Lec 4 Pharmacology (Autonomic Nervous) PDF

Lecture Two Sympathetic division of Autonomic Nervous System By Prof Dr Samar M Mouneir  SYMPATHOMIMETICS These are drugs, which produce effects similar to postganglionic sympathetic nerves stimulation. Classification: A. According to chemical struct...

Lecture Two Sympathetic division of Autonomic Nervous System By Prof Dr Samar M Mouneir  SYMPATHOMIMETICS These are drugs, which produce effects similar to postganglionic sympathetic nerves stimulation. Classification: A. According to chemical structure: Catecholamines Adrenaline Noradrenaline Isoprenaline Dopamine Dobutamine Non-catecholamines: Ephedrine Phenylephrine Amphetamine Tyramine B. According to mechanism of action 1. Direct acting drugs: These act directly on the adrenergic receptors e.g. epinephrine, norepinephrine, isoprenaline and to a large extent dopamine and phenylephrine. 2. Indirectly acting drugs: Produce this effect by causing the release of norepinephrine from nerve endings such as amphetamine, methamphetamine and tyramine. 3. Mixed acting drugs (dual mechanism) These drugs act partly directly and partly by causing the release of norepinephrine from nerve endings as ephedrine, metaraminol. Neurotransmission at adrenergic neurons I.CATECHOLAMINES  I.CATECHOLAMINES Neurotransmission at adrenergic neurons. Adrenergic receptors Adrenergic receptors They are classified according to their type and location into: 1.  receptors which are classified into: 1- postsynaptic receptors 2- Presynaptic receptors 2. -adrenergic receptors which are classified into: – 1 Receptors in the heart. – 2 Receptors: mainly found in the blood vessels of the skeletal muscles, the bronchi and the uterus. – 3 Receptors: present in adipose tissue.   - receptors  1 - postsynaptic receptors: present in the smooth muscles of skin, viscera, pulmonary and radial muscles of the eye, smooth muscles of GIT. They are G - protein coupled receptors, linked to phopholipase C/ IP3 and DAG. 2- Presynaptic receptors: present at the nerve NA terminal for the regulation release, their stimulation inhibits the release of noradrenaline (autoreceptors) & activation of the inhibitory G- protein (G i ) inhibits the enzyme adenyl cyclase responsible for the conversion of ATP to cAMP. Decreased levels of cAMP will inhibit the release of the transmitter.  -adrenergic receptors These are G-protein coupled receptors and Gs is linked to the adenylate /cAMP system. 1- Receptors in the heart (blocked by Atenolol ) Binding of an agonist to the  1 receptors activates the enzyme adenylate cyclase leading to an increase cAMP level. This leads to activation of cAMP dependent protein kinase leading to phosphorylation of calcium channel in the heart muscle. 2- Receptors: mainly found in the blood vessels of the skeletal muscles, the bronchi and the uterus. They are blocked by Butoxamine. 3 - Receptors: present in adipose tissue and responsible for lipolysis. Propranolol is a nonselective  blocker. In the liver, muscle cells (  2 ) and fat cells (  3 ). Increased cAMP production activates various enzymes involved in glycogen and fat metabolism giving glucose.  Adrenaline (Epinephrine) It is the major constituent of the adrenal medulla secretion (80%). Absorption and Fate It is ineffective orally as all catecholamines because of its: – Poor absorption from the GIT – Rapid destruction by digestives juices – Rapid metabolism by the liver It is absorbed slowly from S.C. tissues due to local vasoconstriction (1 -effect) It is more rapidly absorbed from IM sites (2 mediated vasodilatation. Inhaled solutions have a restricted action to the respiratory tract. Intracardiac: emergency Infusion: adrenaline and noradrenaline  Pharmacological actions of adrenaline ( epinephrine): I. Local action: A-On mucous membranes, it produces vasoconstriction. Thus, it is added to local anesthetics to prolong their duration of action. A delay in the absorption of associated drugs when injected subcutaneously(local vasoconstriction –alpha1 effect) B-The local application of adrenaline to the eye has only a limited effect on the size of the pupil because: It is partly destroyed by the alkalinity of tears It causes vasoconstriction of the conjunctival blood vessels and thus hinders its own absorption. II. Systemic actions: Adrenaline stimulates both  and  - receptors (adrenergic) and accordingly produces the following effects 1. Cardiovascular system: (Heart ) 1 receptors Increase heart rate(positive chronotropic action) tachycardia Increase force of contraction (positive inotropic action). Increase cardiac output. Increase heart work and O2 consumption Blood vessels  1 Stimulation leading to vasoconstriction of the blood vessels of the skin, mucous membrane and kidney – 2 stimulation leading to vasodilatation of the skeletal muscle and coronary blood vessels. Blood pressure (B.P) Adrenaline elevates blood pressure by stimulation of  receptors that leads to vasoconstriction The systolic B.P. increases due to increased cardiac output (1) The diastolic pressure decreases due to decreased total peripheral resistance (2). 2. Effect on Eye: The sympathetic supply to the eye is α1 receptors of the radial muscles Adrenaline produces contraction of the muscles leading to active mydriasis 3. Effect on bronchi (powerful bronchodilator) It stimulates  2 - receptors in the bronchioles leading to bronchodilatation. Adrenaline acts on 1 - receptors of blood vessels producing vasoconstriction of blood vessels, decreasing bronchial mucosa congestion. Life saving in anaphylactic shock  M3 receptors on circular muscles Alpha one receptors on radial muscles Constriction of radial muscles by sympathetic stimulation resulted in mydriasis or widening of eye pupil. Adrenaline causes active mydriasis but atropine causes passive mydriasis Constriction of circular or sphincter muscle resulted in Miosis or narrowing of eye pupil. Pilocarpine and eserine causes miosis 4. Gastrointestinal tract: The GIT contains both  and receptors; stimulation of either types of receptors leads to inhibition of tone and motility. 5. Urinary bladder Adrenaline relaxes the detrusor muscle (2- receptors), and contracts the sphincter (1 receptors), causing urine retention. 6. Uterus: It relaxes the pregnant human uterus (2). 7. METABOLIC ACTIONS: Adrenaline increases blood glucose level by two mechanism: – Enhancement of hepatic glycogenolysis (2 – receptors) - Increases the blood concentration free fatty acids (lipolysis 3). There is 20-30% increase in oxygen consumption due to increased metabolism. 8. Action on the CNS: Adrenaline has a weak stimulant action on the CNS. It may cause restlessness, headache and tremors. 9.Skeletal muscle action: Adrenaline facilitates neuromuscular transmission by sensitization of the motor endplate and hastens recovery from fatigue by increasing blood flow to the muscles. 10.Antihistamine and antiallergic action: Adrenaline is the physiological antagonist of histamine Therapeutic Uses: Acute bronchial asthma: It is the drug of choice in treatment of acute asthma and anaphylactic shock Allergy, urticaria and anaphylactic shock. Adrenaline, given with local anesthetics, S.C. to produce vasoconstriction, to prolong the duration of action and decreases bleeding from the operation sites. (1:100000 parts of epinephrine. Cardiac arrest by injecting adrenaline interacardiac. Insulin hypoglycemia. Local hemostatic stop hemorrhage from the nasal mucosa. Contraindications: Coronary heart diseases (may induce anginal attacks) Hypertension may lead to cerebral haemorrhage. In patients receiving digitalis  Noradrenaline (Norepinephrine) or (Levarterenol)’ It is the chemical transmitter released by postganglionic adrenergic nerves. 20% of the secretion of the adrenal medulla. Ineffective orally Given I.V. Strong vasoconstrictor effect. It is not given SC or IM because of its strong vasoconstrictor effect, producing necrosis Pharmacological action NA stimulates - receptors, but it also stimulates 1&B2 adrenergic receptors to a lesser degree and no effect on B3 1. Cardiovascular system A. Heart: a. Force of contraction: positive inotropic effect b. Cardiac output: Slight changes. B. Blood vessels: Skin and mucous membranes (constricte) Total peripheral resistance (increased) C. Blood pressure: Both systolic and diastolic rises. 2. Smooth muscles: Relaxation Therapeutic uses: 1. Used to treat shock, because it increase PVR and blood pressure. 2. It is used as a hypertensive agent in hypotensive states e.g., during spinal anesthesia.  Isoprenaline( non selective B agonist) It mainly stimulates the -adrenergic receptors, with almost no action on the alpha-receptors. Cardiovascular system A. Heart: a. Heart rate: tachycardia b. Force of contraction: increased c. Cardiac output; increased B. Blood vessels: dilation of the skeletal muscle blood vessels resulting in decreased peripheral resistance and diastolic blood pressure.  Smooth muscles: Bronchi (relaxed) Metabolic effects: Similar to adrenaline. Therapeutic uses: – Acute bronchial asthma as it causes relaxation of bronchi – Heart block or bradycardia as it induces tachycardia – Bronchitis and emphysema as it causes relaxation of bronchi Side effects of isoprenaline in bronchial asthma Palpitation Tachycardia Arrhythmia Anginal pain N.B Selective 2 -agonists such as, Salbutamol, Terbutaline and Rimiterol are superior to isoprenaline in the management of bronchial asthma, as they possess fewer side effects.  Dopamine Dopamine, a naturally occurring catecholamine, it has a transmitter role in the CNS (precursor of NE) Dopamine is a substrate for both MAO & COMT Pharmacological actions of dopamine Acting as an agonist at both  and 1 adrenergic receptors Releasing noradrenaline from storage vesicles in adrenergic nerve terminals Therapeutic uses: It is used in treatment of cardiogenic shock due to various causes e.g., myocadial infarction *In shock dopamine is the drug of choice and is given by continuous infusion. * It increases Bp by stimulating B1 receptors in the heart * It enhances perfusion to the kidney and increase blood flow ( D1 effect) * The increased blood flow to the kidney enhances the glomerular filtration rate and causes sodium diuresis * Dopamine is superior than NA which diminishes blood supply to the kidney and decreases the filtration rate  NON-CATECHOLAMINES They have better oral activity (they resist enzyme action), distribution to the CNS or relative selectivity compared to catecholamines 1. Selective 1 agonists a.(Phenylephrine, methoxamine) Powerful direct stimulants of 1 – receptors Produce vasoconstriction leading to increase in peripheral arterial resistance Produce rise in blood pressure with reflex bradycardia Metabolized by MAO but not by COMT since it is non catechol derivative Methoxamine has longer duration of action Uses: 1. Nasal and ocular decongestant to treat rhinitis and conjunctivitis 2. Maintenance of blood pressure during surgery and to treat hypotension caused by excessive doses of vasodilators or drug induced shock 2. Mixed acting adrenergic receptor agonists Drugs which stimulate α and β receptors directly and indirectly by releasing NA from the stores a. Ephedrine & pseudoephedrine It is an alkaloid. Ephedrine is absorbed from G.I.T. and parenteral sites. The drug is not destroyed by MAO; It has a longer duration of action than catecholamines (more stable). Pharmacological action: A. Local actions: Haemostatic, decongestant B. Systemic actions: i. Cardiovascular system: It produces vasoconstriction of blood vessels. Both systolic and diastolic blood pressures are increased. Its pressor effect is slower but more prolonged than that of adrenaline. However repeated administration produces tachyphylaxis. ii. Smooth muscles: Urinary bladder: Relaxation of detrusor muscle and contraction of the sphincter. Bronchi: Bronchodilatation, and decongestion of the bronchial mucosa, slower in onset, longer duration Eye: Mydriasis (active, through stimulation of the dilator pupillae muscle). Accomodation, intraocular pressure and light reflex are not affected by ephedrine iii-CNS actions: Ephedrine has a central stimulant action, producing mental alertness, anxiety and insomnia. iv-Actions on skeletal muscles: Ephedrine facilitates neuromuscular transmission and lowers the tendency to fatigue. Therapeutic Uses: Chronic bronchial asthma (prophylactic) Nasal decongestant Mydriatic To prevent fall in blood pressure during spinal anesthesia. Nocturnal enuresis Narcolepsy 3. Indirect acting adrenergic receptor agonists A- Amphetamine Mechanism of action Indirect stimulation of release of NA from sympathetic nerves Pharmacological actions: Cardiovascular system: Increase in both systolic and diastolic pressures with reflex bradycardia. Repeated administration usually results in tachyphylaxis. Smooth muscle: Eye: Mydriasis upon local application Urinary bladder: Relaxation of the detrusor muscle and contraction of the sphincter. Gastrointestinal tract: relaxation in spastic states Bronchi: insignificant action  Action on central nervous system It stimulates cerebral cortex, reticular activating system, vital medullary centers and spinal cord. Dextro- amphetamine is 3 - 4 times more potent than the L-isomer. It produces: Psychic stimulation: l e a d i n g t o w a k e f u l n e s s , alertness, elevation of mood, euphoria, increased motor and speech activity with improved physical performance. Analeptic action: Stimulation of the medullary centers for respiration Antifatigue action: it renders the subject more tolerant towards fatigue Anorexigenic action: depress appetite and reduce food intake through inhibition of the feeding center in the hypothalamus & reduction of acuity of smell & taste.  Therapeutic uses: Amphetmine is mainly used for its central effects in the treatment of: Obesity Parkinsonism (to elevate the mood). Mental and physical fatigue. Nocturnal enuresis (lighten sleep). Amphetamine is no longer recommended for these uses because of its potential for abuse. Large doses leads to fatigue, mental depression, headache, dizziness, palpitation, agitation, confusion, dysphoria and apprehension. It is not recommended because of it is potential for abuse  Receptor selective sympathomimetics 1. Specific alpha1 adrenergic agonists Phenylephrine………used as nasel decongestat 2. Specific alpha2 adrenergic agonists Clonidine, - methyldopa, guanabenz……..used for treatment of hypertension as these drugs produce central stimulation of the presynaptic 2 receptors leading to inhibition of the release of noradrenaline and produce hypotension. 3.Specific B 1 agonist as dobutamine 4. specific B2 agonist as salbutamol and Salmeterol Used for treatment of bronchial asthma  ADRENERGIC RECEPTOR ANTAGONIST, SYMPATHOLYTICS, SYMPATHETIC DEPRESSANTS The effects of sympathetic nerve stimulation can be inhibited or blocked by: 1-  - blockers 2-  - blockers 3- Adrenergic neuron blockers  Alpha adrenergic blockers Dibenamine or dibenzyline Ergot alkaloids Imidazoline derivatives  - Adrenergic Blockers Propranolol Pronethalol DCI (Dichloroisopretrenol)  Side effects of β-blockers Bronchoconstriction: severe attacks in asthmatic patients Severe bradycardia Aggreviation of heart failure Cold extremities and muscle fatigue due to blocking β2 receptors in BV *** Abrupt or sudden withdrawal of propranolol may lead to severe or rebound hypertension so therapy with B- blockers should be stopped gradually. Contraindications: Bronchial asthma, or COPD Congestive heart failure. Hypotension.  III. Adrenergic neuron blockers These drugs prevent the response to sympathetic nerve stimulation by inhibiting the release, storage or synthesis of NA. 1. Drugs which prevent the release of NA Guanethidine (Ismelin)& Bretylium 2. Drugs that impair storage of NA Reserpine 3. Drugs which interfere with the synthesis of NA Methyldopa 1. Drugs which prevent the release of NA Guanethidine & Bretylium Mechanism of action Guanethidine blocks the release of stored NA s o transient gradual lowering of BP in hypertensive patients and ↓ in cardiac rate (bradycardia). Guanethidine displaces NE from storage vesicles because it is taken up by the same mechanism involved in NA  Therapeutic Uses: Guanethidine is rarely used now. It is restricted to treatment of severe hypertension. (Except due to pheochromocytoma which may lead to hypertensive crisis), The action is delayed. The onset of action is 2-3 days after oral administration of the effective dose. The action persists for 7 days after discontinuation of the drug. Side effects: Postural hypotension. Failure of ejaculation(Discharge of semen) Diarrhea. Nasal congestion. 2. Drugs that impair storage of NA Reserpine It blocks the transport of NE, dopamine and serotonin from cytoplasm into storage vesicles in the adrenergic nerves. It inhibits the vesicular uptake (uptake III), prevents the uptake of NA from cytoplasm to vesicles, so NA is subjected to oxidation by MAO. Pharmacological actions: CNS effect: Sedation and tranquillization by depleting catecholamines and 5-HTstores in the brain. CVS: Hypotension and bradycardia.  Therapeutic uses: 1. Treatment of hypertension that fails to respond to other treatment (except due to pheochromocytoma) 2. Tranquilizer in Psychotic states Side effects: 1. Peripherally: postural hypotension 2: CNS: Sedation, nightmares, suicidal attempts, parkinsonism like disorder and severe mental depression 3. Drugs which interfere with the synthesis of NA Methyldopa 1.It is a dopa decarboxylase competitive inhibitor. It inhibits the biosynthesis of NA. 2.Methyldopa prevents the conversion of dopa to dopamine and hence inhibits the biosynthesis of noradrenaline. It is metabolized to -methylnoradrenaline centrally which can be stored in the sympathetic nerve endings, displacing NA and acting as a false transmitter. 3. -methylnoradrenaline stimulates presynaptic  2 - receptors in the brain leading to inhibition of NA release from adrenergic neurons & reduction in sympathetic tone → ↓ BP. 4.It does not decrease cardiac output or blood flow to vital organs specially the kidney.  Therapeutic Uses: Treatment of hypertension a. The drug of choice in treatment of hypertension during pregnancy b. Treatment of hypertensive patients with renal insufficiency. Side effects: Postural hypotension and central sedative action Contraindications: Phaeochromocytoma and active liver diseases  DRUGS ACTING ON AUTONOMIC GANGLIA The receptors in autonomic ganglia whether sympathetic or parasympathetic are chiefly nicotinic in nature (NN) and ganglionic transmission is mediated by acetylcholine released from the preganglionic fibers. Drugs acting on autonomic ganglia will affect both parasympathetic and sympathetic systems. They can be classified into: Ganglion stimulants. Ganglion blockers.  GANGLION STIMULANTS 1. These drugs stimulate nicotinic receptors in the autonomic ganglia both sympathetic and parasympathetic results in the release of Ach and NA. The effect of these drugs in the body depends on the predominant autonomic tone of the organ. 2. Ganglion stimulants act by depolarization, therefore excessive amounts of these drugs will lead to sustained depolarization and a transmission failure (ganglion block) Drugs – Nicotine and lobeline. – TMA (tetramethylammonium) – DMPP (dimethylphenyl piperazinium) 1. Nicotine It is an alkaloid of tobacco leaves, it has no therapeutic uses, only as insecticide It is absorbed from oral, respiratory tract and from the intact skin. Pharmacological actions: It stimulates the ganglia in small doses, but with large doses the initial stimulatory effect is followed by blockade. CVS: Similar to sympathetic stimulation (it releases adrenaline and noradrenaline from adrenal medulla) Vasoconstriction except the coronary and skeletal muscle blood vessels. Trachycardia Increased BP, force of contraction and cardiac output.  GIT: The effects are similar to parasympathetic stimulation. Increase tone and motility of the intestine. Increased gastric secretion. CNS: Stimulation of the CTZ (chemotrigger zone ) producing vomiting. Small doses stimulate the respiratory centers reflexly. Stimulation of the release of ADH. Tremors and convulsions followed by depression. Repeated administration produce tolerance