saq pharmacology cvs
TRANSCRIPT
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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