SYMPATHOLYTIC SYMPATHOLYTIC AGENTS..2AGENTS..2

Alpha Adrenergic receptor Alpha Adrenergic receptor blockersblockers

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

1- SELECTIVEcompetetive

1 > 2

2- SELECTIVEcompetetive

2 > 1

NON-SELECTIVECompetetive

1 = 2

NON-SELECTIVEIrreversible

1 = 2

- RECEPTOR antagonist

Prazosin Yohimbine Phentolamine Phenoxy-Terazosin Idazoxan Tolazoline benzamineDoxazosin Mianserin DibenamineTamsulosin

Classification

Pharmacological actions

Major actions on Blood pressure

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

CVSVasodilatation – arteriolar and venous

BP PVR

Magnitude dependent on symp. activity at that time More in erect that in supine position – postural hypotensionMore marked if hypovolaemia is presentBaroreflex activation – reflex tachycardia – tends to oppose the fall by HR and CO

•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 blockers2 blockers can NA release (presynaptic action) – CV effects

OTHER EFFECTS

↓contraction of trigone and sphincter in bladder - urine flow

insulin secretion from islet cells (2 blockers)

Miosis

Nasal stuffiness

adrenergic sweating

α1 – blockers : Clinical uses

Reduce blood pressureHypertensive emergenciesLong term treatmentPhaeochromocytoma

VasodilatationPeripheral vascular insufficiency

To reverse vasoconstrictor excess

Improve urine flowBenign prostatic hyperplasia

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

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

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

Clinical use:Phaeochromocytoma

Control of BPPrior to surgery

Adverse effects: Postural hypotension, Tachycardia, Nasal stuffiness, ejaculation

Phenoxybenzamine

Phentolamine : 1 = 2

PVR – blockade + direct (non adrenergic) HR – Reflex + 2 presynaptic on cardiac

symp. terminals

Poorly absorbed orally

Clinical use: PhaeochromocytomaLocal vasoconstrictor excess

Adverse effects: Cardiac stimulation : - tachycardia, arrhythmia, angina GIT Stimulation : - diarrhoea; gastric acid secretion

Tolazoline: Similar to phentolamineSlightly less potentBetter absorption from GITRapidly excreted in urine Limited clinical application: peripheral vasospastic disease

1 Selective AgentsPrazosin & 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 liverPrazosin shows high 1st Pass effect (50%)Oral absorption - goodTerazosin :Bioavailability >90%; >18 h actionUses: Hypertension and BPHAdverse effects First dose effect

Postural hypotensionSalt & water retention ( long term use)

Tamsulosin

Selective α1 anatgonist Has greater selectivity for α1A subtypeHas greater efficacy for BPH Relatively smaller effects on blood vessels

USE: BPH

Doxazosin: Similar to Prazosin but longer t ½ (22 Hr)

Alfuzosin : similar to prazosin

Indoramin & Urapidil : Newer 1-selective agents Have some utility in hypertension

2 selective

YohimbineHardly 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 +

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

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.

ADRENERGIC NEURON BLOCKERS

Inhibit the function of peripheral, post-ganglionic adrenergic neurons

Guanethidine - AntihypertensiveGuanadrel - AntihypertensiveReserpine - AntihypertensiveBretylium - Anti-arrhythmic

Not used now

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 actionsDoes not cross BBB

Widespread sympatholytic effects Leads to several adverse effectsChronic use causes effector supersensitivity

Guanadrel: Similar to Guanethidine

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 actionsCrosses BBB – CNS effects: Depression ,suicidal tendencyAdverse effects due to non specific sympatholysis

These drugs rarely used now for Hypertension

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

Targets for Pharmacological Interference Tyrosine hyhroxylase MPT NA

DOPA decarboxylase Methyldopa Pseudotransmitter*

Dopamine hydroxylase Disulfiram

Release of NA Tyramine Sympathomimetic

Amphetamine

Release of NA Guanethidine SympatholyticBretylium

Reuptake Cocaine, effect of NTImipramine indirect

mimetics

Reuptake into granules Reserpine Release Depletion

Targets for Pharmacological Interference

Presynaptic 2 Catecholamines release

Presynaptic 2 Catecholamines release

Presynaptic M ACh release

MAO Several metabolism

Extrasynaptic uptake PBZ, Steroids Effect

COMT Pyrogallol ---TalcaponeEntacapone

Dale’s Reversal Phenomenon

AdrPBZ

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