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Adrenergic receptors pharmacology

1. ADRENERGIC RECEPTORS Presented by Canon Dr. Alex Okello

2. ADRENERGIC RECEPTOR AGENTS(SYMPATHOMIMETICS) Introduction: Defn : These are drugs that mimic the action of stimulation of the sympathetic nervous system. The sympathetic stimulation is mediated by adrenaline (epinephrine) and nor-adrenaline (nor-epinephrine). The sympathetic system is involved in; C.V.S Increased heart rate Increased force of attraction Vasoconstriction of peripheral vessels Vasodilation of blood vessels of heart, kidney, brain, skeletal muscles. Therefore, it is responsible for maintenance of blood pressure.

3. Respiratory tract It maintains Bronchial airway patent due to Broncho-dilation. Metabolism It causes glycogenolysis by changing glycogen from skeletal muscles and liver into glucose, thereby increasing blood sugar level. It increases free fatty acid of blood by conversion of lipid and this process is called lipolysis. Endocrine glands It increases the release of insulin found in the islet of Langerhans (pancreas) Cause release of renin hormone from the kidney C.N.S Controls mood changes (restlessness) Controls appetite (anorexia)

4. ADRENERGIC RECEPTORS There are two types i.e. α Alpha β Beta Alpha receptor is very sensitive to nor-adrenaline then adrenaline but less sensitive to isoprenaline. Beta receptor is very sensitive to isoprenaline than nor-adrenaline or adrenaline. Some sympathomimetics affect only Alpha receptors while others affect only Beta receptors. Some drugs that inhibit Beta receptors may not inhibit Alpha receptors.

5. SUBTYPES OF SYMPATHETIC RECEPTORS Alpha 1 and Alpha 2 They are distributed to mesenteric vessels and mucus membrane when stimulated they cause excitation to those blood vessels causing vasoconstriction. Beta 1 This is distributed on the heart muscles When stimulated it causes increase in heart rate contraction and force of contraction. Beta 2 This is distributed to the smooth muscles of blood vessels of skeletal muscles, coronary arteries, cerebral arteries. They’re also distributed to smooth muscles of the Bronchi and that of the uterus. Stimulation of Beta 2 causes: Vasodilation of the above vessels Relaxation of smooth muscle of the bronchi causing Broncho-dilation On the uterus it causes the relaxation of myometrium

6. SYMPATHOMIMETIC AGENTS

7. DIFFERENCES BETWEEN CATECHOLAMINE AND NON-CATECHOLAMINE CATECHOLINE NON - CATECHOLINE - Is inhibited by intestinal enzyme therefore not orally given - Is not affected by enzymes -Do not cross blood brain barriers in substantial amount therefore much of it can’t reach the brain. They have minimal effects on the brain. - Crosses blood brain barriers massively causing a lot of restlessness and insomnia. -Easily oxidized by certain enzyme called mono amino oxidase(MAO) therefore the lifespan is short. - Is metabolized slowly by the liver therefore the life span is long.

8. MODE OF ACTION OF SYMPATHOMIMETIC AGENTS Catecholamine They act directly by binding themselves on the adrenergic receptors. Non-catecholamine Acts via the neurotransmitters for example, when adrenaline and nor-adrenaline is released They then stimulate the release through neurotransmitters which then stimulate the target organs.

9. ACTIONS OF SYMPATHOMIMETIC AGENTS ON THE BODY

10. 4. G.I.T •Intestinal muscles are relaxed with reduced peristalsis, sphincter muscles are contracted closing the sphincter. 5.G.U.T •The uterus is relaxed. This can be of benefit to women with premature labor or threatened abortion for example, Salbutamol is the drug of choice. •Urinary bladder relaxed, sphincters closed. 6.Metabolism •There is increased blood sugar and fatty acid 7.Exocrine (sweat gland) •Causes cold sweat due to anxiety.

11. CLINICAL USES OF SYPATHOMIMETIC

12. Surgical application Reduces bleeding from surgical sites Treatment of nasal bleeding for example, adrenaline N/D and ephedrine N/D Mixed with local anesthetic to prolong effect to avoid toxicity G.U.T Management of premature labor and threatened abortion C.N.S Obesity to cause anorexia Neuroleptic (tendency to be sleepy most of the time) Hyperkinetic syndrome in kids Very active child, moves a lot, very restless, they don’t learn. It disappears at age of 2-10 years but more in children of 2-4 year. The drug of choice is amphetamine.

13. SIDE EFFECTS OF SYMPATHOMIMETIC DRUGS 1)C.V.S Cardiovascular accident (C.V.A) due to excessive rise in the blood pressure Overworking of the heart which may lead to ischemia causing angina pain May cause cardiac infarction leading to heart attack C.C.F 2)C.N.S Characterized by anxiety, restlessness, trauma, blurred vision, at times with convulsion 3)Contraindication - Severe heart disease i.e. hypertension

14. SYMPATHETIC ANTAGONISTS (ADRENERGIC RECEPTOR BLOCKING AGENTS) Defn : Sympathetic antagonists are drugs that block the effect of catecholamine on the adrenergic receptors. Both of the receptors i.e. Alpha and Beta can be blocked The drugs are classified into 3 categories: a. Alpha adrenergic receptor blockers b. Beta adrenergic receptor blockers c. Both Alpha and Beta blockers

15. ALPHA ADRENERGIC RECEPTOR BLOCKERS The drugs block the effect of catecholamine on Alpha receptors only They are grouped into 2: Reversible Irreversible REVERSIBLE For example, Phentolamine which blocks Alpha 1 and Alpha 2 Ergotamine Prazosin Some of the drugs above block Alpha 1 and 2 while others block one of the two. IRREVERSIBLE BLOCKERS They form permanent bonding with Alpha receptors For example, Phenoxybenzamine Dibenamine

16. PHARMACOLOGICAL EFFECTS OF ALPHA ADRENERGIC RECEPTOR BLOCKER C.V.S Vasodilation leading to fall in blood pressure Patient is prone to postural hypotensone Respiratory tract Blood vessels of nasal cavity are dilated leading to nasal stuffiness G.U.T Failure of erection in man due to blockage of Alpha 1

17. CLINICAL USES OF ADRENERGIC ALPHA RECEPTOR BLOCKERS Used in the treatment of pheochromocytoma (tumor). A tumor of adrenal glands characterized of massive release of adrenaline by the adrenal medulla causing extensive vasoconstriction of the heart. The drug of choice is Phentonamine . Treatment of hypertensive crisis Peripheral vascular disease like Raynaud’s disease. Characterized by vasoconstriction of limbs in very cold weather. Treatment of urinary retention caused by _ prostatic hypertrophy because it relaxes the smooth muscles of the prostate gland.

18. MAIN SIDE EFFECTS Postural hypertensone with reflexed tachycardia and ischemic heart pain i.e. angina pain. Failure to ejaculate in men

19. BETA BLOCKER ADRENERGIC RECEPTOR DRUGS These groups of drugs have wider uses than other blockers. They block the effect of catecholamine on the Beta-adrenergic receptors. Some of the blockers are selective i.e. they block Beta 1 or Beta 2 but not both. Others block Beta 1 and 2. They are being classified into 2: Non-selective type means they block Beta 1 and 2 For example, propranolol Selective Beta 1 blockers For example, Acetabutalol , Atenolol Beta 2 For example, Butoxamine

20. PHARMALOGICAL EFFECTS OF BETA ADRENERGIC RECEPTOR BLOCKERS C.V.S Reduced heart rate and force of contraction They inhibit production of renin hormone from kidneys Centrally it reduces the action of vasomotor center (VMC) in M.O leading to inhibition of heart contractility and excitability The V.M.C is to send motor impulses to heart and blood vessels. N.B: All these 3 above lead to hypotension Respiratory tract Blockage of Beta 2 receptors on the bronchi leads to Broncho-spasm Eye Reduces formation of aqueous humor Increases drainage of aqueous humor leading to reduction of I.O.P Metabolism It decreases blood glucose. N.B: Most diabetics are also hypertensive when giving Beta adrenergic blocker for example, Inderol take prescription. C.N.S The drug may enter into the brain causing sedation, hallucination, sleep disturbances The drugs have membrane stabilizing action (MSA) or local anesthetic action (L.A.A) on the muscle fibers of the cardiac muscles. They therefore stop excessive transmission of impulses to the heart. This is necessary for control of arrythmia.

21. CLINICAL USES OF ADRENERGIC BETA BLOCKER Treatment of glaucoma – Timolol E/Drop Treatment of hypertensone Treatment of cardiac arrythmia Treatment of thyrotoxicosis or for management of thyroid storm (much thyroxine in blood) during operation i.e. much thyroxine is released in circulation due to surgical manipulation giving signs of thyrotoxicosis and is best controlled by Beta blockers (drug of choice is I.V propranolol or CPZ) Neurological defects i.e. dementia, tremor, anxiety.

22. SIDE EFFECTS Allergic reaction characterized by skin rash C.N.S effects A patient may get sedated Hallucination Depression Patient may get bronco-spasm due to blockage of Beta 2 on the bronchi C.V.S C.C.F especially elderly due to direct effect on the heart

23. NEUROMUSCULAR JUNCTION BLOCKING AGENTS This is also called myoneural blocking agent or peripheral muscle relaxants INTRODUCTION 1.These drugs are very sensitive in surgery where muscle relaxation is required as in laparotomy, neuro-surgery, thoracotomy etc. 2.Muscle relaxation could even be achieved by use of deep anesthesia except that deep anesthesia has hazard of causing cardio-vascular depression, R/complications, delayed recovery. This then calls for the use of muscle relaxant and minimum anesthetic agent. 3.Muscle relaxant was first used by hunters as most arrow poison in South America. Most famous was curare an extract from the plant. 4.The first scientist to note the effectiveness of curare was Sir Benjamin Brodie in 1811. This was still at experimental level. 5.The drug was first put to medical practice in 1942.

24. STRUCTURE OF NEUROMUSCULAR JUNCTION

25. When acetylcholine is released from the vesicles found at the nerve end as a result of its stimulation by nerve impulses, it combines with its receptors found on the muscular junction. This causes the muscle fibers to be depolarized and the process is called depolarization .

26. 2) In the muscle fibers, are contractile tissues, which always contracting when calcium is released and the contractile tissue contract i.e. acetylcholine plus receptors causing depolarization. Muscle fibers then release calcium, then the calcium ions stimulate the contractile tissue which will literally contract first causing the muscle fibers to contract. The activity is called muscle contracting corpling . If this activity takes place at the exocrine gland they are made to secrete, and this is called secretion corpling . Note: That acetylcholinesterase rapid destroys acetylcholine after depolarization.

27. CLASSIFICATION OF NEUROMUSCULAR BLOCKING DRUG There are two categories: -Depolarizing -Non-depolarizing DEPOLARIZING AGENTS (MUSCLE RELAXANT) 1. As the name suggest, they cause muscle relaxation by combining with nicotinic acetylcholine receptors causing prolonged depolarization, subsequently the muscle fibers become fatigued and relaxed. 2. Depolarization is prolonged because the drug is not hydrolyzed by acetylcholinesterase unlike acetylcholine. 3. The drugs in common use are: - Suxamethonium chloride ( scoline ) - Suxamethomium bromide ( Brevedil ) powder

28. SUXAMETHONIUM CHLORIDE (SCOLINE) 1) Is a quaternary amine ester consisting of two molecules of acetylcholine. 2) When given it mimics the action of acetylcholine at the nicotinic receptor (neuromuscular junction) causing prolonged depolarization with fasciculation (twitching of muscle) of skeletal muscle and subsequent muscle paralysis. 3) It’s not broken down by acetylcholinesterase but by the enzyme called pseudocholinesterase 4) Its action lasts up to 6 minutes but the effect may be prolonged in patients with low pseudocholinesterase as seen in patients with dehydration or any condition which causes plasma loss such as burns. 5) It is presented as a colorless solution in ampules 2cc (50mg/ml) 6) Usually it gets hydrolyzed quickly at room temperature. It’s therefore kept at 40c.

29. SYSTEMIC ACTIONS(EFFECTS) 1. C.N.S  No direct effect on C.N.S  Indirectly causes rise in I.O.P secondary any rising of venous pressure as a result of muscular fasciculation. 2. C.V.S  There is bradycardia secondary to stimulation of vagus .  Arrythmia due to massive rise in serum potassium (some potassium ions don’t go back to the axon) 3. Respiratory tract  There is paralysis of respiratory muscle  There is increase in Bronchial secretion 4. It may release histamine triggering malignant hyperpyrexia or anaphylactic reaction.

30. ADVANTAGES OF THE DRUG  It produces profound, rapid, short lived muscle relaxation  It’s the drug of choice for tracheal intubation where vomiting is anticipated DISADVANTAGES  It has to be stored in the freezer to avoid loss of potency  May cause hyperkalemia triggering arrythmia  Post-operative pain due to fasciculation  Anaphylactic reaction due to release of histamine  There could be prolonged apnea with patients with lower pseudocholinesterase as seen in patients with liver disfunction and those who have lost a lot of serum as in burns and dehydration.  The increase of I.O.P may lead to loss of vitreous humor in penetrating injury.  Triggering of malignant hyperpyrexia

31. CLINICAL USES, DOSES AND ROUTES i . It can be given through I.V, I.M, S.C ii. Doses in adult in 1.5mg/kg Doses in children 1.5-2mg/kg Higher dose in children because of: -Large surface area in children -High metabolism in children than adults iii. On set is 40-60 seconds iv. Duration of action is 4-6 minutes N.B: Relaxation is prolonged by intermittent dose of 25% of the original dose. Note that excessive administration of scoline may lead to dual block and this means the drug will behave both as non-depolarizing muscle and depolarizing muscle relaxant. -This has a tendency to prolong muscle relaxation and may cause delayed recovery

32. CLINICAL USES  Entracheal intubation Intermittent doses can be employed to maintain muscle relaxation in reasonably long operation. Treatment of tetanus after sedation Can be used when employing electroconvulsive therapy (mentally ill patients) For facilitation of endoscopies for example, laryngoscope CONTRAINDICATIONS -Penetrating eye injury -Severe liver disfunction with low serum pseudocholinesterase -In a situation where you don’t have air way maintenance facilities don’t give

33. NON-DEPOLARIZING MUSCLE RELAXANT They are also called long muscle relaxant For example, - D- tuberarine ( tuberine , curare) -Atracurium ( Tracurium ) -Gallamine ( Floxedia ) -Pan curanium MODE OF ACTION OF L.M.R They combine with nicotinic receptors at the neuromuscular junction thereby preventing acetylcholine from getting access to the receptors. To reverse the effect of the drug, you have to give the anticholinesterase like neostigmine so as to allow acetylcholine build up at the neuromuscular junction. Increased concentration of acetylcholine at the neuromuscular junction causes displacement of the drug from the receptor site.

34. ATRACURIUM 1.The drug is a modern generation of non-depolarizing agents. 2.The duration of action is intermediate i.e. 20-25 minutes 3.Its effects may get terminated completely with the use of anticholinesterase. 4.It is presented as a solution of Ph 3.5 as 10mg/ml i.e. @ml in 10mg. 5.The dose in bolus is 0.5mg/kg or in N/S drip of 0.5mg/kg to maintain steady degree in relaxation. 6.The drug is stored 40c to avoid degradation. 7.It has no effect on the cardiovasculation system therefore it is the drug of choice in patients with heart disease. 8.It causes mild histamine release therefore can cause Broncho-spasms (not recommended in asthma) 9.Metabolism is optimum at body temperature i.e. 370c but lowered in hypothermia. 10.It is indicated for balanced anesthesia where muscle relaxation is required and tetanus.

35. PANCURONUIM(PAVULON) 1.It’s a synthetic non-depolarizing muscle relaxant. 2.It is supplied in 2ml ampule; each ml is 2mg/ml i.e. 1 ampule is 4mg. 3.It’s stored in the freezer to avoid degradation. 4.The dose is 0.1mg/kg, the onset is affected in 2 minutes and efficiency lasts for 30 minutes to 40 minutes. 5.It causes rise in blood pressure because it blocks the nor-adrenaline uptake, therefore use it with care in ischemia heart disease. 6.It doesn’t release histamine, therefore it’s good for asthmatic. 7.Eliminated unchanged in urine therefore it is not recommended in patients of renal disfunction. 8.The drug is indicated in balanced anesthesia and tetanus. 9.Its contraindicated in severe heart disease and renal failure.