Adrenergics & Antiadrenergic drugs1 Classification of Adrenoreceptor Antagonists α – blockers Non selective Relatively selective Selective β – blockers

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 alfuzosin

tolazoline 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 alkylates the receptors & binds by methyl covalent bond. Thus, it produces irreversible α– blockade which cannot be overcome by increase of NE

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


Cont…. 2) They produce tachycardia more than the α1 – selective

blockers by Producing reflex tachycardia.

All α blocker (selective and non selective) block α1 to inhibit the effect of sympathetic tone on blood vessels. This leads to VD & decrease BP (more obvious during standing ) leading to postural hypotension. This will stimulate the baroreceptors to send impulses to CNS to increase HR

Increase HR by Block α2 cause increase NE in synapse. NE will bind to β1 receptor

leading to ↑HR Phenoxy benzamine

Block NE reuptake. This will increase NE in synapse leading to increase HR. So, more tachycardia with Phenoxybenzamine as compared to phentolamine.

So both drugs block α2 leading to ↑NE but pehnoxybenzamine block reuptake of NE leading to

more NE in synap

So both drugs block α2 leading to ↑NE but pehnoxybenzamine block reuptake of NE leading to

more NE in synap

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

Its action can be overcome by increasing agonist concentration(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).

In heart failure the following happens:.1.Decreased C.O leads to sympathetic stimulation.2 Sympathetic stimulation HR & ↑contractility (which↑ .(increase the pressure on the heart thus, worsening the situation Furthermore, NE will increase the release of renin and this leads to incerease preload and after load

In this case we will useβ blockers to decrease HR and .contractility and inhibit renin release

In heart failure the following happens:1.Decreased C.O leads to sympathetic stimulation.2.Sympathetic stimulation ↑HR & ↑contractility (which increase the pressure on the heart thus, worsening the situation). Furthermore, NE will increase the release of renin and this leads to incerease preload and after load

In this case we will use β blockers to decrease HR and contractility and inhibit renin release.

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) in which prostate compresses the urethra & prevent micturition.

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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

ma

phenoxybenzamine

Alpha 1 , 2 14-48 same

prazosin Alpha 1 3 HypertensionCongestive heart

FailureProtect against

ischemic diseaseRaynaud

phenomenon

terazosin Alpha 1 12 HypertensionUrinary retention

doxazosin Alpha 1 22 same

Tamsolusin & Alfuzosin

Alpha 1A Urinary retention


Adrenoreceptor Antagonists β– blockers:

Non selective Relatively selective

Alpha and beta blockers

Propranolol Atenolol Labetalol

Timolol Esmolol carvedilol

Nadolol Metoprolol

Labetalol Practolol

pindolol Acebutol

bisoprolol

More 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

يطلع بالعربيNE يلقى

الريسيبتور يضطر مقفلةلـ يروح انه

α2

يطلع بالعربيNE يلقى

الريسيبتور يضطر مقفلةلـ يروح انه

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 ↓ intraocular pressure (IOP)

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

Opening of the canal of Schlemm this Increases outflow of aqueous humor which leads 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. So, they will Increase risk of coronary artery disease contraindicated in a patients with familial

hypercholesterolemia because VLDL & TGs are atherogenic & may cause myocardial infarction


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 Some β blockers are effective in treating chronic heart failure but not acute because you want to

decrease the see slide 11)) work load & O2 consumption on the myocardium


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 is excreted in urine as Propranolol or as

Glucouronide conjugate It’s duration of action is increased in

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

inhibits the metabolism of propranolol, so, increase t1/2 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 block α1 in blood vessels. So, causes VD and decrease BP

(postural hypotension). This will stimulate baroreceptors to send impulses to CNS to increase HR (reflex tachycardia) but this tachycardia is less than seen with other α blockers

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)

It is intermittent claudication or peripheral vascular disease It is due to decreased blood supply to the periphary by β blockers due

to Bradycardia Block β 2 in blood vessels to skeletal muscle causing VC and decrease blood

supply


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 can neutralize (scavenge) the free radicals which cause heart failure

It used in renal impairment Because it improves kidney function. So, it’s used

in patients with 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 no

Carvedilol Beta 1,2 No No 7-10 yes

Esmolol Beta 1 No No 10 min no

Labetalol Beta 1,2 Yes Yes 5 yes

Pindolol Beta 1,2 Yes Yes 3-4 yes

Propranolol Beta 1,2 No Yes 3-6 yes

Timolol 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 then It will decrease the sympathetic tone to blood vessels (VD) ↓BP

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

Lead to increase ECF and increase in BP slightly This negates it’s therapeutic use

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.


: جوهرية 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).

•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).

Documents

Adrenergics & Antiadrenergic drugs1 Classification of Adrenoreceptor Antagonists α – blockers Non selective Relatively selective Selective β – blockers