sympatholytics agents

1. PREPARED BY- KAHKESHA SAMSHAD
M.PHARM 1ST YEAR ( PHARMACOLOGY)
Faculty of pharmacy, Integral University.
Lucknow.

2. INTRODUCTION
 These are the drugs which antagonize the receptor action of adrenaline and
related drugs.
 They are competitive antagonist at 𝝰 or 𝛃 or both 𝝰 and 𝛃 adrenergic
receptors.
 CLASSIFICATION:
1. 𝝰 blocker
2. 𝛃 blocker

3. 𝝰-ADRENERGIC BLOCKING DRUGS
 These drugs inhibit adrenergic responses mediated through the 𝝰 adrenergic
receptors without affecting those mediated through 𝛃 receptors.

4. CLASSIFICATION
1. Nonequilibrium type
 β-Haloalkylamines – phenoxybenzamine.
2. Equilibrium type (competitive)
A. Nonselective
1. Ergot alkaloid- Ergotamine, Ergotoxine
2. Hydrogenated ergot alkaloid- Dihydro-ergotamine(DHE), Dihydroergotoxine.
3. Imidazoline- Phentolamine.
4. Miscellaneous- Chlorpromazine.
B. 𝝰1 selective- prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin.
C. 𝝰2 selective- yohimbine.

5. General effect of 𝝰-blockers
1. BLOOD PRESSURE.
 Blockade of 𝝰1 receptor.
 Vasodilation.
 Decrease in peripheral resistance.
 Venous return and cardiac output decrease.
 BP falls.
 Peripheral pooling of blood.
2. REFLUX TACYCARDIA
 occurs due to- Fall in mean arterial BP
 Release of NA due to blockade of pre-synaptic 𝝰2 receptor.
3. NASAL STIFFNESS AND MIOSIS
 Blockade of 𝝰-receptor in nasal blood vessel and in radial muscles of iris.

6. 4. RENIN RELEASE
 Hypotension
 Renal blood flow decreases
 GFR decreases
 Retention of sodium and increase in blood volume.
 Complete reabsorption of sodium and water.
5. SMOOTH MUSCLE
 Intestinal motility is increased
 Loose motion may occur
 Tone of smooth muscle in bladder, trigone, sphincter and prostate is reduced by blockade of alpha
receptor.
6. EJACULATION
 Impotence
 Alpha blocker can inhibit ejaculation.

7. • PHENOXYBENZAMINE
 It cyclizes spontaneously in the body giving rise to a highly reactive ethyleniminium intermediate which
reacts with alpha adrenoreceptors and other biomolecules by forming strong covalent bonds. The alpha
blockade is of nonequilibrium(irreversible) type and develops gradually (after i.v injection) and last for 3-
4days till fresh receptors are synthesized.
 The fall in BP caused by phenoxybenzamine is mainly postural because venodilation is more prominent
than arteriolar dilation.
 It is lipid soluble, penetrates brain and can produce CNS stimulation, nausea, vomiting on rapid i.v.
however oral dose produce depression, tiredness and lethargy.
 Major side effects are- postural hypotension, palpitation, nasal blockage, miosis, inhibition of ejaculation.
PHENTOLAMINE
 This is rapidly acting Alpha blocker with short duration of action(in minutes).
 It equally blocks 𝝰1 and 𝝰2 receptors- NA release is increases.
 Veno dilatation predominates over arteriolar dilatation.
 Action last for approximately 4 hours after single administration.
 Uses as a quick and short acting alpha blocker in-pheochromocytoma, hypertension, benign prostatic
hypertrophy, peripheral vascular disease.

8. PRAZOSIN
 Prazosin is the first of a highly selective 𝝰1 blockers having 𝝰1: 𝝰2 selectivity ratio 1000:1. all subtype of 𝝰1
receptors (𝝰1A, 𝝰1B,𝝰1D) blocked equally.
 It blocks sympathetically mediated vasoconstriction and produce fall in BP which is attended by only mild
tachycardia, NA release is not increased due to 𝝰2 blockade.
 Prazosin dilated arterioles more than veins. Postural hypotension is less marked, occurs especially in the beginning,
which may cause dizziness and fainting as ‘first dose effect’ this can be minimized by starting with low dose and
taking it at bed time.
 Prazosin inhibits phosphodiesterase which degrade cAMP. It is effective orally, metabolized in liver, bound to plasma
protein. Plasma t 1/2 is 2hrs.
 Uses- antihypertensive, Raynaud’s disease, improves urine flow, reduces residual in urine.
TERAZOSIN
 It is chemically and pharmacologically similar to prazosin, differences are higher bioavailability (90%) and longer
plasma t1/2 (12hr), a single dose lowers BP over 24hrs. It is more popular for use in BHP due to single dose and a
probable apoptosis promoting effect on prostate.
ALFUZOSIN.
 This short acting (T1/2 3-5hrs) congener of prazosin has been specifically developed for symptomatic treatment of
BHP. It is nonselective for 𝝰1a, 𝝰1B, 𝝰1D subtypes. The metabolism of alfuzosin is inhibited by CYP34A inhibitors. It is
not approved as an antihypertensives.

9. TAMSULOSIN
 This is relatively uroselective 𝝰1A/ 𝝰1D blocker has been found as effective as terazosin in
improving BHP symptoms, because 𝛼1𝐴 subtype predominates in the bladder base and
prostate.
 Tamsulosin does not cause significant changes in BP or HR at doses which relieve urinary
symptoms, and not used as antihypertensives.
 Postural hypotension is infrequent. Dizziness and retrograde ejaculation are the only
significant side effect.
 Its plasma T1/2 is 6-9hrs.
YOHIMBINE
 It is a alkaloid from the west African plant yohimbehe found as a component of the bark of
the yohimbe tree. a selective competitive 𝝰2 blocker with short duration of action.
 Also block 5-HT receptors.
 Heart rate and BP gradually elevated due to increased central sympathetic outflow as well as
enhanced peripheral NA release. Other CNS effect include excitation, tremor, ADH release,
nausea, vomiting.

10. USES OF 𝝰 BLOCKERS
 Pheochromocytoma- it is a tumor of adrenally medullary cells.
 phenoxybenzamine can be used as definitive therapy for inoperable and malignant
pheochromocytoma. Prazosin is alternative.
 Hypertension- phenoxybenzamine/ phentolamine are of great value in controlling
episodes of rise in BP during cloinidine withdrawal and cheese reaction in patients with MAO
inhibitors.
 Benign hypertrophy of prostate (BHP) –
 𝝰 adrenergic blocker(like prazosin) decreases tone of prostatic/bladder neck muscles.
 5-𝝰 reductase inhibitor arrest growth reduce size of prostate.
 Peripheral vascular disease.
 Congestive heart failure (CHF)
 Secondary shock
 Papaverine/phentolamine induced penile erection (PIPE) therapy for impotence.

11. 𝛃- ADRENERGIC BLOCKING DRUGS
CLASSIFICATION.
Non-selective (𝛃-1 and 𝛃-2)
1. Without intrinsic sympathomimetic activity- propanol, sotalol, timolol.
2. With intrinsic sympathomimetic activity- pindolol
3. with additional 𝝰 blocking property- labetalol, carvedilol.
Cardioselective (𝜷 1)
Metoprolol, Atenolol, Acebutolol,, Bisoprolol, Esmolol, Celiprolol, Nebivolol.
PROPANOLOL IS THE PROTOTYPE.
This drug inhibit adrenergic responses mediated through 𝛃 receptors. All are
competitive antagonists.

12. PHARMACOLOGICAL ACTIONS.
 Propranolol is the 𝜷-adrenergic antagonist and blocks both 𝛃-1 and 𝛃-2 receptors, but has weak activity on 𝛃3 subtype
1.Cardio vascular
 Heart: ↓HR, Force of contraction. A-V conduction
 Cardiac work and oxygen consumption are reduced.
 Propranolol block vasodilatation and fall in BP evoked by isoprenaline and enhance the rise in BP caused
by Adr.
2. Respiratory tract.
 Increased bronchial resistance 𝛃-2 blockade.
3. CNS.
 Behaviour changes, forgetfulness, increased dreaming and nightmares.
 Anti-anxiety effect (peripheral action of propranolol)
4. Metabolic.
 Blocks adrenergically mediated lipolysis.
 Inhibits glygenolysis in heart, skeletal muscle, liver.
 May reduce carbohydrate tolerance (decrease insulin release)

13. 5. Skeletal muscle.
 Inhibits adrenergically proved tremor (𝛃2 blockade)
 Attenuate exercise capacity.
6. Eye
 Reduced secretion of aqueous humor and intra ocular tension.
7. Uterus
 Relaxation of uterus in response to isoprenaline and selective 𝛃2 agonist is blocked by propranolol.
 DOSE: 10mg BD to 160mg QID oral, 2-5mg I.v parentral.
 Pharmacokinetic: Propranolol is well absorbed orally. But has low availability due to first pass
metabolism in liver.

14. SOTALOL
 Nonselective 𝛃 blocker with low lipid solubility. It has additional cardiac rectifier k+ channel
blocking and class 3 antiarrhythmic property.
TIMOLOL
 It is the 𝛃 blocker preferred for topical use in the eye for glaucoma. Orally it is a potent 𝛃
blocker- has been used in hypertension, angina and prophylaxis of myocardial infarction.
METOPROLOL
 It is the prototype of cardio-selective 𝛃1 blockers. Nearly 50 times higher dose is needed to
block isoprenaline induced vasodilatation.
 It worsens asthma. Some measures of inverse agonistic activity on 𝛃1 receptors has also
been demonstrated.
 It is preferred in diabetics receiving insulin or oral hypoglycemics. Also used orally for
hypertension, angina and CHF, I.V injection in myocardial infarction.
 First pass metabolism of metoprolol is less marked than propranolol, but 90% or more is
ultimately hydroxylated by CYP2D6 before excretion.

15. ATENOLOL
 It is a relatively selective 𝛃1 blocker having low lipid solubility. It is incompletely absorbed orally,
but first pass metabolism is not significant.
 Because of long duration of action, once daily dose is sufficient.
 Used in hypertension and angina.
ACEBUTOLOL
 It is a cardioselective agent with significant partial agonistic and membrane stabilizing properties.
 Effect on resting heart rate is less.
 It is rapidly metabolized to an active metabolite diacetolol which is primarily excreted by kidney
and has longer t1/2 (8-12hrs).
 BISOPROLOL
 A cardioselective 𝛃 blocker lacking intrinsic sympathomimetic activity. Suitable for once daily
administration in angina, hypertension and CHF.

16. ESMOLOL
 It is ultrashort acting 𝛃1 blocker devoid of partial agonistic or membrane stabilizing actions.
 It is inactivated by esterases in blood, plasma t1/2 is < 10min. Action disappears 15-20min
after terminating I.V infusion.
 Rapid onset, short lasting fall in BP attends I.V infusion of esmolol.
 Used to terminate supraventricular tachycardia, episodic arterial fibrillation or flutter,
arrhythmias during anaesthesia, to reduce HR and BP during and after cardiac surgery and in
early treatment of myocardial infarction.
CELIPROLOL
 It is a selective 𝛃1 blocker having additional weak 𝛃2 agonistic activity which reduces
vascular resistance and holds promise of safety in asthamatics.
 NEBIVOLOL
 this highly selective 𝛃1 blocker also acts as a NO donor, produces vasodilatation and has the
potential to improve endothelial function, which may delay atherosclerosis.
 Has rapid onset of action. Used in hypertension and CHF

17. USES-
 Hypertension
 Stable angina
 Cardiac arrhythmias
 Myocardial infarction
 Congestive heart failure
 Hypertrophic obstructive cardiomyopathy.
 Dissecting aortic aneurysm.
 Pheochromocytoma
 Thyrotoxicosis
 Migraine
 Anxiety
 Essential tremor
 Glaucoma

18. ADVERSE EFFECT:
 Bradycardia
 Exacerbate variant angina
 Impaired carbohydrate tolerance
 Altered plasma lipid profile
 Tiredness and reduced exercise capacity
 Cold hand and feet.
 Precipitate CHF/ edema.
 Others: upset, nightmares, forgetfulness, hallucinations, sexual distress in male, lack of drive.
CONTRAINDICATION
 Sudden withdrawal: rebound hypertension, worsening of angina, sudden death
 Worsens COPD, can produce acute bronchial asthama
 Partial or complete heart block.