5.Sympathomimetic (Adrenergic Drugs) Drugs 1.pdf

Sympathomimetic (Adrenergic) Drugs 1 Dr Suprava Das, Associate Professor of Pharmacology Learning Outcomes At the end of the lecture the students should be able to: 1. Name the location of different adrenergic receptors. *** 2. List the responses mediated through different adrenergic receptors. **...

Sympathomimetic (Adrenergic) Drugs 1 Dr Suprava Das, Associate Professor of Pharmacology Learning Outcomes At the end of the lecture the students should be able to: 1. Name the location of different adrenergic receptors. *** 2. List the responses mediated through different adrenergic receptors. *** 3. Illustrate adrenergic neurotransmission with examples of drugs acting at different sites. *** 4. Explain the pharmacological actions of adrenaline on: CVS, smooth muscles, metabolism, eye. *** 5. Apply the pharmacological actions of adrenaline to provide the rationale for its uses.*** 6. Explain the important adverse effects and contraindications of adrenaline. *** 2  Introduction  Sympathetic nervous system or adrenergic system is an important regulator of the activities of organs such as the heart & peripheral vasculature especially in response to stress (Fight -Fright-Flight)  Sympathomimetic agents–mimic the response to sympathetic stimulation.  Sympathetic neurotransmitters:  Norepinephrine (Noradrenaline )  Epinephrine (Adrenaline) 3 Sympathetic activity increases in stress - fight or flight response in emergency. many stressful situations such as trauma, fear, hypoglycemia, cold, exercise etc. adaptation to postural changes, exercise or variations in temperature.  Adrenergic Transmission Sympathetic neurotransmitter Synthesis Phenylalanine Hydroxylase In Liver Tyrosine Hydroxylase In Neuroplasm DOPA Decarboxylase Neuron Dopamine Dopamine Inside Granules Beta hydroxylase Noradrenaline N-methyl In Adrenal medulla transferase Adrenaline Uptake 1 Synthesis & Release of NA & Drugs Affecting Noradrenergic Transmission 6  Norepinephrine Synthesis and Storage In the sympathetic nerve endings, norepinephrine is formed from dopamine in the synaptic vesicles where it is stored till release following an impulse. In the adrenal medulla, part of NE is methylated into epinephrine & is stored. About 80% of released NE is taken back into the adrenergic neuron, then into synaptic vesicles, known as reuptake of NE & is essential for (1) to remove and terminate the action of NE (2) to replenishes the stores. Norepinephrine Release In sympathetic neurons, arrival of an action potential leads to influx of calcium resulting in fusion of the synaptic vesicles with the cell membrane & release of NE into the synaptic cleft. Adrenal medulla releases about 80% of Epinephrine & 20% of NE directly into circulation.  Receptor binding of Norepinephrine Adrenergic receptors are G protein-coupled receptors. NE released into the cleft binds either to the –presynaptic receptors on the nerve ending – which by a negative feedback mechanism decrease the release of NE. –postsynaptic receptors on the effector organ which results in formation of intracellular second messengers - –c-AMP and –the phosphatidylinositol (IP3) leading to action. Termination of action of NE Action of NE is terminated by 1. Some NE diffuses out of the synapse & is metabolized in plasma or liver. 2. Neuronal Uptake (NET/Uptake 1): about 80% of the released NE is taken up into the neuron, major mechanism of termination of action. a) Partly stored in intracellular vesicles for further release b) partly metabolized in neuron by MAO. 3. Extraneuronal uptake (Uptake 2): Metabolized in the synapse by COMT in the postsynaptic cell membrane.  Metabolism Epinephrine, Norepinephrine COMT COMT ↓ MAO Metanephrine Dihydroxymandelic acid Metanephrine ↓ COMT MAO MAO Vanillylmandelic acid The end product is Vanillylmandelic acid (VMA) which is increased in pheochromocytoma, an adrenomedullary tumour.  Metabolism of Dopamine Dopamine MAO COMT Dihydroxyphenylacetic acid 3-Methoxytyramine COMT MAO Homovanillic acid The end product is Homovanilic acid Adrenergic receptors (Adrenoceptors) Adrenergic receptors are G protein-coupled receptors.  Based on selective antagonists they are classified into alpha and beta receptors. Receptors Receptor Subclassification antagonists  Receptors Phenoxybenzamine 1, 2  Receptors Propranolol 1, 2, 3 Dopamine -- DA1, DA2 receptors  Receptor location and function Receptor Subtype Location Function Smooth muscles (genitourinary Contraction muscles, prostate) Blood vessels / Vascular smooth Vasoconstriction muscles α α1 Radial muscle of iris / Pupillary dilator Mydriasis (pupillary muscle dilatation) Gut Relaxation Pilomotor smooth muscle Erects hair  Location and function Receptor Subtype Location Function ↓ sympathetic outflow (decrease NA Brain release from sympathetic nerve endings) Platelets Aggregation α α2 Beta cells of pancreas ↓ insulin secretion Ciliary epithelium ↓ aqueous secretion by the ciliary body Blood vessels Vasoconstriction  Location and function Receptor Subtype Location Function ↑ heart rate and Heart force of contraction β β1 Juxtaglomerular cells in ↑ renin secretion kidney  Location and function Receptor Subtype Location Function Smooth muscles (bronchi, bladder wall, blood vessels, pregnant Relaxation uterus) Liver Activation of glycogenolysis β β2 Increases the secretions of Eye ciliary epithelium Skeletal muscle blood vessels Relaxation Skeletal muscle Promotes potassium uptake  Location and function Receptor Subtype Location Function Stimulates lipolysis Adipocytes β β3 Thermogenesis Bladder Relaxes detrusor muscle  Terminology in Cardiovascular actions Vasoconstriction Increase in Peripheral resistance (PR)  Increase in BP Vasodilatation Decrease in Peripheral resistance (PR)  Decrease in BP +ve inotropic Increase Force Of Contraction (FOC)  Increase in COP +ve chronotropic Increase in Heart Rate (HR)  Increase in COP COP Cardiac output  Classification of Adrenergic Drugs Directly acting  Noradrenaline (norepinephrine)*  Clonidine  Adrenaline (epinephrine)*  Phenylephrine  Dopamine*  Methyldopa  Isoprenaline (isoproterenol)*  Xylometazoline  Dobutamine*  Salbutamol  Oxymetazoline  Terbutaline  Ritodrine  Salmeterol  Formoterol * Catecholamines (contain dihydroxy benzene group)  Classification of Adrenergic Drugs Indirectly acting  Amphetamine  Tyramine  Cocaine Mixed action adrenergic agonists  Ephedrine  Pseudoephedrine Manipal University College Malaysia (MUCM) 21 Sympathomimetic amines – Classification based on Structure Catechol nucleus Catecholamines Non-catecholamines Epinephrine Ephedrine Norepinephrine Pseudoephedrine Dopamine Amphetamine Dobutamine Phenylephrine Isoprenaline Non-catecholamines are resistant to metabolism by MAO, COMT Hence, they are Longer acting Effective orally. Receptor Selectivity of Sympathomimetic agents Sympathomimetic agonist 1 2 1 2 DA Adrenaline (epinephrine) + + + + Noradrenaline + + + Amphetamine + + + Ephedrine, Pseudoephedrine + + + + Phenylephrine, Oxymetazoline + Clonidine + Dopamine (DA) (DA receptors are + + ++ more sensitive to Dopamine) Dobutamine +  Pharmacological actions of Adrenaline  Naturally occurring catecholamine in the body  Acts both on α and β receptors At low dose, the β effects (vasodilatation) at the vascular system predominates  At high dose α effects (vasoconstriction) are strongest  α1 = α2, β1 = β2 and weak β3 action Manipal University College Malaysia (MUCM) 22  Pharmacological actions of Adrenaline  Cardiovascular actions:  ↑ FOC (positive inotropic effect) → ↑ CO → ↑ cardiac work & oxygen consumption ( Beta 1 action)  Positive chronotropic action (↑ heart rate)  ↑ in conduction velocity (positive dromotropic effect) ↑ in automaticity  Large doses can cause premature ventricular contractions → ventricular arrhythmias  Activation of β1 receptors in the kidney → ↑renin release → angiotensin II, a potent vasoconstrictor  Renal blood flow is decreased  Constricts arterioles in the skin, mucous membranes and viscera (α effects) and dilates vessels in liver and skeletal muscles (β2) effects  Pharmacological actions of Adrenaline  Cardiovascular actions:  Actions on BP: ↑ SBP (due to β1 action) with slight ↓ in DBP (due to β2 action) – slow IV / SC – ↑ mean BP, PP  Biphasic response: A rise followed by slight fall before returning to normal level  Alpha receptors are more in number, but beta receptors are more sensitive, and action is persistent  Initial rise in BP is alpha action and fall due to beta action  Dale’s Vasomotor reversal phenomenon: addition of α blocker will lead to persistent fall in BP 24  Pharmacological actions of Adrenaline  At lower concentration of adrenaline β2 – receptors are more sensitive  At higher concentration adrenaline acts on all receptors  Now to observe effects on blood pressure of adrenaline we have to give adrenaline intravenous rapidly. (In dog)  When we give adrenaline intravenously, initially the concentration of adrenaline is high. It will act on α1, β2. But actions of α1 (vasoconstriction), will predominate over actions of β2 (vasodilatation). So, there will be rise in blood pressure  Within few seconds level of adrenaline will decrease due to its rapid metabolism and neuronal re- uptake. At lower concentration, only action of β2 will predominate. So only fall in Blood pressure seen  So, at this level you can observe initially rise in blood pressure and then after fall in blood pressure. This is called biphasic response (It is not vasomotor reversal of dale) 25  Pharmacological actions of Adrenaline So, what is vasomotor reversal of dale? After biphasic response if we administer non-selective alpha blocker,  It blocks the alpha receptors, hence α1 mediated vasoconstriction.  Now, if you give Adrenaline again what will happen?  Only β2 mediated action occurs (why?- because α1 receptors are blocked by alpha blocker)  So only fall in blood presser is seen, rather than biphasic response. This phenomenon is called Vasomotor reversal of Dale Manipal University College Malaysia (MUCM) 26  Dale’s Vasomotor Reversal Manipal University College Malaysia (MUCM) 27  Pharmacological actions of Adrenaline  Smooth muscles:  Bronchi: bronchodilatation and inhibition of mast cell secretion (β2)  Relieves mucosal congestion (α1),  Gut: relaxation (α2 & β2) in isolated preparations of gut and constriction of sphincters (α1) → ↓ tone, frequency and amplitude of spontaneous contractions  Urinary tract: detrusor muscle relaxation (β2) and contraction of trigone and sphincter (α1 ) – ↓ micturition and retention of urine  Uterus: Pregnant last trimester and at parturition → inhibition of uterine tone and contractions – β2 action Manipal University College Malaysia (MUCM) 28  Pharmacological actions of Adrenaline  Metabolic actions:  Epinephrine can cause hyperglycaemia due to ↑ glycogenolysis in liver and skeletal muscle (β2) and decreased insulin release from pancreas (α2)  ↑ in free fatty acids due to lipolysis in adipose tissue (β3)  Calorigenic effects – ↑ in basal metabolic rate (β3) due to stimulation of hormone sensitive lipase, triglyceride lipase→ hydrolyzes triacylglycerol to free fatty acids and glycerol  Eye  Contraction of radial muscle of iris (α1) – dilatation of pupil – active mydriasis  ↓ secretions from ciliary epithelium (α2)  ↓ IOT (α1) → ↑ outflow of aqueous humor – open angle glaucoma  Dipivefrine and apraclonidine are used in glaucoma 29  Therapeutic uses of Adrenaline  Anaphylactic shock: It is the drug of choice in anaphylaxis due to allergens. 0.3 to 0.5 ml of 1:1000 solution of adrenaline should be administered IM in anaphylactic shock.  Bronchial asthma: Adrenaline can be used in acute bronchial asthma, however selective beta2 stimulants like salbutamol (albuterol) is presently favoured because of its long duration of action and less cardiac stimulant action.  Cardiac arrest: intracardiac adrenaline may be injected to restore the cardiac rhythm in patients with cardiac arrest due to any cause.  Duration of local anaesthetic action: It can increase the duration of action of local anaesthetics by producing vasoconstriction at the site of injection of local anaesthetics.  Epistaxis (bleeding from nose): A very weak solution of epinephrine (1:100,000) can be used topically to vasoconstrict mucous membranes to control oozing of capillary blood i.e., in epistaxis. 30  Adrenaline ADME: Oral – Poor bioavailability due to first pass metabolism (MAO & COMT in intestine & liver). Does not cross BBB. Routes: SC IM - preferred route Topical use - to control bleeding from mucous membranes - epistaxis Intracardiac – in emergencies like sudden cardiac arrest in drowning, electrocution etc. Inhalational route IV - very rarely used only by specialists as may cause ventricular arrhythmias and death.  Adverse effects of Adrenaline Extension of pharmacological actions: tachycardia, palpitation, headache, restlessness, tremors and rise in BP  Cerebral haemorrhage (large IV doses) as a result of marked elevation in BP  Can precipitate cardiac arrhythmias, angina, MI  CNS effects: Restlessness, palpitation, tremor, anxiety, headache (S.C / I.M)  Pulmonary oedema: Epinephrine can induce pulmonary oedema in high dose due to shift of blood from systemic to pulmonary circulation. 31  Contraindications to the use of Adrenaline  Hyperthyroidism: There is↑ production of adrenergic receptors (up regulation) on the vasculature of hyperthyroid patients → hypertensive crisis  Diabetes: It increases the release of endogenous stores of glucose. The dosage of insulin needs to be increased.  Angina, Hypertension, Cardiac arrhythmias, Congestive cardiac failure  Patients receiving beta blockers: This prevents epinephrine’s effects on β receptors leaving α stimulation unopposed →↑ in peripheral resistance and ↑ in BP.  Drug interaction with cocaine: in presence of cocaine epinephrine produces exaggerated cardiovascular actions because cocaine prevents reuptake of catecholamines into the adrenergic neuron. 32  Adrenaline Precautions: Always check concentrations of adrenaline before injecting. Note: Low concentrations are used for stopping bleeding in epistaxis and to prolong the action of local anaesthetics. High concentrations are used in bronchial asthma & anaphylaxis 0.3 - 0.5 ml of 1 in 1000 solution of adrenaline for anaphylaxis intramuscular. 1 mg. of adrenaline as 1 in 10,000 solution is used IV for sudden cardiac arrest. 1 in 100,000 (lakh) solution is useful to produce vasoconstriction to prolong the duration of action of local anaesthetics. 1 in lakh solution is useful in case of topical oozing in epistaxis.