2. © Assoc. Prof. Ivan Lambev E-mail: itlambev@mail.bg ADRENERGIC DRUGS (Sympathomimetics, Adrenomimetics) Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology

3. The sympathetic preganglionic fibers leave the CNS through the thoracic and lumbar spinal nerves. The sympathetic preganglionic neurons (first neurons) project from the intermediolateral column of the spinal gray matter to the paired paravertebral ganglionic chain lying alongside the vertebral column and to unpaired prevertebral ganglia. These ganglia represent sites of synaptic contact between preganglionic axons (1 st neurons) and nerve cells (2 nd neurons) that emit postgan- glionic axons terminating on cells in various end organs. In addition, there are preganglionic neurons that project either to peripheral ganglia in end organs or to the adrenal medulla.

4. ADRENERGIC AND DOPAMINERGIC NERVES

5. Activation of the Sympathetic Nervous System can be considered a means by which the body achieves a state of maximal work capacity as required in fight or flight situations.

6. Whereas ACh serves as the chemical transmitter at ganglionic synapses between first and second neurons, Norepinephrine (NE, noradrenaline) is the mediator at synapses of the second neuron. Excitation of the neuron leads to activation of a larger aggregate of effector cells, although the action of released NE may be confined to the region of each junction. Excitation of preganglionic neurons innervating the adrenal medulla causes a liberation of ACh. This, in turn, elicits a secretion of epinephrine (adrenaline) into the blood, by which it is distributed to body tissues as a hormone.

9. Adrenoceptors fall into two major groups, designated alpha (α 1, α 2 ) and beta (β 1, β 2, β 3 ) within each of which further subtypes can be distinguished pharmacologically. The different adrenoceptors are differentially distributed according to region and tissue. Agonists at adrenoceptors (direct adrenomimetics) mimic the actions of the naturally occurring cate- cholamines, NA and epinephrine, and are used for various therapeutic effects.

10. Within the varicosities, NE is stored in small membrane-enclosed vesicles (granules, 0.05 to 0.2 µm in diameter). In the axoplasm, L-tyrosine is converted via two intermediate steps to dopamine (DA), which is taken up into the vesicles and there converted to NE by DA-beta-hydroxylase. When stimulated electrically, the sympathetic nerve discharges the contents of part of its vesicles, including NE, into the extracellular space. Liberated NE reacts with adrenoceptors located postjunctionally on the membrane of effector cells or prejunctionally on the membrane of varicosities. Activation of presynaptic α 2 -receptors inhibits NE (regulative negative feedback).

11. Presynaptic receptors in adrenergic synapse and their role in the regulative negative and positive feedback

12. Presynaptic regulation of transmitter release from noradrenergic and cholinergic nerve terminal

13. The effect of released NE wanes quickly, because approximately 90% is actively transported back into the axoplasm, then into storage vesicles (neuronal re-uptake). Small portions of NE are inactivated by the enzyme catechol-O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells, to yield normeta- nephrine), and monoamine oxidase (MAO, present in mitochondria of nerve cells and postjunctional cells) to yield 3,4-dihydroxymandelic acid).

14. The liver is richly endowed with COMT and MAO. It therefore contrib- utes significantly to the degradation of circulating NE and epinephrine. The end product of the combined actions of MAO and COMT is vanillylmandelic acid.

16. Antiparkinsonian dopaminergic drugs moclobemide and selegiline block MAO.

17. Action on alpha-adrenoceptors Contraction of arterioles and veins: raise in BP (α 1 ) Contraction of radial muscules of iris: mydriasis and decreased aqueous secretion (α 1 ) GIT: intestinal relaxation, contraction of sphincters Bladder trigone: contraction Uterus: contraction Splenic capsule: contraction Neuromuscular transmission: increased ACh release Insulin secretion: inhibited (α 2 dominant) Mail sex organs: ejaculation Salivary glands: K + and water secretion (α 1 ) Nictitating membrane in cats: contraction (α 1 )

18. Noradrenaline (  1 ) PLC PIP 2 IP 3 Ca 2+ DAG PKC ADP ATP Ex In (+) Gs

20. PLC (phospholipase C) catalyses the formation of two intracellular messen- gers  InsP 3 and DAG, from memb- rane phospholipids. InsP 3 (inositol-triphosphate) increases free cytosolic calcium by releasing Ca 2+ from endoplasmic reticulum. Free calcium initiates contractions, se- cretion, membrane hyperpolarization DAG activates protein kinase C.

21. Action on beta-adrenoceptors Dilatation of arterioles and veins (β 2 ): fall in BP Cardiac stimulation (β 1 ): increased heart rate, force and conduction velocity Bronchodilation (β 2 ) Eye: enhanced aqueous secretion GIT: intestinal relaxation (β 2 ) Bladder detrusor: relaxation Uterus: relaxation (β 2 ) Neuromuscular transmission: tremor (β 2 ) Augmented insulin and glucagon secretion (β 2 ) Liver: glycogenolysis (β 2 ) Fat – lipolysis (β 3 ), Kidney – renin release (β 1 ) Posterior pituitary: ADH secretion (β 1 )

22. Adr (  1 &  2 ) Gs AC ATP cAMP PKA Effects Ex In (+)

23.  -ad- reno- ceptor 7 sub- units

24. Agents which increase cAMP (adrenaline, salbutamol and other beta-adrenoceptor agonists) inhibit histamine secretion and produce bronchodilation (antiasthmatic effect).

25. Autonomic control of pupil (A) and site of action of mydriatics (B) and miotics (C)

28. Chemical structure of catecholamines and affinity for α- and β-receptors

29. Norepinephrine (noradrenalne): α 1, α 2, β 1 and β 3, but not β 2 action Epinephrine (adrenaline): α 1, α 2, β 1 and β 2 and weak β 3 action Isoproterenol (isoprenaline): β 1 and β 2, but not α action -------------------------------------------------- Clonidine: presynaptic α 2 agonist (with antihypertensive action)

30.  Direct-acting adrenomimetics α-adrenomimetics (activators of phospholipase C) - antihypotensive drugs: Etilefrinе (Effortil  ), NE - local nasal decongestants: Naphazoline, Oxymetazoline, Xylometazoline (0.1% nasal drops) - eye drops in glaucoma: Phenylephrine Cardioselective α 1 -adrenomimetics: Dobutamine DA-ergic adrenomimetics: Dopamine Selective β 2 -adrenomimetics: Fenoterol, Hexoprenaline, Salbutamol, Salmeterol, Terbutaline Non-selective β-adrenomimetics: Iso- and Orciprenaline α- and β-adrenomimetics: Adrenaline (antiallergic): amp. 0,1% 1 ml s.c.; Anapen  (0,3 mg/03 ml i.m.)  Indirect-acting adrenomimetics Antihypotensive drugs Ephedrine, Mephentermine, Midodrine

32. Reactive hyperemia due to α-adrenomimetics (naphazoline, oxymetazoline, xylometazoline) e.g., following decongestion of nasal mucosa

33. Some important catecholamines NB: isoproterenol (isoprenaline)

34. BP – blood pressure, HR – heart rate

35. Effects of intravenous infusion of norepinephrine, epinephrine, or isoproterenol in humans

36. Dose-response curves of Adr (adrenaline), NA (noradrenaline) and Iso (isoprenaline) on isolated aortic strip and isolated bron- chial smooth muscle illustrating two distinct rank orders of po- tencies respectively for α- and β-adrenergic receptors. Isolated aortic strip Isolated bronchial smooth muscle

37. Effect after 3 to 5 min and duration 4–6 h: Salbutamol Fenoterol Effect after 15–20 min and duration 12 h: Salmeterol

38. FACTORS THAT EXACERBATE ASTHMA

39. Primarily sites of bronchodilation action of inhaled β 2 -adrenergic agonists is mainly bronchiolar smooth muscle. Atropinic drugs cause bronchodilation by blocking cholinergic constrictor tone, act primarily in large airways.

40. Selective β 2 -adrenomimetics with tocolytic effect Fenoterol (Partusisten  : tab. 5 mg) Hexoprenaline Salbutamol (Salbupart  ) Terbutaline

42. Ephedra equsetina - Ephedrine with anti- hypotensive and anti- asthmatic effects AR: tachy- phyllaxis

43. Indirect sympathomimetics with central stimulant activity and abuse potential Amphetamine Cocaine

44. Erythroxylon coca L.