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Adrenergic antagonists alpha and beta blockers

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  • a vascular tumor of the adrenal gland; hypersecretion of epinephrine results in intermittent or sustained hypertension.
  • Loss of conciousness due to low blood pressure.
  • Transcript

    • 1. MCMP 407Topic Name:- Adrenerginc Antagonists Zulcaif Ahmad +92 3444737311 1
    • 2. MCMP 407 Clasification1) Adrenergic receptor antagonists A) α-receptor blockers B) β-receptor blockers 2) Adrenergic neuron blockers 1) Drugs affecting NA synthesis 2) Drugs affecting NA release
    • 3. MCMP 407 3
    • 4. MCMP 407 4
    • 5. MCMP 407 5
    • 6. MCMP 407 6
    • 7. MCMP 407 7
    • 8. MCMP 407 Autonomic DrugsDrugs that produce their primary therapeutic effect bymimicking or altering the functions of the autonomicnervous system are called autonomic drugs.These autonomic agents act either by stimulatingportions of the autonomic nervous system or byblocking the action of the autonomic nerves. 8
    • 9. MCMP 407 9
    • 10. MCMP 407 IntroductionAlpha & Beta adrenergic receptor antagonistsprevent the interaction of the endogenousneurotransmitter norepinephrine (N.E) orsympathomimetics (endogenous or syntheticcatecholamines, synthetic noncatecholamines)with the corresponding adrenergic receptor. 10
    • 11. MCMP 407Receptor agonists activate signal transduction pathways HO NH3 HO CH CH2 NH2 OH Norepinephrineα 1 adrenergicreceptor (+) Phospho - Gq lipase C PIP2 COOH IP3 Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response
    • 12. MCMP 407Receptor antagonists block agonist binding to the receptor HO HO CH CH2 NH2 Antagonist NH3 OH Norepinephrine Phospho - Gq lipase CWhat effect would an antagonist alone COOH have on receptor activation?
    • 13. MCMP 407 13
    • 14. MCMP 407Types of adrenoceptorsAlpha-1VasoconstrictionIncreased peripheral resistanceIncreased blood pressureAlpha-2Inhibition of norepinepherine releaseInhibition of insulin release 14
    • 15. MCMP 407 Types of Adrenoceptors – Beta-1 » Tachycardia » Increased lipolysis » Increased myocardial contractility – Beta-2 » Vasodilation (in skeletal vasculature) » Slightly decreased peripheral resistance » Bronchodilation » Increased muscle and liver glycogenolysis » Increased release of glucagon 15
    • 16. MCMP 407Alpha Blockers Bind selectively to alpha receptors Interfere with ability of catecholamines or other sympathomimetics to provoke alpha responses on the heart & peripheral vasculature Inhibitory action of epinephrine on insulin secretion is prevented too (insulin production is not reduced) Side effects: orthostatic hypotension, baroreceptor- mediated reflex tachycardia, impotence Absence of Beta blockade allows maximum expression of cardiac stimulation from N.E. 16
    • 17. MCMP 407Mechanism of Action (alphablockade) Competitive Inhibition (reversible binding with receptors) – Phentolamine – Prazosin – Yohimbine Covalent Bond (irreversible & insurmountable blockade) – Phenoxybenzamine (once blockade in effect, even massive doses of sympathomimetics are ineffective UNTIL METABOLISM OF Phenoxybenzamine takes place 17
    • 18. MCMP 407 18
    • 19. MCMP 407 α1 -adrenergic receptor antagonists O Acyl Quinazoline ring moiety Vary in half-life: N R Prazosin 3 hrsH3CO N N Terazosin 12 hrs Doxazosin 20 hrs N Piperazine ringH3CO Undergo extensive metabolism, excreted NH2 mainly in the bile Vasodilators Prazosin: R = (Minipres) O Relaxation of smooth muscle in enlargedTerazosin: R = prostate and in bladder (Hytrin) O base O “First-dose” effectDoxazosin: R =(Cardura) O
    • 20. MCMP 407 DosagePrazosin Terazosin First dose 0.5mg at bed Initially 1mg at bed time time , orally. orally. Then 0.5mg BD or TDS , Titrate by approx. doubling for 3-7 days. dose at weekly intervals. Followed by 1mg BD or Usual maintenance dose is TDS , for 3-7 days. 2-10 mg OD. Therafter increase gradually as required upto max. of 20mg / day.
    • 21. MCMP 407 Mechanism Of ActionSelective blocked of postsynaptic alpha-1adrenoseptor. PHARMACOLOGICAL EFFECTSCVS:Decreases blood pressureOnly minimal changes in Cardiac output.No reflex Tachycardia.Kidneys:Retension in salt & fluid when administered without adiuretic or during long term Therapy.
    • 22. MCMP 407 Clinical UsesMild to moderate chronic hypertension (moreeffective when used in combination with a diuretic orpropanalol).Acute congestive heart failure (Prazosin).To relieve urinary obstruction ( Terazosin).
    • 23. MCMP 407 Adverse EffectCNSDizziness, headacheResp.TractNasal congestion.GITGI hypermotilityKidneysSalt & Fluidretension
    • 24. MCMP 407 24
    • 25. MCMP 407 25
    • 26. MCMP 407 26
    • 27. MCMP 407 Alpha-2 AntagonistsTolazolineYohimbineRauwolscine 27
    • 28. MCMP 407 28
    • 29. MCMP 407YOHIMBINE (Procomil, Yocon) An alkaloid derived from the bark of the tree Corynanthe yohimbi.It is an alpha- adrenergic blocking agent that in excess causes antidiuresis, increased blood pressure, tachycardia, irritability, tremor, sweating, dizziness, nausea, and vomiting. It is used therapeutically to treat erectile dysfunction.
    • 30. MCMP 407Blocks presynaptic alpha-2 receptors  enhancedrelease of N.E. from nerve endingsToxic effect:– Idiopathic orthostatic hypotension (rare)– Impotence– Crosses BBB, may cause muscle activity & tremor– Overdosetachy, HTN, paresthesia
    • 31. MCMP 407 Non- Selective Sympathetic Antagonists
    • 32. MCMP 407 32
    • 33. MCMP 407 Phentolamine (REGITINE) Mechanism of ActionNon-selective alpha blockadeInhibits response to Serotonin.Stimulate Muscarinic receptor &, H1 H2 histamine reptorPeripheral vasodilation (alpha-1 block) & decreased BP within2 min (lasts 10-15 min) elicit baroreceptor- mediatedcardiac stimulation reflex 33
    • 34. MCMP 407Non-selective adrenergic receptor antagonists ImidazolinesHO Non-selective α receptor N antagonist N CH2 Competitive (reversible) blocker N Potent vasodilator, but induces H pronouced reflex tachycardia Block of presynaptic α2 receptors may promote release of NE H3 C Also blocks 5-HT receptors, and is Phentolamine (Regitine) a muscarinic and histamine receptor agonist
    • 35. MCMP 407Pharmacological Effects Glands Stimulate Lacrimal, Slivary , Pancreatic & Respiratory tract secreations. CVS Vasodilation through both alpha-adrenoceptor blokade & an additional non-adrenergic action on vascular smooth muscle Decrease Peripheral resistance & Increase Venous capacitance Cardiac stimulaiton through Reflex effect & alpha-2-
    • 36. MCMP 407Phentolamine(Clinical Uses) Acute HTN emergencies – Intraop manipulation of PHEOCRHOMOCYTOMA – Autonomic NS Hyperreflexia » 30 to 70 mcg/kg IV (prompt/transient dec in BP) » Drip may be desirable to maintain steady state Accidental extravascular injection of sympathomimetic drug – Local infiltration of phentolamine-containing solution (2.5 to 5mg in 10ml) Frost Bite. 36 To cause erection in male sexual Dysfunction.
    • 37. MCMP 407 Adverse EffectsCVS PrecautionsSevere tachycardia, Pts with coronary arteryarrhythmias, angina, disease.postural hypotension. Pts with peptic ulcer.GITDiarrhea , Increasedgastric acid production.
    • 38. MCMP 407 38
    • 39. MCMP 407 α-ADRENOCEPTOR ANTAGONISTSInteraction with receptors: A) Reversible B) Irreversible • Phentolamine Phenoxybenzamin • Tolozoline • Prazosin • Labetolol(both alpha & beta ) • Ergot alkaloids
    • 40. MCMP 407LABETALOL ( Mixed alpha & beta)Labetalol (Normodyne, Trandate) is a mixed alpha/beta adrenergic antagonist, which is used to treathigh blood pressure.
    • 41. MCMP 407 Non-selective adrenergic receptor antagonist β-Haloalkylamines Non-selective α receptor antagonist CH3 Also blocks acetylcholine, histamine, and serotonin O receptors N Irreversible antagonist resulting from covalent modification of receptor ClPhenoxybenzamine (Dibenzyline)
    • 42. MCMP 407Irreversible blokade long Duration (14-48 hrs)Phenoxybenzamine(Dibenzyline) Non-selective (alpha-1 & alpha-2 blocker) covalent bond Alpha-1 block > Alpha-2 block Slow onset (up to 60 min to reach peak) IV or PO. Long time required for structural change of the molecule needed to render drug active Elimination half-time: 24 hr (cumulative effect with repeated doses) Note: Block can be overcome only by the synthesis of new adrenoseptors. 42
    • 43. MCMP 407 Mechanism of ActionIt bind covalently to alpha adrenoceptors (alpha-1 >alpha-2)It inhibits reuptake of released nor-epinephrine bypresynaptic adrenergic terminals.It also blocks histamine (H1) , acetylcholine, &serotonin receptors.
    • 44. MCMP 407 Non-selective adrenergic receptor antagonist β-Haloalkylamines: Mechanism of receptor inactivation R RR R R R Cl- R R Cl- N N N N Nu Nu Aziridinium ion Cl receptor alkylated receptor
    • 45. MCMP 407 Cliniclal usesTo relieve vasospasm in Raynaud’s phenomenonTo relieve urinary obstructionTo control autonomic hyperreflexia due to spinal cordtransection. – Preoperative treatment of HTN of pt with PHEOCHROMOCYTOMA (0.5-1 mg/kg PO) » With chronic alpha blockaderelieving intense peripheral vasoconstriction, allows expansion of IV volume as reflected by a drop in Hct – Given to Pt with excessive vasoconstriction with associated tissue ischemia (eg. hemorrhagic shock) but only after IV fluid volume is replenished.
    • 46. MCMP 407 Adverse EffectCNS GITFatigue, Sedation Nausea & vomitingEye (with oral admisinstration)Miosis ReproductionCVS Inhibition ofPostural hypotension, ejaculation.Reflex tachycardia. LocalResp.Tract Local tissue irritation byNasal stifness injection.
    • 47. MCMP 407 47
    • 48. MCMP 407 Clinical pharmacology of α -adrenergic receptor antagonists Route ofDrug Receptor admin. Clinical usesPhenoxybenzamine α1, α2 Oral Pheochromocytoma, hypertensive crisisPhentolamine α1, α2 Parenteral Pheochromocytoma, hypertensive crisis, male impotencePrazosin α1 Oral Hypertension, benign prostatic hypertrophyTerazosin α1 Oral Hypertension, benign prostatic hypertrophyDoxazosin α1 Oral Hypertension, benign prostatic hypertrophy Side effects of α 1 receptor antagonists: Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia
    • 49. MCMP 407 Beta BlockersBind to Beta adrenergic receptors and block effects ofcatecholamines & sympathomimetics on the heart &smooth muscles of the airways & blood vesselsBeta blockers should continue during periop period toavoid reflex SNS hyperactivity 49
    • 50. MCMP 407 50
    • 51. MCMP 407 51
    • 52. MCMP 407 52
    • 53. MCMP 407 53
    • 54. MCMP 407 54
    • 55. MCMP 407 55
    • 56. MCMP 407 ClassificationNonselective for beta1 & beta2 receptors (propanolol,nadalol, timolol, pindolol)Cardioselective for beta1 receptors (esmolol,metoprolol, atenolol, acebutolol, betaxolol)Beta receptor selectivity is dose-dependentBeta receptor selectivity is lost when large doses ofantagonist is given 56
    • 57. MCMP 407Non-Selective(Beta1 – Beta 2)Antagonists Propanalol Carteolol Penbutolol Pindolol Timolol Nadolol Sotalol cloranolol
    • 58. MCMP 407 β -adrenergic receptor antagonists Pharmacological effects CH3 CH Decreased cardiac output and O N heart rate H CH3 OH Reduced renin release Increase VLDL, Decrease HDL Inhibit lipolysis Propranolol Inhibit compensatory (Inderal) glycogenolysis and glucose release in response to hypoglycemia Increase bronchial airway resistanceTherapeutic uses for β-adrenergic receptor antagonists:Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)
    • 59. MCMP 407 Propanolol (Inderal la, INNOPRAN XL)First Beta antagonist introduced clinically.Nonselective for beta1 & beta2 receptors (equalantagonism)Pure antagonist (lacks sympathomimetic intrinsicactivity). Mechanism of ActionBlocks both Beta 1 and Beta 2- Adrenoceptor 59
    • 60. MCMP 407Clinical use Hypertension (most often used with either a diuretic or a vasodilator). Angina pectoris & prophylaxis of myocardial infarction. Supraventricular & ventricular arrhythmias. Ventricular ectopic beats, esp if precipitated by catecholamines. Obstructive cardiomyopathy (to increase stroke volume) Dissecting aortic aneurysm (to decrease rate of development of systolic pressure).
    • 61. MCMP 407Hyperthyroidism.Prophylaxis of migraine.Anxiety (to reduce somatic manifestations).Cirrhosis (to reduce portal vein pressure).
    • 62. MCMP 407 Adverse EffectCNS GITSedation, sleep Nausea, vomiting,disturbance, depression. constipation, diarrheaCVS MetabloismPeripheral arterial Hypoglysemiainsufficiency, Cardiac Allergyfailure, bradycardia, cardiacconduction abnormalities. Rash, fever, purpura.Resp.Tract Withdrawal Symptoms Anginal attacks,Bronchoconstriction. arrhythmias or myocardial infarction.
    • 63. MCMP 407Contraindication:- Cardiogenic shock Right ventricular failure secondary to pulmonary hypertension. Congestive cardic failure Asthma Greater than 1st degree heart block Hypotension Raynaud’s phenomenon Pts on MAO inhibitors.
    • 64. MCMP 407 PrecautionsDose Precaution20-80mg TDS or QID, Pts with asthma.orally. Pts with diabetesIn emergency treatment mellitus esp IDDM.of dysarrhythmias1mg over 1 min, IV;repeated at 2 min.interval to a maximumof 10mg
    • 65. MCMP 407Non-selective β -adrenergic receptor antagonists CH3 Less lipophilic than propranolol CH Long half-life: ~20 hours O N Mostly excreted unchanged in urine H CH3 HO OH Administered: Oral Uses: Hypertension, angina, migraine HO Nadolol (Corgard) CH3 Thiadiazole nucleus with morpholine ring C CH3 O N Administered: Oral, Ophthalmic H CH3 O OH Uses: Hypertension, angina, N N migraine, glaucoma N S How will β-blockers affectTimolol (Timoptic, Blocadren) pupil size?
    • 66. MCMP 407 66
    • 67. MCMP 407Selective Beta 1 AntagonistsMetoprololAcebutololAlprenololAtenololBetaxololCeliprololEsmololBisoprolol
    • 68. MCMP 407 68
    • 69. MCMP 407 Effect of chronic β-receptor blockade Na+ Presynaptic neuron Tyrosine Na+ Dopamine TyrosineAction Potential H+ O DA MA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE NE Effector organ
    • 70. MCMP 407 Effect of chronic β-receptor blockade: Receptor up-regulation Na+ Tyrosine Na+ Dopamine TyrosineAction Potential H+ O DA MA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE NE Effector organ
    • 71. MCMP 407Selective β1 -adrenergic receptor antagonists CH3 CH O N CH3 H “Cardioselective” OH Less bronchconstriction Moderate lipophilicity Half-life: 3-4 hours R Significant first-passMetoprolol (Lopressor, Toprol) metabolismR= CH2 O CH3 Administered: Oral,Bisoprolol (Zebeta) CH3 parenteralR= O CH2 CH Uses: Hypertension, CH2 O CH3 angina, antiarrhythmic, congestive heart failure
    • 72. MCMP 407Selective β1 -adrenergic receptor antagonists CH3 CH O N CH3 OH H “Cardioselective” Less bronchconstriction Low lipophilicity NH2 Half-life: 6-9 hours Administered: Oral, O parenteral Atenolol (Tenormin) Uses: Hypertension, angina
    • 73. MCMP 407Selective β1 -adrenergic receptor antagonists CH3 Very short acting CH Half-life: 9 minutes O N Rapid hydrolysis by H CH3 OH esterases found in red blood cells Administered: Parenteral O Note: incompatible with CH3 sodium bicarbonate O Uses: Supraventricular Esmolol (Brevibloc) tachycardia, atrial fibrillation/flutter, perioperative hypertension
    • 74. MCMP 407 74
    • 75. MCMP 407 75
    • 76. MCMP 407 ButoxamineMechanism of ActionBlocks Beta 2EffectsIncrease peripheral resistance.Clinical ApplicationNo clinical indicationToxicityAsthma production.
    • 77. MCMP 407 Adrenergic β3 Receptors AntagonistsSR 59230A is a selective antagonist of thebeta-3 adrenergic receptor.L-748,337 Selective β3 antagonist .SR 59230A hydrochloride Potent and selective β3antagonist.Adrenergic receptor located primarily in the smallintestine, adipose tissue and vascular endothelium
    • 78. MCMP 407Mixed (alpha & beta)Adrenoceptor Antagonists Labetalol ( beta 1 = beta 2 > alpha 1 > alpha 2) Carvidilol
    • 79. MCMP 407 Mixed adrenergic receptor antagonists Non-selective β receptor antagonist, with potency OH somewhat lower then that H of propanalol. N 1 1 α1 receptor antagonist,HO CH3 with potency less then that CONH2 of phentolamine. β-blocking activity preventsLabetalol (Normodyne, Trandate) reflex tachycardia normally associated with α1 receptor antagonists Administered: Oral, parenteral Uses: Hypertension,
    • 80. MCMP 407 Mixed adrenergic receptor antagonists OCH3 O O N H OH N Carvedilol (Coreg) HNon-selective β receptor β-blocking activity preventsantagonist reflex tachycardia normallyα1 receptor antagonist associated with α1 receptorBoth enantiomers antagonize α1 antagonistsreceptors Administered: OralOnly (S)-enantiomer possesses Uses: Hypertension, congestiveβ-blocking activity heart failure (Types II and III)
    • 81. MCMP 407Pharmacologic manipulation of the adrenergic system Na+ Presynaptic neuron Tyrosine Na+ 1 Dopamine Tyrosine 2Action Potential H+ O DA MA NE NE Ca2+ Uptake 1 3 Na+, Cl- NE NE NE NE β Effector organ
    • 82. MCMP 407Adrenergic Neuron BlockerGuanethidineReserpineBretyliumGuanadrel
    • 83. MCMP 407 Adrenergic Neuron Blocker Drugs that reduce storage or release of NE H Possess guanidino moiety N NH2 N C (pKa > 12) NH Effects can be blocked by transport blockersGuanethidine (Ismelin) Uses: Hypertension
    • 84. MCMP 407 Mechanism of Action:It inhibits nor epinephrine release fromsympathetic nerve endings. Clinical UsesModerate to severe hypertension ( usually witha diuretic & a vasodilator)
    • 85. MCMP 407Adverse EffectsCVS: ContraindicationOrthostatic hypertension Pheochromocytoma& syncop esp. duringexercise. Severe coronary artery disease.GIT: CerebrovascularDiarrhea insufficiency.Sk,muscle During MAOAching , weakness inhibitorReroduction administration.Delayed Ejecullation
    • 86. MCMP 407 Catecholamine depleters H3CO N H N OCH3 H H O H OC OCH3 H3CO2C OCH3 OCH3 Reserpine (Serpasil)Indole alkaloid obtained Slow onset of actionfrom the root of Rauwolfia Sustained effect (weeks)serpentina Used in the treatment ofBlock vesicular monoamine hypertensiontransporters May precipitate depressionDeplete vesicular pool of NE
    • 87. MCMP 407 Mechanism of ActionReserpine blocks the ability of adrenergictransmitter vesicles to take up & store biogenicamines by interfering with an uptakemechanism that depend on Mg & ATP ,Depletaion of nor epinephrine, dopamine &serotonin in both central & peripheral neurons.Also exerts a direct vasodilating effect onvascular smooth muscle when administerintraarterially.
    • 88. MCMP 407 HO CH2 CH NH2 TYROSINE COOHInhibition of nor HO X tyro sine hydroxyla s e Metyrosineepinephrine synthesis HO CH2 CH NH2 DOPA COOH aromatic L-amino a cid de carboxyla s e HO HO CH2 CH2 NH2 DOPAMINE dopamine β -hydroxyla s e HO HO CH CH2 NH2 NOREPINEPHRINE OH phenylethanolamine- HO N-methyltran sfera s e HO CH CH2 NH EPINEPHRINE OH CH3
    • 89. MCMP 407 Drugs that reduce storage or release of NE Na+ Tyrosine Na+ Dopamine Reserpine Tyrosine GuanethidineAction Potential H+ O MA NE NE Ca2+ NE Guanethidine, Guanethidine Bretylium β Effector organ
    • 90. MCMP 407 Clinical useMild to moderate hypertension. Adverse EffectCNSSedation , lassitude, nightmares , depression,extrapyramidal signs.CVSPostural hypotension, bradycardia.GITDiarrhea, abdominal cramp, increase gastric acidsecretion.Resp.Tract: Nasal congestion.
    • 91. MCMP 407 ContraindicationPheochromocytomaPeptic ulcerDepressionDuring MAO inhibitor administration.Parkinsonism
    • 92. MCMP 407Centrally Acting Sympatholytics Methyldopa Clonidine Guanfacine Guanabenz
    • 93. MCMP 407 Methyldopa Mechanism of ActionConverted into alpha methylnorepinephrine which isstored in adrenergic nerve granules, where it isstoichiometrically replaces norepinephrine &, isreleased by nerve stimulation to interact withpresyneptic central alpha adrenoseptors, Decreasesympathetic outflow Decrease arterial presure.Inhibit Dopa decarboxylase decrease stor ofnorepinephrine in the sympathetic nervous system.Decrease BP.
    • 94. MCMP 407Clinical Uses:- Mild to moderate severe hypertension. Dosage 1-2 g orally in divided doses.
    • 95. MCMP 407Adverse Effect CNS Blood Sedation, lassitude, Hemolytic anemia, nightmares, depression, positive Coombs test. vertigo, extrapyramidal Endo signs. Lactation CVS Liver Orthostatic hypotension Hepatitis GIT Metabolic GI disturbances. Drug fever.
    • 96. MCMP 407Contraindication Pheochromocytoma. Acute hepatic disease. During MAO inhibitor administration.
    • 97. MCMP 4072) CLONIDINE  Mechanism of Action It stimulates presyneptic alpha-receptor in vasomotor center of brain Decrease sympathetic outflow to the peripheral vessels.  Dosage 0.2 - 1.2 mg/day  Clinical Uses Fall in BP, decrease in cardiac output & heart rate. Decrease plasma Renin activity
    • 98. MCMP 407 Adverse EffectCNS GITSedation , drowsiness. Dry mouthCVS RenalRebound hypertensive Fluid retention.crisis from sudden with-drawl of clonidinecharacterized bynervousness,tachycardia, headache &sweating.
    • 99. MCMP 407Beta Adrenergic Antagonists (TOPICAL) Betaxolol Carteolol Levobunolol Metipranolol Timolol
    • 100. MCMP 407 Mechanism of ActionDecrease of aqueous humor production Side EffectsOcular irritation, contraindicated inpatients with asthma, obstructive airdisease, bradycarida, and congestive heartfailure.
    • 101. MCMP 407 Side effects of β -blockers:Bradycardia, AV block, sedation, mask symptomsof hypoglycemia, withdrawal syndromeMay alter airway resistance, carbohydrate/lipidmetabolism, distribution of extracellular ionsCross CNS/placentaGI: N/V/DFever, rash, myopathy, alopecia,thrombocytopenia with chronic use
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    • 112. MCMP 407 ReferencesBasic & Clinical Pharmacology Bertram G. KatzungPharmacology & Physiology in anesthesia practice.Stoelting, 3rd edition, p 288-301Clinical Anesthesiology. Morgan & Mikhail, 3rdedition, p 212-223http://lysine.pharm.utah.edu/netpharm/netpharm_00/druglPharmacology 5th edition Lippincott’sTextbook of Pharmacology and Therapeutics Vol2011 Maqsood cheema. 112
    • 113. MCMP 407 113