ADRENOCEPTOR AGONISTS & SYMPATHOLYTIC DRUGS

Anatomy of the sympathetic nervous system

The origin is from thoracolumbar segments all thoracic + lumbers L1, L2, L3 and L4

They have short preganglionic fibers, and it release Ach in from this ganglia. They have long postganglionic fibers that innervate their body organs & release Norepinephrine as a neurotransmitter.

Sympathomimetic drugs

Drugs that mimic the actions of epinephrine or norepinephrine have traditionally been termed sympathomimetic drugs..

Biosynthesis of Nor-adrenaline
Tyrosin Tyrosin hydroxylase

Dopa
Dopamine Nor-adrenaline Phenylethanolamine N-Methyl Transferase (PNMT).

Dopa decarboxylase

Dopamine hydroxylase

Adrenaline

Synthesis of Adrenalin

Fate of Adrenaline

About 80-90% of the released nor-adrenalin is reuptaken by nerve terminal by Reuptake-I. Rest of the nor-adrenalin under goes enzymatic destruction- MAO (Monoamine- oxidase) in CNS. -COMT (Catechol-Omethyltransferase) in liver, kidney, GIT.

- 5%

reach the blood and metabolized In the Liver.

Classification of Adrenoceptors

Alpha receptors
1

Beta receptors
1 2 3

Dopamine receptors
D1 D2

Distribution of Adrenoceptor
Type 1 Heart Erectopylorum muscle Male sex organ (vas deference, seminal vesicle, prostate) Dilator pupil muscle of Iris Sphincter of whole body Uterus 2 Pre-Synaptic adrenoceptor Platelet Fat cell cell of pancreas Tissue Most vascular smooth muscle Action Contraction Force of contraction Erection of hair Ejaculation

Dilates pupil Constriction Contruction Inhibit release of Noradrenalin from brain stem. Aggergation Inhibit lipolysis Release of insulin

Distribution of Adrenoceptor
Type 1 - Heart - Brain - Kidney Tissue Action Force of contraction Sympathetic out flow Release renin from juxta glomerular cell.

- Smooth muscle of Respiratory & Uterus.

- Skeletal Muscle vessel - cell of pancreas - Liver

Relaxation of smooth muscle

Vasodilatation of Skeletal Muscle. Glucagon, Glycogenolysis, Activate Lipolysis.

- Fat cell

Distribution of Adrenoceptor
Type Tissue Action

D1

Smooth muscle

Causes vasodilation of Renal,Messenteric, Coronary & Cerebral vessel.

D2

Nerve ending

Modulates neurotransmitter release in CNS.

Adrenergic Drugs

Adrenoreceptor Agonists

Non selective Selective

Classified by mode of action

Adrenoceptor Agonists

I. Non selective drugs (Act on all receptors) Catecholamine Drugs

A. Endogenous: Norepinephrine Epinephrine Dopamine B) Synthetic (exogenous) Isoprenaline , Dobutamine

Non-catecholamine Drugs
- Amphetamine

- Ephedrine - Cocaine

Adrenoceptor Agonists

II. Selective drugs 1 selective agonist.. Phenyl ephrine 2 selective agonists Clonidine 1 + 2 selective agonists Oxymetazoline 1 selective agonistsDobutamine 2 selective agonistsSalbutamol 1 + 2 selective agonist ..Isoproterenol D1 selective agonists Fenoldopam D2 selective agonists.. Bromocriptine

Catecholamines

Def : These are the substance which consist of a catechol ring with an ethylamine side chain (CH2-CH2-NH2).

Natural:

- Nor adrenaline
- Adrenaline - Dopamine

Synthetic :

- Isoprenaline
- Dobutamine

Pharmacokinetics

Natural Catecholamine

Synthetic Catecholamine

H2O soluble Poorly absorbed from G.I.T. Shorter duration of action. Less tissue volume of distribition. Less CNS action. Cant be given orally

Lipid soluble Rapidly absorbed from G.I.T Longer duration of action. Wide tissue volume of distribition. More CNS action. Can be given orally.

Mechanism of action

Adrenergic drugs initially binds to appropriate receptors (whether , or Dopamine ) in the target site. Stimulation of 1 receptors by catecholamines leads to the activation of a Gq coupling protein. The activated subunit of this G protein activates the effector, phospholipase C, which leads to the release of IP3 (inositol 1,4,5-trisphosphate) and DAG(diacylglycerol). IP3 stimulates the release of sequestered stores of calcium, leading to an increased concentration of cytoplasmic Ca++ . Which may then activate Ca ++ dependent protein kinases, which in turn phosphorylate their substrates. DAG activates protein kinase C (PKC).

Mechanism of action Cont

stimulation causes increase adneylyl cyclase activity leading to increase cAMP leading to cellular effect. E.g.

1 in the heart cause increase intracellular Ca++ release leading to increased contractility 2 in smooth muscle cause inhibition of myosin kinase enzyme causing relaxation

Pharmacological effects

On the eye

Mydriasis : Due to 1 mediated contruction of dilator pupil muscle of Iris. Reduce intra ocular pressureThe agonist cause increase outflow of aqueous humor.

On Heart

The effects on heart are mainly mediated by 1 receptors.

1 stimulation causes In S.A node : increase heart rate (HR) (+ve chronotropic) In Myocardium tissue : increase contractility (+ve inotropic) In Conducting system : increase conduction velocity (+ve dromotropic)

In the Juxtaglomerular Apparatus of the kidney. 1 stimulation cause increased renin release.

In brain: Increase sympathetic outflow.

Then causes increase in BP.

On Blood vessel -The vascular smooth constrict or dilate in response to

stimulation of adrenergic receptors. - Most blood vessel constricts in response to stimulation of 1 receptors. - The vessels of skeletal muscle dilate in response to stimulation 2 receptors.

- The stimulation of D1 receptors in renal, coronary, splanchnic vessels lead to vasodilatation.

On respiratory tract:

- Bronchial smooth muscle contain 2 receptors, the

stimulation of which leads to smooth muscle relaxation and bronchodilatation.

- The blood vessels of the upper respiratory tract contain

1 receptors.

On GIT

- Relaxation of smooth muscle (2 stimulation ) of the gut wall.

-

1 stimulation cause contraction of all sphincters

Reduce peristalsis movement.

Constipation

- 2 agonist drugs act presynaptically and reduce release of acetylcholine. So acetylcholine mediated contraction of gut wall is inhibited.

On Genitourinary tract:

-The bladder wall contain 2 receptors, the stimulation of

which produce bladder wall relaxation. So causes retention of urine.
- 1a subtypes stimulation cause contraction and closure of the sphincters (precipitate urinary retention).

- Ejaculation depends on contraction of vas difference,

seminal vesicle& prostate mediate by 1 receptor.

- The uterus contain 2 receptors in the wall and they

cause uterine relaxation.

On CNS

The non-catecholamines can enter the CNS and cause variable effects that range from mood elevation, alertness to euphoria, insomnia and anorexia.

On exocrine glands The exocrine sweat glands are regulated by cholinergic postganglionic sympathetic nerves that activate acetylcholine.

Metabolic effects

In the liver. 2 stimulation causes increased Glycogenolysis & Gluconeogenesis

In the pancreas. 2 stimulation causes increase secretion of glucagon. The 3 receptor stimulation in the fat cells lead to lipolysis and release of free fatty acid into the circulation.

Norepinephrine (NE)

NE is a neurotransmitter released from the postganglionic sympathetic fiber in most organs. It also released from the adrenal medulla (20% of medulla secretion) It is a direct nonselective adrenergic agonist which acts on all adrenoceptors, Except 2 Clinical Uses:
Note: NE is not commonly used in clinical practice like Epinephrine, However it can be used in:

Cardiac Arrest Hypovolumic Shock.

Epinephrine (EP)(Adrenaline)

EP is released from adrenal medulla (80%) and in certain areas of the brain EP is a direct acting non-selective adrenergic agonist in all receptors.

Clinical uses:
In bronchial asthma In cardiogenic shock

It is given I.V to increase SBP,HR and cardiac output (CO)

In anaphylactic shock..

It is given SC to act on

1 cause VC, lead to increase BP & relief of congestion 1 cause increase HR leading to increase CO, so, increase BP 2 cause bronchodilation so, relieve bronchospasm

Cont In cardiac arrest (for Bradycardia)

It is given I.V. if there is no response, EP given directly into the lung, and if there is no response, it given intracardially, and if there is no response, direct current is applied for 3 times at most.

During surgery

EP is added to the local anesthetic to cause VC in the surgery area in order to Decrease bleeding Decrease the amount of local anesthetic which will reach the systemic circulation. Therefore, it will decrease the cardiodepressant effect of the local anesthetic

Dopamine

Clinical Uses :
In small dose (=< 5ug / Kg / min by I.V infusion)

Renal dose:

It will stimulate D1receptors only

It

will cause vasodilatation (VD) in: Renal vascular bed Cerebral vascular bed Coronary vascular bed Mesenteric vascular bed

Therefore, it is useful in treatment of shock to save these vital organs from hypoxia (also Dobutamine)

In medium dose : (5-15ug/Kg/min by I.V infusion) Cardiac dose It will stimulate 1 receptors to cause increase HR, CO and BP

In high dose of DA (> 15ug / Kg / min by I.V infusion) Vascular dose:

It will stimulate 1 receptors (direct + Via release of NE) to cause VC leading to increase BP and decrease organ perfusion

Amphetamine

Acts mainly indirectly via, enhancing NE release and DA.

Since it is non-catecholamine, it can be given orally It is lipidsoluble enough to be absorbed from intestines and goes to all parts including CNS

Clinical use
To suppress appetite
In very obese persons Amphetamine can act centrally on the hunger center in the hypothalamus to suppress appetite

In narcolepsy
Narcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night Amphetamine stimulates the CNS & makes the patient awake

In ADHD Attention Deficit Hyperactivity Disease

Ephedrine

Like amphetamine, it is CNS and respiratory stimulant.

Directly acts on the receptors (,1,and 2) It is Like an oral form of Epinephrine

Indirectly releasing NE

It does not suppress the appetite

Presser agent (used to increase BP)

Decongestant
It is no longer used to treated bronchial asthma. (because its less potent + slow onset of action)

Indication of use

Anaphylactic shock ( Adrenaline) Hypovolumic shock (Volume replacement, Treatment of cause, Nor- adrenaline) Cardiogenic shock ( Dopamine or Dobutamine)

Bronchial asthma (Salbutamol) To secure hemostasis in surgery (oral, nasopharyngeal , facial). ( Adrenaline) Nasal decongestion ( Oxymetazoline, Zylometazoline) To prolong the action of local anesthetics ( Adrenaline)

Sympathetic nervous system & drugs ( Sympatholytics )

Sympatholytics
Anti-adrenergic drugs.
These drugs antagonizes the actions of symapthomimetics at the adrenegic receptor sites.

Classification of sympatholytics

Beta blockers
Selective( 1 receptor) Atenolol. Acebutolol. Esmolol Metoprolol, Carvidilol.

Non-selective ( both 1 and 2 receptor)

Propranolol Timolol Sotalol,Nadolol, Labetalol, Oxprenalol

Both (+ blocker) Labetalol Carvidilol.

1- selective adrenergic antagonists

Atenolol is a b1-selective adrenergic antagonist that is devoid of intrinsic sympathomimetic activity.

It is used for the treatment of hypertension.

Metoprolol is a B1-selective adrenergic antagonist that is devoid of intrinsic sympathomimetic activity. It can be used for treating hypertension ,angina, acute myocardial infarction, heart failure, and arrhythmias.

Nadolol Nadolol is a long-acting antagonist with equal affinity for 1- and 2-adrenergic receptors. It is devoid of both membrane-stabilizing and intrinsic sympathomimetic activity. The half-life of the drug in plasma is approximately 20 hours. Pindolol is a non-subtype-selective b-adrenergic antagonist with intrinsic sympathomimetic activity.

Intrinsic sympathomimetic activity

Also referred to as intrinsic sympathomimetic effect. Some beta blockers (e.g. oxprenolol, pindolol, penbutolol and acebutolol) exhibit intrinsic sympathomimetic activity (ISA).

These agents are capable of exerting low level agonist activity at the -adrenergic receptor while simultaneously acting as a receptor site antagonist.

Difference between Propranolol and Atenolol

Propranolol

Atenolol Water soluble.

Highly lipid soluble. Undergoes extensive first-pass metabolism.

Excreted through the

kidney.

Can penetrate the blood

brain barrier.

Cannot penetrate blood rain barrier.

Frequent dosing needed.

Once daily dosing possible.

 Effect

On the heart

Heart : They competitively inhibit the action of catecholamines on the heart by blocking the 1 receptors. - The force of contractionse, heart rate decre and cardiac output decreases. - and blood pressure falls. Brain:They act centrally to produce sympathoplegic effects. Kidney : They act on the kidney by binding to 1 receptor of the juxtaglomerular apparatus and reduce renin secretion.

Pharmacological effects of sympatholytics

In the eye - Sympatholytics (timolol) a beta blocker will decrease

aqueous humor secretion

- and lower intraocular pressure. - So can be use in glaucoma.

Why timolol?

( *It has good ocular penetration.

- It does not have local anaesthetic action.

- It has efficacy similar to that of pilocarpine.)

Continue.

In the respiratory system - Sympatholytics like non-selective beta blockers block 2 receptor and cause bronchospasm.

 In

the metabolic system

The blockade of 2 receptor in the liver causes delayed recovery from hypoglycamia in diabetic patients on insulin therapy.

In

the Nervous system

- Low dose Propanolol can be used in migraine

Indication of use of blockers

Cardiac indication

Non-cardiac indication Glaucoma (Timolol) Thyrotoxicosis Migraine (Propanolol)

Hypertension Angina pectoris Cardiac arrhythmia Heart failure

Contra indications

Beta blocker
Bronchial Asthma Diabetic Mellitus (Type-I) Peripheral Vascular disease Bradycardia

Classification of sympatholytics

Alpha blockers

1. Selective (1receptor) Prazosin. Terazosin. Doxazosin. Tamsulosin.

Selective (2 receptor) Yohimbin

2.

3. Non-selective( both 1 and 2 receptor) -Phenoxybenzamine -Phentolamine.

PRAZOCIN

It selectively blocks the 1 post synaptic receptors. It has a short half-life (3hour) and short duration of action. This drug cause first-dose hypotension within 2 hours of administration and may lead to loss of consciousness. For this reason 1st dose should be small and given at bed time.

Alpha blockers

Indication of use are

Hypertension Hypertensive emergency

Phaeochromocytoma

Peripheral

vascular disease

Benign
Male

prostatic hyperplasia

erectyle dysfunction

Benign prostatic hyperplasia:

Alpha blockers

( Tamsulosin, doxazosin, terazosin, alfuzosin)

5-alpha Reductase Inhibitors:

The 5-alpha reductase inhibitors work by interfering with the effect of specific male hormones (androgens) on prostate.
This may slow the growth of prostate

and can even cause prostate to get smaller, which may help improve BPH symptoms.
Eg. Avodart (dutasteride), Proscar (finasteride)

 Adverse effect of blockers

- First dose phenomenon/ First dose hypotension
- Postural Hypotension
- Reflex Tachycardia. (When BP lowering drug is given, the body defense mechanism tries to oppose it and causes Tachycardia call Reflex Tachycardia ) - Palpitation - Headache - Flushing - Dependent edema.

Reference : Katzung B.G,Masters S.B, Trevor A.J, " Basic principal", Basic and clinical pharmacology, Lange medical publications, 2009; 11th edition: p 13-106.