anti andrenergic drugs

1. ANTI-ADRENERGIC
DRUGS

2. Alpha receptors Beta receptors
Control vasoconstriction, intestinal
relaxation, pupil dilation
Control vasodilation, relaxation of the
bronchial and uterine smooth muscles
Stimulate effector cells Relax effector cells
2 types - α1 and α2 3 types - β1, β2 and β3
Mainly occur in vascular smooth muscles
and effector tissues and stimulate smooth
muscles
Mainly occur in bronchi muscles, heart
muscles, and uterine muscles and
stimulate both cardiac and smooth
muscles
eg of α1 agonist : Midodrine
eg of α2 agonist : Clonidine
eg of β1 agonist : Dobutamine
eg of β2 agonist : Metaproterenol
eg of β3 agonist : Mirabegron

4. CLASSIFICATION OF ANTI-ADRENERGIC DRUGS

5. GENERAL EFFECTS OF ALPHA BLOCKERS
• Reduction in blood pressure - bockade of vasoconstrictor α1 (also α2 ) receptor
causes pooling of blood in capacitance vessels reduced venous return and
cardiac output fall in mean BP
• Postural reflex is interfered - dizziness and syncope on standing due to marked
hypotension
• Vasomotor reversal of dale – α blockers abolish the pressor action of adrenaline
which then produces only fall in B.P. due to β2 mediated vasodilation

6. • Reflex tachycardia due to fall in mean arterial pressure and increased NA release due
to presynaptic α2 blockade
• Nasal stuffiness and miosis
• Increased intestinal motility may lead to diarrhoea
• Reduced GFR : Sodium retention and expansion of blood volume – also reflex renin
release
• Tone of the bladder trigone, sphincter and prostate is reduced by blockade of α1
receptors leading to increased urine flow in BHP
• Inhibition of ejaculation – due to inhibition of contraction of vas deferens and seminal
vesicles may manifest as impotence

7. Phenoxybenzamine
• Non specific, long acting irreversible alpha antagonist
• MOA: Spontaneously cyclizes in the body to give ethyleniminium intermediate
forms a strong covalent bond with α receptors blockade of alpha receptor (lasts
for 3 – 4 days)
• Blockade of 5-HT, histaminergic and cholinergic receptors
• Postural hypotension: Venodilatation >arteriolar
• In recumbent position , blood flow to many organ increased due to reduction in
peripheral resistance and increased venous return
• CNS stimulation – nausea, vomiting on IV injection but oral doses cause depression,
tiredness and lethargy

8. Pharmacokinetics:
• Erratic oral absorption and painful on i.m. and s.c. injections
• Most of the administered drug gets excreted in urine in 24 hours
• Small amount may remain in tissue bound covalently – leading to accumulation
in adipose tissue
Uses:
• Phechromocytoma , occasionally in peripheral vascular disease
Adverse effects:
• Postural hypotension, nasal stuffiness, miosis and inhibition of ejaculation
Preparation and dosage:
• 20-60 mg orally
• 1 mg/kg i.v. infusion over 1 hour.

9. Phentolamine
• Non specific, short acting reversible alpha antagonist
• Reduction in peripheral resistance - blocking both α1 and α2 receptors - causes NA
release and tachycardia occurs
• Venodilatation more than arteriolar
Uses:
• Diagnosis and intraoperative management of Pheochromocytoma, clonidine
withdrawal, cheese reaction
Dose:
• 5 mg i.v. repeated as required

10. Prazosin
• Highly selective α1 blocker (1:1000)
• Non-specific blocker of all subtypes - α1A, α1B and α1D
• Blockade of sympathetic vasoconstriction - fall in BP
• NA is not released as α2 is not blocked (only mild tachycardia)
• Dilates arterioles more than veins – Postural hypotension is less but maybe only at
beginning causing dizziness and fainting due to “first dose effect” , minimized by
starting with low dose and at bed time
• Also inhibits phosphodiesterase– rise in smooth muscle cAMP - vasodilatation

11. Pharmacokinetics :
• Effective orally (bioavailability of 60%), metabolized in liver and excreted
primarily in bile
• Plasma t1/2 is 2-3 hours
• Effect of single dose lasts for 6-8 hours
Uses:
• Hypertension
• Raynaud`s disease
• BHP
• Scorpion sting
Dose:
• Start with 0.5 – 1 mg at bed time and then 1-4 mg BD or TDS

13. Other alpha Blockers
Terazosin
• Similar to Prazosin but better bioavailability (90%)
• Duration of action is longer – 24 hours
• Use: Preferred in BHP – single daily dose and probable apoptosis promoting
effect on prostate
Tamsulosin
• Uroselective - α1A / α1D blocker
• No significant changes in B.P. or H.R.
• Improves BHP symptoms but lacks apoptosis promoting property
• Only once daily dosing regime (modified release caps), 0.4 mg MR cap
• Adverse effects: Retrograde ejaculation and dizziness

14. β-adrenergic Blockers
Cardioselective:
Metoprolol, atenolol, acebutalol, bisoprolol,esmolol, betaxolol, celiprolol, nebivolol
Nonselective (β1 and β2):
Without intrinsic sympathomimetic activity : Propranolol (membrane stabilizing
action), Sotalol and Timolol
With intrinsic sympathomimetic activity (ISA) : Pindolol and Oxprenolol
Additional alpha blocking property : Labetolol and Carvedilol

15. Actions of Propranolol
Heart:
• Decreases heart rate, cardiac output and force of contraction
• Not prominent in Normal persons, but in presence of sympathetic over activity
(exercise, emotion)
• Cardiac work and myocardial oxygen demand is reduced
• Total coronary flow reduction (aortic pressure) – subepicardial region but not
subendocardial region – benefit in angina
• Delayed AV conduction
• At high doses membrane stabilizing and direct depressant action

16. Blood Pressure:
• No direct and acute action on Blood Pressure
• In fact blocks vasodilatation fall in BP by Isoprenaline and enhances rise in BP by
adrenaline – “re-reversal of vasomotor reversal of dale”
• But beneficial in hypertensives on prolonged administration
• Normally, propranolol would block CA induced vasodilatation and cause increase
in total peripheral resistance(t.p.r) and decrease in cardiac output(CO) – but
negligible change in BP
• After chronic exposure the resistance vessels adapt to low CO so that t.p.r
decreases which is the most likely explanation of the antihypertensive action
Other mechanisms that may contribute are :
• Reduced NA release due to blockade of β receptors
• Decreased Renin release (β1 mediated)
• Central action reducing sympathetic outflow

17. Respiratory:
Bronchoconstriction due to blockade of dilator β2 receptors
Not considerable in normal individual but is dangerous in asthmatics and should be
avoided
β1 selective drugs are preferred
Eye:
Decreases IOP by reducing production of aqueous humor – glaucoma
CNS:
No considerable CNS effect except subtle behavioural changes, forgetfulness and
nightmares on long term use , suppresses anxiety
Metabolic:
Blocks adrenergically induced lipolysis, glycogenolysis is attenuated

18. Pharmacokinetics :
• Most of the drugs are well absorbed after oral administration , peak concentrations
occur 1–3 hours after ingestion
• Propranolol undergoes extensive first pass metabolism
• High oral:parenteral ratio – 40:1
• Lipophilic and penetrates brain easily
• Metabolism dependent on hepatic blood flow, propanolol itself decreases
hepatic blood flow, higher bioavailability on chronic administration
• Higher bioavailability if taken with food
• Dose: 10 mg BD to 160 mg QID (average 40 – 160 mg /day)

19. Adverse effects:
• Precipitation of CCF/Oedema
• Bradycardia
• COAD and Bronchial asthma (life threatening asthma)
• Variant angina exacerbation – unopposed coronary constriction by α receptor
• Withdrawal after chronic use should be gradual , otherwise rebound hypertension,
worsening of angina and even sudden death can occur
• Tiredness and reduced exercise capacity due to blunting of β mediated increase of
blood flow
• Cold hands and feet – worsening of Peripheral vascular disease

20. Other beta blockers
• Cardioselective: Metoprolol, Atenolol, Acebutolol
• More selective in blocking β1 receptors than β2
Advantages:
• Lower propensity to cause bronchoconstriction
• Lesser interference with carbohydrate metabolism – safer in diabetics
• Lower incidence of cold hands and feet
• Lesser impairment of exercise capacity
• Intrinsic sympathomimetic activity : Pindolol
Advantages:
• Lesser bradycardia and depression of contractility – preferred in elderly
• Favourable withdrawal, less/no interference with lipid profile

21. Metoprolol:
• Prototype of cardioselective blockers - β1 selective (also inverse agonist)
• Less first pass metabolism
• Slow and fast hydroxylators (CYP2D6 substrate)
Uses:
• In hypertension, angina and CHF
• In Diabetics receiving insulin or oral hypoglycaemics
• Available in 25, 50,100 mg tab, 5mg/ml injection
Atenolol:
• Selective β1 blocker and low lipid solubility
• Longer duration of action – once daily dose is often sufficient
Uses:
• Commonly for hypertension and angina, but not approved for CHF

22. Uses
• Hypertension
• Angina pectoris
• Cardiac arrhythmias: mainly Propranolol suppresses extrasysoles and tachycardia
• Myocardial infarction: Propanolol and metoprolol are for 2 purposes
o Secondary prophylaxis of MI
o Myocardial salvage during evolution of MI

23. • Congestive Heart failure
• Dissecting aortic aneurysm
• Pheochromocytoma
• Thyrotoxicosis : Propanolol rapidly controls palpitation, nervousness, tremors
• Migraine
• Anxiety: social phobia

24. α + β adrenergic blockers
Labetolol:
• First adrenergic antagonist capable of blocking both α and β receptors
• α1 + β1 + β2 blocking and weak β2 agonistic activity
• β blocking potency is 1/3rd of Propranolol and α blocking potency is 1/10th of
Phentolamine
• Moderately potent antihypertensive that is particularly used in Phaechromocytoma,
clonidine withdrawal, pregnancy induced hypertension
Dose:
• Start with 50 mg BD, increase to 100-200 mg TDS

25. Carvedilol:
• β1 + β2 and α1 adrenoceptor blocker and also Ca++ channel blocker
• Antioxidant property also demonstrated
• Vasodilatation due to α1 blockade + Ca++ channel block + antioxidant property
• Oral bioavailability is 30%
Uses:
• In Hypertension and especially employed as cardioprotective in CHF

26. NEWER DRUGS
• The two new selective α blockers, silodosin and naftopidil showed similar efficacy
in IPSS(International prostate symptoms score) and quality of life compared with
other alpha-blockers
• However, silodosin has more sexual adverse events
• The most recent β blocker to enter the U.S. marketplace is nebivolol approved by
the FDA for the treatment of hypertension
• In Europe, it is registered for use in mild-to-moderate, uncomplicated hypertension
and mild-to-moderate heart failure and has been approved for hypertension

27. THANK YOU