Most of the actions of catecholamines and sympathomimetic agents can be classified into seven broad types: (1) a peripheral

excitatory action on certain types of smooth muscle, such as those in blood vessels supplying skin, kidney, and mucous membranes, and on gland cells, such as those in salivary and sweat glands; (2) a peripheral inhibitory action on certain other types of smooth muscle, such as those in the wall of the gut, in the bronchial tree, and in blood vessels supplying skeletal muscle

(3) a cardiac excitatory action that increases heart rate and force of contraction (4) metabolic actions, such as an increase in the rate of glycogenolysis in liver and muscle and liberation of free fatty acids from adipose tissue (5) endocrine actions of the secretion of insulin, renin, and pituitary hormones (6) actions in the central nervous system (CNS), such as respiratory stimulation, an increase in wakefulness and psychomotor activity, and a reduction in appetite (7) prejunctional actions that either inhibit or facilitate the release of neurotransmitters

Sympatomimetics
Direct Acting

Indirect Acting

Alpha & Beta-agonist Epinephrine Dopamine Ephidrine

Alpha antagonist

-agonist
Non Selective: 1 Selective: isoprenaline Dobutamin e prenalteral 2 Selective: Terbutaline salbutamol

Non Selective: 1 Selective: 2 Selective: Norepinephrine Phenyleephrine Clonidine (1, 2, 1) Methoxamine Methyl-Norepinephrine metaraminol Gaunbenz Gaunfacine Releasers:

Tyramine aphetamine

Reuptake inh.: cocaine

Some of these drugs (eg, norepinephrine and epinephrine) act by a direct mode; that is, they directly interact with and activate adrenoceptors. Others act indirectly; their actions are dependent on the release of endogenous catecholamines. These indirect agents may have either of two different mechanisms: (1) displacement of stored catecholamines from the adrenergic nerve ending (eg, amphetamine and tyramine) or (2) inhibition of reuptake of catecholamines already released (eg, cocaine and tricyclic antidepressants)

The effects of catecholamines are mediated by cell surface receptors. These GPCRs (G protein-coupled receptors) are coupled by G proteins to the various effector proteins whose activities are regulated by those receptors. G proteins of particular importance for adrenoceptor function include Gs, the stimulatory G protein of adenylyl cyclase; Gi, the inhibitory G protein of adenylyl cyclase; and Gq, the protein coupling receptors to phospholipase C.

 Receptor

Types 1. ALPHA RECEPTORS Alpha1 receptors are coupled to polyphosphoinositide hydrolysis, leading to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) G proteins in the Gq family couple alpha1receptors to phospholipase C. IP3 promotes the release of sequestered Ca2+ from intracellular stores, which increases the cytoplasmic concentration of free Ca2+ and the activation of various calcium-dependent protein kinases.

2. Alpha2 receptors : inhibit adenylyl cyclase activity and cause intracellular cyclic adenosine monophosphate (cAMP) levels to decrease. Alpha2-receptormediated inhibition of adenylyl cyclase activity is transduced by the inhibitory regulatory protein, Gi . then activation of Gi leads to the inhibition of adenylyl cyclase In addition, some of the effects of 2 adrenoceptors are independent of their ability to inhibit adenylyl cyclase; for example,alpha 2-receptor agonists cause platelet aggregation and a decrease in platelet cAMP levels, but it is not clear whether aggregation is the result of the decrease in cAMP or other mechanisms involving Gi-regulated effectors.

3. BETA RECEPTORS : The mechanism of action of beta-agonists has been studied in considerable detail. Activation of all three receptor subtypes ( beta1,beta2, beta3) results in activation of adenylyl cyclase and increased conversion of adenosine triphosphate (ATP) to cAMP. Activation of the cyclase enzyme is mediated by the stimulatory coupling protein Gs. cAMP is the major second messenger of receptor activation

Cardiovascular System BLOOD VESSELS: Alpha receptors increase arterial resistance whereas 2 receptors promote smooth muscle relaxation The overall effects of a sympathomimetic drug on blood vessels depend on the relative activities of that drug at alpha- and betareceptors and the anatomic sites of the vessels affected.
1.

 HEART:

positive chronotropic. positive inotropic effect. Direct effects on the heart are determined largely by beta1 receptors BLOOD PRESSURE: Increases peripheral arterial resistance and decreases venous capacitance. The enhanced arterial resistance usually leads to a dose-dependent rise in blood pressure The rise in blood pressure elicits a baroreceptor-mediated increase in vagal tone with slowing of the heart rate.

 Eye

Activation by drugs such as phenylephrine causes mydriasis. Alpha stimulants also have important effects on intraocular pressure. Present evidence suggests that agonists increase the outflow of aqueous humor from the eye and reduce intraocular pressure. In contrast, agonists have little effect, but antagonists decrease the production of aqueous humor. These effects are important in the treatment of glaucoma

 Respiratory

Tract: Bronchial smooth muscle contains beta2 receptors that cause relaxation. Activation of these receptors results in bronchodilation Genitourinary Tract The human uterus contains alpha and beta2 receptors. The bladder base, urethral sphincter, and prostate contain alpha receptors that mediate contraction and therefore promote urinary continence. alpha1A receptors probably play an important role. The beta2 receptors of the bladder wall mediate relaxation.

 Exocrine

Glands The salivary glands contain adrenoceptors that regulate the secretion of amylase and water. However, certain sympathomimetic drugs, eg, clonidine, produce symptoms of dry mouth. The apocrine sweat glands, located on the palms of the hands and a few other areas, respond to adrenoceptor stimulants with increased sweat production.

1.

Epinephrine (adrenaline): is a very potent vasoconstrictor and cardiac stimulant. The rise in systolic blood pressure that occurs after epinephrine release or administration is caused by its positive inotropic and chronotropic actions on the heart (predominantly beta1 receptors) Epinephrine also activates beta2 receptors in some vessels (eg, skeletal muscle blood vessels), leading to their dilation. Consequently, total peripheral resistance may actually fall Activation of these beta2 receptors in skeletal muscle contributes to increased blood flow during exercise. Under physiologic conditions, epinephrine functions largely as a hormone; after release from the adrenal medulla into the blood, it acts on distant cells

2. Norepinephrine (levarterenol, noradrenaline) similar effects on beta1 receptors in the heart and similar potency at alpha receptors. Norepinephrine has relatively little effect on beta2 receptors. Consequently, norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory vagal reflexes tend to overcome the direct positive chronotropic effects of norepinephrine

3. Isoproterenol (isoprenaline): It is a very potent beta-receptor agonist and has little effect on receptors. The drug has positive chronotropic and inotropic It is a potent vasodilator. These actions lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure.

4. Dobutamine: Actions: is a synthetic, direct-acting catecholamine that is a beta1-receptor agonist. It increases cardiac rate and output with few vascular effects. Therapeutic uses: used to increase cardiac output in congestive heart failure as well as for inotropic support after cardiac surgery. The drug increases cardiac output with little change in heart rate, and it does not significantly elevate oxygen demands of the myocardium a major advantage over other sympathomimetic drugs. Adverse effects: Dobutamine should be used with caution in atrial fibrillation, because the drug increases atrioventricular conduction. Other adverse effects are the same as those for epinephrine. Tolerance may develop on prolonged use.

5.Terbutaline : short-acting beta2 agonists used primarily as bronchodilators and administered by a metereddose inhaler. These drugs produce bronchodilation with less cardiac stimulation. Used in the treatment of asthma 6. Salbutamol : beta2-adrenergic (selective), long-acting bronchodilators. A single dose by a metered-dose inhalation device, such as a dry powder inhaler, provides sustained bronchodilation over 12 hours. Used in the treatment of asthma

7. Amphetamine : Amphetamine is an indirect-acting adrenergic drug. The CNS stimulant effects of amphetamine and its derivatives have led to their use for treating hyperactivity in children, narcolepsy, and appetite control. Its use in pregnancy should be avoided because of adverse effects on development of the fetus. It is often mistaken by drug abusers.

8. Cocaine : Cocaine is unique among local anesthetics in having the ability to block the Na+/K+-activated ATPase (required for cellular uptake of norepinephrine) on the cell membrane of the adrenergic neuron. Consequently, norepinephrine accumulates in the synaptic space, resulting in enhancement of sympathetic activity and potentiation of the actions of epinephrine and norepinephrine. Therefore, small doses of the catecholamines produce greatly magnified effects in an individual taking cocaine as compared to those in one who is not. In addition, the duration of action of epinephrine and norepinephrine is increased. Like amphetamines, it can also increase blood pressure.