ANTIADRENERGIC DRUGS

By: Darya Osman Hussein DaoudManal Bala Saeed

The AdrenergicNeuron

• Synthesis and release of norepinephrine from the adrenergic neuron

• MOA – Monoamine Oxidase

• SNRI – Serotonin norepinephrine reuptake inhibitor

α Adrenergic Receptors (α Adrenoreceptors):Equally responsive to naturally occurring catecholamines (i.e. EP and NE)

Classified as α1 and α2

α1 Receptors:Present on postsynaptic membrane

Constrict smooth muscle

Activation initiates series of reaction through G protein

activation or phospholipase C

Ultimately results in generation of 2nd messengers IP3 (initiates

release of Ca2+ from ER into cytosol) and DAG (turns on other

proteins within the cell)

Present on sympathetic presynaptic nerve endings and parasympathetic presynaptic neurons

Controls release of NE via feedback inhibition

Also inhibits Ach release

Binding is mediated by inhibition of adenyl cyclase and fall in intracellular cAMP levels

α2 Receptors:

α Receptors

• DAG – diacylglycerol

• IP3 – Inositol 3 triphosphate

• ATP – Adenosine triphosphate

• cAMP – cyclic adenosine monophosphate

• Vasoconstriction• Increased peripheral resistance• Increase BP• Mydriasis• Increased closure of internal

sphincter of the bladderα1

• Inhibition of NE release• Inhibition of Ach release• Inhibition of insulin releaseα2

β Adrenergic Receptors (β Adrenoreceptors):Equally responsive to naturally occurring catecholamines (i.e. EP and NE)

Classified as β1, β2 and β3

β Adrenergic Receptors (β Adrenoreceptors):β1 have equal affinities to EP and NE

β2 have higher affinity for EP than for NE

β3 are responsible for lipolysis and have effects on detrusor muscle of the bladder

Binding results in activation of adenylyl cyclase and increased cAMP concentration

• Tachycardia• Increased lipolysis• Increased myocardial contractility• Increased release of reninβ1

• Vasodilation• Decreased peripheral resistance• Bronchodilation• Increased muscle and liver

glycogenolysis• Relaxed uterine smooth muscle

β2

Regulation:Desensitization of receptors can occur after prolonged exposure to catecholamines

Occurs via 1 of the following mechanisms:

1. Sequestration of receptors – become unavailable for interaction with ligand

2. Downregulation – disappearance of receptors by destruction or decreased synthesis

3. Phosphorylation - an inability to couple to G protein because of phosphorylation on cytoplasmic side

What are adrenergic antagonists?Drugs which antagonize the action of EP and NE at the receptor level

They occupy adrenergic receptors (α and β ) but do not produce signal transduction.

Can be reversible or irreversible

Classified according to relative affinity for α or β receptors

α adrenergic blockers

PHENOXYBENZAMINE, PHENTOLAMINE, PRAZOSIN, TERAZOSIN AND DOXAZOSIN

Phenoxybenzamine & Phentolamine

Non-selective α blockers

Actions: Block of α1 receptor

vasodilation and postural hypotension.

Block of α2 receptor

reduced NE action on α2 receptors on the varicosity

increases release of NE from varicosity which can cause

tachycardia and increased CO

Phenoxybenzamine & Phentolamine

Mechanism of action:

Binds covalently (and therefore irreversibly) to α receptor and blocks NA action.

Action is reversible in the case of phentolamine.

Phenoxybenzamine & Phentolamine

PharmacokineticsGiven orally, IV and SC injection.

T ½ for Phenoxybenzamine = 12 hours (because of irreversible binding to receptor).

T ½ for Phentolamine = 3 hours.

Phenoxybenzamine & Phentolamine

Clinical Use:Used in treatment of phaeochromocytoma

Adverse effects:Postural hypotension

Tachycardia

Dizziness and headache

Sexual disfunction

Phenoxybenzamine & Phentolamine

Prazosin, terazosin and doxazosin

Selective α1 antagonist

Action:Vasodilatation and reduction in BP.

Increase HR (a reflex β1 receptor resonse to the decrease in BP)

Decrease bladder sphincter tone.

Inhibition of hypertrophy on smooth muscle of bladder neck and prostate capsule.

Prazosin, terazosin and doxazosin

Mechanism of Action:

Block the action of endogenous and exogenous agonists on the α1 receptor.

Decrease peripheral vascular resistanceRelaxes arterial and venous smooth muscleCauses minimal changes in CO, renal blood flow and GFR

Prazosin, terazosin and doxazosin

Pharmacokinetics: Prazosin and Terazosin

absorbed orallyT ½ = 3 – 4 hoursMetabolised by liverExtensive 1st pass metabolism

DoxazosinT ½ = 22 hours

Prazosin, terazosin and doxazosin

Examples of uses of α1 selective blocker

Clinical use:

◦ Severe hypertension.◦ Benign prostatic hypertrophy.

Adverse effects:

◦ Orthostatic hypotension◦ Dizziness◦ Hypersensitivity reactions◦ Insomnia◦ Priapism

Prazosin, terazosin and doxazosin

Caution - SyncopeFirst dose of α1 receptor blocker may produce an orthostatic hypotensive response and result in fainting

β adrenergic blockers

PROPRANOLOL, TIMOLOL, NADOLOL, ACEBUTOLOL, ATENOLOL, METOPROLOL AND ESMOLOL

NON SELECTIVE

Propranolol Timolol Nadolol

Β1 SELECTIVE (CARDIOSELECTIVE)Acebutolol Atenolol Metoprolol Esmolol

β adrenergic blockers

PropranololNon – Selective β blocker

Action:CVS

decreases CO (-ve inotropic and chronotropic effects)Decreased SA and AV node activity

Peripheral vasoconstriction via increased peripheral resistance

Bronchoconstriction

Reduces renin release

Decreased glycogenolysis and glucagon secretion

Mechanism of Action:

Block sympathetic drive

Reducing pacemaker activity and increases AV conduction time

Reduces the slow inward Ca2+ current

Propranolol

Pharmacokinetics:

Orally administered

Almost completely absorbed

Extensive 1st pass metabolism (only 0.25 bioavailability)

Large volume of distribution

Readily crosses blood-brain barrier

Metabolites excreted in urine

Propranolol

Therapeutic uses:

Class II antiarrhythmicHypertensionAngina pectorisMigraineHyperthyroidism Prevention of death by dysrhythima following myocardial infarctionParoxymal atrial fibrillation

Propranolol

PropranololAdverse effects:Bronchoconstriction

Arrhythmias (if stopped abruptly)

Sexual impairment

Metabolic disturbances (fasting hypoglycemia)

CNS effects DissinessLethargy FatigueWeaknessVisual disturbancesHallucinationsShort term memory lossEmotiaonal labilityVivide dreamsDepression

Nadolol and TimololNon selective beta antagonists

Nadolol has very long duration of action

Action:Drecrease intraocular pressure

More potent than propranolol

Nadolol and Timolol Mechanism of action:

Reduce production of aqueous humor in the eye

Decrease secretion of aqueous humor by ciliary body

Do not cause cycloplesia

Nadolol and Timolol Pharmacokinetics:Onset is about 30 minutes when administered intraocularly

D.O.A. = 12 to 24 hrs

Clinical Use:Chronic management of glaucoma

Acebutolol, Atenolol, Bisoprolol, Esmolol, and MetoprololSlective beta blockers – known as cardioselective

Selectivity is lost at high doses

Action:Decrease BP in hypertension

Inrease exorcise tolerane in angina

Pharmacokinetics:

Orally administered

T ½ Atenolol = 6 hoursEsmolol = 10 hours

Acebutolol, Atenolol, Bisoprolol, Esmolol, and Metoprolol

Clinical Use:

Emergency treatment of supraventricular dysrhythmias (Esmolol)

Antianginal

Antihypertensive in diabetic patients reviecing insulin or oral

hypoglycemic agents

Acebutolol, Atenolol, Bisoprolol, Esmolol, and Metoprolol