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Joy B. Johnson Bsc (Hons) Pharmacy, Msc Pharmacology, MPC Pharm. Department of Pharmacology COMAHS, USL.

Joy B. Johnson

Bsc (Hons) Pharmacy, Msc Pharmacology, MPC Pharm.

Department of Pharmacology COMAHS, USL.

Overview

Recap (new) Introduction Summary of alpha receptor responses Classification of alpha blockers Pharmacology of the different classes

Pharmacological actions Mode of actions Pharmacokinetics Clinical Uses Side effects & contraindications

Recap

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Recap new

Introduction

Alpha blockers are agents which inhibit the actions of NA or A or direct acting sympathomimetic agents or SNS stimulation on alpha receptors

They block alpha receptors Blockage is either reversible or irreversible competitive

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Summary of Alpha receptor responses

Alpha- 1

VSMs Eye Pilomotor SMs Vas deferens Liver Intestinal SMs Intestinal sphincters

Responses

Contraction Mydriasis (contraction) Erects hair Contration Glycogenolysis Relaxation contraction

Summary of Alpha receptor responses

Alpha- 2

Some VSMs Nerve terminals (NA & Ach) Platelets Fat cells

Responses

Contraction Inhibit transmitter release

Aggregation Inhibition of lipolysis

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Classification (Receptor selectivity)

Non-selective

Phenylalkylamines e.g.phenoxybenzamine

Imidazoline derivatives: phentolamine, tolazoline

Selective -alpha-1: Quinazoline derivatives: prazosin, doxazosin, terazosin, tamsulosin -alpha-2: yohimbine Others: phenothiazines, TCA, labetalol

Classification (Type of Blockage)

Irreversible competitive

Phenylalkylamines e.g.phenoxybenzamine

Reversible competivitive -Imidazoline derivatives: phentolamine, tolazoline -alpha-1: Quinazoline derivatives: prazosin, doxazosin, terazosin, tamsulosin -alpha-2: yohimbine Others: phenothiazines, TCA, labetalol

Phenoxybenzamine Prazosin Yohimbine

Phenoxybenzamine

Prazosin
Prazosin
Phenoxybenzamine Prazosin Yohimbine

Yohimbine

Pharmacological actions

Phenoxybenzamine

Primarily due to alpha blockage Mostly limited to the CVS

Relative little or no effect on the BP of normal supine subjects

Attenuates catecholamine-induced vasoconstriction

Reduces BP when SNS tone is high such as upright posture (postural hypotension) or reduced BP.

Pharmacological actions

Phenoxybenzamine CVS: vasodilatation →↓TPR → ↓BP

Baroreceptors stimulated → ↑SN input to the myocardium refex tachycardia and may be CO

Blockage of alpha-2 pre-synaptic may also contribute to the HR and CO.

Others: blocks Ach, histamine and serotonin receptors (side effects) Also blocks uptake 1 and 2

% Maximal Increase

EPI EPI + Phenoxybenzamine Phenoxybenzamine alone

Receptors no longer available

Decrease in the maximal efficacy of Epi due to a decrease in the number of receptors

mg/kg[, Agonist]

Pharmacological actions

Phenoxybenzamine Eye - miosis GI tract – Increased motility Urinary bladder – decreased tone in sphincter Metabolic effects – increased insulin secretion

Pharmacokinetics

Absorbed after oral Bioavailability is low Kinetic properties not well established Half-life –life span of the cell

Adverse effects

Postural hypotension (drowsiness/headache) Tachycardia (refex)arrhythmias, MI Palpitations Nasal stuffiness Reversible inhibition of ejaculation Miosis Impotence (inhibits ejaculation) CNS: fatigue, sedation and nausea

Alkylating agent, may have S/Es that have not yet been characterized; causes tumours in animals (clinical importance- unknown)

Phentolamine & tolazoline

Pharmacological effects similar to phenoxybenzamine

In addition: minor inhibitory effect at serotonin receptors, but agonistic effects at muscarinic and histamine (H1&2) receptors.

Parasympathomimetic

Increased gastric acid secretion

Increased secretion from exocrine glands, such as salivary, sweat, lacrimal, pancreatic

Pharmacokinetics

Limited absorption after oral

Pharmacokinetic properties not well known

Peak levels achieved in 1 hour after oral

Half-life is 5-7 hrs

Side effects

Similar but not identical to those of phenoxybenzamine

Principal S/Es are HR, arrhythmias, MI (after IV)

Oral-nasal congestion, HR, headache

Ach-like S/Es- abd. pain, nausea, PUD etc.

Contraindicated in patients with asthma, peptic disease and coronary artery disease.

Clinical Uses

Pheochromocytoma

BPH

Hypertensive crisis secondary to clonidine withdrawal

Prazosin

CVS

Arteriolar and venodilatation →↓TPR BP

Suppresses baroreceptor refex mechanisms

Has little or no alpha-2 blocking effect

Suppresses baroreceptor function

No cardiac stimulating effect

Tolerance develops may be due fuid retention

  • Little or no metabolic effect

Favorable effect on plasma lipids: increase HDL/LDL ratio

  • Relaxation of the SMs of the prostate

Effect of Adrenaline (ADR) on Blood Pressure and Heart Rate Before and After Prazosin

ADR

(µg/Kg)

0.1

1

10

100

500

HR

BP

 

1

10

100

500

PRAZOSIN+

Pharmacokinetics

Bioavailability 50-70%

Peak effect 1-3hrs after oral adm.

Highly (95%) bound to plasma proteins (α-1 acid glycoprotein)

T1/2 - 2-3 hrs (in CHF 6-8 hrs)

Duration of effect 7-10 hrs

Terazosin- less potent than prazosin, bioavailability -90%, t1/2-12hrs, duration-18hrs

Doxazosin- t1/2- 20hrs, duration-36hrs

Alfuzosin- bioavailability-64%, t1/2-3-5hrs (BPH)

Tamsulosin- benzenesulfonamide, very efficacious in the treatment of BPH with little or no effect on BP

Side effects

First-dose phenomenon (marked postural hypotension and syncope) -Limit initial dose at bedtime -Increase dose slowly -Introduce additional antihypertensives cautiously Headache dizziness Impaired ejaculation (tamsulosin)

Alpha-2 selective blockers Yohimbine

Cardiovascular effects – peripheral and central effects (BP) Blocks other receptors also – serotonin, dopamine Increases ADH release

Enhances sexual activity – aphrodisiac (in the past use to treat male sexual dysfunction)

Potential uses: depression, obesity, NIDDM

Additional alpha blockers

Ergot alkaloids- ergotamine, ergonovine Also Interact with serotonin and dopamine receptors Direct smooth muscle contraction Coronary vasoconstriction

Toxicity: GI, vascular insufficiency –ergotism

Use in migraine and post-partum hemorrhage

Additional alpha blockers

Indoramin

Selective alpha-1 blocker Also histamine and serotonin receptors Bioavailability – less than 30% Undergoes extensive first-pass metabolism Some of its metabolites are active T1/2 – 5 hrs

Toxicity: sedation, dry mouth, and failure of ejaculation

Use in hypertension, decrease the incidence of Raynaud’s phenomenon

Additional alpha blockers

Ketanserin Is a typical 5-HT blocker Blocks alpha-1 receptors

Urapidil

Alpha-1 blocker with structure distinct from prazosin and its congeners

Therapeutic Uses of Alpha-Adrenergic Blockers

Hypertension - alpha-1 selective

Conditions associated with increased sympathetic activity – e.g. pheochromocytoma

Hemodynamic shock

Peripheral vascular disease – Raynaud’s disease

Congestive heart failure

Benign prostatic hyperplasia

Pulmonary hypertension – tolazoline

Yohimbine or intracavernous phentolamine+papaverine for impotence

Summary contd

Summary contd

Thanks for your attention