Antiadrenergic Drugs
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Transcript of Antiadrenergic Drugs
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