Adrenergic & Antiadrenergic Drugs

1. Adrenergic & Antiadrenergic Drugs By Prof. Alhaider

2. Anatomy of the sympathetic nervous system • The origin is from thoracolumbar segments “all thoracic + lumbers L1, L2, L3 and L4 ” • They have short preganglionic fibers, and it relays in sympathetic chain ganglia & release Ach in these ganglia • They have long postganglionic fibers that innervate their body organs & release Norepinephrine as a neurotransmitter there

4. Neurotransmission at adrenergic neurons • Synthesis of norepinephrine (NE) • Storage of dopamine (DA) and NE in vesicles • Release of NE • Metabolism (COMT 20% + MAO 80%) • Binding to receptors • Uptake mechanism

6. We ask the doctor about the drugs are they included in the exam he said “it’s up to you”

7. Adrenoceptors • The adrenergic receptors are classified into • α1 • α2 • β1 • β2 • β3 • There are some subtypes

8. α1– Adrenoceptors

9. α1– adrenoceptors (continue) Site of α1– adrenoceptors & the effects of their stimulation • In vascular smooth muscle. • α1 stimulation cause vasoconstriction (VC) : • Vasoconstriction in the skin & viscera cause increase total vascular resistance (TVR) causing increase blood pressure (BP) • α1 – adrenoceptors the most determine of arteriolar tone. When their stimulated no others receptors have an affects on BP. So, hypertension may be treated by blocking α1 • Vasoconstriction in the nasal blood vessels cause relief of congestion • In the radial muscle of iris. • α1 stimulation causes contraction of the radial muscle causing mydriasis (dilation of the pupil)

10. Cont…. • In the smooth muscle of the sphincters of GIT. • α1 stimulation cause contraction of all sphincters • In the smooth muscle of internal sphincter of urinary bladder (Very important). α1a subtypes stimulation cause contraction and closure of the sphincters (precipitate urinary retention) • In the seminal vesicles. (with α2) • α stimulation cause ejaculation. Thus, all α blockers inhibit ejaculation • In the liver. • α1 stimulation causes increase glycogenolysis & gluconeogenesis • In the fat cells. • α1 stimulation causes increased lipolysis

11. Adrenoceptorsα 1 – adrenoceptorsDrugs effects : • α1 selective agonist • E.g. • Phenyl ephrine • α1 selective antagonists • E.g. • Prazosin • Terazosin • Doxazosin • Tamsolusin ( α1a) (has a different clinical use)

12. α2– adrenoceptorsMechanism of action • α2 stimulation leads to either • Decreased adenylyl cyclase activity(mediated by the inhibitory regulatory Gi protein) • Lead to decrease cAMP causing decrease NE release causing • relaxation of smooth muscle & • decreased glandular secretion • Increase K+ channel activity  hyperpolarization So α1 receptors are stimulatory while α2 receptors are inhibitory

14. α2–adrenoceptorsSite of α2– adrenoceptors & the effects of their stimulation • In adrenergic nerve terminals (presynaptic). • α2 stimulation cause decreased Norepinephrine release (autoregulatory mechanism). It opposes the action of sympathetic stimulation. • In pancreas. • causes decreased insulin release • In platelets. • Increase platelets aggregation via c-AMP • In liver (same as α1– adrenoceptors) • Fat cells (same as α1– adrenoceptors).

15. Cont… • In ciliary epithelium. • Increase the out flow of aqueous humor.(good for glaucoma) • In the smooth muscle of GIT wall. (with β2) α2 stimulation cause relaxation of the wall causing decreased peristalsis (indirectly by reducing the release of ACH)

16. α2– adrenoceptors (Continue)Drugs effects : • α2 selective agonists • E.g. • Clonidine • Methyldopa (Antihypertensive) • Apraclonidine (topical for eye) • α2 selective antagonists • E.g. • Yohimbine; Mertazapine (Antidepressant)

17. β1– adrenoceptors • In the heart. • β 1 stimulation causes • In S.A node : increase heart rate (HR) (+vechronotropic) • In Myocardium tissue : increase contractility (+veinotropic) • In Conducting system : increase conduction velocity (+vedromotropic) • Increase ectopic beats • In the Juxtaglomerular Apparatus of the kidney. • β 1 stimulation cause increased renin release. Then causes increase in BP • In fat cells (with α1, α2 & β 3) • β 1 stimulation causes increased Lipolysis

18. Adrenoceptorsβ 1 – adrenoceptorDrugs affecting them • β 1 selective agonists • E.g. • Dobutamine • β 1 selective antagonists • E.g. • Atenolol • Esmolol • Metoprolol

19. β2– adrenoceptors • In the bronchial smooth muscle • β2 stimulation causes relaxation of smooth muscle (bronchodilatation) • In the smooth muscle of blood vessels supplying the skeletal muscle. • β2 stimulation causes relaxation of smooth muscle  Vasodilatation(VD) • This VD effects is usually masked by the potent VC effect of α1 – receptors

20. Cont…. • In the smooth muscle of GIT wall. • β2 stimulation cause relaxation of the wall leading to decreased peristalsis • In the smooth muscle of the wall of urinary bladder. • β 2 stimulation causes relaxation of the wall • Note: Adrenergic stimulation is opposite to the cholinergic in the wall and sphincters in GIT and genitourinary tract .

21. Cont…. • In the smooth muscle of the uterus • β2 stimulation causes relaxation of the uterus (Ritodrine delay the labor) • In the liver. • β2 stimulation causes increased Glycogenolysis & Gluconeogenesis • In the pancreas. • β2 stimulation causes slight increase in insulin secretion (hypoglycemia), but the effect on the liver is predominant. • Effect on potassium . • β2 stimulation increase potassium influx.

22. Cont…. • In ciliary muscle. • β2 stimulation causes relaxation of the ciliary muscle leading to • Accommodation for far vision • Decrease outflow of aqueous humor via the canal of Schlemm • In the ciliary epithelium • β2 stimulation causes increased production of aqueous humor

23. Adrenoceptorsβ 2 – adrenoceptorsDrugs affecting them • β 2 selective agonists • E.g. • Salbutamol (asthma + ref heperkalemia) • Salmetrol • Terbutaline • Ritodrine • Formetrol • β 2 selective antagonists • E.g. • ICI118551 (still under investigation)

24. b1 and b2 – adrenoceptor agonistsMechanism of action • β stimulation causes increase adneylyl cyclase activity leading to increase cAMP leading to cellular effect. E.g. • β 1 in the heart cause increase intracellular Ca++ release leading to increased contractility • β 2 in smooth muscle cause inhibition of myosin kinase enzyme causing relaxation • β 2 in the liver cause increase Glycogen phosphorylase enzyme activity causing increased glycogenolysis

25. β 3 – adrenoceptors • In brown adipose tissue • β 3 stimulation causes increased Lipolysis • β 3 selective agonist • E.g. • BRL 37344 • β 3 selective antagonist • E.g. • CGP 20712A

26. Adrenergic Drugs • Adrenoreceptor Agonists • Non selective • Selective • Adrenoreceptor Antagonists • α– blockers • β– blockers

27. Adrenoceptor AgonistsI. Non selective drugs • These drugs include • 1) Catecholamine Drugs A. endogenous: • Norepinephrine • Epinephrine • Dopamine b) Synthetic (exogenous) • Isoprenaline 2) Non-catecholamine Drugs • Amphetamine • Ephedrine • Pseudo ephedrine • Phenylpropranolamine

28. Norepinephrine (NE)(Noradrenaline) • NE is a neurotransmitter released from the postganglionic sympathetic fiber in most organs • It also released from the adrenal medulla (20% of medulla secretion) • It is a direct non–selective adrenergic agonist which acts on all adrenoceptors, Except β2

30. Cont…. • Sites of metabolism • In adrenergic nerves • 80% by MAO in presynaptic nerve terminals after reuptake (This is very important clinically) • If MAO is inhibited, NE will be reuptake but not metabolized, leads to release of NE again • 15% by COMT in postsynaptic membrane (This is not important clinically) • 5% reach the blood and metabolized In the Liver

31. Norepinephrine Pharmacokinetics • T1/2 of NE = 2 – 3 min • Very short because it has rapid metabolism • NE causes increased systolic blood pressure (SBP) & diastolic blood pressure (DBP) • So, in shock, it will increase BP • Not given orally because it will be inactivated by intestinal enzymes

32. Clinical Uses: • Note: NE is not commonly used in clinical practice like Epinephrine, However it can be used in: • Cardiac Arrest • Shock

33. Epinephrine (EP)(Adrenaline) • EP is released from adrenal medulla (80%) and in certain areas of the brain • EP is a direct acting non-selective adrenergic agonist in all receptors including β2 receptor. • T1/2 = 2 – 5 min • Like NE, It is given parenterally (SC, I.V and I.M) not orally • Has the same pharmacokinetics as NE

34. EpinephrineTherapeutic use b • Epinephrine is commonly used in practice as compared to NE. • In bronchial asthma • It is given SC to act on β2 receptors to cause bronchodilation • Now it is not commonly used because of its side effects (tachycardia and arrhythmia) • In cardiogenic shock • It is given I.V to increase SBP, BP, HR and cardiac output (CO) • In anaphylactic shock • It is given SC to act on • α1 cause VC, lead to increase BP & relief of congestion • β 1 cause increase HR leading to increase CO, so, increase BP • β 2 cause bronchodilation so, relieve bronchospasm

35. Cont… • In cardiac arrest (for Bradycardia) • It is given I.V. if there is no response, EP given directly into the lung, and if there is no response, it given intracardially, and if there is no response, direct current is applied for 3 times at most • During surgery • EP is added to the local anesthetic to cause VC in the surgery area in order to • Decrease bleeding • Decrease the amount of local anesthetic which will reach the systemic circulation. Therefore, it will decrease the cardiodepressant effect of the local anesthetic

36. Isoprenaline (isoproterenol) • It is directly acting syntheticadrenoreceptor agonist acting only on β–receptors, with no effects on a adrenoceptos. • T1/2 = 5 – 7 min • Like all catecholamines, It is given parenterally (not orally) • The I.V must be given carefully because the overdoses cause cardiac arrest

37. Iso pre nalineAction • Isoprenaline will stimulate • β1 in the heart to cause • Increased HR & cause arrhythmia & may lead to cardiac arrest • β2 in the blood vessels to cause • VD leads to decreased BP (mainly DBP)

38. IsoprenalineTherapeutic uses: • It is no longer used to treat the bronchial asthma because of it’s side effects on the heart • It’s only used now to reverse the heart block which is produced by overdoses of β – blockers N.B. cardiac arrest means : complete cessation of heart’s activity. While heart block means : partial or complete inhibition of the spread of conduction of the electrical impulse from the atria to the ventricles

39. Effects of I.V. infusion of Epinephrine, Norepinephrine & Isoprenaline in Humans Epinepherine and isoprenaline decrease DBP because they act on β2 Reflex bradycardia Isoprenaline decrease resistance because it acts on β only without α

40. Dopamine • DA is a non–selective adrenergic agonist, which acts either directly on DA – receptors in addition to b1- adrenergic receptorsor indirectly by releasing NE • Like all catecholamines, It is given parenterally only (not orally) • It doesn’t cause tolerance • T1/2 = 3 – 5 min • Metabolized by either • Converted to NE in adrenergic neurons or • By MAO in the Liver

41. Dopamine (Cont…) • Clinical Uses : • In small dose of DA (=< 5ug / Kg / min by I.V infusion) Renal dose: • It will stimulate DA–receptors only • It will cause vasodilatation (VD) in: • Renal vascular bed • Cerebral vascular bed • Coronary vascular bed • Mesenteric vascular bed Therefore, it is useful in treatment of shock to save these vital organs from hypoxia (also see Dobutamine) N.B : At higher doses, VD effect of DA – receptors is masked by the VC effect of α1–receptors(see next slide)

42. Cont…. • In medium dose : (5-15ug/Kg/min by I.V infusion) Cardiac dose • It will stimulate β1 – receptors to cause increase HR, CO and BP • In high dose of DA (> 15ug / Kg / min by I.V infusion) • It will stimulate α1 receptors (direct + Via release of NE) to cause VC leading to increase BP and decrease organ perfusion So, the high dose of DA is not recommended in shock.

43. What is the effect of Dopamine on Bronchioles? It has no effect on the bronchioles because it doesn’t stimulate β2 receptors (even indirectly , because NE does not stimulate β2 receptors ).

44. Centrally Acting Sympathomimetic Agents: e.g: 1. Amphetamine • It is non-selective adrenergic agonist, noncatecholamine • Acts mainly indirectly via, enhancing NE release and DA. • Since it is non-catecholamine, it can be given orally • It is lipid–soluble enough to be absorbed from intestines and goes to all parts including CNS (This leads to CNS stimulation like Restlessnessقلق and Insomnia الارق). • t1/2 = 45 – 60 min (long duration of action) • It is metabolized in the Liver.

45. Clinical use of Amphetamine-like drugs • To suppress appetite • In very obese persons Amphetamine can act centrally on the hunger center in the hypothalamus to suppress appetite • In narcolepsy • Narcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night • Amphetamine stimulates the CNS & makes the patient awake • In ADHD “Attention Deficit Hyperactivity Disease”

46. Clinical use of Amphetamine-like drugs (controlled Drugs) • Note: Amphetamine is a drug of abuse, that should not be prescribed. However, amphetamine-like drugs can be prescribed for the following conditions: • In ADHD (Methylphenidate, Dexamfetamine) • In narcolepsy • (Dexamfetamine and Modafinil) • To suppress appetite

47. AmphetaminesSide effects • The side effects are due to chronic use • These include : • Tolerance • Dependence • Addiction • Paranoia (thought process heavily influenced by anxiety or fear) • Psychosis (loss of contact with reality)

48. 2. Ephedrine • It is non selective adrenergic agonist • It • Directly acts on the receptors (a,b1,andb2) It is Like an oral form of Epinephrine. • Indirectly by releasing NE • PK almost similar to amphetamine • It causes tolerance but no addiction • Like amphetamine, it is CNS and respiratory stimulant. • It does not suppress the appetite

49. EphedrineClinical uses: • Pressor agent (used to increase BP) • Decongestant • It is no longer used to treated bronchial asthma. (because it’s less potent + slow onset of action)

50. 3. Pseudoephedrine: • Has similar pharmacological activities to ephedrine • It is not controlled : OTC (over the counter) يباع بدون وصفة طبية • It is commonly used as a decongestant.