Classification of Adrenoreceptor Antagonists

Adrenergics & Antiadrenergic drugs 1

Classification of Adrenoreceptor Antagonists α– blockers

Non selective Relatively selective Selective

β– blockers Non selective Relatively selective Selective

Both α and β adrenergic antagonists


α– Adrenoceptor Antagonists (α– blockers)

Non selective Relatively selective

selective

phenoxybenzamine

prazosin tamsolusin

phentolamine terazosin alfuzosintolazoline doxazosin

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األخرى


Non selective α– blockers(act on α1 and α2 receptors)

Phentolamine and Tolazoline (Reversible)

Induce reversible competitive blockade for α1 – adrenoreceptors which can be overcome by increase of NE

T1/2 = 3 – 5 hours

Phenoxybenzamine (Irreversible)

it produces irreversible α– blockade. t1/2 = 14 – 48 hours

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Pharmacological effects of α– blockers

I. Effects Mediated by blocking α– receptors A. Cardiovascular Effects: 1) They block

α1 causing VD. So, decrease TVR The pressor effect of α– agonists So, they decrease BP (hypotension) But they are of limited clinical use in treating

hypertension because they may cause: Tachycardia (Reflex Type) Cardiac arrhythmia Angina pectoris Peptic ulcer Sexual dysfunction

B. Non-cardiac Effects of α– blockers A) Miosis

b) Nasal stuffness c)decrease resistance to the flow of

urine d) They decrease adrenergic sweating. So they

produce dry skin e) Inhibit ejaculation

II. Effects mediated by non- α–adrenergic blocking effects: They induce weak blockade for:

• H 1 receptors (Histamine) (Sedation; antinausea) • Serotonin receptors • Muscarinic receptors (dry mouth)


Side effects of Phenoxybenzamine Fatigue Nausea (because it enters CNS) Diarrhea Postural hypotension. Tachycardia.


α– blockers Relatively selective Prazosin Terazosin Doxazosin


1. PrazosinMechanism of action It is a relatively selective α1 –

adrenoceptor competitive antagonist

reversible T1/2 = 3 hours


PrazosinActions: It produces arterial & venous dilation. So it

decreases BP, so it is used for the treatment of hypertension

It causes less tachycardia than non–selective vasodilators (because it doesn’t act on α2 receptors)

It precipitates less angina & cardiac arrhythmia It may increase HDL / cholesterol ratio. HDL

protects against ischemic heart disease There is tolerance to it’s action Dose 2 – 3 times daily for Hypertension and

congestive heart failure (CHF).

1st dose produce hypotension & syncope, but this disappears after continuous treatment(we prevent this effect by decreasing the 1st dose and giving it at bedtime)

Infrequent postural hypotension (rare and less than the non selective)

Nasal stiffness due to VD & congestion Dizziness, headache & faintness . These

are caused by hypotension Sexual dysfunction but less than the

non-selective.

Side effect of prazosin


α– blockers Relatively selective2. Terazosin & Doxazosin: They are relatively α1 – selective blockers, with

higher selectivity than prazosin T1/2 = Terazosin 12 hours; Doxazosin 22 hrs They produce VD with less tachycardia than

prazosin Like prazosin they produce postural

hypotension They produce relaxation of smooth muscle of

the bladder neck and prostate capsule. So, they facilitate micturition. For this action, they can be used in case of urine retention associated with benign prostatic hyperplasia(BPH).

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α– blockers SelectiveTamsolusin & Alfuzosine

It is selective for α1A – adrenoreceptors in the sphincter of urinary bladder

α1A blockade leads to relaxation of the sphincter. So, it facilitates micturition

Tamsolusin is used clinically in treating urine retention associated with BPH. It is better here than prazosin, Terazosin and Doxazosin

It causes less hypotension than prazosin or terazosin. Because:

It has low potency in inhibiting receptors in vascular smooth muscle


TamsolusinAdverse affects: Retrograde ejaculation 15% Hypersensitivity reaction: skin rash &

urticaria Nausea and vomiting Nasal stiffness Over dose will cause hypotension,

tachycardia and fatigueNote: Similar to prazosin but with less

magnitude.


Tamsolusin Contraindications:

Renal impairment Tamsolusin is metabolized in the liver to

an active metablite which is entirely excreted via the renal tubules, therefore,

In case of renal impairment, Tamsolusin will accumulate in blood & lead to toxicity

Clinical Uses of adrenergic -antagonists:

1) Pheochromocytoma (phenoxybenzamine, phentolamine) with β blockers to reduce cardiac effect from increased catecholamines2) Hypretensive Crisis (Labetalol)3) Essential Hypertension (Prazosin, Terazosin)4) Peripheral Vascular Occlusion Diseases (Raynaud’s phenomenon) e.g: Prazosin (but

Calcium Channel Blockers are better choice) 5) Urinary Obstruction associated with BPH (Tamsolusin)


Name of antagonist

Act on T1/2 treatment

Phentolamine & tolazoline

Alpha 1 , 2 3-5 hours Hypertensionpheochromocyto

maphenoxybenzami

neAlpha 1 , 2 14-48 same

prazosin Alpha 1 3 HypertensionCongestive heart

FailureProtect against

ischemic diseaseRaynaud

phenomenonterazosin Alpha 1 12 Hypertension

Urinary retentiondoxazosin Alpha 1 22 same

Tamsolusin & Alfuzosin

Alpha 1A Urinary retention


Adrenoreceptor Antagonists β– blockers:

Non selective Relatively selective

Alpha and beta blockers

Propranolol Atenolol LabetalolTimolol Esmolol carvedilolNadolol Metoprolol

Labetalol Practololpindolol Acebutol

bisoprololMore potent than atenolol

How could you distinguish between -adrenergic

Blockers ? -adrenergic antagonists (blockers)

differ from each others in the following: Selectivity for 1 as compared to 2. or by the following:

β– blockersPharmacological actions: CVS

BP = CO * TVR. Clinically β blockers lower BP By these mechanisms:

Blockade of β1 in the heart will cause decreased HR and CO Blockade β1 in the kidney will cause decreased rennin

leading to decreased angiotensin 2. this will lead to VD and ultimately decreased BP decrease aldosterone. This will lead to decerased salt and

water retention and finally decreased BP decrease release of NE that will cause VD and decreased BP

Blockade of central β adrenergic in adrenergic nerve terminals. This will makes NE acts at2-adrenergic agonist leading to a decrease in its own release and decrease sympathetic tone to blood vessels, leading to VD and decreased BP

Which one of the above mechanism is more important for treating hypertension? Decreasing renin secretion

Angiotensin normally induces the release of NE

from postganglionic

sympathetic fibers

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α2


Cont…. The respiratory system

Blockade of β2 receptors in bronchi will cause bronchoconstriction

Non–selective β blocker (are contraindicated in the bronchial asthma (propranolol)

The β1 selective blockers (e.g: Atenolol; Bisoprolol) are also should be avoided in the acute bronchial asthma because their selectivity is relative and they may have antagonistic affects on the β2 receptors at therapeutic doses.


Cont…. The eye

β–blockers are used in treatment of glaucoma (Timolol). They act by:

Blocking β2 in ciliary epithelium. This will decrease production of aqueous humor.

Block β2 in ciliary muscle. This will cause of contraction of the ciliary muscle leading to

Decreased IOP


Cont…. Metabolic and endocrine effects

β blocker inhibit lipolysis In type 1 diabetes The patient depends on catecholamines to increase

blood glucose if he took overdose of insulin. If he took β blockers, they will impair the recovery

from hypoglycemia β1 blockers are advised in the case of diabetic

patients β – blockers cause increase VLDL & triglycerides

(TG) and decrease HDL / Cholesterol ratio.


Cont…. Intrinsic sympathomimetic activity (ISA )

Some of the β antagonist produce some action of β agonist e.g. Pindolol & Labetalol…, so, they are less dangerous when given to patients with bronchial asthma or excessive bradycardia

Membrane Stabilizing Action (MSA) Some β blockers stabilize the cell membrane

by blocking Na+ channels. Therefore, produce “local anesthetic action” e.g. Propranolol & Pindolol …


β– blockersSide effects of β blockers Rash & fever Worsening of asthma CNS include

Sedation and Depression and sleep disturbances

These are more sever in Lipid – soluble β blockers (e.g. Propranolol) than in water soluble β blocker (e.g. Atenolol)

Heart failure


β– blockersContraindications of β-blockers: Bronchial asthma Peripheral vascular disease Heart failure (in severe cases only)

(acute)


β– blockersDrug interactions: Verapamil (Ca++ ) channel blocker If it is combined with β – blockers,

this can cause : Congestive heart failure Severe bradycardia Severe hypotension


β– blockersWithdrawal of β blockers:On chronic use, abrupt withdrawal of

β – blockers causes the β receptors to become supersensitive and even the circulating catecholamine can stimulate them & cause severe arrhythmia. So, withdrawal should be very gradual over weeks


β– blockers Propranolol It is non – selective β blocker T1/2 = 2 – 5 h It is Lipid soluble Can be given orally or I.V It undergoes extensive 1st pass

metabolism (90% of the drug)


Cont…. It’s duration of action is increased in

Hepatic disease Decreased hepatic BF Metabolic inhibition e.g. when giving Cimetidine

It has no ISA It has MSA . SO, It is used as antiarrhythmic drug but not in

hypertension. It stabilize the cardiac cell membrane & decrease the

activity of ectopic foci

Side effect of propranolol

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BradycardiaCold extremities Fatigue Sedation Mental depression Sleep disturbances Heart failureA – V block Bronchospasm Impotence


β– blockers Timolol: It is a non – selective β blocker T1/2 = 4 – 5 h No ISA Low MSA so not good for arrethmia. Lipid – soluble

Pass via the cornea. So, it is used as eye – drops to treat glaucoma


β– blockers Labetalol: It is a non-selective β blocker & selective α1

blocker T1/2 = 4 – 6 h Weak lipid – soluble It has ISA Has MSA It differs from other β blockers in that it

produce less bradycardia. It is used in Pheochromocytoma and

hypertension of pregnancy


Cont…. Adverse effects include:

Nausea skin rash tiredness Aching limbs Bronchospasm Heart failure Sleep disturbance & nightmares Sexual dysfunction (more than other β blockers) Postural hypotension (because it is selective α1 blocker) Raynaud syndrome (peripheral vasospasm)


β– blockers Pindolol: It is a non-selective β blocker T1/2 = 3 – 4 h Has ISA (very important) lead to

bradycardia. Weak lipid soluble Has MSA but less than Propranolol


β– blockers Carvedilol : like labitolol It is non – selective β blocker and non –

selective α blocker It can be used in patients with heart

failure due to: It is a peripheral vasodilator (unlike other β

blockers) It has antioxidant activity It used in renal impairment .


β– blockers Atenolol: It is a relative β1 selective blocker Hydrophilic so it has:

Longer t1/2= 12 – 18 h because it stays in tissue for a long time For this reason, the dose is once daily

Less severe side effects on CNS No ISA No MSA Adverse effects include

CNS : insomnia, headache & dizziness Impairment of glucose tolerance Bradycardia Bronchospasm Sexual dysfunction* Fatigue : due to decreased blood supply to the periphery*

*all β blockers cause sexual dysfunction and fatigue.


β– blockers Practolol: It is a relatively β1 selective

blocker It is used in intensive care unit for

severe ventricular arrhythmia It is not used to treat hypertension

because of it’s side effect


β– blockers Esmolol : It is a selective β1 blocker Has very short duration of action (t1/2 = 8min) Has low ISA Has MSA (good for arrhythmia ) It is given I.V when short term β blockade is

required Safer to use than longer acting antagonists in

critically ill patients.


Name of Drug

Selectivity

ISA MSA T1/2 Lipid solubility

Atenolol Beta 1 No no 6-9 noCarvedilol Beta 1,2 No No 7-10 yesEsmolol Beta 1 No No 10 min no

Labetalol Beta 1,2 Yes Yes 5 yesPindolol Beta 1,2 Yes Yes 3-4 yes

Propranolol Beta 1,2 No Yes 3-6 yesTimolol Beta 1,2 No No 4-5 yes


Migraine:•Propranolol


Centrally acting sympatholytic drugs


Centrally acting sympatholytic drugs These drugs have the opposite

effect to those of the sympathomimetic drugs by acting on the CNS.

Examples: α-methyldopa Clonidine


α– methyldopa Mechanism of action

α–methyldopa is given orally then absorbed from GIT & enters the circulation

It freely passes BBB & reaches CNS then it is converted to α– methylenorepinephrine which acts as an agonist at central α2 – adrenoreceptors.

These α2 – adrenoreceptors are found in the medulla & pons

α– methylenorepinephrine is called “false neurotransmitter” or (reactive metabolic of α– methyldopa)

Action of α– methyldopa VD lead to decrease TVR without significant effects on CO

or HR or renal blood flow


Cont…. Clinical uses:

Treat pregnancy – associated hypertension Treat mild to moderate hypertension (not common used)

Side effects include: It may cause fluid retention It may produce postural hypotension when standing from

the sleeping position This not severe like α– blockers

Sedation, insomnia, depression in the beginning of treatment & disappears after continuous

use Serious extrapyramidal signs

It interferes with neurotransmitter of extra pyramidal tract May lead to muscle incoordination


Cont…. Lactation

Even in male : the breast may produce milk Hepatitis & drug fever (can be serious) Impotence A lupus – like reaction : skin rash and

pustules Hemolytic anemia Leukopenia : sometimes


Clonidine: Already mentioned in α2 agonist.

: جوهر2ية قواعد

•All adrenergic blockers reduce BPBut :α blockers produce postural hypotension

•Any α2 agonist is considered an antagonist because it inhibits the release of NE.

•Relatively selective, means in high dose it may act on other receptors. (α1 blocker may act on α2 in high doses).

Classification of Adrenoreceptor Antagonists

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