Adrenergic Drugs. Autonomic Nervous System.pptx

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1. Adrenergic D rug s Dr. Kalim Ullah PhD ( P harmacology) Associate Professor Department of Nursing Superior University, Lahore

2. Adrenergic nervous system Adrenergic nervous system is a group of organs and nerves in which adrenaline and/or noradrenaline are released as neurotransmitters. Adrenergic nerve release neurotransmitters: noradrenaline, adrenaline, dopamine and produce their effect.

3. Mode of Action Three types 1)Directly activate their adrenoceptors 2) I ndirectly to increase the concentration of catecholamine transmitter ( EP , NE ,& Dopamine ) in the synapse. e.g Amphetamine and tyramine 3)Another form of indirect action is seen with cocaine and the tricyclic antidepressants; these drugs inhibit reuptake of catecholamines by the norepinephrine transporter and the dopamine transporter in nerve terminals and thus increase the synaptic conc. of released N.T. .

4. Adrenergic drugs Drugs that produce similar effects to those produced by sympathetic nervous system thus they are also called sympathomimetic drugs. It may refer to something which is susceptible to epinephrine or similar to substances, such as biological receptor especially adrenergic receptor. A great number of drugs available which can affect adrenergic receptors e.g. dopamine, noradrenaline, adrenaline, isoprenaline etc.

5. Adrenergic receptors Adrenergic receptors are broadly classified into three groups i. Alpha receptor: there are two subclasses of alpha receptor – α -1 receptor α -2 receptor ii. Beta receptor: β -receptors are subdivided into – β -1 receptor β -2 receptor β -3 receptor iii. Dopamine receptor: Dopamine receptors are of two types – D-1 receptor D-2 receptor

6. α1 Post synaptic Smooth muscles Salivary glands and liver cells Mydriasis sphincter contraction  Constipation and Urinary retention Gland-secretion Liver-glycogenesis α2 Presynaptic-adrenergic or cholinergic nerve cells Post synaptic- brain, β pancreatic cells Extra junctional- blood vessels and platelets Reduces release of norepinephrine (as a negative feedback mechanism)  bradycardia, hypotension Central sympathetic outflow is decreased β1 Heart and juxtraglomerular apparatus Contraction  Increased heart rate β2 Bronchi, uterus, liver, GIT, Eyes Relaxation  Bronchodilation, urinary retention, constipation, uterus relaxation β3 Adipocyes Lipolysis and thermogenesis

7. Adrenergic Receptors Adrenoceptors are classified as α or β receptors; both groups are further subdivided into subgroups. Three types of the β -adrenergic receptor , called β 1 , β2 ,and β 3, were identified, followed by two different α -adrenergic receptors: α 1 and α 2 . Epinephrine (adrenaline ) may be considered a single prototype agonist with effects at all receptor types (α1, α2, β1, β2, and β3). Alternatively, separate prototypes, phenylephrine (an α agonist) and isoproterenol (β) may be defined . .

8. Vasopressor agents- α1 receptor agonist- N oradrenaline , P henylephrine , M ethoxamine , Cardiac stimulants- Nonselective- A drenaline , I soprenaline β1 receptor agonist- D opamine , D obutamine Bronchodilators- Nonselective- A drenaline , I soprenaline Selective β2 agonist- S albutamol, T erbutaline, S almeterol, F ormoterol Nasal decongestant- α1- receptor agonist- P henylephrine , P seudoephedrine α2 receptor agonist- O xymetazoline , X ylometazoline , N aphazoline

9. Uterine relaxants Selective β2 agonist- S albutamol , T erbutaline , CNS stimulants Amphetamine, M ethamphetamine , D examphetamine , E phedrine

10. Potent stimulant of alpha and beta receptors Complex actions on target organs Adr: α1 +α2+ β1+ β2 and weak β3 action NA: α1 +α2+ β1+ β3 and no β2 action Iso: β1+ β2 + β3 action but no α action

11. Pharmacological action of Adrenergic drugs: Increase heart rate, increase force of contraction of heart, increase tissue perfusion. α agonist causes vasoconstriction β agonist causes vasodilation β 2 agonist causes bronchial dilation Inhibit noradrenaline release. This is called auto inhibitory feedback mechanism noradrenaline release.

12. Adrenergic Receptors Adrenoceptors are classified as α or β receptors; both groups are further subdivided into subgroups. Three types of the β -adrenergic receptor , called β 1 , β2 ,and β 3, were identified, followed by two different α -adrenergic receptors: α 1 and α 2 . Epinephrine ( adrenaline ) may be considered a single prototype agonist with effects at all receptor types (α1, α2, β1, β2, and β3). Alternatively, separate prototypes, phenylephrine (an α agonist) and isoproterenol (β) may be defined. .

13. A drenaline Catecholamine, sympatho-mimetic monoamine, derived - phenylalanine and tyrosine. C9H13NO3 MOL WT:183.20442 g/mol

14. Biosynthesis HO NH 2 CO 2 H L-Tyrosine Tyrosine hydroxylase HO NH 2 CO 2 H L ev od o p a HO HO NH 2 D o pa min e HO Do p a Decarboxylase Dopamine  -hydroxylase HO HO NH 2 O H Norepinephrine ( N o r a drena li ne) HO HO N H M e O H Epinephrine (A dr ena l in e ) N-methyl transferase (in Adrenal medulla)

15. Mechanism of action : the action of adrenaline is receptor mediated. It produces both excitatory and inhibitory effects. Excitatory effects due to stimulation of α receptor except the intestine where it is inhibitory. Inhibitory effect due to stimulation of β receptor except the heart

16. SYMPATHMIMIETICS {adrenergic agents } Pharmacological Action 1)Heart: Direct effects on the heart through β1 receptors. Adrenaline increases the heart rate , force of myocardial contraction ,cardiac output and increased oxygen consumption . 2)Blood vessels: Adrenaline and noradrenaline constrict the blood vessels of skin and mucous membranes. Constriction occur through both α1 and α2 receptors. Adrenaline also dilates the blood vessels of the skeletal muscles on account of the presence of β2 receptors → Decrease of DBP Note : Noradrenaline had no effect on β2 receptors. .

17. 3)Blood pressure: Adrenaline increases the systolic B.P {vasoconstriction (α1) } but lowers the diastolic B.P by its peripheral action {vasodilatation (β2)}. But mean blood pressure rises with increase in pulse pressure . Noradrenaline causes rise in systolic, diastolic and mean blood pressure and does not cause vasodilatation (because of no action on β2 receptors) and increase in peripheral resistance due to its α2 action. Pulse pressure : Recent studies suggests that a 10 mm Hg increase in pulse pressure increased the risk of major cardiovascular complications and mortality by nearly 20% . .

18. The pulse pressure is proportional to  stroke volume , or the amount of blood ejected from the left ventricle during systole That is inversely proportional to the compliance of the aorta. When  aorta has the highest compliance in the arterial system due in part to a relatively greater proportion of elastin fibers →→ reducing the pulse pressure . If the aorta becomes rigid in conditions such as  atherosclerosis →→ pulse pressure would be very high .

19. 4) GIT: Adrenaline causes relaxation of smooth muscles of GIT and reduce its motility. Relaxation of smooth muscles of GIT can be brought about by both alpha and beta stimulants. 5) Respiratory system: The presence of β2 receptors in bronchial smooth muscle causes relaxation → bronchodilation ( acute asthmatic attack) . Among catecholamines , adrenaline and isoprenaline are potent bronchodilators due to its β2 action but not noradrenaline 6)Eye: - Mydriasis occur due to contraction of radial muscles of iris.(through α – recep )….. phenylephrine eye drop - Conjunctival ischemia {white conjunctival sac} due to constriction of conjunctival blood vessels. .

20. 7) Other smooth muscles : a. Urinary bladder: Detrusor muscle is relaxed ( β ) and trigone sphincter is constricted ( alpha ) and both the actions tend to inhibit micturition. b. Adrenaline inhibits insulin release by its α -receptor action whereas it stimulates glycogenolysis by its β receptor stimulant action.{↑blood glucose}. c. Adrenaline causes lacrimation and salivary glands are stimulated. .

21. 9) Action on CNS: Catecholamines do not produce any marked CNS effects because they do not cross blood brain barrier . However, adrenaline may produce restlessness, apprehension (anxiety ), excitement and tremors on intravenous or intracarotid injection. Pharmacokinetics Catecholamines are absorbed from the intestines, but are rapidly degraded in gut and liver by enzymes MAO and COMT. Thus they are inactive on oral administration. .

22. Adverse Effects of catecholamine: Restlessness, anxiety, tremor, headache. Both adrenaline and noradrenaline cause sudden increase in blood pressure, precipitating sub-arachnoid hemorrhage and occasionally hemiplegia, and ventricular arrhythmias. May produce anginal pain in patients with ischemic heart disease. Contraindications a. In patients with hyperthyroidism. Why? b. Hypertension. c. During anesthesia with halothane and cyclopropane . d. angina pectoris. .

23. Therapeutic Uses 1)Allergic reaction: Adrenaline is drug of choice in the treatment of various acute allergic disorders by acting as a physiological antagonist of histamine . It is used in bronchial asthma , acute angioneurotic edema , acute hypersensitivity reaction to drugs and in the treatment of anaphylactic shock . 2) Cardiac uses: Adrenaline may be used to stimulate the heart in cardiac arrest. Adrenaline can also be used in Stokes-Adam syndrome, which is a cardiac arrest occurring at the transition of partial to complete heart block. .

24. 3)Miscellaneous uses : a. Phenylephrine is used in fundus examination as mydriatic agent. c. Anorectic drugs can help the obese people { Sibutramine }. c. Isoxsuprine (uterine relaxant) has been used in threatened abortion and dysmenorrhoea . . .

25. Effects of adrenaline on organs and tissues in the body ORGAN EFFECT RECEPTOR TYPE Heart Increase heart rate Increased contractility β1 β1 Blood vessels V aso c on s triction Vasodilation α 1 β 2 Lungs Bronchodilation β2 Uterus Relaxation β2

26. ORGAN EFFECT RECEPTOR Metabolism Inhibits pancreatic insulin secretion α2β2 Glycogenolysis in liver and muscle α1β2 Glycolysis in muscle α1β2 Gluconeogenesis α1β2 Glucagon secretion in pancreas α2 ACTH secretion by pituitary β Lipolysis in adipose tissue β2β3 Renin secretion from kidney β1β2

27. Indication of Adrenergic drugs: Heart block. Treatment of asthma e.g. salbutamol. Hypertension, cardiogenic shock. Used for prolongation of local anesthetic action by vasoconstriction e.g. adrenaline. To control local bleeding e.g. adrenaline. As nasal decongestant e.g. oxymethaoline. Inhibition of uterine contraction e.g. nylidrine.

28. INOTROPIC SUPPORT Continuous infusion in ICU- via CVP line, with invasive blood pressure monitoring. Indications : profoundly low blood pressure, shock, low cardiac output states and status asthmaticus.

29. ANAPHYLAXIS Adrenaline is the drug of choice. α1- agonist, reverses -peripheral vasodilation by inflammatory mediator release,↓ oedema. β activity dilates bronchial airways, ↑myocardial contractility, ↓ histamine and LT release and ↓ severity of IgE-mediated allergic reactions .

30. There is no single appropriate concentration. 4 mg Adrenaline diluted to 50 ml in saline or 5% dextrose, infused by means of a syringe driver. Rate of infusion -titrated to effect, to achieve target blood pressure. Administration

31. Indication : Treatment of allergic reactions Brad ycardia Hypotension Convulsion Addition with local anesthesia. Contraindication : Pulmonary edema Metabolic acidosis Hypertension

32. Ischemic heart disease Cardiac arrhythmia Hyperthyroidism. Adverse effect : Agitation Throbbing headache, tremor Weakness, dizziness, pallor Respiratory insufficiency Cerebral hemorrhage

33. Noradrenaline It is an important neurotransmitter both in peripheral and central nervous system. The chemical name of norepinephrine or noradrenaline is 3, 4-Dihydroxy phenyl- α -amino ethanol. It is the precursor of adrenaline.

34. Mechanism of action : Noradrenaline acts by binding with α 1, α 2 and β 1 adrenoceptors. At almost has no activity on β 2 receptors. Stress hormone Fight-or-flight response Increases heart rate ( ↑ systolic, diastolic) Triggers the release of glucose Increases blood flow to skeletal muscle. Suppress neuro-inflammation . Causes potent vasoconstriction ( α) Lacks bronchodilating effect Reflex bradycardia Pharmacological Actions

35. Adverse effect : Loss of appetite. Anxiety Irregular heartbeats Shortness of breath Headache. Contraindication: Hyperthyroidism Pregnancy coronary thrombosis.

36. PHARMACOKINETICS Onset- 1-2 min Duration- 1-2 min Metabolism- by COMT ( Catechol-O-methyltransferase) and MAO Monoamine oxidase) Distribution Sympathetic nervous tissue. Crosses the placenta not blood-brain barrier. Excretion- mainly urine (84-96%)

37. HYPOTENSIVE CRISES First-line therapy for maintenance of B.P and tissue perfusion in septic shock. adjunct to correct hemodynamic imbalances Start:8-12 µg/min IV infusion; titrate to effect Maintenance: 2-4 mcg/min IV infusion Septic shock: 0.01-3 mcg/kg/min IV infusion

38. administered through central venous line to minimize the risk of extravasation and subsequent tissue necrosis control rate and strict monitoring must not be stopped suddenly, gradually withdrawn to avoid disastrous falls in blood pressure Noradrenaline infusion

39. Noradrenaline infusion 4mg = 4mL of 1:1000 Add 4mL of 1:1000 Noradrenaline to 46mL 5% Glucose to make 50mL Starting dose- 0.025microgram/kg/minute the rate in mL/hour

40. INFUSION TABLE

41. ADVERSE EFFECTS Hypertension , bradycardia, arrhythmias, palpitations Ischemic injury -potent vasoconstriction. Anxiety, insomnia, confusion, Headaches, psychosis Weakness, tremor Anorexia, nausea and vomiting.

42. C l on i d i ne Clonidine is a α 2 adrenoceptor agonist, lowers blood pressure by decreasing the levels of certain chemicals in your blood. This allows your blood vessels to relax and your heart to beat more slowly and easily.

43. Mechanism of action : Clonidine treats high blood pressure by stimulating α 2-receptors in the brain, which decreases peripheral vascular resistance, lowering blood pressure. It has specificity towards the presynaptic α 2-receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels, thus inhibiting the release of norepinephrine. The net effect is a decrease in sympathetic tone. It has also been proposed that the antihypertensive effect of clonidine is due to agonism on the I1- receptor (imidazoline receptor), which mediates the sympatho- inhibitory actions of imidazolines to lower blood pressure.

44. Pharmacological action : CNS – supress sympathetic outflow thus decrease blood pressure. Periphery – supress noradrenaline release thus decrease blood pressure. CVS – Decrease HR and CO Blood vessel – reduction of capacitance vessels. Reduce in peripheral resistance, decrease blood pressure. Indication : Hypertension Prophylaxis of migraine Diagnosis of phaechromocytoma.

45. Adverse effect : Sedation Dry mouth Drowsiness Rebound hypertension Headache Fatigue.

46. Moderate dose (5-10 μg/kg/minute), stimulates β1- receptors in heart producing positive inotropic and little chronotropic actions Releases Noradrenaline from nerves by β1-stimulation Does not change PR and HR Great Clinical benefit in CVS shock and CCF High dose (10-20 μg/kg/minute), stimulates vascular adrenergic α1-receptors – vasoconstriction and decreased renal blood flow USES- Hypovolaemic shock Cardiac failure

47. Derivative of Dopamine MOA: Acts on both alpha and beta receptors but more prominently in β1 receptor Does not act on D1 or D2 receptors Racemic mixture of dobutamine used clinically (-) dobutamine- α1 agonist (+) dobutamine- α1 antagonist - 8-10 times β1 agonist So benefit of racemic mixture-Increase in force of contraction and cardiac output with little change in heart rate and peripheral resistance Half life- 2min So IV infusion- 2.5-10 µg/kg/min

48. Uses: Clinically give in dose of 2.5-10 µg/kg/min IV infusion Short term emergency treatment of cardiac failure in pt of MI, after cardiac surgery, in pt of CCF. Limitations- Short half life- so IV infusion is required Tolerance develops within few days- so used for short term Dysrhythmias- less chances Avoided in- HT N , cardiac D ysrhythmias

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