PhenylephrinePhenylephrine is a direct-acting, synthetic adrenergic drug that binds primarily to α receptors ( favors α1 receptors over α 2 receptors). It is not a catechol derivative and, therefore, not a substrate for COMT.
Phenylephrine is a vasoconstrictor that raises both systolic and diastolic blood pressures. It has no effect on the heart itself but rather induces reflex bradycardia when given parenterally.
It is often used topically on the nasal mucous membranes and in ophthalmic solutions for mydriasis. Phenylephrine acts as a nasal decongestant and produces prolonged vasoconstriction. Large doses can cause hypertensive headache and cardiac irregular.
ClonidineClonidine is an α2 agonist that is used in essential hypertension to lower blood pressure because of its action in the CNS.Clonidine acts centrally to produce : 1- inhibition of sympathetic vasomotor centers.2- decreasing sympathetic outflow to the periphery.
Albuterol, and Terbutaline are short-acting β2 agonists used primarily as bronchodilators and administered by a metered-dose inhaler.
Indirect-Acting Adrenergic Agonists Indirect-acting adrenergic agonists cause: 1. norepinephrine release from presynaptic terminals 2. or inhibit the uptake of norepinephrine. 3. They potentiate the effects of norepinephrine produced endogenously. These agents do not directly affect postsynaptic receptors.
A. Amphetaminethe drug can increase blood pressure significantly by α-agonist action on the vasculature as well as β-stimulatory effects on the heart. Its peripheral actions are mediated primarily through the blockade of norepinephrine uptake and cellular release of stored catecholamines; thus, 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, appetite control. Its use in pregnancy should be avoided because of adverse effects on development of the fetus.
B-Tyramine Tyramine is not a clinically useful drug, but it is important because it is found in fermented foods, such as ripe cheese. Normally, it is oxidized by MAO in the gastrointestinal tract, but if the patient is taking MAO inhibitors, it can precipitate serious vasopressor episodes.
Like amphetamines, tyramine can enter the nerve terminal and displace stored norepinephrine. The released catecholamine then acts on adrenoceptors. C. Cocaine Cocaine is a 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. In addition, the duration of action of epinephrine and norepinephrine is increased. Cocaine can increase blood pressure by α-agonist actions and β-stimulatory effects.
Mixed-Action Adrenergic Agonists Mixed-action drugs induce the release of norepinephrine from presynaptic terminals, and they activate adrenergic receptors on the postsynaptic membrane.
Ephedrine and pseudoephedrine
are plant alkaloids, that are now made synthetically. They not only release stored norepinephrine from nerve endings but also directly stimulate both α and β receptors. Thus, produce adrenergic actions that are similar to those of epinephrine, although less potent.Ephedrine and pseudoephedrine are not catechols and are poor substrates for COMT and MAO; thus, these drugs have a long duration of action. Ephedrine and pseudoephedrine have excellent absorption orally and penetrate into the CNS; however, pseudoephedrine has fewer CNS effects.
Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation. Ephedrine produces bronchodilation, but it is less potent than epinephrine or isoproterenol and produces its action more slowly. It is therefore sometimes used prophylactically in chronic treatment of asthma to prevent attacks rather than to treat the acute attack.
Therapeutic uses: 1- Ephedrine has been used to treat asthma, 2- as a nasal decongestant (due to its local vasoconstrictor action), 3- to raise blood pressure. [Note: The clinical use of ephedrine is declining due to : a- the availability of better drug. b- more potent agents that cause fewer adverse effects.
Adrenergic Antagonists (blockers or sympatholytic agents)
The adrenergic antagonists bind to adrenoceptors but do not trigger the usual receptor-mediated intracellular effects. These drugs act by either reversibly or irreversibly attaching to the receptor, thus preventing its activation by endogenous catecholamines.The adrenergic antagonists are classified according to their relative affinities for α or β receptors in the peripheral nervous system.
α-Adrenergic Blocking AgentsDrugs that block α -adrenoceptors profoundly affect blood pressure. Because normal sympathetic control of the vasculature through actions on α-adrenergic receptors, blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance. This induces a reflex tachycardia resulting from the lowered blood pressure.
[Note: β receptors, including β 1-adrenoceptors on the heart, are not affected by α blockade.]
A. PhenoxybenzaminePhenoxybenzamine is nonselective, linking covalently to both α1-postsynaptic and α2-presynaptic receptors .The block is irreversible and noncompetitive And the only mechanism the body has for overcoming the block is to synthesize new adrenoceptors, which requires a day or more.
Therefore, the actions of phenoxybenzamine last about 24 hours after a single administration. After the drug is injected, a delay of a few hours occurs before a blockade develops, because the molecule must undergo biotransformation to the active form.
Actions:Cardiovascular effects: By blocking α receptors, phenoxybenzamine prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines. The decreased peripheral resistance provokes a reflex tachycardia.Thus, the drug has been unsuccessful in maintaining lowered blood pressure in hypertension and has been discontinued for this purpose.
Therapeutic uses: Phenoxybenzamine is used in the treatment of pheochromocytoma (a catecholamine-secreting tumor of cells derived from the adrenal medulla). Adverse effects: Phenoxybenzamine can cause postural hypotension, nausea, and vomiting. The drug also may induce reflex tachycardia, and is contraindicated in patients with decreased coronary perfusion.
PhentolamineIn contrast to phenoxybenzamine, phentolamine produces a competitive block of α1 and α 2 receptors. The drug's action lasts for approximately 4 hours after a single administration. Like phenoxybenzamine, it produces postural hypotension .
Phentolamine-induced reflex cardiac stimulation and tachycardia are mediated by the baroreceptor reflex and by blocking the α 2 receptors of the cardiac sympathetic nerves. Phentolamine is used for the short-term management of pheochromocytoma.
C. Prazosin.are selective competitive blockers of the α1 receptor. These drugs are useful in the treatment of hypertension. Cardiovascular effects: this agent decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle.These drugs, unlike phenoxybenzamine and phentolamine, cause minimal changes in cardiac output, renal blood flow, and the glomerular filtration rate.
Therapeutic uses: the first dose of these drugs produces an exaggerated orthostatic hypotensive response that can result in syncope (fainting). This action, termed a (first-dose effect) may be minimized by : adjusting the first dose to one-third or one-fourth of the normal dose and by giving the drug at bedtime.
Adverse effects: α1 Blockers may cause dizziness, a lack of energy, nasal congestion, headache, drowsiness, and orthostatic hypotension .An additive antihypertensive effect occurs when prazosin is given with either a diuretic or a β-blocker, thereby necessary to reduction in its dose. Due to a tendency to retain sodium and fluid, prazosin is frequently used along with a diuretic.
YohimbineYohimbine is a selective competitive α 2 blocker.used as a sexual stimulant. Yohimbine works at the level of the CNS to increase sympathetic outflow to the periphery. It directly blocks α2 receptors. Yohimbine is contraindicated in CNS and cardiovascular conditions because it is a CNS and cardiovascular stimulant.