Slide 1

Adrenergic Agonist & Antagonist

-Guide: Dr R K Solanki SirDr Neelam Mam

Dr Kailash Mittal

Synthesis, Storage , Release and Degradation

The metabolites are excreted in urine as:Vinyl mandelic acid , 3,4 dihydroxy mandelic acid Metanephrine Nor-metanephrine.

Presynaptic regulation of NE release:By Autoreceptors: autoregulation of the release of norepinephrine.1---- positive feed back2 ----- Negative feed back

Subtypes/Locations & Characteristics of AdrenoceptorsReceptorLocationPharmacologic effectsResult of Agonist binding1 subtypes1A1B1DPostsynaptic smooth muscles of BV specially of skin & mucosa. Radial muscle of eyeGIT sphincters

SM of prostate& bladder base (1A ) hair folliclesSplenic capsule

ContractionVasoconstriction

MydriasisContraction Contraction

Through GqStimulation of phospholipase C IP3, DAG , intracellular Ca++

Adrenergic Receptors : Different types. All are GPCR.

subtypes/locations & characteristics of AdrenoceptorsReceptorLocationPharmacologiceffectsResult of Agonist binding2subtype2A2B2CPresynaptic nerve terminals

Postsynaptic effector cells of

plateletslipocytes Some vascular SM

CNSInhibition of N E release

AggregationInhibition of lipolysisContraction

Reduce sympathetic outflow & sedationThrough GiInhibition of Adenylyl cyclase cAMP

subtypes/locations & characteristics of AdrenoceptorsReceptorLocationPharmacologic effectResult of Agonist binding1Postsynaptic effector cells heart JGA of renal tubules ciliary body epithelium

Presynaptic adrenergic & cholinergic nerve terminals, HR & force of contraction renin release secretion of aqueous humor

transmitter releaseThrough GsStimulation of Adenylyl cyclase cAMP

subtypes/locations & characteristics of AdrenoceptorsReceptorLocationPharmacologic effectsResult of Agonist binding2Postsynaptic effector cells Smooth Msl of some BV , specially of skeletal M Brochi u. bladderVasodilation

BronchodilationRelaxation

Promotes potassium uptakeActivates glycogenolysisThrough GsStimulation of Adenylyl cyclase cAMP3Postsynaptic effector cells lipocytes,(fat cells) Activates lipolysisSame

subtypes/locations & characteristics of peripheral Dopamine receptorsReceptorLocationPharmacologic effectsResult of Agonist bindingD1

Postsynaptic SM of renal & other splanchnic BV.

Dilation of BVThrough GsStimulation of Adenylyl cyclase cAMP

D2 Presynaptic Nerve terminalsModulates transmitter releaseThrough GiInhibition of Adenylyl cyclase cAMP

Receptor regulation

Up regulation of receptors: Increase in number of receptors Seen on prolonged use of antagonists.

Desensitization / Down regulation: Prolonged exposure to catecholamines (agonists)reduces the responsiveness.

Example: The therapeutic effect of 2 agonists ( bronchodilation )-decreases on prolonged in Asthma.

Chemical Classification

I.CatecholaminesNatural: Epinephrine (Adrenaline) Nor epinephrine (Noradrenaline) Dopamine Synthetic: Isoprenaline Dobutamine Rimiterol Isoetharine Hexoprenaline

II. Non- Catecholamines Ephedrine Pseudoephedrine Amphetamine Dexamphetamine Orciprenaline Metaraminol Terbutaline Albuterol Phenylephrine Methoxamine& many more

Adrenergic agonist

Relative Receptor AffinitiesAlpha AgonistsPhenylephrine , MethoxamineClonidine, dexmedetomidine1 > 2 >>>>> 2 > 1 >>>>> Mixed Alpha & Beta AgonistsNorepinephrineEpinephrine1 = 2 ; 1>> 21 = 2 ; 1= 2

Beta AgonistsDobutamineIsoproterenolTerbutaline, Metaproterenol, Albuterol, Ritodrine1> 2 >>>> 1= 2 >>>> 2>> 1 >>>>

Dopamine AgonistsDopamineFenoldopamD1 = D2 >> >> D1 >> D2

Epinephrine (Adrenaline)Source: Natural Catecholamine produced by cells of adrenal medulla & certain areas of brain.Released into the circulation 80-90% along with Nor-epinephrine 10-20 % MOA of Epinephrine Acts as agonist on adrenergic receptors

Cardiovascular Heart rate, myochondrial contractality & c o - increase (1)Cutaneous, renal, splachnic vascular beds & pulmonary artery - constricted (1 ) Skeletal muscle vasodilated (2)Coronary blood flow- increase (2)Cerebral ---- no significant change related to systemic blood pressureBlood PressureSystolic (1 effect )Diastolic Generally ( 2 effect)Mean blood pressure Pulse pressure ---

Effects on eye:Mydriasis--- dilation of pupil ; stimulation of 1 in radial muscle of iris

Effect on Lungs:Smooth muscles Bronchodilation 2 BV constricted -- decongestion (1 ) . release of vasoactive mediators from mast cells--- 2.Inhibit microvascular leakage & ciliary activity.

Anti Allergic effects: Physiological antagonist to histamine

Metabolic Effects:Blood glucose: Hyperglycemia due toglycogenolysis in liver, glucose release into the circulation ( 2 ) Insulin secretion --- ( 2 effect). Increased release of Glucagon.

Lipocytes contain 3 & 2: 3 lipolysis--- fatty acids & glycerol (predominant effect) , 2 lipolysis.

K+ Level - activate Na+ K+ pump ( 2 )

Effects on G.I.T: Smooth muscles relaxed ( ) sphincters - contraction (1 )

Effects on G.U.T:Uterine and urinary bladder smooth muscles - relaxed 2 .Ejaculation depends on activation in ductus deference, seminal vesicles, & prostate. U. bladder trigone, sphincter & prostate contracted via 1A .

Effect on Endocrine function.Release of Renin: through 1 & inhibited by 2. Coagulation accelerated by increase platlet aggregation & factor v activity

THERAPEUTIC USESAnaphylactic shock Status AsthmaticsTo prolong action of infiltration L.A & to systemic toxicity.Topical HemostaticCardiac Resuscitation

Anaphylactic shock: Epinephrine is the drug of first choice.IV Dose 100-500mcg repeated if necessary followed by infusion 2-20mcg/min IM - 1:1000 sol 0.3-0.5 ml. May be repeated after 10-20 minutes

Status Asthmatics / Acute severe Asthma:S/C injection of epinephrine 0.3 ml of 1 in 1,000 solution, . Repeated in 20. min (max. 3 dose).

To prolong action of infiltration L.A & to systemic toxicity.1 in 200,000 solution of Epinephrine is added to LA. This prolongs the DOA due to vasoconstriction & systemictoxicity.

Topical Hemostatic: 1 : 200,000 or 1:400,000 Nasal packs for epistaxis orgingival string for gingivectomy.

Cardiac Resuscitation: in complete heart block & cardiac arrest. dosage - .5 1 mg repeated over 3-5 min.

Adverse Effects:Cardiac arrhythmias: due to increased automaticity of latent pacemakersAnginal pain Cerebral hemorrhagePulmonary edema may be produced.CNS : Only at high doses fear, Anxiety, Restlessness, Headache ,Tremors.

Interactions:

Hyperthyroidism: Enhanced CVS effectsWith Cocaine: Enhanced CVS effectsDiabetes: Risk of HyperglycemiaBeta blockers: Marked effect on alpha receptors--- Rise in blood pressure.With Inhalational General anesthetics: Inhalational General anesthetics sensitize the heart to action of epinephrine---- risk of Cardiac arrhythmias

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norepinphrine

released from postganglionic sympathetic nerve endings Also released from adrenal medulla (10-20 %) with Epinephrine.In pheochromocytoma ,it may be 97% MOA: Effects similar to epinephrine on & 1 receptors.Relative little effects on 2 receptorsClinical ConsiderationsDirect 1-stimulation in the absence of 2-activity induces intense vasoconstriction of arterial and venous vessels. 1 stimulation increased contractility of myocardiumIncease systemic vascular resistance, diastolic &systolic blood pressure , mean arterial pressure& minimal change in heart rate( baroreceptor reflex)

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USE : refractory hypotention in severe sepsisSeptic shock bolus (0.1mcg/kg) or infusion at a rate of 312 g/min.

Adverse effects :Use cautiously in pt with right ventricular failureExtravasation of norepinephrine at the site of intravenous administration can cause tissue necrosis.

dopamine Dopamine is an endogenous catecholamine D1-vasodialation in renal, mesentric, coronary & cerebral vascular bedsD2- inhibit release of norepinephrine ,leading vasodialation. Activate emetic center in medulla- nausea & vomiting , suppress secretion &function of ant. Pitutatary harmoneAct on 1 & receptor (high dose)The clinical effects of dopamine (DA), a nonselective direct and indirect adrenergic agonist, vary markedly with the dose. Small doses ( .5-2 g/kg/min) renal dose d1 and d2 receptors. moderate doses (210 g/kg/min)- 1-stimulation . higher doses(>10g/kg/min)-1-effects become prominent

Uses

Shock to improve cardiac output, support blood pressure, and maintain renal function.Refractory CHF.Combination therapy dopamine with dobutamine to increase cardiac output & coronary perfusion Dosage as a continuous infusion at a rate of 120 g/kg/min.

dobutamine Synthetic Catecholamine - 50:50 racemic mixture of two stereoisomers.Levorotary (- ) potent 1 adrenergic agonist & weak 1 ,2 adrenergic agonist Dextrorotary (+) 1 adrenergic antagonist & potent 1 ,2 adrenergic agonist

Pharmacodynamics Its primary cardiovascular effect is a rise in cardiac output as a result of increased myocardial contractility. Minimal effect on mean arterial pressure as increased cardiac output offset decreased in peripheral vascular resistance. Heart rate increases are less marked than dopamine & isoproterenol but may be greater than norepinephrine

UsesFavorable effects on myocardial oxygen balance make dobutamine a good choice for patients with the combination of congestive heart failure and coronary artery disease, particularly if peripheral vascular resistance already elevated. Dosageinfusion at a rate of 2.510 g/kg/min.

Isoproterenol (Isoprenaline)

Synthetic CatecholamineRelative selective agonist Activates both 1 & 2 receptors equally . 1-Effects increase heart rate, contractility, and cardiac output. 2-decreases PVR and diastolic BP .Myocardial oxygen demand increases while oxygen supply falls, making isoproterenol or any pure -agonist a poor inotropic choice in most situations.

Therapeutic Uses:In emergencies (bradycardia , heart blocks) to stimulate HR specially before insertion of artificial pace maker.Pulmonary hypertention & right ventricular dysfunction Bronchial asthma (2 selective drugs preferred).To overcome the cardiac effects of beta blockers overdose---cardiodepression ,heart blocks.

phenylephrine

Noncatecholamine with predominantly 1-agonist activity (high doses may stimulate 2- and -receptors) & small part due to release of norepinephrine.Increase systemic bp with decrease co (baroreceptor mediated reflex bradycardia)Oral clonidine premedication augment pressor response of phenylephrine (potentiat 1 mediated vasoconstriction). Continuous infusion during acute potassium loading interfere with transfer of k in to cells Use Systemic blood pressure decreases in presence of sympathetic blockade produce by regional anesthesia or hypotention due to inhaled or injected anesthetic.Maternal hypotention in cesarean section because not altered uterine blood flow & higher umblical artery ph compare to ephedrine

Dosage Small intravenous boluses of 40100 g of phenylephrine rapidly reverse reductions in blood pressure caused by peripheral vasodilation (eg, spinal anesthesia). continuous infusion (10-20 g/min) in adult to maintane normal blood pressure during surgery.Nasal spray 1% for nasal decongestant

ephedrineNon catecholamine sympathmimetic act partly due to direct stimulation of adrenergic receptors ( & ) & partly due to stimulation of release of endogenous norepinephrine (indirect)Increase systolic & diastolic blood pressure, heart rate, cardiac output Renal ,splanchnic blood flow decrease & coronary ,skeleton muscle increase.Use Increase systemic bp in presence of sympathetic blockade produce by regional anaesthesia or hypotension due to inhaled or injected anaesthetic Decongestant oralyDosage adults: bolus of 2.525 mg IV 25-50 mg IM children :bolus of 0.1 mg/kg. Subsequent doses produce less effect ( tachyphylaxis) due to depletion N E store

2 adrenergic receptor agonists

An 2-agonist by negative feedback - decrease norepinephrine release Inhibit insulin , increase glucagon release have sedative properties. on withdrawal present with rebound effect increase in heart rate and hypertension

clonidineUses- in regional anesthesia, including peripheral nerve block, clonidine prolongs the duration of the block.. Other benefits include decreased postoperative shivering, inhibition of opioid-induced muscle rigidity, attenuation of opioid withdrawal symptoms, and the treatment of some chronic pain syndromes. Side effects :: bradycardia, hypotension, sedation, respiratory depression, and dry mouth Dosage ::oral (35g/kg)intramuscular (2 g/kg)intravenous (13 g/kg), transdermal (0.10.3 mg released per day) intrathecal (10-50g)epidural (12g/kg)

dexmedetomidine Higher affinity for 2-receptors than clonidine. (1600:1) Uses as sedative, analgesic, due to central sympatholytic effects iv infusion .1 1.5 g/kg/min large intravenous bolus( .25-1 g/kg) over 3 to 5 min.Result paradoxical hypertension with decrease heart rate Extensive biotransformation is in liver and excreted in urine.Physiological dependance- as potent binding and short half life.Withdrawal phenomenon present as clonodine.

Selective 2 Adrenergic AgonistsRelax bronchiole and uterine smooth musclesUsed in bronchospasm in asthmaMetabolic response- hyperglycemia, hypokalemia, hypomagnesemia.Side effects- tremors due to direct stimulation of B2 receptors in skeletal muscles.Route of administration- oral, sc, MDI

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DOSES- Albuterol- MDI-100 mcg/puff. 2 puffs repeated over 4-6 hrs.max 16-20 puffs dailyNebulization- 0.5-1 ml .5% solution in 5 ml NS. Rpted every 15 min for 4 doses then hourly in initial hrs.Metaproterenol-650 mcg/puff. Max 16 puffs.Terbutaline-SC- .25 mgMDI- 200mcg/puff. Max 16 puffs.Oral

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Blockade of 1 ReceptorsInhibition of 1 mediated contraction of arterial & venous smooth muscles.Inhibition of contraction of other smooth muscles i.e. eye, GIT , UB & prostate.Inhibition of ejaculation in males. Blockade of 2 Receptorsincrease of sympathetic outflow from CNS (VMC ) to periphery Inhibit Negative feed back control of NE release----- increase NE release

PhentolamineReversible/ competetive antagonistTransient (10-15min) nonselective alpha blockadePeripheral vasodilation (alpha-1 block) & decreased BP within 2 min (lasts 10-15 min) elicit baroreceptor- mediated cardiac stimulation reflexEnhanced neural release of N.E. (alpha-2 block) increase HR/CO, angina, dysrhythmiasParasympathetic override: hyperperistalsis, abdominal pain, diarrhea.

Clinical Uses-

Acute HTN emergencies- 30 to 70 mcg/kg IVIntraop manipulation of pheocrhomocytoma- infusion 0.1-2 mg/minAccidental extravascular injection of sympathomimetic druglocal infiltration of phentolamine-containing solution (5 to 15mg in 10ml NS)erectile dysfunction: phentolamine with papaverine,

Phenoxybenzamine Non-selective / irreversable blocker.Alpha-1 block > Alpha-2 blockSlow onset (up to 60 min to reach peak) IV or PO. Long time required for structural change of the molecule needed to render drug activeElimination half-time: 24 hr (cumulative effect with repeated doses)

Cardiac EffectsOrthostatic hypotension (if HTN or hypovolemia)Impairement of compensatory vasoconstriction exaggerated drop in BP in response to blood loss or vasodilating drugs(e.g. volatile anesthetics) CO, renal blood flow unchanged (unless preexisting renal vasoconstriction) Cerebral/coronary vascular resistances dont change

Non-Cardiac effectsincreases insulin secretionCatecholamine-induced Glycogenolysis in skeletal muscle or lipolysis not alteredmiosisSedationNasal stuffiness (d/t unopposed alpha blockade vasodilation in mucous membranes)

Clinical Uses

Preoperative treatment of HTN of pt with pheochromocytoma (0.5-1 mg/kg po)

Given to Pt with excessive vasoconstriction with associated tissue ischemia (eg. hemorrhagic shock) but only after IV fluid volume is replenished

Raynauds disease

Alpha-1 Selective Blockers

Generally reflex tachycardia is less prevalent as negative feed back by NE ,mediated by 2 is not blocked.

Syncope is noted when first administered in a large group of patients. Caution should be taken to avoid sudden postural changes.

Postural hypotension is much less pronounced than the non-selective -blockers possibly because of lower effect on veins.

Therapeutic Uses mild hypertension alone or in combination with other antihypertensives benign prostatic hypertrophy: Blockade of 1-adrenoceptors at the base of the bladder and the prostate possibly reduces the symptoms of obstruction and the urinary urgencyTamsulosin has antagonistic affinity to 1A receptors (in vas deferens) more than to 1B in vascular smooth muscles

Prototype Alpha-1 Blocker : Prazosin

Highly selective for 1 receptors , 1000 fold > 2Relaxes vascular smooth muscle PVR & blood pressure ---- useful anti-hypertensive.preoperative treatment of HTN in pheochromocytoma (0.5-1 mg/kg po)Relaxes vascular smooth muscle in the prostate & bladder base useful in urinary obstruction , improves urinary flow.A/E: First dose phenomenon marked hypotension with first dose specially in patients who are volume & salt depleted.. So first dose should be small & given at bed time.

Other -Blockers

YohimbineSelective 2 blocker improves erectile functionMay cause anxiety(crosses BBB)

TolazolineReversible non selective antagonistuses: persistent pulmonary hypertension in new bornA/E: hypotension, reflex tachycardia, pulmonary and git haemorrhage.

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-Adrenergic Receptor Blockers Mode of action: Bind to Beta adrenergic receptors and block effects of catecholamines & sympathomimetics on the heart & smooth muscles of the airways & blood vessels.Chemistry: Resemble Isoproterenol.Beta blockers should be continued during periop period to avoid reflex CNS hyperactivity.Beta blockade can be reversed by Beta agonist by displacement from occupied receptors if large amount of agonist is given

Significance of Cardioselectivity/ Non-selectivity:

Some drugs like Atenolol block 1 preferentially than 2but the selectivity may be lost at higher conc.as they are not receptor specific ,only selective

Use of selective 1 blockers is safer in patients with : - Asthma /COPD as 2 receptors in bronchial smooth muscles are not blocked which may produce bronchoconstriction--- worsening of Asthma -Insulin dependent Diabetics--- less chances of hypoglycemia & recovery is not delayed. - Severe peripheral vascular disease or spastic disorders.

Intrinsic Sympathomimetic Activity (ISA)

Partial agonistic activity at - receptors.ISA can prevent A/E like precipitation of bronchoconstriction in patients of COPDLess likely to cause Bradycardia & plasma lipid abnormalitiesBeneficial in patients with brady arrhythmias or peripheral vascular disease.Not as effective as pure antagonist in secondary prevention of Myocardial Infarction.Examples: Acebutolol, Pindolol, Carteolol, Oxpranolol , Celiprolol, Penbutolol.

Effects not related to - blockade

Membrane stabilizing Activity (MSA) Local anesthetic action due to Na+ channel blockade. Not important for systemic effects but for topical use in Glaucoma. Local anesthetic action produces loss of sensation of cornea--- absent corneal reflex ,which is protective. So blockers without MSA are used as eye drops in Glaucoma e.g. Timolol, Betaxolol . eg: Propranolol, Pindolol, Labetalol, Acebutolol, Metoprolol,

Inverse Agonistic Activity : Some drugs like Betaxolol ,Metoprolol have inverse agonist activity they reduce the constitutive activity of Beta receptors in some tissues .

Propranolol

Non-selective blocker with MSA.First Beta antagonist introduced clinicallyHighly lipid soluble ---- crosses BBB(produce some drowsiness) Low oral bioavailability (30%) due to extensive 1st pass hepatic metabolism . Dose- PO dose 40-800mg/day is much higher than IV dose (0.05mg/kg in increments of 0.5-1mg q5min)Elimination half life --- 2 3 hrsElimination is decreased when hepatic blood flow decreases. May decrease its own clearance rate by decreasing C.O. and hepatic blood flowRenal failure does not alter elimination half-life BUT accumulation of metabolites takes place

Propanolol & Local Anesthetics

Decreases clearance of amide L.A. by decrease hepatic blood flow & inhibition of liver metabolismBupivacaine clearance is decreased 35%Higher chance of systemic toxicity of bupivacaine and other amide L.A. Propanolol & OpioidsPulmonary first-pass uptake of Fentanyl is highly decreased in pts taking propanolol2-4 times as much injected Fentanyl enters systemic circulation right after injection (more chance of overdosing with Fentanyl in pt who takes Propanolol)This response reflects ability of one basic lipophilic amine (propanolol) to inhibit pulmonary uptake of another basic lipophilic amine (fentanyl)

Pharmacological Actions(A)Effects on CVS:Heart: Mainly blocks 1 receptors HR ----- Contractility ----- Excitability --- Automaticity --- Conduction velocity.---- Stroke volume ---- Cardiac output ---- Work load ---- oxygen demandECG: PR interval in ECG due to slowed AV conduction

Blood Vessels & Blood PressureInitially there is PVR due to inhibition of 2 receptor mediated vasodilatation.On long term ---- peripheral resistance & blood pressure due to 1-blockade :a) COb) Anti Renin effects

(B)Effects on Respiratory System:Bronchoconstriction (blockade of 2) by non-selective blockers Increased airway resistance--- worsening of asthma.No 1-Selective antagonist is sufficiently specific for 1 , so generally they should be avoided in patients with concomitant asthma. 1-Selective antagonists are relatively safe in patients with concomitant COPD. (C)Effects on Eye: IOP---- synthesis of aqueous humour due to blockade of 1 in ciliary epithelium. blockers without MSA are used in glaucoma.e.g. Timolol, Betaxolol topically as eye drops

(D) Metabolism:

1.Effect on lipid metabolism: lipolysis (3 blockade)

2. Effect on carbohydrate metabolism: glycogenolysis in liver (2 blockade)Delay in recovery from hypoglycemia in Insulin dependent Diabetics; specially in patients with low Glucagon reserve

3.Effect on lipoprotiens: VLDL & HDL cholesterol ----- risk of coronary artery disease (CAD).Less likely to occur with blockers possessing ISA.

Atenolol

Most selective Beta1 Blocker50% of PO dose (50-100mg/day) absorbed by GILittle/no hepatic metabolismRenal excretionElimination half-life: 6-8hrs (more than 24 hrs in renal failure)IV dose for acute MI (5mg over 5min followed by another 5mg 10min later)Periop Tx will decrease incidence of post op MI in CAD ptsEnters CNS in very small amounts but fatigue/depression still occursCan be used with caution in IDDM pts whose HTN is not controlled with other antiHTN (does not potentiate Insulin-Induced Hypoglycemia seen with nonselective Beta blockers)

Metoprolol

Beta 1 selectiveHigh hepatic first-pass metabolism (only 40% reaches systemic circulation)Low protein binding (10% bound)Elimination half-life 3-4hrsCan be used in COPD/PVD pts since no Beta2 blocking properties at normal dose (2-15mg IV).

Esmolol Rapid onset, short acting Beta1 blocker given ONLY IV (0.5mg/kg)T1/210min (rapid hydrolysis in blood by plasma esterases, independent of renal & hepatic function)Plasma esterases that hydrolyze Esmolol are different than Plasma CholinesteraseDose: 0.5-1mg/kg (peaks 5min). Return of HR to predrug level within 10-30minPoor lipid solubility limits crossing into CNS/placentaEsmolol (1mg/kg) iv followed by 250 mcg/kg/min decreases plasma conc of propofol required to prevent patient movement in response to surgical incision.

Uses

HTN/Tachy in response to intraop noxious stimulation & intubation (eg 150mg IV 2min before Laryngoscopy) prior to ECT : attenuation of increased HR & decrease length of seizure (dose 500 mcg/kg/min)In Pheochromocytoma, thyrotoxicosis, PIH, epinephrine- or cocaine-induced cardiovascular toxicity

Therapeutic Uses of -blockers(1) Treatment of hypertension: Selective 1-blockers are preferable in asthmatic & diabetic patients and in patients with Raynauds diseasePostural hypotension is not prominent. very useful as mono therapy in mild to moderate hypertensionIn hypertensive emergencies (Labetalol , Esmolol)Intraoperative & Postoperative hypertension (Esmolol)Hypertension with chronic heart failure (Carvedilol , Metoprolol, Bisoprolol)Hypertension with pheochromocytoma use - blocker after blocker.

(2)Myocardial Infarction (MI): given immediately (few hours) after MI reduces the infarct size and enhance cardiac reperfusion and recovery; esmolol,atenolol, propranolol, and metoprolol are used-blockers administered 1-4weeks after MI reduce much the probability of myocardial re-infarction possibly by reducing cardiac work.(3)Angina: Useful for prophylaxis of Classical angina. They reduce the frequency of anginal attacks.Improve exercise tolerance. Not useful in acute attack. The beneficial effects are related to hemodynamic effects HR ,force of contraction Work load ---- oxygen demand

(4)Cardiac supraventricular arrhythmias 1-receptor blockade results in the following:decreased firing rate of SA node decreased AV conduction & prolongation of AV-nodal refractory perioddecreased ventricular response to atrial flutter

Esmolol is a cardio-selective 1-blocker that is used only by IV route for emergency treatment of supraventricular arrhythmias arising during surgery

(5)Dissecting aortic aneurysm:

- blockers decrease the rate of rise in the systolic blood pressure. - blockers are also useful in selected high risk patients in the prevention of adverse cardiovascular outcomes resulting from non-cardiac surgery.

(6) Pheochromocytoma :- blockers may be given after Alpha blockers to reverse the cardiac effects of catecholamines.If given before Alpha blockers,there will be enhanced effects of catecholamines on alpha receptors--- further rise in blood pressure.

(7)Hyperthyroidism: antagonists are beneficial as they :Block the excessive catecholamine action. (there is upregulation of receptors in hyperthyroidism).Inhibit peripheral conversion of Thyroxine (T4)to Tri-idothyronine (T3); which is more potent.Are useful in thyroid storm to control supraventricular tachycardia that often precipitates cardiac failure.

(8)Glaucoma: blockers without MSA are used in glaucoma. e.g. Timolol, Betaxolol as topical eye drops.

(9)Migraine prophylaxis Propranolol reduces the frequency & intensity of migraine headache(10)Skeletal muscle tremor : antagonists reduce certain tremors as sympathetic activity may enhance skeletal muscle tremor through receptors.(11)Alcohol withdrawal syndrome: antagonists reduce symptoms .(12)Anxiety: antagonists reduce symptoms of anxiety Low dose Propranolol ,specially when taken prophylactically ; is effective to control stage fright--- performance anxiety.

ADVERSE EFFECTS of -blockers

1.On CVS: Generally the extensions of pharmacologic effects. Bradycardia AV block Hypotension Heart failure---- in patients where CO is dependent upon sympathetic drive. Antidote: Isoproterenol & glucagon. Coldness of extremities, fatigue with non -selective -Blockers , specially in patients of peripheral vascular disease or vasospastic disorders

Drug withdrawal in patients of IHD: on abrupt discontinuation of -antagonists therapy in IHD after chronic use-- Angina or acute myocardial infarction may occur:-this may be due to adrenergic receptor super-sensitivity mediated by receptor up-regulation or re-enhancement of sympathetic cardiac drive

So the dose should be tapered over 2-3 weeks in Hypertension & IHD

2.Metabolic : Hypoglycemic episodes in insulin dependent diabetics (type I) with non selective -Blockers Masking of premonitory symptoms of hypoglycemia(such as tachycardia)Delay in recovery from hypoglycemia

Effect on lipoprotiens: VLDL & HDL cholesterol ----- risk of Coronary Artery Disease..Less common with blockers possessing ISA.

3.Respiratory : Worsening of pre-existing disease ---- asthma or COPDs (with non selective -Blockers).

4. CNS: Sedation, sleep disturbances, & depression.

5. Drug interactions: With Verapamil severe hypotension, bradycardia, heart failure & conduction defects.

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CONTRAINDICATIONS of -blockers

DO NOT use in pts with AV Block or h/o heart failure not caused by tachycardia

Be cautious in hypovolemic pt since Beta Blockade may cause profound hypotension

Nonselective Beta Blockers or high dose of Selective Beta Blockers are not recommended for pts with COPD (can cause broncoconstriction), PVD (can cause peripheral vasoconstriction), Diabetes (hypoglycemia may be masked no increase in HR)

Combined & blocker

Ex:- Labetalol , Carvedilol , Medroxalol Non selective & 1 selective blocker.Used as antihypertensive ----less tachycardia than blockers . CarvedilolHighly lipid soluble Also has antioxidant properties and protect against vascular thickening (remodeling) Very dramatic results in CHF clinical trials.Decreased mortality by 65%

Labetalol

Selective Alpha1 and Nonselective Beta BlockerPresynaptic Alpha2 receptors are spared Beta to Alpha potency ratio 7:1 (IV) and 3:1 (PO)T1/2 = 5-8hrs, prolonged in liver dz, unchanged in renal dzBlood pressure is ed by PVR without significant change in HR & COBP should be lowered within 5-10min of 0.1-0.5mg/kg IV dose

UsesHTN emergencies (eg epi overdose from local)20-80mg IV q10minPheochromocytoma pts with rebound HTN after withdrawal of ClonidineUsed in surgeries where Controlled Hypotension needed (10mg intermittently) Side effectsOrthostatic hypotension (most common)Bronchospasm (susceptible pts)Other Beta Blockade S.E.CHFBradycardiaHeart Block

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