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ß₂ Selective Adrenergic Agonists

• At low concentration ß₂ selective adrenergic agonists have relatively minor ß₁ cardiac receptor-mediated effects.

• Effective in managing asthma, ß₂ selective adrenergic agonists are orally active and metabolized more slowly compared to catecholamines

• In asthma, pulmonary ß₂ receptors are targeted by drug administration by inhalation.

  • This route of administration results in low systemic drug concentration, reducing likelihood of cardioacceleration ( ß₁) or skeletal muscle tremor (ß₂ ).

• Activation of pulmonary ß₂ adrenergic receptors result in smooth-muscle relaxation and bronchodilation.

  • ß₂ receptor-mediated relaxation of vascular smooth muscle may be due to cAMP-dependent kinase phosphorylation of myosin light chain kinase (producing an inactive form)

• ß adrenergic receptor agonists also decrease histamine and leukotriene release from lung mast cells. Recalling that asthma is first and foremost an inflammatory disease, reduction in histamine and leukotriene release would be beneficial.

• ß adrenergic receptor agonists enhance mucociliary activity and diminish microvascular permeabilty.

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Metaproterenol (Alupent)

• ß₂ adrenergic receptor-selective: resistant to COMT (catechol-O-methyl transferase) metabolism

• Less ß₂ selective compared to terbutaline (Brethine) and albuterol (Ventolin,Proventil).

• May be used for long-term and acute treatment of bronchospasm

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Terbutaline [Brethine]

• ß₂ adrenergic receptor-selective: resistant to COMT

• Active after oral, subcutaneous, or administration by inhalation

• Rapid onset of action.

• Used for management of chronic obstructive lung disease and for treatment of acute bronchospasm (smooth muscle bronchoconstriction), including status asthmaticus

Albuterol [Ventolin]

• ß₂ adrenergic receptor-selective

• Effective following inhalation or oral administration.

• Commonly used in chronic and acute asthma management.

Ritodrine (Yutopar)

• ß₂ adrenergic receptor-selective: developed as a uterine relaxant

• May be administered by i.v. in certain patients for arresting premature labor; if successful, oral therapy may be started.

• ß₂ adrenergic receptor-selective agonists may not improve perinatal mortality and may increase maternal morbidity.

• In women being treated for premature labor, ritodrine (Yutopar) or terbutaline (Brethine) may cause pulmonary edema .

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 Adverse Effects-Agonists

• Excessive cardiovascular stimulation

• Skeletal muscle tremor (tolerance develops, unknown mechanism) due to ß₂ adrenergic receptor activation

• Overusage may be a factor in morbidity and mortality in asthmatics.

Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.213-216.

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Alpha₁ Selective Adrenergic Agonists

• alpha₁ selective adrenergic agonists activate a adrenergic receptors in vascular smooth muscle producing vasoconstriction.

  • Peripheral vascular resistance is increased.

  • Blood pressure may be increased, causing a reflex reduction heart rate

  • a₁ adrenergic agonists are used clinically in management of hypotension and shock.

  • Phenylephrine (Neo-Synephrine) and methoxamine (Vasoxyl) are direct-acting vasoconstrictors.

  • Mephentermine (Wyamine) and metaraminol (Aramine) act both by direct receptor activation and by promoting epinephrine release.

• Smooth muscle tone is determined by modulation of myosin light-chain kinase activation.

  • Myosin light-chain kinase phosphorylates myosin--a step that initiates myosin-actin interaction. (by contrast in skeletal or cardiac muscle Ca²⁺ interaction with troponin is central to initiation of muscle contraction)

  • Increases in intracellular Ca²⁺ with Ca²⁺ calmodulin complex formation results in activation of myosin light-chain kinase.

• alpha₁ receptor activation causes Ca²⁺ influx

• In some cells, a₁ receptor activation causes IP₃ production, which releases sequested Ca²⁺.

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Methoxamine (Vasoxyl)

• specific alpha₁ receptor agonist

• increases peripheral resistance

• causes an increase in blood pressure that precipitates sinus bradycardia (decreased heart rate) due to vagal reflex.

• Reflex bradycardia may be block by atropine (muscarinic antagonist)

  Clinical use:

  • hypotensive states

  • termination (by vagal reflex) of paroxysmal atrial tachycardia (adenosine may be preferable)

Phenylephrine (Neo-Synephrine)

• Specific alpha₁ receptor agonist

• Increases peripheral resistance

• Causes an increase in blood pressure that precipitates sinus bradycardia (decreased heart rate) due to vagal reflex.

• Reflex bradycardia may be block by atropine (muscarinic antagonist)

• Clinical use:

  • hypotensive states

  • mydriatic

  • nasal decongestant

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Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.216-219.

alpha₂ Selective Adrenergic Agonists and Miscellaneous Adrenergic Agonists

Introduction

• alpha₂ selective adrenergic agonists are used to treat essential hypertension.

• Mechanism of action:

  • activation of central a₂ adrenergic receptors at cardiovascular control centers

  • activation decreases sympathetic outflow, reducing sympathetic vascular tone.

Clonidine (Catapres)

• Clonidine (Catapres) is primarily used in treating essential hypertension.

•  A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.

• This response is due to a₂ selective adrenergic receptor activation.{Vertebral arterial or intra cisterna magna injection results in hypotension. This experiment demonstrate clonidine central action.}

  Adverse Effects:

  • dry mouth

  • sedation

  • sexual dysfunction

• Clonidine's a₂ selective adrenergic receptor activation of vascular smooth muscle may increase blood pressure in patients with severe autonomic dysfunction with profound orthostatic hypotension (in these patients the reduction of central sympathetic outflow in not clinically important.

Guanabenz Wytensin)

• Guanabenz (Wytensin)is primarily used in treating essential hypertension.

•  A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.

• This response is due to a₂ selective adrenergic receptor activation.

  Adverse Effects:

  • dry mouth

  • sedation

Guanfacine

• Guanfacine is used for treating essential hypertension.

•  A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.

• This response is due to a₂ selective adrenergic receptor activation. a₂ receptor selectivity is greater than that observed with clonidine despite similar efficacy in treating hypertension.

• Adverse Effects:

  • dry mouth

  • sedation

Alpha-methyl DOPA-- (methyldopa (Aldomet))

• Alpha-methyl DOPA (methyldopa (Aldomet)), metabolically converted to alpha-methyl norepinephrine, is used for treating essential hypertension.

•  A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.

• This response is due to a₂ selective adrenergic receptor activation.

  Adverse Effects:

  • dry mouth

  • sedation

Amphetamine

• CNS stimulant (releasing biogenic nerve terminal amines:

  • respiratory center

  • mood elevation

  • decreased perception of fatigue

• Other effects: headache, palpitations, dysphoria

  • Appetite suppression

  • Weight loss due to decrease food intake

  • psychological tolerance/dependence

• Indirect acting sympathomimetic

•  Toxicity:

  • CNS: restlessness, tremor, irritablity, insomnia, aggressiveness, anxiety, panic, suicidal ideation, etc.

  • Cardiovascular: arrhythmias, hypertension or hypotension, angina

  • GI: dry mouth, anorexia, vomiting, diarrhea, cramping

  • Treatment:

    • urinary acidification by ammonium chloride

    • hypertension: nitroprusside or a adrenergic receptor antagonist

    • CNS: sedative-hypnotic drugs

• Therapeutic Use:

  • Narcolepsy

  • Obesity

  • Attention-deficit hyperactivity disorder

Methylphenidate (Ritalin)

• Mild CNS stimulant, chemically related to amphetamine

• Effects more prevalent on mental than motor activities

• General pharmacological profile similar to amphetamine

• Major Therapeutic Use:

  • Narcolepsy

  • Attention-deficit hyperactivity disorder

Ephedrine

• alpha and ß adrenergic receptor agonist

• Indirect sympathomimetic also, promoting norepinephrine release

• non-catechol structure, orally active

• Pharmacological effects:

  • increases heart rate, cardiac output

  • usually increases blood pressure

  • may cause uriniary hesitancy due to stimulation of a smooth muscle receptors in bladder base.

  • bronchodilation: ß adrenergic receptor response

• Limited Clinical Use due to better pharmacological alternatives (asthma, heart block, CNS stimulation)

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Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.216-219

Amphetamine & related drugs

•  use (very limited) as appetite suppressant with high abuse potential

•  Fenfluramine: appetite suppressant; cardiotoxic (withdrawn from market)

• Methylphenidate (Ritalin) similar but with fewer peripheral effects, useful in Attention Deficit Disorder

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