Lecture 5 - Neuropharmacology PDF

Lecture 5 - Pharmacology of Nervous System Dr Parveen Gul Content  Drugs acting on CNS  Parasympathetic NS  CNS depressants  Adrenergic drugs  CNS stimulants  Antiadrenergic drugs  Drugs acting on PNS  Cholinergic drugs  Sympathetic NS  Anti...

Lecture 5 - Pharmacology of Nervous System Dr Parveen Gul Content  Drugs acting on CNS  Parasympathetic NS  CNS depressants  Adrenergic drugs  CNS stimulants  Antiadrenergic drugs  Drugs acting on PNS  Cholinergic drugs  Sympathetic NS  Anticholinergic drugs  NERVOUS SYSTEM CNS PNS Brain Spinal Efferent Afferent Cord Division Division Nerves ANS SNS (Sk. Muscles - Motor) Sm. Sk. Enteric Muscles Muscl Sympathetic Parasympathetic & Glands es (ANS) (Sensor y)  Structural & Functional Unit Neurons: of NS (10 billion neurons in brain) Chemical substances Carry messages from Neuro- one neuron to another transmitters: or from a neuron to body tissues e.g. Sk. muscles A Neuron Synapse: Small gap separating neurons Receptors:  Macro-molecules  Lipoprotein in nature Axon terminal  Situated on or inside the cell of Presynaptic neuron membrane Synapse  Having recognition properties Dendrite of Postsynaptic neuron Fig: Synapse Process of Typical Synaptic Connection Presynaptic membrane or element Action Potential Activates Ca++ ion Channel Ca2+ Channel Neurotransmitters Exocytosis of neurotransmitter ++ s - Released in Synaptic Cleft +AP++ Na+ -- + K+ - Post synaptic membrane (receptors or ion channels) Exert action Neurotransmitters in CNS I. Amino acids : Ach, GABA, Glutamate, Glycine II. Monoamines : NE, Dopamine, Serotonin III. Peptides : Opioid peptides, Neurotensin, Substance P, Somatostatin, Neuropeptide Y IV. Nitric oxide V. Endocannabinoids VI. Histamine VII. Tachykinins CNS Pharmacology Antidepressants Medications that increase levels of certain neurotransmitters in the brain to improve mood and treat depression These are medications specifically designed to treat depression. Modulate specific neurotransmitter systems without necessarily slowing down overall CNS activity. Antidepressants: SSRIs (e.g., Prozac), SNRIs, TCAs, MAOIs. Depressants Drugs that lower neurotransmission levels and decrease electrical activity in the brain, reducing arousal or stimulation They can reduce anxiety, but are not primarily used to treat depression. Used for anxiety, insomnia, seizures, and as muscle relaxants Depressants: Alcohol, benzodiazepines (e.g., Xanax), barbiturates, opioids. CNS stimulants Used to treat ADHD (Attention Deficit Hyperactivity Disorder) Narcolepsy Depression (in some cases) They typically work by increasing levels of neurotransmitters like dopamine and norepinephrine in the brain Prescription drugs: Amphetamines (e.g., Adderall), methylphenidate (e.g., Ritalin), modafinil Common legal substances: Caffeine, nicotine Illegal drugs: Cocaine, methamphetamine, MDMA (ecstasy) Drugs acting on CNS Sedatives …. Diazepam, Oxagepam etc. Mainly two groups: Hypnotics …. Clobazepam, Nitrazepam etc.  CNS depressants Narcotics …. Morphine, Codeine etc.  CNS stimulants (Neuraleptics) GA Barbiturates, Halothane etc. ….. Directly acting on CNS Reflexly acting on CNS Caffeine, Aminophylline, Cortical …. Amphetamine, Ephedrine etc. (Nicotine, Lobetine etc.) Medullary …. Picrotoxin, Adrenaline, Nikethamide etc. Spinal …. Strychnine, Brucine etc. Drugs acting on CNS Psychedelics Anxiolytics Sedatives Barbiturates Hynotics Parkinson’s disease drugs Tranquilizers CNS stimulants Antipsychotics Benzodiazepines Anaesthetics Anticonvulsants Antidepressants Dopamine antagonists Antiemetics & Cholinergics & anticholinergic emetics CNS Depressants: Anxiolytics and Sedative-Hypnotics Sedatives (anxiolytic): Hypnotics:  Anxiolytic drug Depress CNS to the point that they cause  Reduce anxiety, excitement, nervousness, normal sleep irritability  Exert calming effect  Mild depression of CNS  Don’t cause sleep  Little or no effect on motor or mental functions CNS Depressants: Anxiolytics and Sedative-Hypnotics Non Benzodiazepine Progressive Sedative-Hypnotic drugs Depression of CNS Sedation Dose dependent Hypnosis Higher Lower depression of CNS Dose Dose Narcosis Coma Sedatives Hypnotics GA Death Classification: Sedatives-Hypnotics I. Benzodiazepines II. Barbiturates III. Newer agents (Non- benzodiazepines )  Sedatives-Hypnotics: Benzodiazepines Benzene ring fused Classification to seven membered diazepine ring a) Short acting (t1/2 < 5 hrs) Frequently Midazolam, Triazolam etc. prescribed b) Intermediate acting (t1/2 8-40 hrs) Favourable side Lorazepam, Temazepam etc. effect c) Long acting (t1/2 40-250 hrs) Efficacy, safety Diazepam, Nitrazepam etc.  MOA of Benzodiazepines Benzodiazepines Opening of Cl- channels (Enhancement of Cl- Binds with specific regulatory conductance) site on GABA receptor in brain Hyperpolarization of cells Enhance GABA activity Depression of CNS  Pharmacological action: Benzodiazepines Periphe Anxiolytic ral Sedation & induction of action: CNS sleep Neuromuscu effec Muscle relaxation (skeletal) Anticonvulsant effects lar blockade (high dose) ts: Anterograde amnesia Coronary Decrease dose of vasodilation anaesthetic (IV)  Adverse effects & Choice: Benzodiazepines Adverse effects Antianxiety a)Normal dose:  Dry mouth (Diazepam) Hypnotics  Light headache (Temazepam)  Confusion Anticonvulsants  Ataxia (Lorazepam) Choice Anti-tetanus  Impair driving skill (Diazepam) b)Acute overdose: Prolong sleep Antidepressant c) Tolerance & dependency (Alprazolam) d)Decrease libido  Sedatives-Hypnotics: Barbiturates Classificatin Ultra-short Malonic acting DOA: 30 mins acid (e.g. Main use: IV anaesthetic Thiopental-Na) Short acting DOA: 2 hours (e.g. Main use: Sedative Barbituric Pentobarbital) acid Intermediate acting DOA: 3-5 hours (e.g. Main use: Hypnotic Amobarbital) Barbiturat Long acting  DOA: > 6 hours es (Phenobarbito  Main use: ne) Anticonvulsant  Barbiturates: MOA Barbiturates + AMPA Barbiturates + GABAA receptor receptor Activation of GABA receptor Inhibition of AMPA receptor Opening of Cl- Channel Inhibition of Glutamate duration of GABA gated channels opening Hyperpolarization of cells Depression of CNS Potentiate GABA inhibitory action  Barbiturates: Indications & Adverse effects Indications Adverse effects Anticonvulsants Drowsiness Over excitement Sedative & Hypnotics Night mares & night terrors IV anesthesia Weakness Hyperbilirubinemia Allergic skin reaction Localized or diffuse pain Kernicterous Psychologic dependence Cholestasis Tolerance  Sedatives-Hypnotics: Newer drugs Anxiety & Sleep Disorder Buspirone & analogs (ipsapirone, Zolpidem Zaleplon gepirone, tandospirone)  CNS Depressants: Tranquilizers  Produce calmness & quietness  Reduce anxiety, tension & aggression  Also called “PEACE PILL” Example: Major: Phenothiazine derivatives (Chlorpromazine, Promethazine etc.), Reserpine etc. Minor: Benzodiazepines, Phenobarbitone etc  CNS Depressants: Anticonvulsant Drugs Examples Used to treat epileptic seizures carbamazepine (Epitol, Tegretol) clonazepam (Klonopin) More accurately called antiepileptic diazepam (Valium) drugs divalproex (Depakote) phenytoin (Dilantin)  Anticonvulsant Drugs: MOA Principle: Depolarization of nerve: Blocking of Na+ Convulsion channels Enhance GABA mediated synaptic Repolarization of nerve: inhibition Returning to normal state Ca2+ channel blockade  Analgesics Narcotic Relieve pain Natural (Opium Synthetic: alkaloid): Pethedine, Morphine, Fentanyl etc codeine etc: Don’t impair degree of consciousness Non-Narcotic Salicylat Paraceta NSAIDs es mol  Opioids: Affects & MOA (General) Affects MOA Analgesia Stimulation of opioid receptors: Respiratory depression mu(µ), delta(δ), kappa(ƙ) Constipation Urinary Retention Increase K+ efflux, Reduce Ca+ influx, Decrease cAMP Cough suppression Emesis (vomiting) Inhibition of cell firing Miosis (pupil construction) Sedation Euphoria/ Dysphoria Elimination of pain  CNS Stimulants Directly acting on CNS: Progressive Grade of CNS i. Cortical stimulants (Amphetamine, excitation Aminophylline) Mild hyper- excitability ii. Medullary stimulants (Picrotoxin, Severe hyper- Nikethamide) excitability iii. Spinal stimulants (Strychnine, Brucine) Reflexly acting on CNS: Mild convulsion Nicotine, Ammonia etc. Severe convulsion  Miscellaneous Levodopa, Parkinsonism Amantadine etc. Baclofen, Multiple Sklerosis Tizanidine etc. Alzheimer’s Disease Donepezil, tacrine etc. Myasthenia Gravis azathioprine Schizophrenia Psychotropic Drugs PNS Pharmacology  PNS: Autonomic VS Somatic NO. AUTONOMIC SOMATIC 01 Two neurons…to supply smooth Single neuron to connect CNS to muscles & glands skeletal muscle 02 Peripheral ganglia present Peripheral ganglia absent Synapses are entirely within CNS 03 Pr.G. nerves are myelinated Nerves are myelinated Po.G. nerves are non-myelinated 04 Dessection of nerve: some level Dessection of nerve: Paralysis & of spontaneous activity atrophy of sk. muscles 05 Ach(ganglia & parasym. Ach at neuroeffector junc. Neuroeffector junc.) NE(sym. Neuroeffector junc.) DUAL INNERVATION AT MOST SITES  ANS: Classification Two sets of neurons:  Afferent: Send impulses to CNS for interpretation  Efferent: Receive impulses from the brain & transmits from the spinal cord to effector organ cells 2 branches:  Sympathetic NS Preganglionic nerve: connects CNS to ganglia  Parasympathetic NS Postsynaptic nerve: connects ganglia to organs *Ganglia: Contains nerve endings of pre-G. nerve fibers & cell bodies of post-G. nerve fibers  Sympathetic VS Parasympathetic Nerves SL. SYMPATHETIC PARASYMPATHETIC NO. 01 Arise from thoraco-lumber (T1 to Arise from cranio-sacral (III, VII, IX, L3) region of spinal cord X, S2 – S4 region of CNS 02 Ganglia are nearer to CNS. Ratio Ganglia are away from CNS (close of Pre & PostG. fibers is generally to organs). Ratio is generally 1:1. 1: 20 or more. So, PostG. fibers So, postG. fibers are shorter are longer 03 Ach (in ganglia) & NE (at Ach in both ganglia & neuroeffector neuroeffector junc.) junc. 04 Sym. Activities increases in stress Parasym. Activity predominates & emergency during rest  Sympathetic VS Parasympathetic: EFFECTS SL. NO. TISSUES SYMPATHETIC PARASYMPATHETIC 01 Eye(Pupil) Dilation Constriction 02 Sali. gland Saliva reduction (Dry mouth) Increased salivation 03 Heart Increases heart rate Decreases heart rate 04 Bronchus Smooth muscle relaxation SM contraction 05 Arteries Constriction Dilation 06 GIT Decreased motility, secretion Increased motility, secretion 07 Liver Convert glycogen to glucose Stimulates secretion of bile 08 Bladder Sphincter contraction & sm Sphincter relaxation & sm relaxation contraction 09 Kidney Decreased urine Increased urine 10 Uterus Contract(Pg.),Relax(Non-Pg) Contraction in both condition  ANS: Neuro-Humoral Transmission CNS Principal neurotransmitters:  Sympathetic nerves (adrenergic) : NE or NA (PostG.)  Parasympathetic nerves (cholinergic): Ach (PostG.)  PreG. nerve endings of both (Sym. & Parasym.-in Other: ACh ganglia) neurotransmitters: NO GABA Serotonin Purines ATP Dopamine peptides Effector Autonomic Nervous system drug Classification​ Cholinergic or choline agonists Anti-Cholinergic or choline antagonists Adrenergic or Adrenaline agonists Anti-adrenergic or adrenaline antagonists Drugs for Parasympathetic Nervous System Diseases  PNS (Cholinergic) : Classification Cholinergic or choline agonists:  Direct acting (e.g. Ach, Pilocarpine, Arecoline)  Indirect acting  Irreversible AChE agents (e.g. Malathion, Carbaryl)  Reversible AChE agents (e.g. Physostigmine,Neostigmine)  Anticholinergic (Parasympatholytic) Drugs  Nonselective muscarinic receptor antagonists (Atropine, Scopolamine)  Selective muscarinic antagonists (e.g. Pirenzepine-M1 antagonists) Clinical uses As spasmolytic To dilate pupil (Homatropine) hypermotility of GIT In bronchial asthma (Ipratropium) hypertonicity of uterus, UB, Ureter, Bronchioles In OPI, carbamate & As pre-anesthetic (Atropine Myshroom poisoning) sulfate) As anti-parkinsonism drug Peptic ulcer (Pirenzepine) As anti-emetic Drugs for Sympathetic Nervous System Diseases  SNS (Adrenergic) : Receptors & action 4 types of adrenergic receptors in organ cells: α1 : Vasoconstriction of blood vessels, Inc. BP, Dec. GI motility, Contracts UB sphincter, Dilates pupil, Contracts uterus α2 : Inhibits release of NE, Dec. BP, Dec. intestinal secretion β1 : Inc. heart rate & force of contraction of heart (cardiac stimulant) β2 : Relaxation of sm in bronchi (Bronchodilator), uterus, peripheral BV, Stimulates insulin secretion  SNS (Adrenergic) : Classification  Based on MOA: (3 categories) i. Direct acting  α agonists  β agonists  Nonselective  Nonselective e.g. NE, Epinephrine e.g. Isoproterenol  Selective (α1 & α2  Selective (β1 & β2 agonists) agonists) e.g. Clonidine, ii. Indirect acting (e.g. e.g. Dobutamine, Phenylephrine Salbutamol Amphetamine) iii. Mixed acting (e.g. Ephedrine)  Anti-adrenergic Drugs (Sympatholytic Drugs) Classification General Indications Hypertension  Adrenergic neuron blockers Visceral ischemia (e.g. Methyldopa, Reserpine) Angina pectoris  Adrenergic receptor blockers Myocardial infarction Cardiac dysrhythmias (α & β antagonists) α-agonists β-agonists Adverse effects α1 (e.g. Prazocin) β1 (e.g. Atenolol) Hypotension α2 (e.g. Idazoxan) β2 (e.g. Butoxamine) Bradycardia Non-selective (e.g. Non-selective (e.g. Tolazoline) Propranolol) Edema  Adrenergic Drugs: Clinical Uses 1) Cardiovascular system 3) Miscellaneous Cardiac arrest (Adrenaline) Prolong action of LA by vasoconstriction (Adrenaline) Heart block (Isoproterenol) Bronchial asthma by Bronchodilation (salbutamol, Cardiogenic shock adrenaline) (Dobutamine, Dopamine) Allergic rhinitis (Adrenaline) 2) Anaphylactic reaction Dilating pupil (Ephedrine) Adrenaline Thanks