Sympathetic Drugs

Stress and The Adrenal Glands

Adrenal Medulla: A Modified Sympathetic Ganglion

Mechanism: Norepinephrine Release and Recycling

Review of Efferent Pathways: Motor and Autonomic

Catechalomines: Activity

• Stimulates the “fight or fight” reaction • Increased plasma glucose levels• Increased cardiovascular function• Increased metabolic function• Decreased gastrointestinal and genitourinary

function

Activity of Epinephrine

Sympathomimetics

• Drugs that partially or completely mimic the actions or norepinephrine (NE) and epinephrine (Epi).

• Act either - directly on α- and/or β-adrenoceptors or indirectly on

presynaptic terminals, usually by causing the release of NE.

• See Below

• β2-Adrenoceptor Agonists – cause bronchial dilation - used for the treating asthma, prevent pre-term labor (relaxing uterine muscle).

• β1-Adrenoceptor Agonists – (e.g., dobutamine) sometimes used to increase the force of heart contraction in severe low-output heart failure.

• α1-Agonists – (e.g., phenylephrine) – used as mydriatics, decongestants.

• α2-Agonists – (e.g., clonidine, methyldopa) – centrally acting hypotensive drugs.

• Sympathomimetics act mainly by causing release of NE (e.g., amphetamine) have the α1/α2 selectivity of NE.

• β-Adrenoceptor antagonists (β-blockers) – used to treat hypertension, angina, cardiac arrhythmias, CHF, and glaucoma.

• α-Adrenoceptor antagonists (α-blockers) – limited clinical application – prazosin (selective α1-antagonist – used to treat hypertension.

• Adrenergic neuron blocking drugs – either deplete the nerve terminals of NE or prevent its release – used as hypotensive agents.

Metabolism of Norepinephrine

• Reuptake• Monoamine Oxidase• Catechol-O-methytransferase (COMT)• α1-Adrenoceptors – in several tissues (e.g., smooth

muscle, salivary glands) incr IP3 and [Ca2+]in vasoconstriction or glandular secretion

• α2-Adrenoceptors – on noradrenergic nerve terminals. Activation by NE inhibit AC, decr cAMP, Ca2+ channels close decr further nt release.

• β-Adrenoceptor – stim AC incr [cAMP] 2nd messenger intracellular signaling physiol response.

Indirectly-Acting Sympathomimetics

• Transported into nerve terminals where they displace vesicular NE into the cytoplasm. Some is metabolized by MAO, but the remainder is released by carrier-mediated transport to activate adrenoceptors.

• Amphetamines – resistant to MAO.- Peripheral actions - tachycardia, hypertension - mainly caused by catecholamine release.- Dexamfetamine and methylphenidate used for hyperactive children.

• Cocaine – NE reuptake inhibitor (also dopamine) – Intense central stimulant popular drug of abuse.

Acute and chroniceffects of Indirectly acting sympathomimetics

G = Guanethidine

Mechanism of actionof cocaine and reserpine

Directly-Acting Sympathomimetics• Effects in humans depends on their receptor specificity (α and/or

β) and on the compensatory reflexes they evoke.• Epi incr bp by stim the rate and force of the heart beat (β1 effects).• Stimulation of vascular α-receptors causes vasoconstriction

(viscera, skin), whereas…,• Stimulation of vascular β2-receptors vasodilation (skeletal muscle)

…• And the total peripheral resistance may actually decrease.• NE has little-to-no effect on the vascular β2-receptors; thus, the α-

mediated vasoconstriction is unopposed.• The resulting rise in bp reflexively slows the heart, usually

overcoming the direct β1-stimulant action on the heart rate.

β-Receptor-Selective Drugs

• Isoprenaline – stimulates all β-receptors incr rate and force of heart beat and vasodilation full diastole and MAP, with little change in systolic pressure.

• β2-Adrenoceptor Agonists – relatively selective class of drugs that produce bronchodilation – used for asthma (resistant to MAO, not uptaken into neurons).

Adrenoceptor Antagonistsα-Blockers

• Decr artiolar and venous tone decr peripheral resistance hypotension.

• Reverse the pressor effects of Epi, because its β2-mediated vasodilator effects are unopposed by α-mediated vasoconstriction peripheral resistance falls (Epi reversal).

• Cause reflex tachycardia – this is greater with non-selective drugs that also block α2-presynaptic receptors on the heart, because the augmented release of NE further stimulates the cardiac β-receptors (e.g., prazosin).

Adrenoceptor Antagonistsβ-Blockers

• Vary in lipid solubility and cardioselectivity• All block β1-receptors and decr bp and prevent

angina.• Higher Kow-drugs more rapid absorption from GIT,

1st-pass hepatic elimination more rapidly eliminated.

• Also more likely to enter CNS and cause central effects (e.g., nightmares).

• Cardioselectivity diminishes with higher doses.

Adrenoceptor Antagonistsβ-Blockers (Cont’d)

• Nevertheless, selective β1-blockade less peripheral vasoconstriction (cold hands and feet) and does not reduce the response to exercise-induced hypoglycemia (stim of gluconeogenesis in liver is mediated by β2-receptors).

• Cardioselective drugs may have sufficient β2-activity to ppt severe bronchospasms in patients with asthma – these patients should avoid β-blockers .

• Some possess intrinsic sympathomimetic activity (partial agonists), but this is debatable.

Catecholaminesynthesis, storage,release, and reuptakepathways