Group – B - Group – B - حسان حسانثامرثامر

PhenylephrinePhenylephrine Phenylephrine is a Phenylephrine is a direct-acting, direct-acting,

synthetic adrenergic synthetic adrenergic drug that binds drug that binds primarily to primarily to αα receptors receptors ( favors ( favors αα11

receptors over receptors over αα 22 receptors). receptors). It is not a It is not a catechol derivative catechol derivative and, and,

therefore, not a substrate for therefore, not a substrate for COMT. COMT.

Phenylephrine is a Phenylephrine is a vasoconstrictor vasoconstrictor that raises both that raises both systolic and diastolic systolic and diastolic blood pressuresblood pressures. .

It has no effect on the It has no effect on the heart itself heart itself but but rather rather induces reflex bradycardia induces reflex bradycardia when given parenterallywhen given parenterally. .

It is often used It is often used topically on the topically on the nasalnasal mucous membranes and in mucous membranes and in ophthalmicophthalmic solutions solutions for for mydriasis.mydriasis.

Phenylephrine Phenylephrine acts acts as a nasal as a nasal decongestantdecongestant and produces prolonged and produces prolonged vasoconstriction.vasoconstriction.

Large doses can cause Large doses can cause hypertensive hypertensive headache and cardiac irregularheadache and cardiac irregular..

ClonidineClonidine Clonidine is an Clonidine is an αα22 agonist agonist that is used in that is used in

essential hypertension essential hypertension to lower to lower blood blood pressurepressure because of its action in the CNS. because of its action in the CNS.

Clonidine Clonidine acts centrally to produce : acts centrally to produce :

1- 1- inhibition inhibition of of sympathetic vasomotor sympathetic vasomotor

centers.centers.

2- decreasing sympathetic outflow to the 2- decreasing sympathetic outflow to the

periphery.periphery.

Albuterol, and TerbutalineAlbuterol, and Terbutaline are are short-acting short-acting ββ22 agonists used agonists used

primarily as primarily as bronchodilatorsbronchodilators and and administered by a administered by a metered-dose inhaler. metered-dose inhaler.

Indirect-Acting Adrenergic AgonistsIndirect-Acting Adrenergic Agonists Indirect-acting adrenergic agonists Indirect-acting adrenergic agonists cause:cause:

1. norepinephrine release1. norepinephrine release from from

presynaptic terminals presynaptic terminals

2. or 2. or inhibitinhibit the the uptake of norepinephrine. uptake of norepinephrine.

3. They 3. They potentiate the effects of potentiate the effects of

norepinephrine norepinephrine produced produced endogenouslyendogenously.. These agents do not directly affect These agents do not directly affect

postsynaptic receptors.postsynaptic receptors.

A. A. AmphetamineAmphetamine the drug can the drug can increase blood pressure increase blood pressure

significantly by significantly by αα-agonist -agonist action on the action on the vasculature as well as vasculature as well as ββ-stimulatory -stimulatory effects on the hearteffects on the heart. .

Its peripheral actions are mediated Its peripheral actions are mediated primarily through the primarily through the blockade of blockade of norepinephrine uptake and cellular release norepinephrine uptake and cellular release of stored catecholamines; of stored catecholamines; thus, amphetamine thus, amphetamine is an indirect-acting adrenergic drug. is an indirect-acting adrenergic drug.

The CNS stimulant effects of amphetamine The CNS stimulant effects of amphetamine and its derivatives have led to their and its derivatives have led to their use foruse for

treating treating hyperactivity in children, narcolepsyhyperactivity in children, narcolepsy, , appetite controlappetite control. . Its use in pregnancy Its use in pregnancy should be avoided should be avoided

because of adverse effects on because of adverse effects on development development of the fetus.of the fetus.

B-TyramineB-Tyramine Tyramine is Tyramine is not anot a clinically useful drugclinically useful drug, but it , but it

is important because it is found in is important because it is found in fermented fermented foods, such as ripe cheesefoods, such as ripe cheese. .

Normally, it is Normally, it is oxidized by MAO in the oxidized by MAO in the gastrointestinal tract, gastrointestinal tract, but if the patient is but if the patient is taking taking MAO inhibitorsMAO inhibitors, it can precipitate , it can precipitate serious vasopressor episodes. serious vasopressor episodes.

Like amphetamines, tyramine can Like amphetamines, tyramine can enter the enter the nerve terminal and displace stored nerve terminal and displace stored norepinephrine. norepinephrine. The released catecholamine The released catecholamine then acts on adrenoceptors.then acts on adrenoceptors.

C. CocaineC. Cocaine Cocaine is a local anesthetics in having the Cocaine is a local anesthetics in having the

ability to ability to block the Nablock the Na++/ K/ K++-activated -activated ATPase ATPase (required for cellular (required for cellular uptake of norepinephrine)uptake of norepinephrine) on the cell membrane of the adrenergic on the cell membrane of the adrenergic neuron. neuron.

Consequently, norepinephrine Consequently, norepinephrine accumulates accumulates in the in the synaptic space, synaptic space, resulting in resulting in enhancement of enhancement of sympathetic activitysympathetic activity and and potentiation of the actions of epinephrine potentiation of the actions of epinephrine and norepinephrine. and norepinephrine.

In addition, the In addition, the duration of action duration of action of of epinephrine and norepinephrine epinephrine and norepinephrine is increasedis increased. .

Cocaine can increase blood pressure by Cocaine can increase blood pressure by αα--agonist actions and agonist actions and ββ-stimulatory effects.-stimulatory effects.

Mixed-Action Adrenergic Mixed-Action Adrenergic AgonistsAgonists

Mixed-action drugs Mixed-action drugs induceinduce the the release of release of norepinephrine norepinephrine from from presynaptic terminalspresynaptic terminals,,

and they and they activate activate adrenergic receptors adrenergic receptors on on the postsynaptic membrane.the postsynaptic membrane.

Ephedrine and Ephedrine and pseudoephedrinepseudoephedrine

are plant alkaloids, that are now made are plant alkaloids, that are now made synthetically. synthetically.

They They not only not only release release stored norepinephrinestored norepinephrine from nerve endings but from nerve endings but also directly also directly stimulate both stimulate both αα and and ββ receptors receptors. .

Thus, produce adrenergic actions that are Thus, produce adrenergic actions that are similar to those of epinephrine, similar to those of epinephrine, although although less potent. less potent.

Ephedrine and pseudoephedrine Ephedrine and pseudoephedrine are not are not catechols and are catechols and are poor substrates for poor substrates for COMT and MAOCOMT and MAO; ;

thus, these drugs have a thus, these drugs have a long duration of long duration of action.action.

Ephedrine and pseudoephedrine have Ephedrine and pseudoephedrine have excellent absorption orally excellent absorption orally and penetrate and penetrate into the CNS; however, into the CNS; however, pseudoephedrine pseudoephedrine has has fewer CNS effects.fewer CNS effects.

EphedrineEphedrine raises systolic and diastolic blood raises systolic and diastolic blood pressures by vasoconstriction and cardiac pressures by vasoconstriction and cardiac stimulation. stimulation.

Ephedrine Ephedrine produces produces bronchodilationbronchodilation, but it is , but it is less potent than less potent than epinephrine or isoproterenol epinephrine or isoproterenol and produces its action and produces its action more slowly. more slowly.

It is therefore sometimes used It is therefore sometimes used prophylacticallyprophylactically in in chronic treatment chronic treatment of asthma to of asthma to prevent prevent attacks rather than to treat attacks rather than to treat the acute attack.the acute attack.

Therapeutic uses: Therapeutic uses:

1- Ephedrine has been used to treat asthma1- Ephedrine has been used to treat asthma, ,

2- as a nasal 2- as a nasal decongestantdecongestant (due to its local (due to its local

vasoconstrictor action), vasoconstrictor action),

3- to raise blood pressure.3- to raise blood pressure. [Note: The clinical use of ephedrine is [Note: The clinical use of ephedrine is declining due to :declining due to :a- the availability of a- the availability of better drug. better drug. b- more potentb- more potent agents that cause agents that cause fewer fewer adverse effects. adverse effects.

Adrenergic AntagonistsAdrenergic Antagonists(blockers or sympatholytic (blockers or sympatholytic agents)agents)

The adrenergic antagonists The adrenergic antagonists bind to bind to adrenoceptorsadrenoceptors but do not trigger the usual but do not trigger the usual receptor-mediated intracellular effectsreceptor-mediated intracellular effects. .

These drugs act by either These drugs act by either reversibly or reversibly or irreversibly attaching to the receptorirreversibly attaching to the receptor, thus , thus preventingpreventing its activation by its activation by endogenous endogenous catecholamines. catecholamines.

The The adrenergic antagonists adrenergic antagonists are are classified according to their classified according to their relative relative affinities for affinities for αα or or ββ receptors in the receptors in the peripheral nervous systemperipheral nervous system. .

αα-Adrenergic Blocking Agents-Adrenergic Blocking Agents Drugs that Drugs that blockblock α α -adrenoceptors -adrenoceptors

profoundly profoundly affect blood pressureaffect blood pressure.. Because Because normal sympathetic normal sympathetic control of the control of the

vasculature through vasculature through actions on actions on αα-adrenergic -adrenergic receptors, receptors, blockade of these blockade of these receptors receptors reduces reduces the sympathetic the sympathetic tonetone of the of the blood vesselsblood vessels, , resultingresulting in decreased in decreased peripheral vascular peripheral vascular resistance. resistance.

This induces a This induces a reflex tachycardia resultingreflex tachycardia resulting from the from the lowered blood pressure. lowered blood pressure.

[Note: [Note: ββ receptors, including receptors, including β β 11--

adrenoceptors on the heart, are not affected by adrenoceptors on the heart, are not affected by αα blockade.] blockade.]

A. PhenoxybenzamineA. Phenoxybenzamine Phenoxybenzamine Phenoxybenzamine is nonselective,is nonselective,

linking linking covalentlycovalently to both to both αα11--

postsynaptic and postsynaptic and αα22-presynaptic -presynaptic

receptors .receptors . The block is The block is irreversible and noncompetitive irreversible and noncompetitive And the only mechanism the body has for And the only mechanism the body has for

overcomingovercoming the the blockblock is to is to synthesize synthesize new new adrenoceptors, which adrenoceptors, which requires a day requires a day or moreor more. .

Therefore, the actions of Therefore, the actions of phenoxybenzamine phenoxybenzamine last about 24 hours last about 24 hours after a single administration. after a single administration.

After the drug is injected, After the drug is injected, a delay of a delay of a a few hours occurs before a few hours occurs before a blockade blockade develops, develops, because the because the molecule must molecule must undergo biotransformationundergo biotransformation to the to the active active form.form.

• Actions:Actions:

• Cardiovascular effects:Cardiovascular effects:

By By blocking blocking αα receptors, phenoxybenzamine receptors, phenoxybenzamine prevents prevents vasoconstriction vasoconstriction of peripheral blood vessels by of peripheral blood vessels by endogenous catecholamines. endogenous catecholamines.

– The decreased peripheral The decreased peripheral resistance provokes a reflex resistance provokes a reflex tachycardiatachycardia..

• Thus, the drug has been Thus, the drug has been unsuccessful in maintaining lowered unsuccessful in maintaining lowered blood pressure blood pressure in in hypertension hypertension and has been and has been discontinued discontinued ffor this purpose.or this purpose.

• Therapeutic uses: Therapeutic uses: Phenoxybenzamine is used in the treatment of Phenoxybenzamine is used in the treatment of

pheochromocytoma pheochromocytoma ((a catecholamine-a catecholamine-secreting tumor of cells derived from the secreting tumor of cells derived from the adrenal medulla)adrenal medulla)..

• Adverse effects:Adverse effects: • Phenoxybenzamine can cause Phenoxybenzamine can cause postural hypotension,postural hypotension,

nausea, and vomiting. nausea, and vomiting. • The drug also may The drug also may induce reflex tachycardiainduce reflex tachycardia, and , and

is contraindicated in patients with is contraindicated in patients with decreased decreased coronary perfusion.coronary perfusion.

PhentolaminePhentolamine In contrast to phenoxybenzamine, In contrast to phenoxybenzamine,

phentolamine produces phentolamine produces a competitive a competitive block of block of αα11 and and α α 22 receptors receptors. .

The drug's action lasts for The drug's action lasts for approximately approximately 4 hours 4 hours after a single administration. after a single administration.

Like phenoxybenzamine, it produces Like phenoxybenzamine, it produces postural hypotension .postural hypotension .

Phentolamine-induced reflex Phentolamine-induced reflex cardiac cardiac stimulation and tachycardiastimulation and tachycardia are mediated are mediated by the baroreceptor reflex and by blocking the by the baroreceptor reflex and by blocking the α α 22 receptors of the cardiac sympathetic receptors of the cardiac sympathetic

nerves. nerves. Phentolamine is used for the Phentolamine is used for the short-term short-term

management of pheochromocytoma. management of pheochromocytoma.

C. C. Prazosin.Prazosin. are are selective competitive blockers of the selective competitive blockers of the αα11 receptorreceptor. .

These drugs are useful in the treatment of These drugs are useful in the treatment of hypertension.hypertension.

• Cardiovascular effects:Cardiovascular effects:• this agent this agent decrease peripheral decrease peripheral vascular resistance and vascular resistance and

lower arterial blood lower arterial blood pressure by pressure by causing the relaxation causing the relaxation of both arterial and venous smooth muscle.of both arterial and venous smooth muscle.

These drugs, unlike phenoxybenzamine and These drugs, unlike phenoxybenzamine and phentolamine, phentolamine, cause minimal changescause minimal changes in cardiac in cardiac output, renal blood flow, and the glomerular filtration output, renal blood flow, and the glomerular filtration rate.rate.

• Therapeutic uses:Therapeutic uses:• the first dose of these drugs produces an the first dose of these drugs produces an

exaggerated exaggerated orthostatic hypotensive orthostatic hypotensive response that can result in syncope response that can result in syncope (fainting). (fainting).

• This action, termed a This action, termed a (first-dose effect) (first-dose effect) may be minimized by :may be minimized by :

1.1. adjusting the first dose to adjusting the first dose to one-third or one-one-third or one-fourth fourth of the normal doseof the normal dose

2.2. and by giving the and by giving the drug at bedtime. drug at bedtime.

• Adverse effects:Adverse effects:

• αα11 Blockers Blockers may cause dizziness, a lack of may cause dizziness, a lack of

energy, nasal congestion, headache, energy, nasal congestion, headache, drowsiness, and orthostatic hypotension .drowsiness, and orthostatic hypotension .

• An additive antihypertensive An additive antihypertensive effect occurs effect occurs when prazosin is given with either a when prazosin is given with either a diuretic diuretic or a or a ββ-blocker, -blocker, thereby necessary to reduction thereby necessary to reduction in in its dose. its dose.

• Due to a tendency to Due to a tendency to retain sodium and fluidretain sodium and fluid, , prazosin is frequently used prazosin is frequently used along with a along with a diuretic.diuretic.

YohimbineYohimbine Yohimbine is a Yohimbine is a selective competitive selective competitive α α 22

blocker.blocker. used as a sexual stimulant. used as a sexual stimulant. Yohimbine works at the level of the Yohimbine works at the level of the CNS to CNS to

increase increase sympathetic outflow sympathetic outflow to the periphery. to the periphery. It It directly blocks directly blocks αα22 receptors receptors.. Yohimbine is contraindicated in Yohimbine is contraindicated in CNS and CNS and

cardiovascular conditionscardiovascular conditions because it is a because it is a CNS and cardiovascular stimulant.CNS and cardiovascular stimulant.