Pharmacology in good subject, Cheat Sheet of Pharmacology

Download Pharmacology in good subject and more Cheat Sheet Pharmacology in PDF only on Docsity! Nehal V. Trambadiya Asst. professor Smt. N. m. padalia pharmacy college Parkinsonism "Rau pyramidal motor function disorder characterized ” Rigidity is stiffness and resistance to limb mover ment caused byincreased muscle tone - involuntary contraction of one or more’muscles — active an passive 1. Tremor: remmor is an involuntary, somewh rhythmic, muscle moyen mt ity ving to-and-fro movements (oscillations) of one or more body parts Jokinesia /Bradykinesia: Slowness of movements - active and BROS "ee ostural Tega a progressive degenerative disorder, mainly affecting older Dre e ® jauses es! rkinson, sD seqse, E E ephalitis, sae itis, metoclopramide, ingand bis etc.) ete, eee , | athophysiology - Recall Anatomy * Progressive degeneration of neurones in (1) substantia nigra pars compacta (SN-PC) ee and (2) nigrostriatal subi (dopaminergic) pathway ™ Cansdane nucteus Glatbus plies Thalarmur —Cerebelum * Deficiency of Dopamine (DA) in Striatum — loss of muscle tone and coordination of movements * Inhibitory DA less — but Cholinergic (excitatory) more — Imbalance — Motor defect * Anticholinergics - help NS PD Pathophysiology - contd. * Imbalance primarily between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia . Causes: Parkinson's Disease, Drugs (metoclopramide, haloperidol etc.), Encephalitis, Meningitis, Stroke, CO poisoning and brain damage etc. Ach i) Etiology of PD - contd. * Free Radical: Oxidation of DA by MAO and aldehyde dehydrogenase — generates free radicals (OH) in presence of Fe++ in basal ganglia * Normally — quenched by glutathion = Agerelated changes or others — defect in this protective mechanism — damage to Lipid membrane and DNA * Genetic: s ccsinuclein (synaptic protein), Parkin (a ubiquitin protein ligase), UCHL1, DJ-1 protein * Excitotoxicity: = Glutamate, the normal excitatory transmitter in neurones in excess ® Mediated by activated NMDA receptor = Ca++ overload — destructive processes * Environmental triggers: = Infectious agents — Encephalitis lethargica (epidemic) ® Environmental toxins - MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) = Acquired Brain Injury * Energy metabolism and aging: = Reduction in function of complex 1 of mitochondrial-electron transport chain Classification of antiparkinsonian Drugs: * DRUGS ACTING ON DOPAMINERGIC SYSTEM ° Dopamine precursors — Levodopa (I-dopa) = Peripheral decarboxylase inhibitors — carbidopa and benserazide = Dopaminergic agonists: Bromocriptyne, Ropinirole and Pramipexole = Selective MAO-B inhibitors — Selegiline, Rasagiline 2 COMT inhibitors — Entacapone, Tolcapone = Dopamine facilitator - Amantadine * DRUGS ACTING ON CHOLINERGIC SYSTEM ° Central anticholinergics — Teihexyphenidyl (Benzhexol), Procyclidine, Biperiden ° Antihistaminics — Orphenadrine, Promethazine Antiparkinsonian Drugs - contd. * Dopamine and Tyrosine Are Not Used for Parkinson Disease Therapy, Why? = Dopamine Doesn't Cross the Blood Brain Barrier = Huge amount of tyrosine decreases activity of rate limiting enzyme Tyrosine Hydroxylase Biosynthesis of Catecholamines Phenylalanine ln Tyrosine Alpha-methyl-p- |r «— Rate limiting Enzyme tyrosine DOPA [eve —— 5-HT, alpha Methyldopa Dopamine “49+—“°s popac Ss Hva [ps cOMT Norepinephrine ““2+ DHPG ——» MHPG [ene Epinephrine  Il Levodopa (Pharmacokinetics) - contd. Levedepa alone 30% Levodopa dose a Levodopa (Pharmacological actions) ° CNS: « Effective in Eliminating Most of the Symptoms of Parkinson Disease ¢ Bradykinesia and Rigidity Respond Quickly = Reduction in Tremor Effect with Continued therapy « Handwriting , speech, facial expression and interest in life improves gradually « General alerting response — excitement, psychosis “ Disproportionate increase in sexual activity « L- Dopa less Effective in Eliminating Postural Instability and Shuffling Gait - meaning Other Neurotransmitters are Involved in Parkinson Disease  Levodopa - contd. ° CVS: = Cardiac Stimulation due to Beta adrenergic effect on Heart - Propranolol reduces * Though stimulates peripheral adrenergic receptor — no rise in BP * Orthostatic Hypotension - some individuals — central DA and NA action = In elderly cardiovascular problems - transient tachycardia, cardiac arrhythmias and hypertension * Tolerance to CVS action develops within few weeks * CTZ: DA receptors cause stimulation — nausea and vomiting — tolerance e Endocrine: Decrease in Prolactin level and decrease in GH level NE | Levodopa - Prolonged therapy - contd. ¢ Fluctuation in Motor Performance: 2 — 5 years = “End of dose phenomenon” - Prolonged therapy — “buffering” capacity is lost — each dose causes fluctuation of motor state - each dose has short duration of action— short therapeutic effect (1 — 2 Hrs) — bradykinesia and rigidity comes back quickly — Wearing off Phenomenon = Increase in dose and frequency — DYSKINESIA — excessive abnormal involuntary movements = Dyskinesia often with high plasma conc. of levodopa = "QOn/off" Phenomenon - Like a Light Switch: Without Warning = Due to progressive Degeneration of neurons and ability to store DA * Dyskinesia (diminished voluntary movement — increased involuntary movements) — due to Denervation Supersensitivity: = In Basal Ganglia — destruction of Dopaminergic Neurons — increase in Dopamine Receptors postsynaptically (up regulaton) = L Dopa Therapy - increase Dopamine at synaptic Cleft — due to increased number of Receptors - Effect - Increased Postsynaptic Transmission Levodopa - Drug Interactions * Pyridoxine — abolishes therapeutic effect of levodopa . lntipsychotic Drugs — Phenothiazines, butyrophenones block the action of levodopa by blocking DA receptors (Also Metoclopramide) » Antidopeminergic — domperidone abolishes nausea and vomiting — no influence on primary antiparkinsonian effect * Anticholinergics — synergistic action but delayed gastric emptying — reduced effect of levodopa * Nonspecific MAO Inhibitors — Prevents degradation of peripherally athesized DA — hypertensive crisis — ANS action - tyramine-cheese like etfect (Cheese reaction)  Levodopa and Peripheral decarboxylase inhibitors combined - Why ?? * Carbidopa and Benserazide: Do not penetrate BBB — Peripherally, Inhibits conversion of levodopa into Dopamine — but not in brain — higher bioavailability of Levodopa - more CNS entry — In practice, almost always administered * Benefits: 1. Plasma ti/2 — prolonged - Dose of levodopa — 30% reduction 2. Reduction in systemic complications * Nausea and Vomiting — less and Cardiac — minimum complications 1. Pyridoxine reversal of levodopa — do not occur 2. On/Off effect — minimum (sustained DA level) 3. Better overall improvement of patient — even in non responding patients to levodopa * Drawbacks: Involuntary movements, behavioural abnormalities and postural hypotension  Bromocriptine - ee Synthetic ergot derivative a sa Y~ * Basically used in hyperprolactinemia and acromegally * Levodopa like action in CNS — Dez agonist and D1 partial agonist/antagonist ° pus improvement of PD symptoms and longer lasting (1-2 hr Vs 6-10 rs e Why not use then commonly ? - Monotherapy 2 High doses and expensive 2 Jntolerable side effects — vomiting, hallucinations, hypotension and nasal stuffiness 2 1*dose phenomenon — marked fall in BP * Uses: late cases as supplement to levodopa — 1.25 mg OD at night and increasing upto 5-10 mg tds ° Benefits: = End of Dose phenomenon smoothening and less “on-off” phenomenon 2 Also less DYSKINESIA Ropinirole and Pramipexole Newer agents with selective Dz/D3 and D4 agonist property with low D: activity Like Bromocriptine, both are well absorbed orally (40%), metabolized in liver Similar therapeutic action and used in advance cases as supplementary drugs Advantages over Bromocriptine = less GIT symptoms (vomiting) ° Dose titration for maximum improvement in 1-2 weeks Vs Bromocriptine > Adverse effects ° Nausea, dizziness, postural hypotension and hallucination ° Episodes of day time sleep Ropinirole and Pramipexole - contd. » Started using as monotherapy — comparable efficacy with levodopa ° Supplementary levodopa is not required (but with Bromocriptine) = Meta analysis — slower degeneration ¢ Restless leg syndrome COMT inhibitors: Entacapone and Tolcapone 3-OMD — 3-0 -methyldopa DOPAC - 3,4 dihydroxy phenylacetic acid  Entacapone and Tolcapone - contd. * Reduce wearing off phenomenon in patients with levodopa- carbidopa * Common adverse effects similar to levodopa « Entacapone: = Peripheral action on COMT Ho - = Duration of action short (2 hrs) Nt ° No hepatoxicity 4 * Tolcapone: = Central and peripheral inhibition of COMT = Long duration of action — 2 to 3 times daily = Hepatoxicity (2%) * Both are available in fixed dose combinations with levodopa/carbidopa * ADRs: worsening of levodopa ADRs, diarrhea, yellow orange discolouration of urine Central Anticholinergics: Teihexyphenidyl (Benzhexol), Procyclidine, Biperiden » These are the Drugs with higher central : peripheral anticholinergic action than Atropine * Reduce unbalanced cholinergic activity in striatum * Duration of action is 4-8 Hrs * Tremor is benefited more than rigidity — least to hypokinesia * Overall activity is lower than levodopa * Used alone in mild cases and when levodopa is contraindicated * Combination with levodopa to reduce its dose « Also used in Drug Induced Parkinsonism * Antihistaminic like Orphenadrine, Promethazine are used in PD for their anticholinergic action