    y NO activate gunaylate cyclasey Guanylate cyclase increase cGMPy cAMP cause relaxation of smooth muscle

    absorption

    y administered as a continuous IV infusionby a calibrated pump,y with continuous IABP monitoringy due to the rapid onset of action

    metabolism

    y Organic nitrates undergo reductivehydrolysis in the liver

    y reaction catalyzed by glutathione-organicnitrate reductase

    y biotransformation converts the lipidsoluble organic esters into more watersoluble denitrated metabolites andinorganic nitrite

    metabolites

    y dinitrated metabolites have ~ 1/10th thepotency as vasodilators

    y elimination tb ~ 40 mins

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    cyanocobalamin

    4. combination with tissue cytochrome oxidaseresult in toxicity

    factor cause tachyplaxis

    y toxicity with cyanidefactor causes tachyplaxis

    y biotransformation is the principaldeterminant of the duration of actionmetabolites

    Chemical compound

    y ferrous iron center complex with fivecyanide moieties and a nitrosyl group(44% cyanide by weight)

    Stability

    y SNP is broken down to cyanide ions onexposure to light

    y Solution change to dark blue from orangebrown> discardy Wrapped in aluminum foilPreparation

    y 0.01% solution in 5% dextrose or NSy Freed dried crystalsy 50 mg/ampoule

    Chemical compound

    y polyol esters characterized by a C-O-Nsequence,

    y these agents act via nitric oxidenitrovasodilators

    Stability

    y Must be protected from ultraviolet lighty in the pure form, without an inert carrier such

    as lactose, NG is explosive

    Additive

    y Contain thio compound, therefore doesn'tgenerate NO spontaneously like SNP

    Chemical interaction

    y Absorbed by plasticy Must use in glass containery the solution is not compatible with PVC tubing

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    CVSBP

    y decreased in BP with increase in heart rate

    Heart rate

    y Increased heart ratey secondary to activation of

    symphathotoadrenal

    y increased myocardial contractility and reninrelease

    Mechanism for BP reduction

    y NO > dilates both resistance and capacitancevessels

    y > decrease SVR > decrease Venous return>decrease BP

    CO

    y the induced hypotension activates thesympathoadrenal system,

    y resultant tachycardia, increased myocardialcontractility and renin release

    y the usual response is an increase in CO

    CVSBP

    y decrease in blood pressure with unchangedheart rate

    y systolic BP decrease more than diastolicHeart rate

    y Unchanged heart rate

    Mechanism of BP reduction

    y predominant effect of low doses --------venodilation

    y NG and the organic nitrates relax venoussmooth muscle in low doses

    y SVR usually remains unchanged

    CO

    y LV pressure , end diastolic pressure ,myocardial oxygen demand ; all reduced

    y CO; decrease minimallyy doesn't causes rebound hypertension

    y rebound hypertension

    Cerebral blood flow

    y SNP increases CBF and cerebral volumey how-----by a direct effect on cerebral vessels

    Bronchomotor tone

    y no rebound hypertension like sodiumnitroprusside

    Cerebral blood flow

    y cerebral vasodilation may lead to an increasein ICP in patients with reduced cerebralcompliance

    Bronchomotor toney relaxation on smooth muscle including

    bronchi,

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    Clinical

    y Rapid onsety Short duration of action

    Clinically

    y Tachyplaxis to hypotensive effecty Low thiosulphate levely Increased SNS reflex activityMechanism

    y The release CN-directly antagonises thevasodilatation of SNP

    y exaggerated SNS reflexes are the mostcommon cause of tachyplaxks

    Clinical

    Clinical

    y tachyplaxis to hypotensive effectMechanism

    Outline

    y Pharmacokineticy Pharmacodynamicy causes of tolerancey Tolerance to SNP due cyanide poisoningy tolerance to GTN due to formation of inactive denitrated compound

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    Q. Compare the hemodynamic effect of adrenaline , noradrenaline , isoproterol, dopamine.

    adrenaline noradrenaline isoprenaline

    BP

    y rise in systolic pressurebeing greater thandiastolic pressure

    y therefore, increase thepulse pressure

    Heart ratey HR, initially raised,y however it may be

    slowed markedly atthe height of thepressure rise due toreflex vagal activity;

    Cardiac output

    y Cardiac output ,y Stroke volume ,y HR ,y left ventricular worky right artrial pressurey all increases

    Regional blood flow

    overviewy has significant effects

    on smaller arteriolarand precapilliarysmooth muscle.

    y the effect is mediatedvia alpha 1 ( ATSK)and beta 2 ( BNS) ,and beta 1 ( renal

    BP

    y elevation of systolicand diastolic pressure

    y smaller elevation ofpulse pressure

    Heart ratey decrease heart ratey may be due to reflex

    bradycardia

    Regional blood flow?

    y skeletal muscley splancnicy skiny coronaryy cerebral

    Special note

    y Wood & Wood states

    BP

    y systolic BP is usuallymaintained,

    y diastolic BPconsequently falls----------special

    y mean BP fallsy larger doses may

    cause a dramatic fallin mean arterialpressure

    Heart rate

    y increase in heart rate

    Cardiac output

    y increases cardiacoutput

    y Stroke volumeincrease

    y SVR -decreases in SVRy VR- venodilation -

    increased venouscapacitance

    Regional blood flow

    Renal blood flow

    y RBF is decreased innormotensive subjects,y RBF markedly

    increased insepticaemic orcardiogenic shock

    Coronary blood flow?

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    juxta)

    Vasodilation TO ALLRESERVOIR

    y skeletal muscley

    splanchnic vascularbeds.

    y liver;y skin--------- alpha1

    receptors

    y kidney------- alpha1receptors

    y specialy Renin release increases

    due to epinephrineeffects mediated by

    1-receptors associated

    with juxtaglomerularcells

    Vasoconstriction

    y constriction otherabdominal viscera

    Cerebral circulation andcoronary ?

    Inotropyy Direct Responses to

    adrenaline

    y increased contractilityy increased rate of

    isometric tensiondevelopment

    y increased rate ofrelaxation

    eletrophysiology

    y increased slope ofphase-4depolarization

    y increasedautomaticity(predisposes to ectopicfoci)

    that cerebral bloodflow is reduced

    y G&G states that the aconstrictor effect onthe cerebralcirculation is minimal

    y and the associatedincrease in BPincreases CBF, theincrease being limitedby autoregulation

    ComparisonDifferences

    y small doses of NA donot cause vasodilation

    or lower the BPcompared to that ofadrenaline

    y This due to the lack ofb2-agonist activity

    electrophysiology

    y sinus bradycardia,y due to reflex vagal

    action,

    y with or withoutprolongation of thePR interval

    y Other rhythm:y nodal rhythm,y AV dissociation,y bigeminy,y VT & VF may be seen

    Drug interaction

    y serius hypertensionwith MAOI

    skeletal muscle blood flow?skin blood flow ?

    Pulmonary pressure

    ypulmonary pressure isunchanged

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    Q. Describe briefly the pharmacology of adenosine

    Overview

    y Purine nucleoside compound that used as an anti-arrythmic drug that causestransient heart block on AV node

    Clinical uses

    To treat paroxysmal SVT;

    y rapid onsety high efficacy,

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    y short duration of actionTo treat WPW

    To diagnose between wide complex tachycardia or SVT

    y Not effective for; AF, flutter, or VTy To produce stable level of hypotension that promptly reversed with dis-continoution

    of infusion

    Contraindication

    y known hypersensitivity to adenosiney second or third degree AV block (except in patients with a functioning artificial

    pacemaker).

    y sick sinus syndrome (except in patients with a functioning artificial pacemaker)y bronchial asthma

    Structure activity relationship

    Chemical compound

    y Purine nucleotidey Comprises of purine base that linked to pentose sugar ribosey important autocoid and endogenous vasodilator in man

    Synthesis

    y end product of ATP metabolismy Synthesis by product of breakdown of either adenosinetriphosphate (ATP) or s-

    adenylhomocysteine

    physicochemical properties

    y Adenosine is a white crystalline powdery slightly soluble in watery molecular weight of 267.2y Adenocor is a sterile solution for intravenous injection (rapid bolus),y provided in clear glass vials.y Each vial contains 6 mg of adenosine in 2 mL of a 0.9% w/v solution of sodium

    chloride in sterile water for injection.

    mechanism of action

    y rapid intravenous injections depresses conduction through the AV node.y it increases effective refractory period and depressed conduction velocity >

    depressed SA and AV node activity > terminate SVT

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    y interrupt re-entry circuits involving the AV node and restore normal sinus rhythmy Once the circuit has been interrupted, ---------the tachycardia stops and

    normal sinus rhythm is re-established.

    Adenosine receptor

    y adenosine receptor is purine receptory adenosine receptor , two subtype A 1 and A2y A1 receptor is subtype of P1 receptor that inhibit adenylate cyclase P1 receptory The other subtype of P1 receptor is A2 recepto that activate adenylate cyclasey adenosine receptor is G-protein coupled receptorsy adenosine -A1 receptor interaction result inhibition of Ca2+ conductance.

    drug action on A1 receptor

    y binding of adenosine to A1 receptor----activate G inhibitory proteiny Gi-protein---coupled with adenylate cyclase----lead ---inhibition of adenylate

    cyclase

    y inhibition of adenyl cyclase----reduce cAMP-------increase the outflux ofK+------hyperpolarisation of cell membrane at AV node ---- transient heart

    block in the AV node

    drug action on A2 adenosine receptor

    y Adenosine also activate adenosine A2 receptors > arterial and coronary vasodilationy Adenosine also> prolonged AV refractoriness and conductiony Adenosine also> antiadrenergic and negative inotropic effect> decrease myocardial

    oxygen consumption

    y it increases effective refractory period and depressed conduction velocity >depressed SA and AV node activity > terminate SVT

    Drug interaction

    y the adenosine uptake inhibitor, dipyridamole, potentiates the hypotensive effect

    pharamacokinetic

    dose and administration

    y 3-12 mgy Initial Dose - 3 mg given as a rapid intravenous bolus (over 2 seconds).y

    Second Dose - If the first dose does not result in the elimination of thesupraventricular tachycardia within 1 or 2 minutes, 6 mg should be given also as a

    rapid intravenous bolus.

    y Third Dose - If the second dose does not result in the elimination of thesupraventricular tachycardia within 1 or 2 minutes, 12 mg should be given also as a

    rapid intravenous bolus.

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    onset of action

    y rapid onset, stable and readily reversibleduration of action

    y very short action

    Pharamacokinetic

    y Intravenously administered Adenocor (adenosine) is removed from the circulation veryrapidly.

    y Following an intravenous bolus, adenosine is taken up by erythrocytes and vascularendothelial cells.

    y half-life ----estimated to be less than 10 seconds.y Adenosine enters the body pooly primarily metabolised to inosine and adenosine monophosphate (AMP).

    pharamacodynamic

    CVS

    y depresses conduction through the AV node.y interrupt re-entry circuits involving the AV node and restore normal sinus rhythm in

    patients with paroxysmal supraventricular tachycardias and paroxysmal

    supraventricular tachycardias associated with Wolff-Parkinson-White Syndrome.

    y Once the circuit has been interrupted, the tachycardia stops and normal sinus rhythmis re-established

    y after rapid IV , drug causes---increases in systolic and distolic BPy folwed by decrease in BP, and secondary tachycardiay can be use in controlled hypotensiony intravenous bolus dose of 3 or 6 mg Adenocory usually has no systemic haemodynamic effects.y Rarely significant hypotension and tachycardia have been observed

    Overview

    y ypotensive effect mediated via decrease SVROther cardiac parameter

    venous toney decreased SVR,

    CO

    y Reflex increased in COHR

    y Unaffected HR,

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    preload

    y Unaffected ventricular filling pressures andMRO2

    y Unaffected whole body MRO2inotropy

    y direct negative inotropic effectPVR

    y Decrease pulmonary vascular resistance but not to the same extent as SVRelectrophysiology

    y Decreases action potential duration,y SA node---reduces automaticityy AV node ----Increases A-V nodal refractoriness

    Renin angiotensin system

    y lack of Cathecholamines releasey activate renin-angiotensin systemy Result in; the stability of the hypotension, without tachyphylaxis or rebound

    ANS

    y also inhibits the release of NA from SNS nerve terminalsRegional blood flow

    cerebral circulationy adenosine regulate the regional regulation of blood flow by ,y a. dilatation of cerebral and coronary vessels and causing dose dependent

    increased in blood flow

    y b. slowing the discharge rate of CNS neurones and cardiac pacemaker cellsrenal circulation

    y c. causing arteriolar constriction with noradrenaline and angiotensin II thatdecrease GFR and tubular MRO2

    coronary circulation

    y Increase coronary blood flowy however this may result in unfavorable redistribution and steal in subjects with

    IHD >

    Side effect

    CVS

    y myocardial ischaemia may occur during adenosine hypotension in humansy If given to VT> cardiac arrest

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    y Profound bradycardia ; may need pacingCNS

    y Syncopey Facial flushing

    Respiratory

    y Bronchospasm; secondary to A1 action on bronchial smooth muscleRenal system

    y decreased GFR in the kidneyMetabolic

    y Inhibit lipolysisy Stimulate glycolysis

    Hematology

    y Inhibit platelet aggregationy Mass cell degranulation

    GIT

    y Mediate chloride secretion by ephithelial cellDrug interaction

    y the adenosine uptake inhibitor, dipyridamole, potentiates the hypotensive effecty Antagonist Bh methylxanthines (caffeine and theophyline

    Adverse effect

    Cardiovascular

    y Facial flush (18%),y headache (2%),y sweating,y palpitations,y chest pain,y hypotension (less than 1%).

    Respiratory

    y Dyspnoea (12%),

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    y chest pressure (7%),y hyperventilation,y head pressure (less than 1%).

    Central Nervous System

    y Lightheadedness (2%),y dizziness,y tingling in arms,y numbness (1%),y apprehension,y

    blurred vision,

    y burning sensation,y heaviness in arms,y neck and back pain (less than 1%).

    Gastrointestinal

    y Nausea (3%), metallic taste, tightness in throat, pressure in groin (less than 1%)

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    Q. List the potential uses of alpha2 adrenoreceptor agonist and outline the limitation of clonidine

    Clonidine

    Overview

    y centrally acting alpha 2 receptor agonist that act as antihypertensiveDrug action

    y act on alpha 2 receptor at medulla imidazoline receptor

    specific site

    y activation of postsynaptic alpha 2 receptor in substantia glutinosa of spinal cordy alpha 2 receptor occur in highest density in locus ceroleus: source of symphathetic nervous system

    innervation

    Physiological action

    y decrease symphathetic outflowy decerase heart rate ---decerase CO , decerase BPy vasodilation ----dcerase SVR, decerase BPy alpha 2a : sedation analgesia , and symphatholysis

    Preanesthetic medication

    overview

    y preanesthetic oral dose : 5 ug/kgInduction agent

    y decreased doses of IV induction agentsIntubation

    y blunt tachycardia a/w laryngoscopyy reduction in intraocular pressure /

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    y blunted response to intubationmaintenance

    y improved haemodynamic stabilityy lower plasma catecholamine levelsy

    decreased dose requirements for induced hypotension ~ 33%

    y reduction in intraoperative ischaemic episodes:y decreases the myocardial ischemia, dose: 0.2 mg orally or transdermally evening before surgeryy decreased blood loss

    inhalational

    y decreased MAC of volatile agentsy decreases the myocardial ischemia, dose: 0.2 mg orally or transdermally evening before surgeryy , continue post-op after 4 days , reduce post-operative moratality up to 2 years

    Reversal

    y decreased times to extubationy decreased CVS effects of opioid/cocaine withdrawal syndromes perioperativelyy antisialogogue

    Post-operative

    y continue post-op after 4 days , reduce post-operative moratality up to 2 yearsDose

    y usual oral dose ~ 0.2 to 0.8 mg/d,y administered in two or more divided dosesy administration of unequal doses, with the larger dosing at bedtimey eliminates some of the unwanted effects of the drug

    Decreased postoperative and epidural associated shivering :

    y 75 ug IV inhibit central thermoregulatory controly inhibit thermoregulatory vasoconstrictiony core hypothermiay inhibit shivering :y clonidine decrease vasoconstriction and shivering threshold

    Diagnosis of phemochromocytoma:

    y 0.3 mg orally will decrease plasma cathecholamine concentration in normal patienty but not pheochromocytoma patient

    Treatement of opiod and alcohol withdrawal :y clonidinde 10 ug/kg decreases the symphathetic response a/w cardiac stimulationy attenuate the incrases in cathecholamine concentration when nalaoxone given to opiod addicted ptn

    under GA

    adverse effect

    CVS

    y problems of prolonged hypotension after clonidiney Transient hypertension with intravenous IV bolus dosing due to reflex tachycardia ---baroceptor reflex

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    SVRy Pallor,

    Excessive NA

    y miosis,y dryness of the mouth,y sedation,y somnolence,y hypotension,y orthostatic symptoms,y bradycardia,y possibly AV block,y rare increase in blood pressure after high doses;y in severe cases, respiratory depression with short phases of apnoea; rarely vomiting.

    DEXMETOMIDINE

    y selective full agonist with a2:a1 ~ 1600:1streoisomers

    y dextro isomer of medemetomidine compound which is use as hypnotic sedative in animal

    drug target

    y alpha 2 , more than alpha 1drug action

    y 7- 10 x more selective than clonidine for alpha 2y full agonist at alpha2 receptor

    Sedationy use as sedation in mechanically ventilated patienty dexmetamidine do not cause significant ventilation depression compared to ramifentanily post-operative extubation result : calm and relaxed

    Duration of action

    y shorter than clonidine

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    Dose

    y loading dose 1 mcg/kg IV,y then 5- 10 mcg/kg/hr > total IV anesthesia without depression of ventilation

    Q. What are the side-effects of amiodarone and what problems may develop during

    concurrent anaesthesia?

    CVS effectEffect on cardiac electrophysiology

    SA node:---------- automaticity in the SA node by reducing the slow phase 4

    depolarisation ----phase 3 or phase 4 ?

    ARP----------- increase in the ARP of atrial fibres ------responsible for

    its effectiveness in SVT's

    AV node :--------- increase the conduction velocity and the effective

    refractory period of AV node

    H-P and myocardial fibres ----------increases ERP,

    atrial, nodal and ventricular tissues ---------- prolongs the APD, and hence

    the ERP

    Side effectPulmonary:

    Most serious adverse---------progressive pulmonary fibrosis

    Frequency------------ 5%-15% treated patients

    Mortality rate----------------: 5% to 10%

    Cause---------: unknown ----------possibly related to amiodarone-

    mediated generation of free oxygen radicals in the lung)

    More common:-------- Slow, insidious, progressive dyspnea, cough, weight loss,

    pulmonary infiltration (chest x-ray)

    Acute onset:----------- dyspnea, cough, arterial hypoxemia.

    Anesthetic Implications: pulmonary

    Suggested restriction of inspired oxygen concentration in patients receiving

    amiodarone and undergoing general anesthesia close level possible while retaining

    adequate systemic oxygenation

    Postoperative pulmonary edema-------- has been reported in patients treated

    with amiodarone chronically

    resembles acute onset form of amiodarone toxicity.

    In patients with preexisting amiodarone-cause pulmonary damage ----------are

    at increased risk for adult respiratory distress syndrome following surgery

    Cardiovascular Effects:

    Prolongation of QT interval (ECG); ------------increased incidence of

    ventricular tachyarrhythmias (including torsades de pointes)Bradycardia -------------------(atropine-resistant)

    Catecholamine responsiveness:-------------- diminished due to alpha and

    beta-receptor blocking activity

    Hypotension;-------------- A-V block (following IV administration)

    Anesthetic Implications: cardiovascular..

    With general anesthesia -- enhanced antiadrenergic action, presentation as:

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    A-V block, sinus arrest, decrease cardiac output, hypotension

    Sinus arrest more likely in the presence of anesthetics that inhibit SA nodal

    automaticity (e.g. lidocaine, halothane)

    Ocular and other Side Effects:

    Corneal microdeposits-- common;usually no visual impairment

    Photosensitivity, rash: 10% frequencyRare: cyanotic discoloration (slate-gray facial pigmentation)

    Neurological:

    peripheral neuropathy;

    sleep disturbance,

    headache,

    tremor,

    y some skeletal muscle weaknessendocrine effect

    ythyroid dysfucntion

    Drug Interactions

    y digoxin ----------- potential severe bradycardiay b-blockers --------------- potential severe bradycardiay Ca-antagonists -------------- potential severe bradycardiay disopyramide ---------------- long QT syndromey procainamide -------------------- serum levels are significantly

    increased

    y quinidine ----------- long QT syndrome & atypical VTy mexiletine --------------- long QT syndromey

    warfarin ----------------- inhibits metabolism

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    Q. Classify anti arrhytmics

    Mechanism of action

    Sodium channel blocker Drug target

    y voltage gated sodium channelSodium channel

    y sodium channel ----integral membrane proteinsfunction

    y conduct sodium ions (Na+) through a cells plasma membraneanatomy

    y complex of two types of protein subunits, a and .y An a subunit forms the core of the channely alpha subunit---responsible for selectivity and gatingy beta subunit----responsible to stabilze the alpha subunit

    Cellular action

    y Voltage-gated sodium channels ---- three types of states:y deactivated (closed),y activated (open)y inactivated (closed).y Channels in the deactivated state -----due to the presence of

    activation gate,

    y activation gate----can be remove---thus allow the opening ofsodium channel by stimulation

    y The opening of sodium channel---- sodium current ---enter---thecell----rapid and intense

    y Na+ ions will move into the cell down their electrochemical gradient, ----further depolarizing the cell.

    y the more Na+ channels localized in a region of a cells membrane, thefaster the action potential will propagate, and the more excitablethat area of the cell will be

    Physiological action

    y generation of action potentialy responsible for phase 0 ( rapid depolarisation ) of myocardiac cell

    action potential-------------ventricular muscle action potentialhyperlink

    y SA node and AV node have few sodium channel -----lack of rapid

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    depolarisation-------------ventricular muscle action potentialhyperlink

    TORCAINIDE

    class 1b antiarrythmic drug thathas lowest potency to bind toinactivated phase of sodiumchannel

    Sodium channel blockade

    y block the sodium channel especially the inactivated and activatedchannel

    MEXILTINE

    class 1b antiarrythmic drug thathas lowest potency to bind toinactivated phase of sodiumchannel

    similar as above

    FLECAINIDE

    class 1c antiarrythmic drug thatis the most potent Na channelblocker

    Sodium channel blockade

    y block the sodium channel potent blockerother

    y K channel potent blockery Ca channel - not mentionedy adrenergic receptor - not mentioned

    note

    y Prolongation of PR interval (ECG)y Prolongation ofQRS complex (> 25%)y Sinoatrial nodal depression

    ECAINIDE

    class 1c antiarrythmic drug thatis the most potent Na channelblocker

    summary of class 1affectconduction velocityautomaticityPR interval

    BETA BLOCKERSCLASS 11

    Drug target beta adrenergic receptor

    Beta adrenergic receptor adrenergic receptors (or adrenoceptors) are a class of G protein-

    coupled receptor that are targets of the catecholamines

    receptors are linked to Gs proteins

    Gs protein are linked to adenylyl cyclase

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    Ligand-receptor activation

    When a ligand binds to the receptors site on the outside of the cellmembrane ,

    G-protein that comprises of 3 subunit will change conformation

    T

    he GT

    P will replace the GDP on the alpha subunits of G-protein The activated alpha subunit then separate from beta and gamma

    subunits

    The alpha subunit with GTP attached then activate adeylate cyclase

    activated adenylate cyclase-----increased production of cAMP

    cAMP will bind to protein kinase to produce cAMP-dependentprotein kinase

    cAMP dependen protein kinase result in::::

    Physiological action

    Beta direct effect on smooth muscle : phosphorylation of substrate ie phosphorylation of light chain myosin

    kinase to inactive form

    effect relaxation of smooth muscle ---vasodilation

    Beta direct effect on heart :

    y increase cAMP ---> increase Ca influx across cell membrane ---sequestration of Ca inside membrane ---

    y ca---- bind to actin myosin complex --- greater force of contraction ----increase contractility

    Beta adreneoreceptor effect on ionic conductance

    sympathetic drive results in increased in Ca2+ ,K+ ,and Cl- currents.

    affect SA node activity Increased sympathetic tone result --

    Effect of adreneoreceptor stimulation to slow action potential increases phase 4 depolarization ---------(heart rate goes up),

    increases DAD (delayed afterdepolarizations) mediated arrhythmias EAD (early afterdepolarization) mediated arrhythmias.

    Drug action

    block symphathetic mediation----of adrenoreceptor

    decrease heart rate

    decrease DAD (delayed afterdepolarizations) mediated arrhythmias

    decrease EAD (early afterdepolarization) mediated arrhythmias

    PROPRANOLOL

    class 11 antiarrythmic drug thatblock beta adrenergic receptors

    Drug effect

    Adrenergic receptor- non-selectively bind to beta 1 and beta 2adrenergic receptor

    affect phase 4 of slow action potential

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    that affect phase 4electrophysiology effect

    decrease ionic conductance of Na, Ca, ---- decrease slope of phase 4

    prolonged AV conduction time prolonged AV nodal refractoriness,

    to terminate nodal reentrant arrhythmias

    ATENOLOL

    class 11 antiarrythmic drug thatblock beta adrenergic receptorsthat affect phase 4

    similar as above

    ESMOLOL

    class 11 antiarrythmic drug thatblock beta adrenergic receptorsthat affect phase 4

    similar as above

    POTASSIUM CHANNELBLOCKERS

    AMIODARONE

    class 111 antiarrythmic drug an

    analogue of thyroid hormonethat block potassium channelhas properties of class 1, 11, 111, 1V

    Drug target

    y Potassium channel ---primarilyy also---------sodium channelPotassium channel

    ion channel that form potassium-selective pores

    channel span cell membranes

    several type :

    1. voltage gated potasssium channel ,

    2. delayed rectifier current ,

    3. Calcium-activated potassium channel ,

    4. tandem pore domain potasssium channelDelayed rectifier K channel

    when ?

    activated during phase 3 of action potential ----repolarization phase

    what?

    when potassium channel open ---there is outflux of potassium down

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    its concentration gradient

    In equilibrium, the influx and outflux of potassium ions is in balance

    influx of potassium ---------that is due to the electrical gradient

    is in balance

    with outflux of potassium ----------due to concentration gradient

    Phase 3

    Repolarization phase.

    when does it first open?

    The delayed rectifier K+ current starts to activate upondepolarization.

    function of channel

    As the delayed rectifier K+ current increases,

    the net balance is tipped in favor of the outward current, andrepolarization begins.

    all the K+-channels open,

    large amounts of K+

    diffuse out of the ventricular fibre. The equilibrium potential for K

    +(-94 mV) and the RMP is rapidly

    approached.

    IK1 increases during repolarization during the last third of therepolarization phase and thus helps to restore the Vm to theresting potential faster.

    so basicly---want to get rest again ler

    Drug effectaffect to K channel ----primarily

    block K channel

    prevent the outflux of potasium reduce outward movement of K+ ---

    decrease outward current

    slow repolarisation

    decerase slope of phase 3 in fast AP

    slow AP--- prolonged ERP

    affect Na channel

    block the sodium channel

    especially the inactivated channel

    affect Ca channel

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    block Ca channel---weakly

    affect adrenoreceptor block adrenergic receptor---non-competitive binding of alpha and

    beta receptors

    altered physiological effect

    Prolongs effective refractory period in:slow AP

    SA node --slow AV node

    fast AP ventricle atrium His-Purkinje system accessory bypass tracts (Wolff-Parkinson-White syndrome)

    antiadrenergic effect also has antiadrenergic effect via non-competitive blockade of alpha

    and beta receptors has minor inotropic effect : that may be offset by drug vasodilating

    effect

    BRETYLIUM

    class 111 antiarrythmic drug thatblock potassium channel

    similar as above

    SOTALOL

    class 111 antiarrythmic drug thatblock potassium channel

    similar as above

    CLASS IVCALCIUM CHANNELBLOCKERS

    Drug target alpha subunit ofL-type calcium channel

    calcium channel

    L-type calcium channels is voltage dependent calcium channel

    Location

    vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes).

    Physiological function Regulate the influx of calcium into muscle cells, ------ stimulates smooth muscle contraction cardiac myocyte contraction.

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    Start of phase 4 of slow AP

    At the end of repolarization, when the membrane potential is very negative (about -60 mV), ion channels open that conduct slow, inward (depolarizing) Na

    +

    currents. ---- funny currents funny currents --------- depolarizing currents cause the membrane

    potential to begin to spontaneously depolarize, thereby------------- initiating Phase 4.

    end of phase 4 when the membrane potential reaches about -50 mV, another type

    of channel opens.

    opening ofT-type calcium channel called transient or-------------- T-type Ca

    ++channel.

    effect Ca

    ++enters the cell through these channels down its electrochemical

    gradient, These influx of Ca++ currents -------further depolarize the cell. membrane continues to depolarize to about -40 mV,

    opening ofL- type channel Once the depolarization reach -40 msec , a second Ca

    ++channel

    opens. : long-lasting, or L-type Ca++

    channels. Opening of these channels causes more Ca

    ++to enter the cell

    further depolarization of cell occur until an action potential thresholdis reached (usually between -40 and -30 mV).

    Phase 0 depolarization of slow AP

    causes caused by increased Ca++ conductance (gCa++) through theL-type

    Ca++

    channels

    effect to other channel that previoluly open The funny currents, and Ca

    ++currents through the T-type Ca

    ++

    channels, -----decline during this phase as their respective channelsclose.

    the movement of Ca++

    through these channels into the cell is notrapid,

    the rate of depolarization (slope of Phase 0) is much slower thanfound in other cardiac cells (e.g., Purkinje cells).

    VERAPAMIL

    class 1V antiarrythmic drug thatblock calcium channel

    Drug effect Block Ca channel---- decrease influx of Ca slow depolarization slow to achive phase 0 effect----decrease slope of phase 4 affect prepotential---or automaticity

    Physiological effect

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    decrease conduction via AV node

    block Ca channel----inhibit Ca influx into arterial smooth muscle----arteriolar dilatation ----lowering of BP

    other Na channel, K channel, adrenergic receptor no effect

    DILTIAZEM

    class 1V antiarrythmic drug thatblock calcium channel

    similar as above

    CLASS V

    DIGOXIN/DIGITALIS

    Inotropic and antarrythmicagent that inhibit action of Na-K ATPase by binding to thealpha subunit of Na

    +-K

    +-

    ATPase causing inhibition ofsodium and potassiumtransmembrane transport

    Drug target Na-K ATPase

    Na-K ATPase Na+/K+-ATPase Na

    +/K

    +pump

    Location enzyme --------- located in the plasma membrane -------that

    maintain cell membrane potential consist of ----------alpha and beta subunits

    Binding site: 3 binding site 1. Na, 2 : K+, 3. digoxin that located at alpha

    Cellular action

    pump,------------ bound ATP,

    then---------------binds 3 intracellular Na+ions.

    ATP ------------- hydrolyzed,

    leading to ----------phosphorylation of the pump

    release of ADP.

    effect--------conformational change in the pump

    effect of

    conformational changes---- exposes the Na

    +

    ions to the outside. phosphorylated form of the pump ------- a low affinity for Na

    +ions,

    so they ------------3 Na are released.

    Then--------- pump binds---------- 2 extracellular K+ ions.

    causes ----------- dephosphorylation of the pump,

    depohosphorylation -----------reverting it to its previousconformational state,

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    Therefore, transport the K+ ions------------ into the cell.

    The unphosphorylated form of the pump has a higher affinity for Na+

    ions than K+

    ions,

    Therefore, the two bound K+

    ions are released.

    ATP binds, and the process starts again

    http://en.wikipedia.org/wiki/Image:NaKpompe-cycle.jpg" \o "NaKpompe-cycle.jpg

    Physiological function Na-K ATPase To maintain the cell potential, ---by mainataining appropriate ions

    distribution

    why are you mentioning about Na-K ATPase rather than ions that involve ininotropy---Ca

    Na---transport ---coupled with Ca transport when sodium ---transported out---Ca is co-transport maintain low intracellular Na , Ca concentration

    Dose dependent effect low concentration ---stimulate the enzyme high concentration-----inhibit enzyme

    Direct effect selectively and reversibly inhibit Na-K ATPAse transport system agent bind to alpha subunit on exctracellular of ATPase enzyme > conformational change > interfere with outward movement of sodium ion across cardiac cell

    membrane therefore : ---------gradual increase in sodium concentration

    intracellularly with small decrease in K final effect --------> decrease extrusion of calcium from intracellular

    that normally co-transport with Na > finally : increased in intracellular calcium

    Effect on inotropy >increased intracellular calcium > stimulate release of ca from sarcoplasmic reticulum ---- > incrased calcium for binding to actin-tropomyosin complex---- >increased cyling of actin myosin---- >incrased force of contraction ----- > increased inotropic effect

    ADENOSINE

    Purine nucleoside compoundthat used as an anti-arrythmicdrug that causes transientheart block on AV node

    Drug target A1 receptor or P1 receptor

    A1 receptor A1 receptor is type of P1 receptor that inhibit adenylate cyclase P1

    receptor The other subtype of P1 receptor is A2 receptor that activate

    adenylate cyclase adenosine receptor is G-protein coupled receptors

    A1 receptors couple to Go,

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    A1 receptor mediate adenosine inhibition of Ca2+ conductance

    Ligand : adenosine endogenous purine nucleoside mediate several physiological process

    CNS : inhibitory neurotransmitter, role in promoting sleep and suppressing arousal,

    Biochemical action , energy transfer - as adenosine triphosphate (ATP) and adenosine

    diphosphate (ADP) as well as in signal transduction as cyclic adenosin monophosphate,

    cAMP.

    CVS

    y endothelial dependent relaxation of smooth muscle as is found insidethe artery walls.

    y This causes dilatation of the normal segments of arteries where theendothelium is not separated from the tunica media byatherosclerotic plaque

    Immunology cytoprotection preventing tissue damage during hypoxia,

    ischemia, and seizure activity.

    drug action on A1 receptor binding of adenosine to A1 receptor----activate G inhibitory protein Gi-protein---coupled with adenylate cyclase----lead ---inhibition of

    adenylate cyclase inhibition of adenyl cyclase----reduce cAMP------- reduce cAMP----increase the outflux of K+ hyperpolarisation of cell membrane at AV node

    transient heart block in the AV node Adenosine also> prolonged AV refractoriness and conduction Adenosine also> antiadrenergic and negative inotropic effect>

    decrease myocardial oxygen consumption Adenosine also> depressed SA and AV node activity > terminate SVT

    drug action on A2 adenosine receptor Adenosine also activate adenosine A2 receptors > arterial and coronary vasodilation Adenosine also> prolonged AV refractoriness and conduction Adenosine also> antiadrenergic and negative inotropic effect>

    decrease myocardial oxygen consumption Adenosine also> depressed SA and AV node activity > terminate SVT

    Drug interaction

    y the adenosine uptake inhibitor, dipyridamole, potentiates thehypotensive effect

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    Q. What drugs are used in cardiac arrest?

    adrenaline

    yEpinephrinehydrochloride ----------

    Mechanismofaction

    y its -adrenergicreceptor-stimulating (ie, vasoconstrictor)properties.

    Pharmacodynamic

    y Increased SVRy Increasecoronaryandcerebralperfusionpressureduring CPR

    Dose

    y administera 1-mgdoseofepinephrineIV/IOevery 3 to 5 minutesduringadultcardiacarrest (ClassIIb).atropine

    Overview

    y Anticholinergicdrugs

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    Mechanismofaction

    y Atropinesulfate ------------------reversescholinergic-mediatedeffect

    Pharmacodynamic

    ydecreasesin

    heartrate,systemic vascularresistance,andbloodpressure

    Dose

    y recommendeddose -------------- forcardiacarrestis 1 mgIV,y canberepeatedevery 3 to 5 minutes(maximumtotalof3 dosesor3 mg)ifasystolepersists (Class

    Indeterminate).

    vasopressin

    y Vasopressin -------------- nonadrenergicperipheral vasoconstrictorthat

    alsocausescoronaryandrenalvasoconstriction.

    antiarrythmic:

    amiodarone

    y IV amiodarone --------------affectssodium,potassium,andcalciumchannelsaswellas - and -adrenergicblockingproperties.

    y treatmentofVF orpulseless VT -----------unresponsivetoshockdelivery, CPR,anda vasopressor.y initialdoseof300 mgIV/IOcanbefollowedbyonedoseof150 mgIV/IO

    Lignocaine

    y Lidocaine ------------- alternativetreatmenttoamiodaroney Theinitialdoseis 1 to 1.5 mg/kgIV.y IfVF/pulseless VT persists, --------additionaldosesof0.5 to 0.75 mg/kgIVpushmaybeadministeredat 5-to

    10-minuteintervals,

    y toamaximumdoseof3 mg/kg.Magnesium

    y When VF/pulseless VT cardiacarrest ------------associatedwithtorsadesdepointes,magnesiumsulfateatadoseof1 to 2 gdilutedin 10 mL D5WIV/IOpush,

    y typicallyover5 to 20 minutesy Whentorsadeswithpulses,------------- thesame 1 to 2 gismixedin 50 to 100 mL ofD5Wandgivenasa

    loadingdose.

    y canbegivenmoreslowly (eg,over5 to 60 minutesIV)undertheseconditions

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    Q. Outline the pharmacological effect of vasopressin.

    Overview

    Vasopressin is a peptideMentioned the relationship between peptide nature and administrationPeptide --low oral bioavailibility due to action of intestinal proteasesReceptors subtype in which va opressin actSpecific evrnt from vasopressin -receptors interactionSub-cellular events and mediatorsIndication of vasopressin and DDAVPClinical usesSynergistic activity with cathecholaminesDDAVP is prrferable for treatment in diabetes insipidus compared to vasopressin because vasopressin hasvasoconstriction