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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

slide2

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
slide3

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

slide4

Pharmacological actions

  • Major actions on Blood pressure
  • Other effects based on - role of  receptors in different tissues - selectivity of the agent (2 vs1)
slide5

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

slide6

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
slide7

OTHER EFFECTS

  • ↓contraction of trigone and sphincter in bladder - urine flow
  • insulin secretion from islet cells (2 blockers)
  • Miosis
  • Nasal stuffiness
  •  adrenergic sweating
slide8

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

slide9

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
slide10

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

slide11

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

slide12

Phenoxybenzamine

Clinical use:

Phaeochromocytoma

Control of BP

Prior to surgery

Adverse effects:

Postural hypotension,

Tachycardia,

Nasal stuffiness,

 ejaculation

slide13

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

slide14

Tolazoline:

Similar to phentolamine

Slightly less potent

Better absorption from GIT

Rapidly excreted in urine

Limited clinical application:

peripheral vasospastic disease

slide15

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)

slide16

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

slide17

Indoramin & Urapidil :

Newer 1-selective agents

Have some utility in hypertension

slide18

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 + 

slide19

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
slide20

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.

slide21

ADRENERGIC NEURON BLOCKERS

Inhibit the function of peripheral, post-ganglionic

adrenergic neurons

Guanethidine - Antihypertensive

Guanadrel - Antihypertensive

Reserpine - Antihypertensive

Bretylium - Anti-arrhythmic

Not used now

slide22

Guanethidine :

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

slide23

Bretylium :

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

slide24

Autonomic Drugs Used for Glaucoma:

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

slide25

Targets for Pharmacological Interference

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

slide26

Targets for Pharmacological Interference

Presynaptic 2 Catecholamines  release

Presynaptic 2 Catecholamines  release

Presynaptic M ACh  release

 MAO Several  metabolism

 Extrasynaptic uptake PBZ, Steroids  Effect

 COMTPyrogallol ---

Talcapone

Entacapone

slide27

Dale’s Reversal Phenomenon

Mean arterial blood pressure

PBZ

Adr

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