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SYMPATHOLYTIC AGENTS..2. Alpha Adrenergic receptor blockers. ALPHA BLOCKERS Several agents Chemically heterogeneous and with different specificities According to nature of action : Two Groups, Competitive & Irreversible According to selectivity : Three Groups,

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Sympatholytic agents 2

SYMPATHOLYTIC AGENTS..2

Alpha Adrenergic receptor blockers


Sympatholytic agents 2

  • ALPHA BLOCKERS

  • Several agents

  • Chemically heterogeneous and with different specificities

  • According to nature of action : Two Groups, Competitive & Irreversible

  • According to selectivity : Three Groups,

  • 1 > 2; 1 = 2; 2 > 1


Sympatholytic agents 2

Classification

 - RECEPTOR antagonist

1- SELECTIVE

competetive

1 > 2

2- SELECTIVE

competetive

2 > 1

NON-SELECTIVE

Competetive

1 = 2

NON-SELECTIVE

Irreversible

1 = 2

Prazosin Yohimbine Phentolamine Phenoxy-

Terazosin Idazoxan Tolazoline benzamine

Doxazosin Mianserin Dibenamine

Tamsulosin


Sympatholytic agents 2

  • Pharmacological actions

  • Major actions on Blood pressure

  • Other effects based on - role of  receptors in different tissues - selectivity of the agent (2 vs1)


Sympatholytic agents 2

CVS

Vasodilatation – arteriolar and venous

 BP

 PVR

Magnitude dependent on symp. activity at that time

More in erect that in supine position

– postural hypotension

More marked if hypovolaemia is present

Baroreflex activation

– reflex tachycardia

– tends to oppose the fall by  HR and CO


Sympatholytic agents 2

  • Reflex tachycardia more marked with non selective agents – WHY?

  • Compensatory salt and water retention with long term use

  • Prevent pressor response to usual doses of  agonists

  • Convert pressor response of Adrenaline to depressor – Dale’s reversal

  • Vascular 2 receptors also vasoconstrictor but activated by circulating and not synaptic NA --no marked effects of 2 blockers

  • 2 blockers can  NA release (presynaptic action) – CV effects


Sympatholytic agents 2

  • OTHER EFFECTS

  • ↓contraction of trigone and sphincter in bladder - urine flow

  • insulin secretion from islet cells (2 blockers)

  • Miosis

  • Nasal stuffiness

  •  adrenergic sweating


Sympatholytic agents 2

α1 – blockers : Clinical uses

Reduce blood pressure

Hypertensive emergencies

Long term treatment

Phaeochromocytoma

Vasodilatation

Peripheral vascular insufficiency

To reverse vasoconstrictor excess

Improve urine flow

Benign prostatic hyperplasia


Sympatholytic agents 2

α1 – blockers : Adverse effects

  • Postural hypotension

  • ( less with α1 selective - venodilatation is less)

  • Reflex tachycardia ( less with α1 selective)

  • Salt and water retention

  • Nasal stuffiness

  • Miosis

  • Failure of ejaculation


Sympatholytic agents 2

Specific Agents

Ergot alkaloids (ergotamine):

Partial agonist & blocking property

Also affect other receptors (eg. 5-HT, )

Therapeutic effects (migraine, uterus) not related to  blockade.

Uses:

Migraine (acute attack)

Uterotonic – (methylergonovine) in PPH


Sympatholytic agents 2

Phenoxybenzamine: 1>2 ;

Irreversible : Covalent binding with receptor

Long duration of action (14 - 48 hrs)

Also blocks 5-HT, ACh & H1 receptors

-- ? significance

Inhibits neuronal & extra-neuronal uptake of NA

Absorbed from GIT, low bioavailability


Sympatholytic agents 2

Phenoxybenzamine

Clinical use:

Phaeochromocytoma

Control of BP

Prior to surgery

Adverse effects:

Postural hypotension,

Tachycardia,

Nasal stuffiness,

 ejaculation


Sympatholytic agents 2

Phentolamine : 1 = 2

 PVR –  blockade + direct (non adrenergic)

 HR – Reflex + 2 presynaptic on cardiac symp. terminals

Poorly absorbed orally

Clinical use:

Phaeochromocytoma

Local vasoconstrictor excess

Adverse effects:

Cardiac stimulation : - tachycardia, arrhythmia, angina

GIT Stimulation :

- diarrhoea;  gastric acid secretion


Sympatholytic agents 2

Tolazoline:

Similar to phentolamine

Slightly less potent

Better absorption from GIT

Rapidly excreted in urine

Limited clinical application:

peripheral vasospastic disease


Sympatholytic agents 2

1 Selective Agents

Prazosin & Terazosin: 1 >>>> 2

Effective in management of hypertension

Low affinity for 2

Relative absence of tachycardia

↓ Triglycerides & LDL, ↑ HDL (favourable)

Both are extensively metabolized by liver

Prazosin shows high 1st Pass effect (50%)

Oral absorption - good

Terazosin :Bioavailability >90%; >18 h action

Uses: Hypertension and BPH

Adverse effects

First dose effect

Postural hypotension

Salt & water retention ( long term use)


Sympatholytic agents 2

Doxazosin:

Similar to Prazosin but longer t ½ (22 Hr)

Alfuzosin : similar to prazosin

Tamsulosin

Selective α1 anatgonist

Has greater selectivity for α1A subtype

Has greater efficacy for BPH

Relatively smaller effects on blood vessels

USE: BPH


Sympatholytic agents 2

Indoramin & Urapidil :

Newer 1-selective agents

Have some utility in hypertension


Sympatholytic agents 2

2 selective

Yohimbine

Hardly used clinically

Idazoxan

Mianserin :

Used as an antidepressant;

2 – blocking action within CNS contributes

to its effect.

Other receptor actions also (eg. 5-HT)

Labetalol : 1 + 


Sympatholytic agents 2

  • Clinical Uses Of  Blockers

  • Pheochromocytoma

  • Hypertensive emergencies

  • Chronic hypertension – non selective blockers are not used

  • Peripheral vascular diaease

  • – spastic (Raynauds), not morphological

  • Local vasoconstrictor excess

  • – phentolamine useful- local infiltration

  • Urinary obstruction – BPH

  • – prazosin, terazosin, tamsulosin

  • CHF

  • α2- selective antagonists do not have any recognised clinical use


Sympatholytic agents 2

Some neuroleptic agents (eg. chlorpromazine, haloperidol) used in psychiatry possess α receptor blocking activity (in addition to Dopamine receptor antagonism) which may lead to cardiovascular adverse effects with these agents.


Sympatholytic agents 2

ADRENERGIC NEURON BLOCKERS used in psychiatry possess

Inhibit the function of peripheral, post-ganglionic

adrenergic neurons

Guanethidine - Antihypertensive

Guanadrel - Antihypertensive

Reserpine - Antihypertensive

Bretylium - Anti-arrhythmic

Not used now


Sympatholytic agents 2

Guanethidine used in psychiatry possess :

Sympathoplegic,

Taken up and concentrated by neurons

Blocks NE release (LA like action on terminal)

Displaces NE from granules

IV : initial release – initial mimetic actions

Does not cross BBB

Widespread sympatholytic effects

Leads to several adverse effects

Chronic use causes effector supersensitivity

Guanadrel: Similar to Guanethidine


Sympatholytic agents 2

Bretylium used in psychiatry possess :

Inhibits release of NE from terminals

Also has direct anti-arrhythmic activity

Reserpine :

Blocks vesicular uptake of NE – depletes vesicles Displaces NE from terminal – initial mimetic actions

Crosses BBB – CNS effects:

Depression ,suicidal tendency

Adverse effects due to non specific sympatholysis

These drugs rarely used now for Hypertension


Sympatholytic agents 2

Autonomic Drugs Used for Glaucoma: used in psychiatry possess

Cholinomimetics

Muscarinic agonists Pilocarpine

AChE inhibitors Physostigmine, Increased outflow

Ecothiophate

Alpha agonists

Non – selective Epinephrine Increased outflow

Dipevefrine

Selective α2 Apraclonidine Decreased aqueous

Brimonidine secretion

Beta Blockers Timolol, betaxolol Decreased aqueous

secretion

Other drugs

Carbonic anhydrase inhibitors – acetazolamide – ↓ formation

Prostaglandins – lanatoprost – ↑ outflow


Sympatholytic agents 2

Targets for Pharmacological Interference used in psychiatry possess

Tyrosine hyhroxylase  MPT  NA

DOPA decarboxylase  Methyldopa Pseudotransmitter*

Dopamine  hydroxylaseDisulfiram

Release of NATyramine Sympathomimetic

Amphetamine

Release of NA Guanethidine Sympatholytic

Bretylium

Reuptake Cocaine,  effect of NT

Imipramine  indirect mimetics

Reuptake into granules Reserpine Release Depletion


Sympatholytic agents 2

Targets for Pharmacological Interference used in psychiatry possess

Presynaptic 2 Catecholamines  release

Presynaptic 2 Catecholamines  release

Presynaptic M ACh  release

 MAO Several  metabolism

 Extrasynaptic uptake PBZ, Steroids  Effect

 COMTPyrogallol ---

Talcapone

Entacapone


Sympatholytic agents 2

Dale’s Reversal Phenomenon used in psychiatry possess

Mean arterial blood pressure

PBZ

Adr

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