Adrenergic Agonists and Antagonists (for MD Pharmacology)

Dr. Advaitha

CATECHOLAMINES

• These are compounds containing a catecholmoiety

(a benzene ring with two adjacent hydroxyl groups and an amine side chain.)

Dopamine :

• It is the metabolic precursor of noradrenalineand adrenaline.

• Main neurotransmitter in the Brain.

• Noradrenaline (norepinephrine) : a transmitter released by sympathetic nerve terminals.

• Adrenaline (epinephrine): a hormone secreted by the adrenal medulla

Synthesis, Storage, Release, andRemoval of Norepinephrine

In Noradrenergic Neuron

• It starts with the amino acid tyrosine (from diet)

• It enters the Noradrenergic neuron by active transport.

In the neuronal cytosol….

• Tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa).

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Drug :

• Tyrosine hydroxylase enzyme inhibitor :

“α-Methyl-p-tyrosine”

• Can be Used to control the discharge of NE and E in surgical removal of adrenal tumor.

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• DOPA is converted to dopamine by the enzyme L–amino acid decarboxylase or DOPA decarboxylase

• The dopamine is actively transported into storage vesicles.

In storage vesicles…..

• It is in here, Dopamine, is converted to Norepinephrine by dopamine –beta-hydroxylase (exclusively present in synaptic vesicles)

In the adrenal medulla..

• The synthesis is carried one step further.

• The enzyme phenyl-ethanolamine N-methyltransferase converts norepinephrine to epinephrine.

• The human adrenal medulla contains approximately 80% epinephrine and 20%norepinephrine.

• NE is stored in the synaptic vesicles.

• Noradrenergic transmitter is released during action potentials through exocytosis.

Action Potential causes : Na+, Ca2+ and Cl- enter while K+ efflux…

Ca2+ entry causes disruption of Vesicles to release NE

Drugs :

• Release of NE is inhibited by bretylium and guanethidene.

• Can be used in HTN (now obsolete)

• So.. after Action Potential and effect…..

• There is removal of norepinephrine from Synapse.

Three processes contribute :

1. Transport back into the noradrenergic neuron (uptake1)

• For vesicular storage or enzymatic inactivation

by mitochondrial MAO.

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About , Monoamine Oxidase (MAO) and Catecholamine-O-Methyltransferase (COMT) :

• Both enzymes inactivates NE and E.

• Both are widely distributed (Liver, Intestine, Kidney, Brain)

• However, COMT is absent In ADRENERGIC Neuron.

• So it is only MAO which metabolises NE, intraneuronally…

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2.Diffusion from the synapse into the circulation

For ultimate enzymatic destruction in the liver ( by COMT and MAO ) and renal excretion

3. Active transport of the released transmitter into effector cells (extraneuronal uptake or uptake2)

followed by enzymatic Inactivation by COMT

Drugs :

• Neuronal reuptake (uptake1) inhibitors :

Cocaine and Tricyclic antidepressants.

-potentiates effect of NE and E

• Vesicular reuptake inhibitors : Reserpine

(used in HTN, obsolete)

• Inhibitors of MAO-A (present in Adrenergic neuron, intestine, liver, Kidney and Placenta) :

Clorgyline and Meclobemide ( rarely used in depression)

• Inhibitors of MAO-B (present in Dopaminergicneuron, brain, Platelets and Iiver) :

Selegeline ( used in parkinson’s disease)

Termination of NE, E

Termination of Dopamine

Adrenergic Receptors

• The liberated NE at Synaptic junction stimulates postsynaptic adrenoreceptors---

Alpha1, Alpha2. Beta1, Beta2, Beta3

to elicit end organ response.

So what are the end organ responses of each receptor ????

• All belong to the superfamily of G-protein-coupled receptors

• α1 receptors activate phospholipase C, producing

inositol trisphosphate and diacylglycerol as second messengers

• α2 receptors inhibit adenylyl cyclase, decreasing

cAMP formation

• All types of β receptor stimulate adenylyl cyclase

• All receptors Are mostly present Postsynapticallyexcept α2 which is in Presynaptic region.

α1 Receptors

• When activated produces Excitatory effects on in most organs.

• E.g, Vascular smooth muscle, Salivary glands, Bronchi, Uterus, Radial muscle of iris etc.

• Except in intestine where they produce Relaxation.

α2 Receptors• Present Presynaptically in Post ganglionic

Adrenergic and Cholinergic (gut) Neuron.

• When activated by NE in synaptic cleft-

it inhibits further release of NE from presynaptic Adrenergic neuron.

They also inhibit Ach in cholinergic neuron (in gut)

• They are also present Postsynaptically in blood vessels etc. where it behaves like α 1 (vasoconstriction)

In Brain, whether Pre or Post synaptically present it decreases sympathetic outflow.

β1 receptors

• located Postsynaptically.

• found in heart.

- Produce Positive ionotropic and Chronotropic effects.

• found in Kidney

- Promotes Renin release.

β2 Receptors

• Their action causes smooth muscle relaxation (Except in Myocardium)

• It is present in Bronchi, Blood vessels supplying Skeletal Muscles, coronary artery, uterus , GIT, Heart smooth muscle.

• There are also some presynaptic β2. these facilitates NE release unlike α2.

• Uterus

Non pregnant Contraction α1

Pregnant Relaxation β2

Classification of SympathomimeticDrugs

Classified as :

• Direct-acting,

• Indirect-acting,

• Mixed-acting sympathomimetics.

• Direct-acting sympathomimetic drugs act directly on one or more of the adrenergic receptors.

• Indirect-acting drugs are those increase the availability of norepinephrine (NE) or epinephrine to stimulate adrenergic receptors.

By releasing or displacing NE from vesicles of sympathetic nerve varicosities

or by blocking the transport of NE into sympathetic neurons

or by blocking the metabolizing enzymes, (MAO ,COMT)

Epinehrine or Adrenaline• Acts on β2 > β1= α1= α2, and weak β3 action

• Cardiac Effects : β1, β2 effects

• Final effect : increase in SBP

Vascular Effects :

• Constricton of arterioles in skin,mucousmembrane, viscera and renal beds-- α1 effect

• Dilation predominates in skeletal muscle, liver and coronaries– β2 effect. Decrease in peripheral vascular resistance

• So the cumulative effect decease in DBP

• What happens when adrenaline is given after pretreatment of α Blocker ?

ANS : Hypotension

( Dale’s vasomotor reversal phenomenon ) predominant β2 effect.

• What happens when adrenaline is given after pretreatment of β Blocker ?

ANS : Accentuated Hypertensive effect.

• Effects on smooth muscle :

• Bronchial :

bronchodilation- β2 effect.

Decrease in bronchial secretion α1 effect

• GIT :

• Constriction on sphincters α1 effect

• Gut relaxation α2 and β effect

Uses of AdrenalineAnaphylactic Shock :

• Relieves Bronchospasm and Angioneuroticedema of larynx

• Prevents release of histamine from mast cell.

• Dose : 0.3 – 0.5 ml IM. 1: 1000 solution IM or SC

• Bronchial Asthama : Rarely used.

• Cardiac resusitation : Intracardiac route to reverse sudden cardiac arrest in drowning and electrocution

(Absolute Containdication in Ventricular Fibrillation)

• To prolong duration of loacal Anaesthetic agents.

• To control Epistaxis : Rarely

Adverse effects• Cerebral Haemorrage

• Angina

• Palpitation

• Arrhythmias

• CNS side effects : Anxiety, tremors and headache.

Contraindications/ interactions

• Angina and Hypertension

• Hyperthyroidism ( upregulation of receptors)

• Concomitant use of MAO

Noradrenaline• Acts on α1=α2>β1, β3.

• Poor β2 action.

Cardiovascular effects :

• Raises both SBP and DBP. (because β1-SBP,α1-DBP )

Uses

• Cardiogenic Shock

• Hypotensive states in Surgical shock and MI ( it increases peripheral vascular resistance)

• Dose : 0.5 to 1 ml per minute. IV infusion.

Facts :

• Should be careful of renal shut down. So Dopamine is preferred.

• As it is a powerful vasoconstrictor, if given undiluted via SC or IM causes, Necrosis.

Dopamine• Acts on D1, D2, β1, little α action

• No β2 and β3 action.

• Does not enter the BBB when given Parentrally.

• Effects :

It is dose dependent.

Uses

• Cardiogenic Shock

• CCF, liver and renal failure

• Hypotensive states (after correcting hypovolemia)

• Dose is 5mcg-10mcg/kg/min IV

Adverse effects

• Nausea vomitting

• Tachycardia

• Hypertension

• Ectopic beats

• Arrhythmias

Dobutamine

• Synthetic Catecholamie.

• Racemic Mixture of -

L-form (α1 agonist )

D- form (α1 antagonist and β1 agonist)

• So it is relatively selective β1 agonist.

Effects :

• More selective ionotropic and chronotropiceffects.

Uses :

• Heart failure : it increases CO and stroke Volume without increasing Heart rate.

Adverse effects :

• Sharp rise in BP in HTN patients

• Angina can be aggravated

Dopexamine• Synthetic Catecholamie.• Acts on D1, D2, and β2 receptors

• Effects : Peripheral Vasodilation, increase Cardiac output and increased renal blood flow.

• Uses : To provide Haemodynamic suppport in CCF and Shock

Adverse Effects :• Tachycardia and Hypotension

Fenoldapam• Synthetic. Selective D1 agonist

Effects :

• vasodilation in peripheral arteriole, coronary, Renal and Mesentric vessels

Uses :

• Short term management of Severe Hypertension in Patients with severe Renal impairement.

• Adverse Effects : Reflex Tachycardia, Headache.

“ α1 Selective agonists ”

Phenylephrine

• Non Catecholamine

• So not metabolized by MAO or COMT

• Effects : α1 stimulation increases Peripheral vascular resistance and BP ( associated with reflex Bradycardia)

Uses :

• Nasal decongestant

• Mydriatic

• Hypotension (rarely)

Other similar drugs are :

• Oxymetaxoline

• Xylometazoline

• Midodrine

• Naphazoline

α 2 Selective Agonist

ClonidineUses with MOA :

1) Moderate Hypertension

Mechanism : Not properly elucidated.

• stimulates central α 2 receptors to decrease sympathetic outflow.

• Stimulates presynaptic α2 on postganglionic sympathetic neuron to supress NE release.

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• When given I.V there is transient rise in BP ( post syaptic α2 effect which causes vasoconstriction) and then Decrease.

• However when given oral, there is only hypotensive effects

• 100 % bioavailability.

• Dose :100-300 mcg BD.

• Also available as Transdermal Patch.

• Major limitation is Rebound Hypertension.

2) In the Prophylaxis of migraine

• It reduces cerebral blood flow

3) Management of opiate, alcohol and Nicotine Withdrawl

• It reduces sympathetic effects associated with withdrawl

4) Preanaesthetic Medication:

• For its slightly sedative, anxiolytic and analgesic effect

5)Menopausal Hot flushes :

• For counteracting symptoms

6) To control diarrhoea in diabetic patients with autonomic neuropathy

α2 in GIT decreases sodium,water retention and reduces motility by inhibiting Ach

Adverse Effects :

• Dry mouth

• Sedation

• Nasal stuffiness

• Constipation

• Impotence

• Contact dermatitis (in patch usage)

Newer congeners of clonidine

• Moxonidine

• Rilmenidine

In these rebound hypertension is less frequent

longer acting than Clonidine

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• Apraclonidine

• Brimonidine

Used in Glaucoma (reduces Aqueous Humor by α2 action in cilliary muscles)

β2 selective Agonists

Salbutamol

Effect : Produce relaxant effect on bronchi, uterus.

• Has minimal cardiac stimulant property.

• Half life : 4hr

Uses :

• Immediate relief of Asthama

• Dose : 100mcg in Metered dose inhaler

• or 2-4 mg PO TDS

• To arrest uncomplicated premature labour(inbetween 24 to 34 weks of gestation) by slow IV injection

Adverse effects :

• Tremors in hands, Palpitations, hypokalemia

• Terbutaline

• Salmetrol and Formetrol ( longer acting 12hr)

• Pirbuterol

• Clenbuterol ( anabolic strength on skeletal muscle, illicit use in sports)

Indirectly acting drugsTyramine

• Not used clinically

• It is found in cheese, beef, wine, beer, yoghurt yeast.

• Metabolized by MAO.

• Significance : If patient on MAO inhibitor, it can trigger hypertensive crisis

Amphetamine

• Powerful CNS stimulant .

CNS effects :

Stimulation of

• cortical region

• Reticular activating system.

• Medullary respiratory centre.

Causes

• Wakefullness

• Alertness

• Decreased sense of fatigue

• The performance of simple task increases but errors increase

• Physical performance improves

CVS effects :

• Increases SBP and DBP

• Tachycardia followed by bradycardia

Other effects

• Suppression of appetite by depressing lateral hypothalamic centre

Uses :

• Narcolepsy : prevents attacks of daytime time sleep

• ADHD (excitability, impulsiveness, difficulty in sustaining attention) : Paradoxically improves with low dose

• Weight reduction

Other Analogues…

• Methylphenidate : more prominent action on mental function.

• Methamphetamine : High potential of abuse

• Pemoline : minimal CVS effects and longer plasma half life. Used in ADHD

Mixed Action drugs Ephedrine

• Non catecholamine alkaloid

• Has direct action on α and β. Also enhance NE release.

• CNS : powerful stimulant

• CVS: increase in BP, CO, HR.

• RS : Bronchodilation.

Uses : Very restricted.

• Hypotension following Spinal Anaesthesia

• Chronic asthma.

Adverse effects :

• HTN,

• Insomnia,

• Tachyphylaxis.

Pseudoephedrine :

• Stereoisomer of ephedrine used as nasal decongestant.

Adrenergic Antagonists

Phenoxybenzamine

• Irreversible, nonselective, Non competitive Antagonist at α1,α2

• Also inhibits reuptake of NE by adrenergic nerve terminal.

• Crosses BBB.

Effects :

• Vasodilation

• Decrease Peripheral vascular Resistance

• Hypotension ( this triggers baroreceptorscausing sympathetic discharge)

• Tachycardia (sympathetic discharge action on β 1 )

Uses :

Treatment Phaeochromocytoma :

• Controls episodes of severe hypertensionduring surgical manipulation .

• Dose : 1mg /kg , slow IV infusion

In Raynaud’s syndrome and

Frostbite.

Dose 10mg TDS PO

Adverse effects :

• Marked Postural Hypotension with initial doses.

• Tolerance develops later.

• Inhibition of ejaculation

• Salt and water retention

• Sedation

• Fatigue

• Nausea

Phentolamine and Tolazoline

• Competitive, Reversible antagonist of α1, α2.

Effects :

• Vasodilation

• Decrease Peripheral vascular Resistance

• Hypotension ( this triggers baroreceptorscausing sympathetic discharge)

• Tachycardia (sympathetic discharge action on β 1 )

Other effects

• Nasal stufiness

• Miosis (loss of tone of radial muscles)

• Failure of ejaculation

• Nausea vomitting diarrhoea

( inhibition of inhibitory sympathetic influence of GIT and agonist action on H2 receptors, Tolazoline)

Uses

• Treatment Phaeochromocytoma.

• In peripheral vascular disease

• To prevent dermal necrosis ( after incidental extravasation of NE after IV infusion)

• To treat hypertensive crisis

α1 selective blockers Prazosin

Effects :

• Peripheral vasodilation

• Fall in arterial pressure

• Lesser tachycardia

Because of lack α 2 blocking no promotion of NE release, so no β1 stimulation.

Also partly because it decreases sympathetic outflow from CNS

It decreases cardiac preload

• It is also potent phosphodiesterase inhibitor

this leads to rise in cAMP in smooth muscle

So vasodilating effect.

• It relaxes smooth muscle - in bladder neck

Prostate capsule

Prostatic urethra

• So improves urine outflow in BPH

• Uses :

• In Hypertension : oral dose is 1mg bed time to avoid postural hypotension

• In BPH : 1-5 mg BD PO, however newer ones are preferred.

• In raynaud’s disease : rarely, because CCB are preferred.

Adverse effects :

• Postural hypotension

• Impotence

• Nasal congestion

Terazosin and doxazosin

• Longer duration of action

• Terazosin : 12 hr

• Doxazosin : 20hr..

• So OD dosing in HTN and BPH

Bunazosin and Alfuzosin

• Similar to Prazosin profile

• Alfuxosin : to be cautiously used in hepatic impairement as it is metabolized there.

• Bunazosin : longer acting but no favourableprofile than Prazosin

Tamsulosin and Silodosin

They are α 1A antagonist .

• α 1A is located on bladder neck and urethra

• α 1B is located in blood vessels

• It is more efficacious in BPH with little effect on BP unlike non-selective ones.

• Better bioavailability

• Plasma Half life 8hr

Dose :

Tamsulosin 0.2 to 0.4mg OD, PO

Silodosin(longer acting analogue of Tamsulosin) 4-8mg , PO

Adverse effects :

• Abnormal ejaculation

• Floppy iris syndrome – which creates problem in cataract surgery.

Alpha2 Antagonists Yohimbine

• Natural alkaloid from Pausinystalia Yohimbe

• Other than Alpha2 blocking action, has 5HT antagonist action.

Uses are unestablished

• To teat male sexual dysfunction

• To treat diabetic neuropathy

Propranolol• Nonselective, Competitive blocker . acts on

beta1 and beta2.

• It is prototype drug in the group

( all features are characteristic except that its not used in glaucoma even though it does reduces IOP)

• Cardiovascular effects :

The blockade of β1 causes

decrease of

heart rate,

myocardial contractility

conduction velocity

cardiac output

Automaticity ( suppression of SA Node)

This causes reduced myocardial oxygen demand

Consequent to all these BP falls

Blockade of β 2

• Peripheral vascular resistance rises, because α1

adrenoreceptor is no longer opposed by β 2

• This reflex vasoconstriction is maintained.

So Postural hypotension is least troublesome.

• Patient show a gradual fall in BP after chronic use.

Other minor mechanism to lower BP

• β1 blockade decrease release of renin.

(however pindolol which has no effect in renin is also effective antihypertensive)

• Blockade of facilitatory effect of presynaptic β 2

receptor on NE release.

• Chronic decrease in Cardiac output

Other effects on circulation :

• Plasma lipid profile is worsened in long term intake.

• Total TG, LDL increase and HDL level falls.

Respiratory effects

• Least affected in normal individuals

• In Asthmatic patients, it causes severe bronchoconstriction because of β 2 effect

• Metabolic effects

• In normal persons , minimal effects on basal glucose level.

• Normally ,

In stress-induced hypoglycemia and insulin induced hypoglycemia in diabetics, there is protective adrenaline induced glycogenolysis ( β 2 effect in liver )

This is protective mechanism to overcome hypoglycemia

Therefore Patients on Propranolol

blocking β 2 has adverse delay on recovery of hypoglycemia.

• Also it blocks sympathetic manifestations like palpitations and sweating

CNS effects

• It is lipid soluble . Enters BBB.

• Upto some extent decreases sympathetic outflow

• Produces sedation, lethargy and disturbances in sleep.

• It supresses performance anxiety ( more of peripheral action rather central)

• At higher doses it has Antipsychotic effects

Ocular effects

• It decreases formation of Aqueous Humor in glaucoma patients.

• But seldom used - low potency, Local Anesthetic action on cornea which is not desired

Miscellaneous effects :

• It prevents platelet aggregation and promotes fibrinolysis

• It reduces portal vein pressure in cirrhotic patients

• increases synthesis and release of PGs

Pharmacokinetics :

• Low bioavailability, extensively metabolized in liver.

• Plasma T ½ is 4-6 hrs.

• It has L and D forms.

• L is 100 times potent than D form

• D form has more membrane stabilizing property ,quinidine like effects.

• Commercial available is racemic mixture.

Uses :

Essential Hypertension :

• Used alone or with a diuretic

• Dose : 20-40 mg TDS PO

or 80mg sustained release single dose.

Congestive cardiac failure :

• It can worsen the condition.

• However now its established that it is beneficial in mild to moderate HF

• To be started with low dose and increased gradually.

• It is said to retard progression of condition and prolong life

How ?

• In CCF, there is damaging hyperactivity of β1

which causes remodeling of myocardium

• So these prevent the hyperactivity, the remodeling.

Angina Pectoris

• Used only in stable or effort-induced angina

• It decreases cardiac workload

• Decreases myocardial oxygen demand

• But absolute contraindicated in Prinzmetal’s angina

Because beta blocking will unmask Alpha receptor to cause coronary vasoconstriction

Cardiac arrhythmias :

• It is effective in all supra ventricular arrhythmias.

• Effect is mainly due to increase in refractory period at AV node

Myocardial infarction

• It will decrease the incidence , recurrence and mortality on long term use

• Prevent platelet aggregation

• Promotion of fibrinolysis

• Prevents ventricular fibrillation in the 2nd

attack of MI

• Non cardiovascular uses :

Migraine

• Used in prophylaxis

• Mechanism is uncertain

• Dose : 10 to 20 mg BD or TDS

Anxiety provoking situation

• It only blocks peripheral manifestation (palpitations, tremors and sweating)

• Dose : 10-20 mg TDS

no action in Parkinson’s tremors

Hyperthyroidism

• Reduces sympathetic over activity

• It also inhibits conversion of T4 to T3 ( independent of beta action)

• Dose : 20mg BD

Phaeochromocytoma

• Given in combination with alpha blockers to antagonize beta1 effects of catecholamines during surgery

• Dose : 20 mg TDS, 3 days before surgery

Alcohol withdrawal

• To reduce sympathetic over activity

• Dose 20mg TDS

Esophageal varices and Portal hypertension

• It induces splanchnic vasoconstriction (beta2 blocking and unopposed alpha1 action)

• This reduces bleeding and reduces portal pressure by 40%

Adverse effects :

• Bronchoconstriction

• Bradycardia

• Cold extremities (loss of beta2,loss of cutaneous vasodilation)

• Hypoglycemia

• Fatigue , sleep disturbances.

• Rebound hypertension on withdrawal ( upregulation of beta receptors)

• Adverse lipid profile

Other non selective 1st Gen

• Timolol

Main use :

wide angle glaucoma as eye drops 0.25%

Sotalol

• Uses and side effects are similar to propranolol (less lipid soluble, less CNS side effects)

• It has additional K+ blocking property and this makes it class III anti arrhythmic drug

• Dose : 80- 320mg BD PO

Nadolol

• Uses and side effects are similar to propranolol ( does not cross BBB)

• Longer plasma half life- 20 hrs

• Least first pass metabolism

β1 selective blockers• At high doses it can even block beta2

Advantages

• Safer in Asthmatics

• Safer in hypoglycemic conditions ( glucose release is not inhibited )

• Safer in PVD ( no beta2 blockade)

• Less deleterious effect on lipid profile.

Metoprolol :

• Uses are similar to Propranolol

• Dose : extended release 50-100 mg .

Atenolol :

• Uses are similar…

• Do not cross BBB

• Dose : 25-50 mg once daily

• Nebivolol

• Highly selective antagonist

• Additional action : enhances NO production and release . Used in effective reduction of BP

• Dose : 5-10 mg OD

Esmolol

• Ultra short acting selective antagonist

• Plasma half life 8-10min.

Uses :

• Only in emergency conditions/ during surgery/ critically ill patients as IV preparations

To treat SVT, AF etc

Non selective β blocker with intrinsic sympathomometic Activity

Beneficial properties are

• Lesser bradycardia, myocardial depression

• Rebound hypertension after withdrawal is less likely. Because β agonist property of this group prevents upregulation of receptors

• Lipid profile is less worsened.

• Disadvantages

• Cannot be used in migraine- intrinsic Beta2 agonistic action causes further dilation of cerebral vessels

• Less suitable for secondary prophylaxis MI

Acebutolol :

• It is a prodrug , converted to ‘Diacetolol’

• T1/2 10-12 hrs

• Dose : 400 mg OD

Celiprolol :

• It has partial agonist action on β 2 as well

• Also causes direct vasodilation by releasing NO.

• Preferred in HTN+ bronchial asthma patients

• Dose : 200-400 mg OD

• Drugs are : Pindolol and Oxprenolol

• Dose : Pindolol 10 mg OD

Oxyprenolol 20 mg BD or TID

selective β1 blocker with intrinsic sympathomimetic Activity

• They offer all the advantages of “ non selective β1 blocker with intrinsic sympathomometic Activity “ group

with

• Membrane stabilizing Action ( however its of no clinical use as it appears to significant at higher doses)

• Drugs are : Acebutolol and Celiprolol

Mixed(α+ β ) antagonist

• Labetolol and Carvedilol

• Labetolol

• It is racemic mixture of 4 diastereomers.

• Racemic mixture exhibits

selective blockade of α1 , β1

Partial agonist action on β2

Effects :

• Fall in BP (α1 , β1 blockade)

• Also peripheral vasodilation and bronchodilation(β2 agonistic)

Main Uses :

• Hypertension in pregnant women

• In pheochromocytoma

• Rebound hypertension in clonidine withdrawl

Adverse effects :

• Postural hypotension, hepatotoxicity

Carvedilol :

Actions :

• Has prominent β1 β 2 blockade , lesser α1

blockade.

• Inhibits free radical induced lipid peroxidation.

• Inhibits smooth muscle mitogenesis.

• It blocks L-type voltage gated Ca2+ channels.

• All these prove to be cardio protective In CCF

Uses

• Hypertension/ angina : Dose is 6.25mg BD

Reference • Sharma. Principles of Pharmacology.

• Goodman and Gilman

• Rang and Dale

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