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Transcript
PHL. 313 Dr. Khairy M A Zoheir 1 Introduction to NS Pharmacology & Dose – Response Curve 2 Central Nervous System Brain stem Afferent Efferent Cerebrum Sensory division Autonomic Spinal cord 3 Peripheral Nervous System Somatic Afferent It is known as sensory or • receptor neurons which carry nerve impulses from receptors or sense organs toward the central nervous system. 4 Efferent It is known as motor or effector • neurons which carry nerve impulses away from the central nervous system to effectors such as muscles or glands 5 The Peripheral Nervous System Efferent nervous system Somatic nervous system Autonomic nervous system (voluntary) (involuntary) Skeletal muscle Heart, blood vessels, glands, other visceral organs, smooth muscle 6 Anatomic classification 1- sympathetic (fight or flight) To maintain homeostasis 7 2- Parasympathetic (rest and digest) Its actions can be summarized • as "rest and digest", as opposed to the "fight-or-flight" effects of the sympathetic nervous system.. 8 9 Neurotransmitter: A chemical that transmits signals from one neuron to another or from a neuron to an effector cell. Chemical (intracellular messengers) Electrical Chemical Physiological Stimulation (neurotransmitter) functions (impulse) Electrical (membrane ion channels) 10 Neurotransmitter-based classification 1- Cholinergic, 2- Adrenergic, and 3- Dopaminergic 11 1- Cholinergic transmitter It means related to the • neurotransmitter. Acetylcholine. The parasympathetic nervous system is entirely cholinergic. Neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, and the sweat glands 12 2- Adrenergic It means "having to do with • adrenaline (epinephrine) and/or noradrenaline (norepinephrine)". 13 3- Dopaminergic It means related to the neurotransmitter • dopamine. For example, certain proteins such as the dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2) 14 15 Definition of Agonist and Antagonist Agonist: A structural analog that is capable of stimulating a biological response. Antagonist: A receptor-specific blocker (e.g., enzyme inhibitor) or a physiologic agent (e.g., hormone), that prevents the action of another molecule. 16 17 Mode of Action Direct-acting: Molecule that physically binds to the target for its effect. Example: carbachol activates cholinergic receptors. Indirect-acting: Molecule that exerts effect on the target by interacting with another molecule. Example:neostigmine blocks AchE, causing Ach accumulation. 18 Neurotransmitter Acetylcholine •Preganglionic synapses of both sympathetic and parasympathetic ganglia •Parasympathetic postganglionic neuroeffector junctions •All somatic motor end-plates on skeletal muscle 19 20 Acetylcholine Acetylcholine is an ester of acetic acid and • choline with chemical formula CH3COOCH2CH2N+(CH3)3. 21 Muscarinic Autonomic Effects of Ach Affect on gatsrtointestinal tract (GIT) as • follow 1- Motility • 2- Secretion • 3- Sphincters • 22 23 24 Muscarinic Actions The “Muscarinic Actions” -- Similar to • those of parasympathetic stimulation (M1): CNS, PNS, gastric parietal cells • • (M2): conducting tissue • • (M3): exocrine glands; smooth muscle • • 25 Practice Lab. 1 Dose – Response Curve 26 Tyroide Apparatus Solution NaCl: Isotenicity physiogragh CaCl2: H2O Contraction of muscle Glucose: Energy NaHCO3: valve 25 ml PH MgCL2: Intestine part relaxation Valve 27 Oxygen supply (Wash) Dose – Response Curve • It is a relationship between Dose and (Response %) • From this curve we can see : 28 1. Potency (a measure of the activity of a drug in a biological system) 2. Efficacy (the capacity to produce an effect) Dose – Response Curve 3- Therapeutic index (dose of a drug for » 50% of the population divided by the minimum effective dose for 50% of the population (ED sub 50/sub ) 4- ED 50 :dose in pharmacology is the » amount of drug that produces a therapeutic response in 50% of the people taking it 29 Dose – Response Curve D+R DR complex Response wash cm 0.1ml 30 0.2ml 0.4ml 0.8ml 1.6ml Dose – Response Curve Dose (ml) Response (cm) Response % (x/ max )*100 31 0.1 1 16.6 0.2 3 50 0.4 4 66 0.8 6 100 1.6 6 100 Dose – Response Curve 120 80 60 40 Response % v (%) Response 100 20 ED 50 = 3.75 ml 0 1 2 3 4 Dose (ml) 32 5 6 Lab. 2 Effect of cholinergic drugs on intestine and % of antagonism. 33 34 The “Muscarinic Actions” -- Similar to those of parasympathetic stimulation •(M1): CNS, PNS, gastric parietal cells •(M2): conducting tissue •(M3): exocrine glands; smooth muscle 35 36 Cholinergics agonist •Cholinergic agonists (direct acting ) •Bethanechol •Pilocarpine •Carbachol •Anticholinesterases (indirect acting ) • reversible : Neostigmine, physostigmine, pyridostigmine •Irreversible : (e.g Organophosphates ) (isoflurophate, echothiophate ) 37 Cholinergics antagonist Antimuscarinics Atropine Scopolamine Ipratropium Ganglionic Blockers (non selective ): Hexamethonium Pentamethonium Neuromuscular Blockers A. Non-depolarizing : e.g. D-tubocurarine B. Depolarizing : e.g. suxamethonium 38 Depolarization and Hyperpolarization • depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential. Hyperpolarization is the opposite of depolarization, and inhibits the rise of an action potential. 39 Effect Of Nicotine & Hexamethonium % of antagonist X1 – X2 * 100 X1 X1 Wash Dil. Nicotine 40 No Wash Hexamethonium (C6) x2 Dil. Nicotine Effect Of Ach & Atropine % of antagonist X1 – X2 * 100 X1 X1 Wash Ach 41 No Wash Atropine x2 Ach Effect Of Bacl2 & Atropine % of antagonist X1 – X2 * 100 X1 X1 x2 No Wash Wash Bacl2 42 Hexamethonium (C6) x2 Wash Bacl2 No Wash Atropine Bacl2 Lab. 3 Effect of adrenergic drugs on intestine and identification of unknown. 43 44 Adrenergic Receptors α1 receptor α2 receptor • vasoconstriction • inhibit release of (nor-epinephrine) blood pressure •negative feedback 45 Adrenergic Receptors β1 receptor β2 receptor • heart rate • vasodilatation • bronchodilatation • Force of contraction • glycogenolysis • release of glucagons 46 47 Catecholamines • They are sympathetic hormones • They are released by the adrenal glands in response to stress • They are part of sympathetic nervous system • They contain a catechol group and amino acid tyrosin 48 49 Production and degradation • Catecholamines are produced mainly by the chromaffin cells of the adrenal medulla and postsganglionic fibers of sympathetic nervus system. • Dopmaine is the first catecholamine to be synethesied. Ep. And NE are createdand modified from dopamine. • Tyrosin is created from phenylalanine by hydroxylation by enzyme phenylalanine hydroxylase. 50 • Catecholamine synthesis is inhibited by alpha- methyl-p- tyrosine (AMPT) which inhibits tyrosine hydroxylase. 51 52 53 Catecholamines degradation • Catecholamines have a half- life of a few minutes when circulating in blood. • They are degraded by COMT or MAO. • Amphetamines and MAOIs bind to MAO in order to inhibit its action of breaking down catecholamines. • This is the primary reason why the effects of amphetamines have a longer lifspan than cocaine and other substances 54 • Amphetamines not only cause a rlease of dopamine, ep,and NE into blood stream but also supress re- absorption. • Two catcholamines,NE and dopamine act as neuromodulators in CNS and as hormones in blood circulation. • High catecholamine level in blood are associated with stress. 55 56 57 Receptor type Agonist potency order : α1 norepinephrin e≥ epinephrine >> isoprenaline smooth muscle contraction Gq: phospholipas e C (PLC) activated, IP3 and calcium up norepinephrin e≥ epinephrine >> isoprenaline smooth muscle contraction and neurotransmitte r inhibition Gi: adenylate cyclase inactivated, cAMP down :α2 58 Selected action of agonist Mechanism Agonists Antagonists α1 agonists α1 blockers Alfuzosin• Doxazosin• Phentolamin• e Prazosin• Tamsulosin• Terazosin• norepinephrine• Phenylephrin• e Methoxamin• e Cirazoline• α2 agonists Clonidine• Lofexidine• Xylazine• Tizanidine• α2 blockers Yohimbine• Idazoxan• Receptor type Agonist potency order β isoprenaline > 1 epinephrine = norepinephrin e β2 isoprenaline > epinephrine >> norepinephrin e Selected action of agonist Mechanism Agonists heart muscle contraction Gs: adenylate cyclase activated, cAMP up norepinephrine• smooth muscle relaxation Gs: adenylate cyclase activated, cAMP up Short/long) Salbutamol• Formoterol • Isoprenaline • Salmeterol • Terbutaline • Direct Relaxant : e.g papaverine 59 Isoprenaline • Dobutamine • Antagonists (Beta blockers) Metoprolol • Atenolol• Propranolol• (Beta blockers) Propranolol• 60 Identification of unknown If the unknown produce contraction of the tissue , it may be nicotinic agonist ,muscarinic agonist or direct drug 1- 0.2ml of dil.nicotine , record & wash 2- 0.3ml of C6- blocker, leave 2 min. , add 0.2ml of dil. Nicotine (must block) without wash add 0.2ml of unk. , block ,,,,, nicotine-like drug . If response is found the agonist may be muscarinic or direct- like drug. Agonist on effect muscarinic or direct 3- 0.2ml of Ach. , record & wash 4- 0.3ml of atropine , leave 2 min. , add 0.2ml of Ach. without wash add 0.2ml of unk. , block ,,,,, muscarin-like drug . 61 Lab. 4 Effect of Nm blockers on Frog Rectus Abdomens Muscle 62 Rectus Abdomens Muscle . Voluntary muscle which receive motor somatic innervations (lack the ganglia ) Receptor is Nm which is different from receptor in the autonomic ganglia. It contains Ach-esterase for destruction if Ach. 63 Nm drugs Cholinergic agonists (direct acting ) • Ach • Carbachol • Anticholinesterases (indirect acting ) • reversible : Neostigmine, physostigmine, pyridostigmine • Irreversible : (e.g Organophosphates ) (isoflurophate, echothiophate ) Neuromuscular Blockers A. Non-depolarizing : e.g. D-tubocurarine B. Depolarizing : e.g. suxamethonium 64 Requirements •Frog-ringer solution -No Mg+2 (no relaxation) -(Ca ,K ,PO4, Na ,HCO3 ) -Glucose -Tension 0.5-4 gm -Temp. 25 C 65 Procedure 1- Add 0.2ml of Ach ,record ,wash . 2- Add 0.2ml of prostigmine , wait 2 min. ,add 0.2ml Ach , record ,wash. 3- Add 0.2ml carbacol ,record ,wash . 4- Add 0,2ml succinylcholine ,record , No wash , add 0.2ml of Ach 5- Add 0.2ml Ach , record ,wash ,Add 0.2ml atracurium 66 Lab. 5 Effects of drugs on Isolated Rabbit’s Heart 67 Na for depolarization K for repolarization Glucose for energy Ca to prevent arrhythmias HCO3 for adjust PH Temp. 37 Oxygenation 68 Heart rate : Beats/Min Force of contraction Coronary Flow Rate: ml/min 69 A) Adrenergic Drugs - Epinephrine ( adrenaline ) Heart Rate Force of contraction of cardiac Muscle (β- Receptor) (--) Flow Rate - Norepinephrine ( noradrenaline ) Heart Rate less effect on Force of contraction (more on α) (--) Flow Rate - Isoproterenol ( Isoprenaline non selective β-Agonist ) Heart Rate Force of contraction (β - Receptor) (--) Flow Rate 70 B) Cholinergic Drugs : - Acetylcholine Heart Rate and cardiac output (--) Force of contraction of cardiac Muscle (Beta2- Receptor) (--) Flow Rate - Atropine ( ) Heart Rate (--) Flow Rate C) Calcium channel blockers - Verapamil Heart rate Force of Contraction (--) Flow rate Heart rate Force of Contraction (--) Flow rate - Amlodipine 71 D) C.H.F : - Digoxin Heart rate Force of Contraction - Bretylium ( Adrenergic Neuronal Blocker ) Heart rate Force of Contraction - Amiodarone ( Adrenergic Neuronal Blocker ) Heart rate Force of Contraction - β1- agonist ( Dobutamine) Heart rate 72 Force of Contraction Flow rate E) Vasodilator Drugs : - Isosorbide (Isordil) Heart rate Force of Contraction (--) Flow rate F) Anti-arrhythmic : - Procainamide Heart rate Force of Contraction (--) Flow rate Heart rate Force of Contraction (--) Flow rate - Lidocaine - β- blocker ( Propranolol ) Heart rate Force of Contraction (--) Flow rate 73