1. Sympathetic Drugs

2. Stress and The Adrenal Glands

3. Adrenal Medulla: A Modified Sympathetic Ganglion

4. Mechanism: Norepinephrine Release and Recycling

5. Review of Efferent Pathways: Motor and Autonomic

6. Catechalomines: Activity Stimulates the “fight or fight” reaction Increased plasma glucose levels Increased cardiovascular function Increased metabolic function Decreased gastrointestinal and genitourinary function

7. Activity of Epinephrine

8. 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

9. β 2 -Adrenoceptor Agonists – cause bronchial dilation - used for the treating asthma, prevent pre-term labor (relaxing uterine muscle). β 1 -Adrenoceptor Agonists – (e.g., dobutamine) sometimes used to increase the force of heart contraction in severe low- output heart failure. α 1 -Agonists – (e.g., phenylephrine) – used as mydriatics, decongestants. α 2 -Agonists – (e.g., clonidine, methyldopa) – centrally acting hypotensive drugs.

10. Sympathomimetics act mainly by causing release of NE (e.g., amphetamine) have the α 1 /α 2 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 α 1 - antagonist – used to treat hypertension. Adrenergic neuron blocking drugs – either deplete the nerve terminals of NE or prevent its release – used as hypotensive agents.

11. Metabolism of Norepinephrine

12. Reuptake Monoamine Oxidase Catechol-O-methytransferase (COMT) α 1 -Adrenoceptors – in several tissues (e.g., smooth muscle, salivary glands)  incr IP 3 and [Ca 2+ ] in  vasoconstriction or glandular secretion α 2 -Adrenoceptors – on noradrenergic nerve terminals. Activation by NE  inhibit AC, decr cAMP, Ca 2+ channels close  decr further nt release. β-Adrenoceptor – stim AC  incr [cAMP]  2 nd messenger intracellular signaling  physiol response.

13. 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.

14. Acute and chronic effects of Indirectly acting sympathomimetics G = Guanethidine

15. Mechanism of action of cocaine and reserpine

16. 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 (β 1 effects). Stimulation of vascular α-receptors causes vasoconstriction (viscera, skin), whereas…, Stimulation of vascular β 2 -receptors vasodilation (skeletal muscle) … And the total peripheral resistance may actually decrease. NE has little-to-no effect on the vascular β 2 -receptors; thus, the α-mediated vasoconstriction is unopposed. The resulting rise in bp reflexively slows the heart, usually overcoming the direct β 1 -stimulant action on the heart rate.

17. 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. β 2 -Adrenoceptor Agonists – relatively selective class of drugs that produce bronchodilation – used for asthma (resistant to MAO, not uptaken into neurons).

18. Adrenoceptor Antagonists α-Blockers Decr artiolar and venous tone  decr peripheral resistance  hypotension. Reverse the pressor effects of Epi, because its β 2 - 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 α 2 -presynaptic receptors on the heart, because the augmented release of NE further stimulates the cardiac β- receptors (e.g., prazosin).

19. Adrenoceptor Antagonists β-Blockers Vary in lipid solubility and cardioselectivity All block β 1 -receptors and decr bp and prevent angina. Higher K ow -drugs  more rapid absorption from GIT, 1 st -pass hepatic elimination  more rapidly eliminated. Also more likely to enter CNS and cause central effects (e.g., nightmares). Cardioselectivity diminishes with higher doses.

20. Adrenoceptor Antagonists β-Blockers (Cont’d) Nevertheless, selective β 1 -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 β 2 -receptors). Cardioselective drugs may have sufficient β 2 - 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.

21. Catecholamine synthesis, storage, release, and reuptake pathways