Adrenergic bockers (VK)

ADRENERGIC ADRENERGIC BLOCKERS BLOCKERS

IntroductionIntroduction Alpha & Beta adrenergic receptor Alpha & Beta adrenergic receptor

antagonists prevent the interaction of the antagonists prevent the interaction of the endogenous endogenous neurotransmitterneurotransmitter norepinephrine (N.E) or norepinephrine (N.E) or sympathomimetics (endogenous or sympathomimetics (endogenous or synthetic catecholamines, synthetic synthetic catecholamines, synthetic noncatecholamines) with the noncatecholamines) with the corresponding adrenergic receptorcorresponding adrenergic receptor

Such interference attenuates SNS Such interference attenuates SNS homeostatic mechanisms & evokes homeostatic mechanisms & evokes predictable pharmacologic responsespredictable pharmacologic responses

Alpha Blockers Alpha Blockers Interfere with ability of catecholamines or Interfere with ability of catecholamines or

other sympathomimetics to provoke alpha other sympathomimetics to provoke alpha responses on the heart & peripheral responses on the heart & peripheral vasculaturevasculature

Inhibitory action of epinephrine on insulin Inhibitory action of epinephrine on insulin secretion is prevented too (insulin production secretion is prevented too (insulin production is not reduced)is not reduced)

Side effectsSide effects: orthostatic hypotension, : orthostatic hypotension, baroreceptor mediated reflex tachycardia, baroreceptor mediated reflex tachycardia, impotenceimpotence

Absence of Beta blockade allows maximum Absence of Beta blockade allows maximum expression of cardiac stimulation from N.E.expression of cardiac stimulation from N.E.

They are both competitive antagonist of They are both competitive antagonist of αα or or ββ or both. or both.

NH3

COOH

Gq

Phospho-lipase C

(+)

PIP2

IP3 Diacylglycerol

Increase Ca2+ Activate ProteinKinase C

Response

Receptor agonists activate signal transduction pathwaysReceptor agonists activate signal transduction pathways

1 adrenergic

receptor

HO

HO CH

OH

CH2 NH2

Norepinephrine

Receptor antagonists block agonist binding to the receptorReceptor antagonists block agonist binding to the receptor

NH3

COOH

Gq

Phospho-lipase C

Antagonist

CLASSIFICATIONCLASSIFICATION

Non selectiveNon selective ReversibleReversible: : Phentolamine , TolazolinePhentolamine , Tolazoline Irreversible Irreversible :: PhenoxybenzaminePhenoxybenzamine

SelectiveSelective Alpha 1 selective-Alpha 1 selective- Prazosin , terazosin , Doxazosin , Tamsulosin , Prazosin , terazosin , Doxazosin , Tamsulosin ,

AlfuzosinAlfuzosin Alpha 2 selective-Alpha 2 selective- Yohimbine, IdoxaminYohimbine, Idoxamin

MiscellaneousMiscellaneous Ergot alkaloidsErgot alkaloids:: Ergotoxine , Ergotamine Ergotoxine , Ergotamine

Pharmacological Effects -Pharmacological Effects -

CVSCVS• Fall in BP (Fall in BP (αα11 & & αα2 2 blockade)blockade)• Postural hypotensionPostural hypotension• Reflex tachycardiaReflex tachycardia• Vasomotor reversal of DaleVasomotor reversal of Dale• Hypovolemia accentuates hypotensionHypovolemia accentuates hypotension• Hypotension-Hypotension- g.f.r reducedg.f.r reduced

Na & water retentionNa & water retentionrenin release ↓BPrenin release ↓BP

Pharmacological EffectsPharmacological EffectsNasal stuffinessNasal stuffiness

EyeEye – Miosis – Miosis

Urinary bladderUrinary bladder -Decreased tone in sphincter and -Decreased tone in sphincter and prostate (prostate (αα1A blockade)1A blockade)

Metabolic effectsMetabolic effects – Increased insulin secretion – Increased insulin secretion

Reproductive systemReproductive systemInhibition of contraction of Vas deference and related Inhibition of contraction of Vas deference and related

organs is blocked by organs is blocked by αα1 blockade…..inhibition of 1 blockade…..inhibition of ejaculation…impotenceejaculation…impotence

PhenoxybenzaminePhenoxybenzamine

Alpha blockade develops gradually and Alpha blockade develops gradually and lasts for 3-4 days.lasts for 3-4 days.

Fall in BP by Phenoxy. is mainly due to Fall in BP by Phenoxy. is mainly due to venodilatation…postural hypotension.venodilatation…postural hypotension.

Shifts blood from pulmonary to Shifts blood from pulmonary to systemic circulation, extravascular to systemic circulation, extravascular to vascular compartments.vascular compartments.

Lipid soluble drug can penetrate CNS Lipid soluble drug can penetrate CNS may cause nausea & vomiting on rapid may cause nausea & vomiting on rapid i.v administration i.v administration

Adverse effectsAdverse effects

Postural hypotensionPostural hypotension TachycardiaTachycardia SedationSedation Nasal stuffinessNasal stuffiness MiosisMiosis Impotence (inhibits ejaculation)Impotence (inhibits ejaculation) Exercise care in hypovolemic Exercise care in hypovolemic

patientspatients

USESUSES

Diagnostic and intraoperative Diagnostic and intraoperative

management of pheochromocytoma.management of pheochromocytoma.

Secondary shock (occasionally)Secondary shock (occasionally)

Peripheral vascular diseases.Peripheral vascular diseases.

PhentolaminePhentolamine Congener of TolazolineCongener of Tolazoline Rapidly acting Rapidly acting αα blocker with short DOA blocker with short DOA Many other effects including:Many other effects including:

ParasympathomimeticParasympathomimeticIncreased gastric acid secretionIncreased gastric acid secretionCardiac stimulationCardiac stimulationIncreased secretion from exocrine glands, Increased secretion from exocrine glands, such as salivary, sweat, lacrimal, pancreaticsuch as salivary, sweat, lacrimal, pancreatic

Coronary artery disease and peptic ulcer Coronary artery disease and peptic ulcer relative contraindication to it.relative contraindication to it.

Phentolamine : usesPhentolamine : uses

Diagnostic and intraoperative Diagnostic and intraoperative management of pheochromocytomamanagement of pheochromocytoma

For control of hypertension due to For control of hypertension due to clonidine withdrawal.clonidine withdrawal.

Cheese reaction.Cheese reaction. To counteract vasoconstriction due To counteract vasoconstriction due

to extravasation of noradrenaline / to extravasation of noradrenaline / Dopamine given IV.Dopamine given IV.

Dose: 5mgDose: 5mg

Ergot alkaloidsErgot alkaloids

Interact with serotonin and Interact with serotonin and dopamine receptors alsodopamine receptors also

Direct smooth muscle contractionDirect smooth muscle contraction Structure-activity relationshipsStructure-activity relationships Coronary vasoconstrictionCoronary vasoconstriction Toxicity: GI, vascular insufficiency –Toxicity: GI, vascular insufficiency –

ergotismergotism Use in migraineUse in migraine

Ergot alkaloidsErgot alkaloids

Ergotoxine, Ergotamine are partial Ergotoxine, Ergotamine are partial agonist and antagonist at adrenergic agonist and antagonist at adrenergic αα, 5HT and DA receptors., 5HT and DA receptors.

Ergotoxine, dihydroergotoxine are Ergotoxine, dihydroergotoxine are more potent more potent αα blocker and less blocker and less potent vasoconstrictor than potent vasoconstrictor than ergotamine.ergotamine.

USE: MigraineUSE: Migraine

Alpha-1 selective Alpha-1 selective blockersblockersPrazosinPrazosin Highly selective Highly selective αα1 blocker, selectivity ratio 1 blocker, selectivity ratio

1000: 11000: 1

Less cardiac stimulation since it preserves Less cardiac stimulation since it preserves αα2 2 mediated negative feedback + other mechanismsmediated negative feedback + other mechanisms

Fall in BP with no/ minimal tachycardia.Fall in BP with no/ minimal tachycardia. Used in CHF and in HT but tolerance develops Used in CHF and in HT but tolerance develops

with time, may be due to fluid retention.with time, may be due to fluid retention. Adverse effectsAdverse effects: First dose phenomenon i.e : First dose phenomenon i.e

postural hypotension with initial doses.postural hypotension with initial doses. Favorable effect on plasma lipids: increase Favorable effect on plasma lipids: increase

HDL/LDL ratioHDL/LDL ratio

ADR (µg/Kg)

1 10 100 5000.1

1 10 100 500

+PRAZOSIN

BP

HR

Effect of Adrenaline (ADR) on Blood Pressure and Heart Rate Before and After Prazosin

Prazosin : usesPrazosin : uses

Antihypertensive Antihypertensive DOC: Benign prostatic hyperplasia DOC: Benign prostatic hyperplasia

( BPH)( BPH) Blocks Blocks αα1 in bladder trigone & prostate1 in bladder trigone & prostate Decreases toneDecreases tone Improves urine flowImproves urine flow Decreases residual urineDecreases residual urine

Dose :1-4 mg BD/ TDSDose :1-4 mg BD/ TDS TerazosinTerazosin : longer t1/2 , OD dosing : longer t1/2 , OD dosing

TamsulosinTamsulosin

Uroselective Uroselective αα1A/ 1A/ αα1D blocker.1D blocker. As effective as Terazosin in BPHAs effective as Terazosin in BPH α α 1A are predominant in bladder 1A are predominant in bladder

base and prostate. 30 times high base and prostate. 30 times high affinity for affinity for αα1A1A

No effect on BP and heart rate.No effect on BP and heart rate. Dizziness and retrograde ejaculation Dizziness and retrograde ejaculation

are the only AE.are the only AE.

α α 2 selective blockers2 selective blockersYohimbineYohimbine

Cardiovascular effects – peripheral Cardiovascular effects – peripheral and central effectsand central effects

Blocks other receptors also – 5HT, DABlocks other receptors also – 5HT, DA Increases ADH releaseIncreases ADH release Enhances sexual activity – aphrodisiacEnhances sexual activity – aphrodisiac Potential uses: depression, obesity, Potential uses: depression, obesity,

NIDDMNIDDM

α α Blockade—Adverse Blockade—Adverse EffectsEffects Orthostatic hypotensionOrthostatic hypotension

Reduces blood flow to brain causing dizziness, Reduces blood flow to brain causing dizziness, lightheadedness and fainting lightheadedness and fainting

Due to vasodilation of veins lowering blood flow to Due to vasodilation of veins lowering blood flow to brainbrain

Reflex tachycardiaReflex tachycardia Increase heart rate by stimulating baroreceptor Increase heart rate by stimulating baroreceptor

reflex which causes and increased heart rate to reflex which causes and increased heart rate to compensatecompensate

Nasal CongestionNasal Congestion Dilates vessels of nasal mucosaDilates vessels of nasal mucosa

Inhibition of ejaculationInhibition of ejaculation α α 11, sympathetic reaction needed, sympathetic reaction needed

Sodium retentionSodium retention Decreased blood pressure decreases filtering by Decreased blood pressure decreases filtering by

kidneys and causes retention of water and saltkidneys and causes retention of water and salt

α α Blockade—UsesBlockade—Uses Therapeutic ApplicationsTherapeutic Applications

Essential hypertension Essential hypertension

Benign prostatic hyperplasiaBenign prostatic hyperplasia

PheochromocytomaPheochromocytoma

Raynaud’s disease Raynaud’s disease

Overdose of Overdose of αα1 agonist 1 agonist

Therapeutic Uses ofTherapeutic Uses ofAlpha-Adrenergic BlockersAlpha-Adrenergic Blockers

Hypertension - Hypertension - αα1 selective1 selective Conditions associated with increased Conditions associated with increased

sympathetic activity – e.g. sympathetic activity – e.g. pheochromocytomapheochromocytoma

Hemodynamic shockHemodynamic shock Peripheral vascular disease – Raynaud’sPeripheral vascular disease – Raynaud’s CHFCHF Benign prostatic hyperplasia-prazosinBenign prostatic hyperplasia-prazosin Pulmonary hypertension – tolazolinePulmonary hypertension – tolazoline Yohimbine or intracavernous Yohimbine or intracavernous

phentolamine+papaverine for impotencephentolamine+papaverine for impotence

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Beta BlockersBeta Blockers

Selective Affinity for Beta-adrenergic receptorsSelective Affinity for Beta-adrenergic receptors

All beta blockers are competitive antagonistsAll beta blockers are competitive antagonists

Beta blockade can be reversed by Beta agonist Beta blockade can be reversed by Beta agonist

by displacement from occupied receptors if by displacement from occupied receptors if

large amount of agonist is givenlarge amount of agonist is given

Chronic Beta Blocker use = increased number Chronic Beta Blocker use = increased number

of beta-adrenergic receptors (up regulation)of beta-adrenergic receptors (up regulation)

Structure Activity Structure Activity RelationshipsRelationships

Beta Blockers: derived from isoproterenol Beta Blockers: derived from isoproterenol (beta agonist)(beta agonist)

Substitutions on the benzene ring Substitutions on the benzene ring determines if drug is antagonist or agonistdetermines if drug is antagonist or agonist

Levorotatory forms of beta Levorotatory forms of beta agonists/antagonists more potent than agonists/antagonists more potent than Dextrorotatory formsDextrorotatory forms

Example: Dextrorotatory isomer of Example: Dextrorotatory isomer of Propranolol has <1% of the potency of the Propranolol has <1% of the potency of the Levorotatory formLevorotatory form

ClassificationClassification

Pharmacological actions Pharmacological actions

CVS:CVS: HeartHeart: : Propranolol ↓ss HR, FOC, COP. Propranolol ↓ss HR, FOC, COP.

↓ss cardiac work and oxygen consumption.↓ss cardiac work and oxygen consumption. Blood vesselsBlood vessels: : fall in BP both diastolic and fall in BP both diastolic and

systolic after continuous treatment.systolic after continuous treatment. Decrease in COPDecrease in COP Initial increase followed by decrease in TPRInitial increase followed by decrease in TPR Decreased release of NE from symphathetic Decreased release of NE from symphathetic

neuronsneurons Decrease renin release from kidneyDecrease renin release from kidney Central action decreasing symphathetic Central action decreasing symphathetic

outflowoutflow

OTHER SYSTEMSOTHER SYSTEMS R SR S: : BronchoconstrictionBronchoconstriction CNSCNS: : ↓ss anxiety, tremors, other actions. ↓ss anxiety, tremors, other actions.

lightheadedness, forgetfulness, lightheadedness, forgetfulness, nightmares, rarely hallucinationsnightmares, rarely hallucinations

Local anesthetic actionLocal anesthetic action: : Propranolol-Propranolol-membrane stabilizing actionmembrane stabilizing action

MetabolicMetabolic : : increases LDL, triglycerides, ↓ss HDL by increases LDL, triglycerides, ↓ss HDL by

inhibiting lipolysis.inhibiting lipolysis. Adversely effects recovery from insulin Adversely effects recovery from insulin

induced hypoglycemia.induced hypoglycemia. Skeletal musclesSkeletal muscles : : Propranolol inhibits Propranolol inhibits

adrenergically evoked tremors.adrenergically evoked tremors. EyeEye : : decreases synthesis and releases of decreases synthesis and releases of

aqueous humour … ↓ iop aqueous humour … ↓ iop

ContraindicationContraindication

CHFCHF BradycardiaBradycardia COPDCOPD Bronchial asthmaBronchial asthma Diabetis mellitusDiabetis mellitus HypertriglygeridemiaHypertriglygeridemia Partial –complete heart blockPartial –complete heart block

Adverse effectsAdverse effects Adverse Effects of betaAdverse Effects of beta11 blockade blockade

BradycardiaBradycardia Reduced cardiac outputReduced cardiac output Heart failureHeart failure AV blockAV block Long-term use can sensitize heart to catecholamines. If Long-term use can sensitize heart to catecholamines. If

withdrawn abruptly, angina pain and/or ventricular withdrawn abruptly, angina pain and/or ventricular dysrhythmias can develop= dysrhythmias can develop= rebound excitationrebound excitation. Withdraw . Withdraw drug graduallydrug gradually

COPD, Bronchial asthmaCOPD, Bronchial asthma Tiredness , reduced exercise capacity.Tiredness , reduced exercise capacity. Rebound hypertension on abrupt withdrawal.Rebound hypertension on abrupt withdrawal. Cold hands and feets Cold hands and feets hypoglycemiahypoglycemia OthersOthers: gi upset, lack of drive, lightheadedness, : gi upset, lack of drive, lightheadedness,

forgetfulness, nightmares, rarely hallucinationsforgetfulness, nightmares, rarely hallucinations

CARDIOSELECTIVE (BETA CARDIOSELECTIVE (BETA 1 )1 )

MetoprololMetoprolol AtenololAtenolol AcebutololAcebutolol BisoprololBisoprolol EsmololEsmolol

No effect on bronchus, carbohydrate No effect on bronchus, carbohydrate metabolism, lipids.metabolism, lipids.

Lower incidences of Cold hands and feets.Lower incidences of Cold hands and feets. Less liable to impair exercise tolerance Less liable to impair exercise tolerance

and essential tremors.and essential tremors.

MetoprololMetoprolol

Cardioselective Cardioselective Preferred in diabetics on insulin or Preferred in diabetics on insulin or

oral hypoglycemics.oral hypoglycemics. Less likely to worsen asthmaLess likely to worsen asthma Side effects are milder.Side effects are milder. USE: AMI without bradycardiaUSE: AMI without bradycardia

AtenololAtenolol

Selective beta 1 blocker with low lipid Selective beta 1 blocker with low lipid solubility.solubility.

Longer duration action. OD dosingLonger duration action. OD dosing Side effects related to CNS are less Side effects related to CNS are less

prominentprominent No effect on bronchus, carbohydrate No effect on bronchus, carbohydrate

metabolism, lipidsmetabolism, lipids USE: Most commonly used inUSE: Most commonly used in

HypertentionHypertention angina angina

AcebutololAcebutolol

Cardioselective with intrinsic Cardioselective with intrinsic

symphathomimetic and membrane symphathomimetic and membrane

stabilizing activity.stabilizing activity.

Side effect profile is like that of Metoprolol.Side effect profile is like that of Metoprolol.

Preferred in those prone to severe Preferred in those prone to severe

bradycardia and low cardiac reserve.bradycardia and low cardiac reserve.

EsmololEsmolol Ultra short acting cardioselective beta Ultra short acting cardioselective beta

blocker.blocker. DOA 15-20mins after iv infusionDOA 15-20mins after iv infusion Rapid onset short lasting fall in BPRapid onset short lasting fall in BP USES: USES:

To terminate supraventricular tachycardiaTo terminate supraventricular tachycardia Atrial fibrillation or flutterAtrial fibrillation or flutter Arrythmias during anaesthesiasArrythmias during anaesthesias During cardiac surgery to decrease HR & BPDuring cardiac surgery to decrease HR & BP Early treatment of AMIEarly treatment of AMI

Celiprolol & NebivololCeliprolol & Nebivolol

Beta 1 blocker + beta 2 agonismBeta 1 blocker + beta 2 agonism Acts as NO donor …vasodilatationActs as NO donor …vasodilatation Uses:Uses:

Hypertension Hypertension CHFCHF

Intrinsic Intrinsic symphathomimetic activitysymphathomimetic activity

PindololPindolol Used primarily as antihypertensive, Used primarily as antihypertensive,

Preferred in those prone to severe Preferred in those prone to severe bradycardia and low cardiac reserve.bradycardia and low cardiac reserve.

Chances of rebound hypertention Chances of rebound hypertention are less. are less.

Without intrinsic Without intrinsic symphathomimetic activitysymphathomimetic activity

Sotalol : Class III antiarrhythmicSotalol : Class III antiarrhythmic Timolol : topical use in eyeTimolol : topical use in eye

Uses of Beta blockersUses of Beta blockers HypertensionHypertension Angina pectorisAngina pectoris Cardiac arryhythmiasCardiac arryhythmias AMIAMI CHFCHF Dissecting aortic aneurysmDissecting aortic aneurysm PheochromocytomaPheochromocytoma ThyrotoxicosisThyrotoxicosis MigraineMigraine Essential tremors.Essential tremors. GlaucomaGlaucoma AnxietyAnxiety

alpha + beta blockeralpha + beta blocker

LabetalolLabetalol ββ 1 + 1 + αα1 blocking as well as 1 blocking as well as ββ2 2

agonism.agonism. 5 times more potent 5 times more potent ββ blocker than blocker than αα.. Fall in BP is due to decrease in COP Fall in BP is due to decrease in COP

and TPRand TPR Uses : pheochromocytoma, clonidine Uses : pheochromocytoma, clonidine

withdrawl, essential hypertention.withdrawl, essential hypertention. A/E: postural hypotension, impotence.A/E: postural hypotension, impotence.

Carvedilol Carvedilol

ββ 1 + 1 + ββ2+ 2+ αα1 blocker, calcium 1 blocker, calcium channel blocker.channel blocker.

Antioxidant property.Antioxidant property. Use: Use:

HypertensionHypertension CHF CHF Angina.Angina.

Action Potential

Na+

Effect of chronic -receptor blockade

Presynaptic neuron

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

Action Potential

Na+

Effect of chronic -receptor blockade: Receptor up-regulation

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

Action Potential

Na+

Pharmacologic manipulation of the adrenergic system

Presynaptic neuron

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

DA

NE

Uptake 1Na+, Cl-

NE

NENENE

NE

MAO

1

2

3

Inhibition of Inhibition of norepinephrine norepinephrine

synthesissynthesis

tyrosine hydroxylase

aromatic L-amino acid decarboxylase

dopamine -hydroxylase

phenylethanolamine-N-methyltransferase

MetyrosineX

Tyrosine

DOPA

Dopamine

Norepinephrine

Epinephrine

Action Potential

Na+

Drugs that reduce storage or release of NE

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

NE

NE

NE

MAO

ReserpineGuanethidine

GuanethidineGuanethidine,

Bretylium

Slow onset of actionSlow onset of action Sustained effect Sustained effect

(weeks)(weeks) Used in the treatment Used in the treatment

of hypertensionof hypertension May precipitate May precipitate

depressiondepression

Reserpine (Serpasil)

Indole alkaloid obtained Indole alkaloid obtained from the root of from the root of Rauwolfia Rauwolfia serpentinaserpentina

Block vesicular Block vesicular monoamine transportersmonoamine transporters

Deplete vesicular pool of Deplete vesicular pool of NENE

Catecholamine depletersCatecholamine depleters

Almost completely protonated at physiological pHAlmost completely protonated at physiological pH

““Pharmacologic sympathectomy”Pharmacologic sympathectomy”

Effects can be blocked by transport blockersEffects can be blocked by transport blockers

Uses: HypertensionUses: Hypertension

Guanethidine (Ismelin)

Drugs that reduce storage or release of NEDrugs that reduce storage or release of NE

Action Potential

Na+

Drugs that reduce storage or release of NE

H+

Effector organ

Ca2+

Na+

Tyrosine

Tyrosine

Dopamine

NE

NE

NE

MAO

Guanethidine

GuanethidineGuanethidine,

Drugs that reduce storage or release of NEDrugs that reduce storage or release of NE

Aromatic quaternary ammoniumAromatic quaternary ammonium Precise mechanism unknownPrecise mechanism unknown Displace and release NE and prevent further Displace and release NE and prevent further

release (depletion)release (depletion) Local anestheticLocal anesthetic Administered: ParenteralAdministered: Parenteral Uses: Antiarrhythmic (ventricular fibrillation)Uses: Antiarrhythmic (ventricular fibrillation)

Bretylium tosylate (Bretylol)

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