sympathetic drugs. stress and the adrenal glands
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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
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