Pharmacology Sem1 PDF

Tan Si Yuan (00000032054) ME121 FPP1 Notes Cholinergic drugs (parasympathetic) Drug type Example MOA PK Pharmac...

Tan Si Yuan (00000032054) ME121 FPP1 Notes Cholinergic drugs (parasympathetic) Drug type Example MOA PK Pharmacological effect Clinical use Adverse effects/CI Additional info Direct acting: Muscarinic agonists M1 + (gastric parietal cells) - increase gastric secretion and motility M2 - (myocardium, pre-synaptic, sphincter) - myocardial suppression, inhibit neurotransmitter release, sphincter relaxation M3 + (sweat glands, smooth muscles of glands and viscera of eye) - increase secretions, bronchoconstriction, cyclospasm (fixation of eye for near vision), decrease IOP M4 -, M5 + (CNS) - modulate release of neurotransmitters, stimulate CNS Muscarinic + Acetylcholine Predominantly controlled by Short duration Increase gastric NOT USED Bradycardia, Rapid inactivation nicotinic inhibitory Gi-coupled M2 of action secretions, inhibit CLINICALLY hypotension, by cholinesterase and excitatory Gq-coupled (rapidly myocardial contraction, sweating, flushing, M3 muscarinic acetylcholine hydrolyzed by sphincter relaxation, Used in surgeries difficulty breathing Only used receptors (mAChRs) AChE) increase sweating, where miosis is experimentally/ miosis, decrease IOP, required (e.g Increase release of not frequently used stimulate/depress CNS cataract surgery) NO from M3 receptor activation endothelium results in airway SM Methacholine contraction → stimulation of Non selective induce used to diagnose Bradycardia (+ other calcium-dependent muscarinic bronchoconstriction bronchial CVS effects, signalling pathways → receptor through M3 receptors hyperreactivity in asthmatic patients bronchoconstriction agonist subjects who do not have clinically M2 activation → inhibition of apparent asthma neuronal ACh release Muscarinic Pilocarpine Direct acting cholinergic Applied locally Miosis, decrease IOP, Glaucoma, Local irritation, Stimulates all the M parasympathomimetic agent to eye increase secretions xerostomia (dry blurred vision, GIT receptors, too toxic → stimulates muscarinic (salivation) mouth) hyperreactivity for systemic use receptors and smooth muscle (e.g in iris and CI: asthma, peptic secretory glands) ulcer, coronary vascular disease Direct acting: Nicotinic agonists NM (neuromuscular junction) - skeletal muscle contraction NN (autonomic ganglia) - facilitate neurotransmission E.g Nicotine, Suxamethonium chloride Tan Si Yuan (00000032054) ME121 FPP1 Notes Indirect acting: Cholinesterase inhibitors/anticholinesterase Acetylcholinesterase inhibitors Similar effect to cholinergic agonists: blocks AChE → ACh accumulates → stimulate cholinergic effect *AChE is a cholinergic enzyme primarily found at postsynaptic neuromuscular junctions → hydrolyzes ACh into choline and acetic acid Reversible Edrophonium Binds electrostatically by Binds for 2-10 Increases strength of Used to diagnose - The test involves an short acting weak H-bonds to AChE → minutes muscle contraction for MG injection of Tensilon increases conc. of ACh in a few minutes (edrophonium), NMJ for a short period of after which your time muscle strength is evaluated. Reversible Neostigmine Forms a moderately stable - Increase strength for up Myasthenia gravis, Missing doses or Neostigmine is medium bond with AChE → increase to hours paralytic ileus (due ingesting excess preferred for acting conc. of ACh at NMJ for to low GIT tone), produces the same treatment of MG hours atonic bladder effect (muscle over physostigmine (low bladder tone) weakness) because there is np with CNS in MG Physostigmine Highly lipid Glaucoma, vomiting, diarrhoea, soluble (can treatment of abdominal cramps, cross BBB) anticholinergic diaphoresis, seizures toxicity (atropine (rarely) poisoning) Reversible Tacrine Reversible inhibition of vv lipophilic, Acts on CNS Alzheimer's Hepatotoxicity These adverse long acting AChE → slows the has longer disease effects does not breakdown of ACh in the duration of Excessive doses may occur in direct Binds for brain action cause muscle acting cuz they do hours paralysis, death from not act on nicotinic respiratory failure receptors *Irreversibly *Organo- NOT PHARMACOLOGICAL DRUG SLUDGEM: (See organo- binds to AChE phosphates phosphate Binds permanently → body must make new cholinesterase salivation, poisoning in E.g nerve gas lacrimation, PATHOLOGY (sarin, soman, Forms a very strong bond with AChE → undergoes aging (water is added to both ends) → urination, defecation, notes) insecticide AChE cannot be regenerated → prolonged increase in ACh levels → toxic effects GI upset, emesis, “malathion”) miosis, muscle spasm Tan Si Yuan (00000032054) ME121 FPP1 Notes Cholinergic blockers Nicotinic antagonist → binds to nicotinic receptors → prevent opening of ligand-gated ion channel (ANS ganglia) Muscarinic antagonist → binds to muscarinic receptors → prevent activation of GPCR Side effects: Hot, dry, blind, red, mad Drug type Example MOA PK Pharmacological effect Clinical use Adverse effects Additional info Muscarinic Atropine Competitively blocks Blocks all muscarinic Reduces secretions in Sedation, reduce tremor Restlessness, No effect on antagonist the effects of receptors, long ½ life the mouth, respiratory in Parkinson disease, heart blurred vision, NMJ (muscle acetylcholine at passages, relieves block, sinus bradycardia, increased IOP, paralysis or muscarinic cholinergic Reversible antagonist airway constriction, bronchial asthma, PU, inhibition of weakness, receptors on smooth pupil dilation, organophosphate sweat → fever, fasciculations or muscle, cardiac Well absorbed orally tachycardia, reduce poisoning, overactive atropine flush, tremors) muscle, secretory and topically centrally-mediated urinary bladder, correct dry mouth gland cells, and in respiratory paralysis vestibular disturbances peripheral autonomic Crosses BBB (prevent motion sickness), CI: glaucoma, ganglia and CNS pre-anesthetic med, use prostatic before ophthalmoscopy hyperplasia Scopolamine - - - Motion sickness, Less ADR than parkinson disease atropine Ipratropium Act on M3 receptor Inhalation can reach - COPD - site of action fast Pirenzepine - - - Peptic ulcer disease - Botulinum Blocks the release of - Progressive paralysis, Localised injections used - Produced by toxin ACh blurred vision, to treat blepharospasm Clostridium dysphagia, dysarthria, (eye twitching) and skin botulinum (gram Transmit via food, respiratory paralysis wrinkles +ve anaerobe) infantile, wound Ganglion blocking agent Hexamethonium Tan Si Yuan (00000032054) ME121 FPP1 Notes Neuromuscular blockers Neurotransmitter → acetylcholine Drug type Example MOA PK Clinical use Adverse effects CI/DDI Additional info Non- d-Tubocurarine Competitively antagonizes ACh IV administration Primary therapy in Progressive paralysis DDI: + effect No effect on depolarizing at nicotinic receptor site facilitating endo- (face, limbs, respiratory of general cardiac and NM blockers Low volume of tracheal intubations, muscles), hypoxia, anesthetics smooth muscles; Increased amounts of ACh can distribution provide skeletal bronchospasm, and no effect on CNS eliminate the effect of NDNMB muscle relaxation hypotension aminoglycosid Duration of during surgery es action: 80-120 (perioperative Antidote: neostigmine *Release histamine → minutes maintenance of (anticholinesterase) Neostigmine hypotension anesthesia) reverse the actions of antagonizes NDNMB NDNMB Depolarizing Succinylcholine Depolarizing and desensitising IV administration Endotracheal Hyperkalemia, malignant No effect on Resemble NM blockers intubation, adjuvant hyperthermia, muscle neostigmine, acetylcholine (2 Phase 1: Bind to receptor → Fast onset, short to general rigidity, muscle soreness, general acetylcholine open sodium channels and duration anesthesia, prolonged apnea anesthetics, molecules linked cause brief depolarization → intubation, muscle aminoglyco- through acetate fasciculation → persistent Low volume of paralysis, reduce Persistent release of Ca sides methyl groups) depolarization → flaccid distribution fractures (easing of 2+ from sarcoplasmic paralysis develops because it joint during bone reticulum via RyR1 Acts on NM does not get degraded by Metabolised by and joint channel → muscle cholinergic AChE plasma manipulation), contraction, heat receptors cholinesterase prevent trauma production, lactic Phase 2: Continued infusion of (butrylcholines- during acidosis, increase body drug → NM ACh receptor terase) electroconvulsive temp desensitized → unresponsive to therapy, patients in ACh for some time → new AP Duration of the ICU and contraction not elicited action: 5-8 mins Spasmolytics Diazepam Bind with GABA receptor - Multiple sclerosis, Drowsiness, dizziness, - Centrally acting cerebral palsy, relief sedation, weakness, muscle relaxants from acute muscle mental confusion spasm Less effective in Withdrawal → presence improving of dependence functional status Tan Si Yuan (00000032054) ME121 FPP1 Notes Baclofen GABA agonist → interferes with Act in the spinal Used to treat pain Somnolence and - Produce less release of excitatory neuro- cord and certain types of respiratory depression sedation than transmitters → muscle stiffness and diazepam tightness from multiple sclerosis, spinal cord injuries, or other spinal cord diseases. Tizanidine Significant alpha 2-adreno- - - Drowsiness, - - receptor agonist effects hypotension, dry mouth, asthenia Dantrolene Interferes with release of - Malignant Muscle weakness, - - calcium from SR via ryanodine hyperthermia, acute sedation, occasional receptor channel → prevents muscle spasm, hepatitis excitation contraction coupling torticollis, backache, → cardiac SM depressed neuralgia, ECT, slightly tetanus, spastic neurological conditions Tan Si Yuan (00000032054) ME121 FPP1 Notes Adrenergic agonists a1 + (vascular smooth muscles (skin and mucosa), bladder trigone, sphincter and prostatic urethra, radial muscle of the iris) - vasoconstriction, contraction, mydriasis a2 - (presynaptic neuron, pancreas) - inhibition of transmitter release, inhibition of insulin release b1 (heart, kidney) - myocardial stimulation, renin secretion b2 (respi, uterine, vascular SM, sk muscle, pancreas, liver, muscle spindles) - muscle relaxation, vasodilation, increase in glucagon secretion, tremor b3 (adipose tissue) - lipolysis Tan Si Yuan (00000032054) ME121 FPP1 Notes d1 (renal vascular smooth muscles) - dilation d2 (nerve endings in CNS and GIT) - modulation of transmitter release, CNS stimulation Drug type Example MOA Effect Clinical use Adverse effects CI Additional info Direct acting sympathomimetics Non-selective Adrenaline Binds non-selectively Heart: positive (b1) → increase Cardiac arrest, - - As the dose to all adrenergic cardiac output, systolic BP anaphylactic increases, a1 receptors (a1/2, b1/2), shock, severe receptor especially b2 BV: (a1 and b2) → acute asthma, predominates vasoconstriction; vasodilation used in dental Rapidly inactivated by procedure Adrenaline causes COMT and MOA Other effect: (b2) → bronchial (prolongs local an increase in SBP, (catechol-O- dilation, other sympathetic anesthetics due to decrease in DBP, methyltransferase, effects local increase in HR monoamine oxidase) vasoconstriction) Noradrenaline Neurotransmitter Act on a1, a2, b1 receptors Septic shock Reflex bradycardia - NE may lead to released by reflex bradycardia sympathetic nerve CVS: (b1) → increased CO and *Increased BP may which will worsen terminals systolic BP, vasoconstriction activate baroreceptor cardiogenic shock, reflex → bradycardia so dopamine is (a1) → increased TPR, increased preferred because it DBP causes tachycardia Dopamine Neurotransmitter in Dose dependent effect: Cardiogenic shock, - - IV route CNS Low conc → D1→ increase renal insufficiency, administration renal blood flow congestive heart Metabolic precursor failure (esp with of A/NA Moderate conc → B1 → oliguria) stimulate heart → increased CO High conc. → a1 → vasoconstriction Isoproterenol Direct acting → Stimulate B1 → increase HR, Limited, relaxes Tachycardia (highly - - stimulate B1/B2 contractility, cardiac output bronchial and GIT affects B1) Tan Si Yuan (00000032054) ME121 FPP1 Notes Stimulate B2 → decrease TPR, muscles, AV block, diastolic BP bradycardia Selective Phenylephrine Selective a1 receptor Arterial vasoconstriction → Nasal congestant Caution in elderly: - Topical and IV route agonist increase in BP (treatment of hypertension, administration All selective rhinitis), vasospasm, arrhythmia, drugs lose Mucosal decongestion hypotension, stroke Provides dilation selectivity at (constriction of mucosa) mydriatic agent without cycloplegia high conc. (does not act on Mydriasis (radial muscle of the ciliary muscles) eye) Clonidine Selective a2 receptor Reduce BP, bradycardia Hypertension Rebound hypertension - Oral route of agonist in CVS center administration of CNS (upregulation of receptor so abrupt Prevent the release of withdrawal may lead to NA → reduces surge of stimulation) sympathetic outflow Activates parasympa- thetic regulation in CVS Dobutamine Selective B1 agonist Positive inotropic, chronotropic, Acute congestive Caution in patient with Acute MI, IV route of action at cardiac B1 dromotropic, bathmotropic heart failure, hypotension: unstable administration receptors → enhance cardiogenic shock Has moderate B2 effect angina, myocardial so may cause severe contractility peripheral vasodilation HTN, etc Salbutamol Selective B2 receptor Smooth muscle dilation, Bronchial asthma Tremor, palpitation High BP in Inhalation, oral and agonist bronchial dilation, vasodilation, (significantly increases pregnancy IV route of uterine relaxation HR), headache, nausea administration Tan Si Yuan (00000032054) ME121 FPP1 Notes Drug type Example MOA Effect Clinical use Adverse effects CI Additional info Indirectly acting sympathomimetics Releasing Amphetamine Stimulate the release CNS: euphoria, excitation, Very limited, - - - agent of NE from storage delirium ADHD, appetite vesicles in nerve suppressant terminals into synapse CVS: increased BP, myocardial stimulation Uptake Amitriptyline Block reuptake of NA CNS: improves mood, Depression - - - inhibitor from synapse back antidepressant into nerve terminal → higher NA conc. in CVS: tachycardia, arrhythmias the synapse MAO Selegiline MAO metabolise Block metabolism of dopamine Parkinson disease Hypertensive crisis if - People who already inhibitor catecholamines in in nerve terminals through food high in tyramine have high blood adrenergic nerve inhibition of MAO-B (cheese) is taken pressure need to be (MAO-A NA/ terminals (CNS, careful when A, serotonin; peripheral tissues) MAO-A inhibitors increase Depression Tyramine can trigger consuming foods MAO-B D) synaptic NA concentration by nerve cells to release with high tyramine MAOI inhibits this inhibiting degradation NE → increase BP and levels. process HR COMT inhibitor Metabolises catecholamines in CNS and peripheral tissues (adrenal medulla) Mixed acting sympathomimetics α1/α2 β1/β2 Ephedrine Non-selective a1, a2, CVS: Increase TPR, positive Very, very limited Drug of abuse - Oral route of + release NA B1, B2 agonist inotropic, chronotropic, administration bathmotropic and dromotropic Nasal Increase NA release effect decongestant Respi: bronchial dilation CNS stimulation Tan Si Yuan (00000032054) ME121 FPP1 Notes Adrenergic alpha antagonists Alpha blockers Effects: ○ General → vasodilation → decrease TPR, venous pooling and BP ○ a1 (vascular SM, prostate, radial muscle) - vasodilation, relaxation of muscles around prostate and bladder, miosis, nasal stuffiness ○ a2 (presynaptic, pancreas) - stimulate NE release (tachycardia), stimulate insulin release Drug type Example MOA Effect Clinical use AE Additional info Non-selective Phentol- Competitively blocking alpha 1/2 a1 block → Used parenterally to reverse OH (venous a2 blockade is not used in reversible amine -adrenergic receptors reversibly vasodilation, reduction vasoconstriction resulting pooling), humans in BP from release of tachycardia, catecholamines that occurs nasal stuffiness, a2 block → during surgery for fail to ejaculate sympathetic activation, pheochromocytoma tachycardia Non-selective Phenoxy- Blocks both a1 and a2 receptors Pheochromocytoma, control Pheochromocytoma= a rare, irreversible benzamine irreversibly episodes of hypertension usually benign tumor that (effects of increase develops in an adrenal gland. catecholamine) Selective a1 Prazosin Selectively binds to a1 receptor → CVS: decrease TPR → Essential hypertension, BPH OH, syncope, May cause Na+ and H2O blocker acts in arterioles and veins decrease BP headache, retention nasal stuffiness, Tamsulosin Potent *Less tachycardia than BPH (preferred) dizziness non selective a blocker Selective a2 blocker Yohimbine Tan Si Yuan (00000032054) ME121 FPP1 Notes Adrenergic beta antagonists Beta blockers Effects: ○ b1 (heart, kidney) - reduce HR, conduction, contractility, CO, TPR, reduce renin release (antihypertensive, antiarrhythmic, anti ischemic effects) ○ b2 (BV, bronchial/GI SM, uterine, detrusor muscle of urinary bladder) - vascular SM contraction, contraction of SM and uterine muscles, increased motility ○ b3 (adipose tissue) - decrease lipolysis, dyslipidemia ○ Others: decreased IOP, inhibits adrenaline tremors, sedation and lethargy Drug type Example MOA Effect Clinical use AE CI Additional info Non-selective Propranolol Blocks existing sympathetic tone Decrease HR, CO, Hypertension, IHD, Dizziness, Asthma, Well absorbed pacemaker activity, slow hyperthyroidism, fatigue, COPD, HF, orally, can penetrate decrease in peripheral migraine depression heart block, BBB, extensive first resistance prophylaxis, shock, DM-II pass metabolism glaucoma, essential Sudden Cardioselective Metoprolol Less risk of broncho- tremors withdrawal: DDI: anti Does not help with constriction, less risk of rebound HTN, HTN drugs, suppressing tremors Atenolol metabolic abnormalities angina, MI insulin, CCB, oral hypo- With ISA Pindolol Has some B1 and B2 agonist Suitable for patients Withdrawal less glycemic Not suitable in abilities to have likely to cause drugs patients with IHD bradycardia/ rebound HTN, bronchial asthma angina With α blocking Labetalol Block a1, b1 and b2 → decrease Pregnancy induced effect systemic arterial BP and vascular HTN, hypertensive resistance emergencies *Does not reduce HR, CO, SV *ISA = Intrinsic sympathomimetic activity Tan Si Yuan (00000032054) ME121 FPP1 Notes Drugs used for malaria Species Falciparum → only present in blood (trophozoite) Vivax, ovale → present in hepatic tissue (schizont) and blood Treatment of malaria Clinical cure (suppressive prophylaxis) → relieve symptoms Radical cure (causal prophylaxis) → completely eliminate parasite from body Drug type Example MOA PK effects Therapeutic use Adverse effects Additional info Group I Chloroquine Prevents conversion Large Vd and extensive tissue P. vivax, P. ovale GI symptoms, parenteral may Falciparum may be of haem → binding and storage, remains in malaria (clinical cure), lead to toxicity → CVS, CNS resistant (pushes QC out Effective (Quinolones hemozoin (food the tissue for a vv long time CQ sensitive (hypotension, arrhythmia, of the RBC) against compounds) source of parasite) falciparum (radical coma, convulsions), hemolytic erythrocytic → haem build up in Oral administration cure), RA, amoebic anaemia (in G6PD def) Prolonged therapy in RA stage only trophozoite → liver abscess is related to retinopathy toxicity Cinchonism is a collection of Quinine symptoms described as hearing Severe and CQ Triad: cinchonism, Blood schizonticide loss, tinnitus, dizziness, flushing, resistant falciparum, hypoglycemia, hypotension against all species and blurry vision stemming from cerebral malaria the ingestion of quinoline Hypersensitivity, cardiotoxicity, BWF: marked hemolysis + derivatives. BWF hemoglobinaemia Artemisinin Generates highly Potency x100 times greater than Higher sensitivity in Serious toxicity is rare, better First line treatment of compounds reactive free radicals other drugs, relapse rate is high CQ resistant parasite, tolerated than other drugs falciparum if used alone, used together as multi drug resistant ACT (artemisinin comp + malaria mefloquine/ lumefantrine) Fansidar Inhibits DHPS and - CQ resistant Steven Johnson’s syndrome Slow acting blood DHFR steps in the falciparum, (from sulfadoxine component) schizonticide Sulfadoxine + synthesis of purines toxoplasmosis pyrimethamine and pyrimidines Cannot give as prophylaxis (resistant) Tan Si Yuan (00000032054) ME121 FPP1 Notes Antibiotics Inhibit protein Used in combination with - Tetracycline may cause bone Slow acting blood synthesis through quinine and teeth deformities schizonticide against all (Tetracycline/ reversible binding to doxycycline/ bacterial 30 S Doxycycline is given as clindamycin) ribosomal subunits Clin given in children prophylaxis Group II Proguanil Inhibiting the Effective against primary liver - - Slow acting blood enzyme, forms, not used alone (in schizonticide Effective dihydrofolate combination with atovaquone) against reductase, which is erythrocytic involved in the and primary reproduction of the hepatic parasite stage Atovaquone Interferes with - - GI adverse effects, not to be Targets sexual stage of life mitochondria given to children and in cycle functions of parasite pregnancy Group III Primaquine Inhibit respiratory - Radical cure and Severe hypotension in Used as prophylaxis process in parasite prevention of relapse parenteral route Effective in vivax and ovale Only drug effective against infections CI: G6PD deficiency (decrease against primary and latent primary and NADPH, decrease RBC hepatic stages, no effect latent integrity) on erythrocytic forms hepatic stage