Special Pharmacology PDF

SPECIAL PHARMACOLOGY 1. Basic principles in peripheral neurotransmission Neurotransmission is when neurotransmitter is released from the nerve ending to bind to a receptor and elicit a response. The nervous system is divided into CNS (brain & spinal cord) and peripheral NS (neurons located outside...

SPECIAL PHARMACOLOGY 1. Basic principles in peripheral neurotransmission Neurotransmission is when neurotransmitter is released from the nerve ending to bind to a receptor and elicit a response. The nervous system is divided into CNS (brain & spinal cord) and peripheral NS (neurons located outside of brain/spinal cord, connects CNS to muscles and organs). PNS is divided into afferent division (bring info from periphery to CNS) and efferent division (info from CNS to periphery). Efferent division is divided into somatic (voluntary control of function, control skeletal muscles) and autonomic (involuntary control of function, control internal organs). ANS is divided into sympathetic and parasympathetic. Most organs have dual innervation, organs w/ only symp innervation: sweat glands, adrenal medulla, kidney, pilomotor muscle. Sympathetic NS – “fight or flight”, adjusts body to stress, functions as unit, discharges as complete system, preganglionic neurons: thoracic/lumbar region, acetylcholine release; preganglionic fibers: short and highly branched, postganglionic neuron: long, many activated by 1 preganglionic, nicotinic receptor, norepinephrine release; target organ: adrenergic receptor; function: ↑HR, BP, blood flow to skeletal mm and heart, mydriasis, bronchodilation. Parasympathetic NS – “rest and digest”, maintain homeostasis, doesn’t discharge as complete system, preganglionic n: cranial nerves 3,6,9,10 and sacral region, acetylcholine release; preganglionic f: long with ganglia next to organ; postganglionic n: short one-to-one connection, nicotinic receptor, acetylcholine release; organ: muscarinic receptor; function: opposite to symp. Somatic NS: motor n. axon is highly branched, one somatic neuron innervate 100 muscle fibers, no ganglia, fast response, acetylcholine release, target organ: nicotinic receptor on skeletal muscle. Nicotinic/Inotropic receptors: direct link to ion channels, Muscarinic and adrenergic/Metabotropic receptors: no direct link to ion channels, second messenger (adenylyl cyclase, phosphatidylinositol system)àresponse. 2. Pharmacological effects of adrenergic neurotransmitters Adrenergic drugs act on receptors that are activated by norepinephrine or epinephrine (sympathetic ns-fight or flight). ALPHA RECEPTORS rank order = epinephrine > norepinephrine >> isoproterenol A1: Gq, prosympathetic, present on effector organs, vasoconstriction, ↑BP, ↑peripheral resistance, mydriasis, ↑closure of internal sphincter of the bladder (decrease urination), ↑glycogenolysis, ejaculation, location: vascular smooth muscles, prostate, heart, papillary dilator muscle, pilomotor smooth muscles A2: Gi, antisympathetic, decrease norepi release, present in sympathetic presynaptic nerve ending and presynaptic parasym neuron, inhibit Ach release, inhibit insulin release, platelet aggregation. Further subdivisions: A1a, A1b, A1c, A1d, A2a, A2b, A2c (ex. tamsulosin is a selective A1a antagonist used to treat benign prostatic hyperplasia) BETA RECEPTORS isoproterenol>epinephrine >norepinephrine B1: Gs, equal affinity for E and NE, inhibitory of everything except heart, hormones and metabolism, tachycardia, ↑myocardial contractility, ↑conduction velocity, location: heart, kidney B2: Gs, vasodilation, ↓peripheral resistance, bronchodilation, ↑muscle and liver glycogenolysis, ↑release of insulin, relaxed uterine smooth mm, location: lungs, uterine and vascular smooth mm, skeletal mm of liver. DELTA RECEPTORS D1: vasodilation of vasculature (coronary, renal, mesenteric), ↑renal blood flow, ↑GFR, ↑Na+ excretion, location: smooth mm D2: location: nerve ending ← important extra info for a-receptors and G-protein mechanism 3. Drugs affecting adrenergic neurotransmission. Adrenergic neurons release norepinephrine as the primary neurotransmitter. Synthesis: tyrosine is transported inside the neuron and hydroxylated to DOPA (enzyme: tyrosine hydroxylase), this is a rate-limiting step, DOPA is decarboxylated to form dopamine (enzyme: aromatic L-amino acid decarboxylase). Storage: dopamine is transported into the synaptic vesicles by amine transporter system (inhibition: reserpine), Dopamine is hydroxylated to form norepinephrine (enzyme: dopamine B-hydroxylase). Release: AP arriving at the nerve junction triggers influx of Ca2+, excretion of vesicle content (inhibition: guanethidine). Binding: norepinephrine binds to post-synaptic receptors, formation of second-messenger (cAMP and phosphatidylinositol cycle). Removal: can diffuse out of synaptic space and enter systemic circulation, be metabolized to inactive metabolites in the synaptic space (enzyme: COMT), undergo reuptake into the neuron by Na/Cl dependent transporter (inhibition: tricyclic antidepressants). Potential fates: once norepinephrine re-enters the neuron it may be taken up into vesicles, persist in a protected pool in cytoplasm, oxidized by monoamine oxidase (MAO) present in mitochondria. *Mention characteristic responses of adrenoceptors *Talk about agonists (question 4) and antagonists (question 5) Maybe this too → Drugs affecting neurotransmitter release or uptake – Reserpine: slow onset, long duration, blocks Mg2+/ATP transport of NE, dopamine, and serotonin from cytoplasm into storage vesicles, replaced w/ newer drugs with better SE and less drug interactions. 4. Adrenergic agonists (sympathomimetics) Adrenergic drugs act on receptors that are activated by norepinephrine or epinephrine. Sympathomimetics activate adrenergic receptors. DIRECT-ACTING directly act on α/β receptors. Epinephrine: interact with both α and β receptors (β> α), PK: IM, IV in emergency, SC, inhalation; actions: CV-strengthen contractility of myocardium (B1) and ↑HR (B1), ↑cardiac output, release renin (B1), constrict arterioles in skin, mucous memb and viscera (α), dilates vessels of liver and skeletal mm (B1), Respiratory-bronchodilation (B2), inhibits release of allergy mediators ex. histamine, Hyperglycemia-↑glycogenolysis in liver (B2), ↑glucagon release (B2), ↓insulin release (a2), Initiates lipolysis; therapeutic use: bronchospasm, acute asthma, cardiac arrect, ↑ duration of anesthetics; SE: CNS effects (anxiety, fear, tension, headache, tremor), trigger cardiac arrhythmias, pulmonary edema. Norepinephrine: α>β, PK: IV, 1-2min duration, metabolized by MAO/COMT, urine excretion, actions:CV-vasoconstriction (a1), ↑systolic and diastolic BP, Baroreceptor reflex- ↑BPàbaroreceptor stimulationà↑vagal activityàbradycardia, therapeutic use: shock, SE: similar to epinephrine, blanching of skin, tissue necrosis. Isoproterenol: β1= β2, actions: ↑HR, ↑contractility, ↑cardiac output, dilates arterioles of skeletal mm (B2), bronchodilation (B2). Dopamine: D>β>α, actions: CV-vasoconstriction (a1) at high dose, stimulation of B1 receptors of heart at low dose, ↑blood flow to kidney (D receptor), therapy: cardiogenic and septic shock, diuresis, hypotension and severe heart failure, SE: nausea, hypertension, arrhythmias. Fenoldopam: D1, PK: extensive first pass metabolism, 10min elimination half-life after IV, therapy: rapid-acting vasodilator for hypertension, SE: headache, flushing, dizziness, nausea, vomiting. Dobutamine: β1, ↑HR, ↑cardiac output, therapy: acute heart failure, SE: caution in atrial fibrillation, tolerance. Oxymetazoline: a1-a2, PK: ophthalmic drops, nasal spray, action: vasoconstriction, decongestant, SE: headache, nervousness, sleeping problems, sneezing, dependence. Phenylephrine: a1, action: vasoconstriction, induces reflex bradycardia, therapy: hypotension, SE: headache, cardiac irregularities. Clonidine: a2, actions: inhibits sympathetic vasomotor centers, therapy: hypertension, minimize withdrawal symp of opiates, tobacco, SE: lethargy, sedation, constipation. Albuterol, Terbutaline: β2, short-acting, actions: bronchodilators, therapy: acute asthma, uterine relaxant to suppress premature labor, SE: tremor, restlessness, anxiety, don’t use w/ MAOI. Salmeterol, Formoterol: β2, long-acting, combined with corticosteroids for more efficacy, actions: 12h bronchodilation. Mirabegron: β3, actions: relax detrusor mm., ↑bladder capacity, SE: ↑BP so don’t use with hypertension. INDIRECT-ACTING don’t directly affect postsynaptic receptors, inhibit reuptake or degradation of E or NE. Amphetamine: a1 and B1, ↑BP, release of catecholamines (dopamine and NE) by inhibiting MAOI. Tyramine: not clinically useful, found in fermented food, displaces NE from storage vesicles, metabolized by MAO. Cocaine: block Na/Cl dependent Ne transporter requited for reuptake of NEàaccumulation of NEà ↑sympathetic activity. MIXED-ACTING Ephedrine: directly stimulate α/β receptors, release stored NE, vasoconstriction, ↑alertness, ↑athletic performance, therapy: asthma attack, hypotension 5. Adrenergic antagonist (sympatholytics) Adrenergic drugs act on receptors that are activated by norepinephrine or epinephrine. Sympatholytics block activation of adrenergic receptors. α -BLOCKERS ↑vasodilation, ↓BP, ↓ peripheral resistance, provoke reflex tachycardia. Non-selective (a1 & a2) Phentolamine: short acting, 4h, competitive, therapy: short-term pheochromocytoma, hypertensive crisis, SE: postural hypotension, anginal pain, arrhythmias. Phenoxybenzamine: long acting, 24h, non-competitive, therapy: pheochromocytoma, raynaud disease, frostbite, SE: postural hypotension, nasal stuffiness, nausea, vomiting. Selective (a1) Prazosin, Terazosin, Doxazosin (longest acting), Tamsulosin, Alfuzosin - therapy: hypertension, SE: dizziness, low energy, headache, inhibition of ejaculation, floppy iris syndrome. Yohimbine: a2, competitive, therapy: erectile dysfunction. β-BLOCKERS (B1 receptor sites mainly in heart, B2 in bronchi, blood vessels and uterus) Non-selective (B1 & B2) Propranolol (less potent): action: ↓cardiac output, decrease SA and AV node activity, vaso- and bronchoconstriction, ↓glycogenolysis; therapy: hypertension, angina pectoris, myocardial infarction, migraine, hyperthyroidism; SE: bronchoconstriction, arrhythmias, sexual dysfunction, fatigue. Nandolol, Timolol: intraocular application (12-24h effect), ↓aqueous humor production, therapy: glaucoma. Selective (B1) Acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, nebivolol - action: ↓BP without affecting pulmonary function (cardioselective), therapy: hypertension, chronic stable angina, SE: hypotension OTHERS Antagonist-partial agonist Acebutolol, pindolol: stimulate B- receptors but inhibit stimulation of catecholamines, ↓HR and output, don’t decrease HDL. α and β antagonists Labetalol, carvedilol: vasodilation, ↓BP, SE: orthostatic hypotension, dizziness, therapy: hypertension. Drugs affecting neurotransmitter release or uptake – Reserpine: slow onset, long duration, blocks Mg2+/ATP transport of NE, dopamine, and serotonin from cytoplasm into storage vesicles, replaced w/ newer drugs with better SE and less drug interactions. ← extra info?? 6. Acetylcholine as a cholinergic neurotransmitter Ach is a quaternary ammonium compound, can’t penetrate membranes, acts on muscarinic and nicotinic receptors, rapidly inactivated by the action of cholinesterase, lacks therapeutic importance. Locations of functioning: preganglionic fibers of adrenal medulla and autonomic ganglia of sympathetic and parasympathetic, postganglionic fibers of parasymp and symp (sweat glands), NMJ, CNS. Actions: IV injection leads to ↓HR and cardiac output, ↓BP, vasodilation, activates M3 receptors → production of nitric oxide → production of protein kinase G → hyperpolarization and smooth mm relaxation, ↑GI secretion and motility, ↑bronchiolar secretions, urination, miosis. Synthesis: choline is transported inside cholinergic neuron (inhibition: hemicholinum), rate-limiting step, choline+AcetylCoA=Ach (enzyme: choline transferase) Storage: Ach stored in vesicles by active transport, mature vesicle contains Ach, ATP, and proteoglycan Release: AP arrives at nerve ending→Ca2+ channels open (influx of Ca2+)→release Ach in synaptic cleft (inhibition: botulinum toxin) Binding: Ach binds to nicotinic and muscarinic receptors leading to biological response Degradation: Ach=choline+acetate (enzyme: acetylcholinesterase). Recycling: choline may be recaptured by a Na+ coupled uptake system that transports it back into the neuron. 7. Cholinergic agonists (parasympathomimetics) Cholinergic drugs act on receptors that are activated by Ach. Cholinergic agonists mimic the effect of Ach by binding to cholinoreceptors (muscarinic or nicotinic). DIRECT-ACTING Endogenous choline esters Ach: quaternary ammonium compound, can’t penetrate membranes, acts on muscarinic and nicotinic receptors, rapidly inactivated by the action of cholinesterase, lacks therapeutic importance. Actions: IV injection leads to ↓HR and cardiac output, ↓BP, vasodilation, activates M3 receptors → production of nitric oxide → production of protein kinase G → hyperpolarization and smooth mm relaxation, ↑GI secretion and motility, ↑bronchiolar secretions, urination, miosis. Synthetic esters of choline Bethanechol: unsubstituted carbamoyl ester, inactivated through hydrolysis, lack of nicotinic action but strong muscarinic activity, actions: ↑GI motility, stimulate urination, therapy: stimulate atonic bladder in post-partum, non-obstructive urinary retention, megacolon, SE: sweating, salivation, flushing, ↓BP, nausea, abdominal pain, diarrhea, bronchospasm. Carbachol: ester of carbamic acid and poor substrate for AchE, actions: stimulate then depress CV and GI, release of epinephrine from adrenal medulla, miosis, spasm of accommodation (eye in constant contraction), therapy: glaucoma, SE: little or none. Naturally occurring Pilocarpine: alkaloid, tertiary amine, stable to hydrolysis by AchE, less potent than Ach but can penetrate CNS. Actions: miosis, spasm of accommodation, stimulator of secretions (sweat, tears, saliva), ↑salivation in xerostomia patients, therapy: glaucoma (decrease intraocular pressure), SE: blurred vision, night blindness, brow ache, poisoning (antidote: atropine). INDIRECT-ACTING REVERSIBLE prevents degradation of Ach by inhibiting AchE Short-acting Edrophonium: rapid absorption, 10-20min duration, rapid renal elimination, quaternary amine, actions limited to periphery, therapy: diagnosis of myasthenia gravis (autoimmune disease), SE: IV injection→ ↑of muscle strength, cholinergic crisis when in excess. Intermediate acting Physostigmine: 30min-2h, tertiary amine, carbamic acid ester, ↑ cholinergic activity in the body, actions: stimulate nicotinic and muscarinic receptors of ANS, stimulate nicotinic recept of NMJ, therapy: ↑intestinal and bladder motility, overdose of anticholinergic drugs (atropine), SE: convulsions, bradycardia, ↓cardiac output, paralysis of skeletal mm (by accumulation of Ach in NMJ). Neostigmine: 30min-2h, synthetic carbamic acid ester, actions: greater effect on skeletal mm than physostigmine, more polar, poorly absorbed from GIT, doesn’t enter CNS, therapy: stimulate GIT and bladder, antidote for competitive neuromuscular-blocking agents, myasthenia gravis, SE: salivation, flushing, ↓BP, nausea, abdominal pain, diarrhea and bronchospasm. Pyridostigmine, ambenonium: 3-6h/4-8h, therapy: chronic management of myasthenia gravis, SE like neostigmine. Donepezil, rivastigmine, galantamine: treatment of Alzheimer (delay progression). INDIRECT-ACTING IRREVERSIBLE bind covalently to AchE and induce long-lasting ↑ of Ach. Ecothiophate: binds via phosphate group to active site of AchE (permanent inactivation), actions: generalized cholinergic stimulation, paralysis, convulsions, miosis, therapy: open-angle glaucoma, SE: cataracts. 8. Cholinergic antagonists (parasympatholytics) Cholinergic drugs act on receptors that are activated by Ach. Cholinergic antagonists prevent the effect of Ach by binding to cholinoreceptors (muscarinic or nicotinic). ANTIMUSCARINIC AGENTS: aka anticholinergic drugs, block muscarinic rec, effects of parasymp innervation are blocked, block few sympathetic neurons that are cholinergic (salivary and sweat glands), don’t block nicotinic rec (no effect on NMJ/autonomic ganglia). Atropine: natural, tertiary amine belladonna alkaloid (cross BBB), competitive binding, acts centrally and peripherally, 4h duration, lasts days in the eye, PK: readily absorbed, partially metabolized by liver, eliminated by urine, half-life 4h, actions: eye (block M3→mydriasis, unresponsiveness to light, cycloplegia), GIT (block M3→antispasmodic, ↓GIT activity, no effect on HCl production, reduce salivary secretion and urination), CV (low dose→block M1→↓HR; high dose→block M2→↑HR), secretions (xerostomia); therapy: ophthalmic (mydriatic and cycloplegic effects), antispasmodic (relax GI tract), treat bradycardia, block secretions of upper and lower respiratory tracts, antidote for cholinergic agonist (treat organophosphate poisoning and anticholinesterase overdose), SE: dry mouth, blurred vision, sandy eyes, tachycardia, urinary retention, constipation, CNS (restlessness, confusion, hallucinations, delirium, death). Scopolamine: M1 antagonist, tertiary amine plant alkaloid (cross BBB), greater action on CNS, longer duration of action, actions: anti-motion sickness, block short-term memory, sedation, euphoria (high dose), therapy: motion sickness (topical patch), postoperative nausea. Ipratropium, tiotropium: M3 antagonist, quaternary derivatives of atropine (don’t cross BBB), by inhalation, don’t enter CNS, bronchodilator for treatment of bronchospasm associated with COPD. Tropicamide, cyclopentolate: duration of action shorter than atropine, ophthalmic solutions for mydriasis and cycloplegia. Benztropine, trihexyphenidyl: used with other antiparkinsonian agents and EPS. Darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, trospium chloride: M3 blockers un bladder, treat overactive bladder, SE: dry mouth, constipation, blurred vision. 9. Ganglionic blocking agents and peripheral myorelaxants Cholinergic drugs act on receptors that are activated by Ach. Cholinergic antagonists prevent the effect of Ach by binding to cholinoreceptors (muscarinic or nicotinic). GANGLIONIC BLOCKERS: block nicotinic receptors of both parasymp and sympathy ganglia, some block ion channels of autonomic ganglia, not effective as neuromuscular antagonists, are clinically the least important of the cholinergic antagonists. Nicotine: poison, no therapeutic use, depolarization of autonomic ganglia→stimulation and paralysis of all ganglia → ↑ release of neurotransmitters (dopamine and norepineph), ↓ transmission between preganglionic and postganglionic neurons, actions: ↑BP and HR, ↑peristalsis, ↑secretions, at high doses: ↓BP because of ganglionic blockade, ↓GIT and bladder activity. MYELORELAXANTS: block transmission of efferent impulses between motor nerve endings and nicotinic receptors on skeletal mm, similar to Ach, useful in surgery to facilitate tracheal intubation and total muscular relaxation (low anesthetic doses). Nondepolarizing/competitive blockers Cisatracurium, pancuronium, rocuronium, vecuronium: PK: IV, IM, don’t cross BBB, poor membrane penetration, not metabolized, actions terminate by redistribution, pancuronium excreted unchanged in urine, cisatracurium degraded in plasma, vecuronium and rocuronium deacetylated in liver and excreted unchanged in bile. Actions: low dose (block Ach at nicotinic rec→prevent depolarization of the muscle cell membrane, inhibit mm contraction. Competitive action is overcome by use of neostigmine and edrophonium→shorten duration of neuromuscular blockade), high dose (block ion channels of motor endplate→weakening of neuromuscular transmission, ↓ ability of cholinesterase inh. to reverse actions of nondep blockers→mm don’t respond to direct electrical stimulation), small rapidly contracting mm of face and eye are paralyzed first, then fingers, limbs, neck, trunk mm, diaphragm. SE: minimal. Drug interactions: cholinesterase inhibitors (neostigmine, pyridostigmine, physostigmine, edrophonium) overcome action of nondepolarizing myorelaxants, at high doses cause depolarizing block; halogenated hydrocarbon anesthetics (desflurane) ↑neuromuscular blockade by stabilizing NMJ; aminoglycoside antibiotics (gentamicin, tobramycin) inhibit Ach by competing w/ Ca+ ions; calcium channel blocker ↑neuromuscular blockade. Depolarizing agents Succinylcholine: attach to nicotinic receptors and acts like Ach to depolarize the junction, persists at high concentration in synaptic cleft and remains attached to receptor for long time (constant stimulation), opens Na channel on receptor→depolarization of rec→ twitching of mm.→recep cannot transmit impulses→repolarization due to Na channel block→ flaccid paralysis. PK: IV, short duration of action, given as continuous infusion. Actions: muscle fasciculations causing muscle soreness, therapy: rapid endotracheal intubation, electroconvulsive shock treatment, SE: hyperthermia, apnea, hyperkalemia, contraindicated in burn patients and patients w/ electrolyte imbalance who are receiving digoxin. 10. Basic principles in CNS neurotransmission Neurotransmission in CNS is in many ways similar to ANS ex. info is transmitted by release of neurotransmitters that bind to receptors on the postsynaptic neuron, recognition of neurotransmitter by receptor triggers intracellular change. However, some differences are that the circuitry of the CNS is more complex, number of synapses is greater, has networks of constantly acting inhibitory neurons that modulate the rate of neuronal transmission, communicates with multiple neurotransmitters while ANS only has Ach and norepinephrine. Synaptic potentials: receptors are coupled to ion channels, binding of neurotrans causes opening of ion channels, ions outside and inside cell memb flow down their concentration gradient, change in ionic composition alters postsynaptic potential & produces depolarization or hyperpolarization of postsynaptic memb. Excitatory pathways: the flow of ions after stimulation of excitatory neuron leads to depolarization of postsynaptic memb. Excitatory postsynaptic potentials (EPSP) are generated by 1)stimulation of an excitatory neuron →release of neurotransmitter (glutamate, Ach) which bind to receptors→↑ permeability of Na+ ions 2)influx of Na+ →weak depolarization→postsynaptic potential moves toward its firing threshold 3) ↑number of stimulated excitatory neurons excitatory→ ↑excitatory neurotransmitter release→EPSP depolarization of the postsynaptic cell exceeds threshold→generating all-or-none action potential. Inhibitory pathways: the flow of ions after stimulation of inhibitory neuron leads to hyperpolarization of postsynaptic memb. IPSP are generated by 1)stimulation of inhibitory neurons →release of neurotransmitter (GABA or glycine) which bind to receptors→ ↑ permeability of K+ and Cl− 2)influx of Cl− and efflux of K+ →weak hyperpolarization→postsynaptic potential moves away from its firing threshold→ ↓ generation of action potentials. Combined effects of EPSP and IPSP: neurons in the CNS receive both EPSP and IPSP signals so different types of neurotransmitters act on the same neuron but on different receptors. Neurotransmitters are not uniformly distributed, located in clusters. 11. Classical (typical) antipsychotic drugs Antipsychotic drugs are used to treat schizophrenia and other psychotic/manic states, they are not curative but ↓intensity of symptoms. Schizophrenia is a type of chronic psychosis characterized by +symptoms (delusions, hallucinations, though disorders) and - symptoms (low motivation, emotional abnormalities, cognitive deficits, language problems). Occurs in 1% of population and onset is during late adolescence/early adulthood, strong genetic component, might be caused by excess dopaminergic activity. Dopamine pathways in brain 1)Mesolimbic pathway: ↑DA→ worsens delusions/hallucinations; D2 blockage→ alleviate delusions/ hallucinations, 2)Mesocortical pathway: DA→motivation, D2 blockage→ worsens neg symptoms, 3)Nigrostriatal pathway: DA→essential for extrapyramidal motor function, D2 blockage→produce extrapyramidal symptoms (EPS), 4) Tuberifundular pathway: DA→inhibits prolactin release, D2 blockage→hyperprolactinemia. Antipsychotic drugs are divided into first generation (typical) and second generation (atypical). PK: absorption not affected by food, pass BBB, metabolized by CYP450 in liver. Actions: antipsychotic effects (↓ +symptoms by blocking D2 receptors in mesolimbic system, ↓ -symptoms), extrapyramidal effects (dystonias, parkinson-like symptoms, akathisia, tardive dyskinesia; caused by blockage of D receptors in nigrostriatal pathway), antiemetic effect (by blocking D2 receptors of chemoreceptor trigger zone of medulla, exception: aripiprazole). SE: EPS (acute onset: acute dystonia-spasm of mm of tongue, face, neck, akathisia-motor restlessness, parkinsonism-bradykinesia, tremor, rigidity, mask facies; late onset: tardive dyskinesia-oral facial dyskinesia, fly-catching motions of tongue); Neuroleptic malignant syndrome (fatal reaction to drugs, mm rigidity, fever, altered mental status, weight gain, stupor, unstable BP, management: stop use of drug, bromocriptine), sedation, dry mouth, weight gain, urinary retention, postural hypotension, sexual dysfunction, seizures. 12. Atypical antipsychotic drugs Antipsychotic drugs are used to treat schizophrenia and other psychotic/manic states, they are not curative but ↓intensity of symptoms. Schizophrenia is a type of chronic psychosis characterized by +symptoms (delusions, hallucinations, though disorders) and - symptoms (low motivation, emotional abnormalities, cognitive deficits, language problems). Occurs in 1% of population and onset is during late adolescence/early adulthood, strong genetic component, might be caused by excess dopaminergic activity. Antipsychotic drugs are divided into first generation (typical) and second generation (atypical). PK: absorption not affected by food, pass BBB, metabolized by CYP450 in liver. Actions: antipsychotic effects (↓ +symptoms by blocking D2 receptors in mesolimbic system, ↓ -symptoms), extrapyramidal effects (dystonias, parkinson-like symptoms, akathisia, tardive dyskinesia; caused by blockage of D receptors in nigrostriatal pathway), antiemetic effect (by blocking D2 receptors of chemoreceptor trigger zone of medulla, exception: aripiprazole). SE: EPS (acute onset: acute dystonia-spasm of mm of tongue, face, neck, akathisia-motor restlessness, parkinsonism- bradykinesia, tremor, rigidity, mask facies; late onset: tardive dyskinesia-oral facial dyskinesia, fly-catching motions of tongue); Neuroleptic malignant syndrome (fatal reaction to drugs, mm rigidity, fever, altered mental status, weight gain, stupor, unstable BP, management: stop use of drug, bromocriptine), sedation, dry mouth, weight gain, urinary retention, postural hypotension, sexual dysfunction, seizures. ATYPICAL ANTIPSYCH DRUGS as effective as typical w/ regard to + symptoms, more effective than typical w/ regard to -symptoms, ↓incidence of EPS, ↑ risk of metabolic side effects, tardive dyskinesis occurs at lower incidence Selective D2/D3 antagonists Sulpiride, amisulpiride: low affinity to 5HT2A receptors, transiently occupies D2 receptors, low doses- antagonism of presynaptic D2/D3 receptors in prefrontal cortex and nigrostriatal area→ ↑dopamine secretion→ less - symptoms and EPS, high doses- antagonism of postsynaptic D2/D3 receptors → less +symptoms and EPS; SE: ↑prolactin (galactorrhea, gynecomastia, erectile dysfunction, menstruation irregularity), insomnia, somnolence, irritability. Serotonin-dopamine antagonist lower affinity to D2, higher affinity to 5HT2A. Sertindole, paliperidone, risperidone: good at low doses, use in elderly, kids, adolescents, doesn’t block H1 receptors=less weight gain, SE: ↑prolactin (galactorrhea, gynecomastia, erectile dysfunction, menstruation irregularity). Multi-acting receptor-targeted antipsych apart from D2 and 5HT2A they also block adrenergic, cholinergic, and histaminergic receptors, low or no EPS and TD, no increase in prolactin. Clozapine (greatest efficacy but highest SE: life-threatening agranulocytosis, seizures, myocarditis), Olanzapine, Quetiapine, Ziprasidone Partial dopamine receptor agonis considered a “3rd generation”. Aripiprazole: ↓EPS due to agonism of D2, antipsychotic effect due to partial agonism of D2 and 5HT1A and antagonism of 5HT2A, no antiemetic effect, SE: nausea, vomiting, restlessness, diabetes mellitus. 13. Antidepressants Symptoms of depression are hopelessness, lack of interest, loss of appetite, suicidal thoughts SELECTIVE SEROTONINE REUPTAKE INHIBITORS (SSRI) oral, onset of action: 2-12 weeks, block reuptake of serotonin leading to ↑ of neurotrans in synaptic cleft, fewer/less severe SE than TCAs and MAOIs because of little blocking activity at muscarinic, a-adrenergic, and histaminic H1 receptors. Fluoxetine: longer half-life, inhibits CYP450 (CYP2D6), only SSRI approved for bulimia nervosa; Paroxetine, fluvoxamine, citalopram, escitalopram, fluvoxamine. SE: anxiety, headache, nausea, vomiting, insomnia, sexual dysfunction, discontinuation syndrome. SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS (SNRI) block reuptake of serotonin and norepinephrine, unlike TCA they have little blocking activity at muscarinic, a- adrenergic, and histaminic H1 receptors. Venlafaxine, desvenlafaxine, duloxetine levomilnacipran. SE similar to SSRI. TRICYCLIC ANTIDEPRESSANTS (TCA) inhibit reuptake of serotonin and norepinephrine like SNRI, differ from SNRI in that they block muscarinic, a- adrenergic, and histaminic H1 receptors=more SE, oral, lipophilic, penetrate CNS, metabolized by liver, excreted via kidney. Tertiary amines→ Imipramine, clomipramine, trimipramine, amitriptyline, doxepin; secondary amines→ Desipramine, notriptyline, protriptyline; Amoxapine, maprotiline. SE: weight gain, dry mouth, blurred vision, nausea, constipation, urinary retention, tachycardia, arrhythmias, drowsiness. MONOAMINE OXIDASE INHIBITORS (MAOI) oral, antidepressive effect after 2-3 weeks, MAO is enzyme found in nerves, gut and liver which metabolize excess neurotransmitters (NE, serotonin, dopamine), MAOI inactivate MAO so neurotransmitters avoid degradation and accumulate, used when patients don’t respond/allergic to TCA and SSRI. Phenelzine, tranylcypromine, isocarboxazid, selegiline (transdermal patch). SE: can’t degrade tyramine (hypertensive crisis), drowsiness, orthostatic hypotension, blurred vision, dry mouth, contraindication: MAOI + antidepressants. ATYPICAL ANTIDEPRESSANTS Bupropion: weak dopamine and norepin reuptake inhibitor, metabolized by CYP2B6, therapy: smoking cessation aid, SE: dry mouth, sweating, tremor. Mirtazapine: not a reuptake inhibitor, antagonist at a2-receptors, SE: ↑appetite, weight gain. Nefazodone, trazodone: weak serotonin reuptake inhibitor, block 5HT2A and H1 receptors. 14. Antianxiety and hypnotic drugs Anxiety is an unpleasant state of physical and emotional distress which interferes with normal life. Antianxiety drugs also cause sedation, so they are used as both anxiolytics and hypnotics. BENZODIAZEPINE are indirect GABAa receptor agonists (GABA is main inhibitory neurotrans in CNS). ↑affinity of GABA to GABAa receptors→↑GABA action→↑opening of Cl- channels→ influx of Cl- causes hyperpolarization on postsynaptic memb→↓neurotransmission. Long acting (1-3days): clorazepate, chlordiazepoxide, diazepam, flurazepam, quazepam; intermediate acting (10-20h): alprazolam, estazolam, lorazepam, temazepam; short acting (3-8h): oxazepam, triazolam. PK: oral, lipophilic, cross CNS, metabolized by liver, urine excretion, cross placenta and depress CNS in babies. Actions: anxiolytic, hypnotic, anterograde amnesia, anticonvulsant, muscle relaxant. Therapy: anxiety related to depression and schizophrenia, sleep disorders (↑stage 2 REM, Temazepam in patients experiencing frequent awakening, Triazolam in patients w/ difficulty falling asleep), amnesia (short acting agents before procedures ex. endoscopy, Midazolam), seizures (Lorazepam, diazepam for status epilepticus and chlordiazepoxide, oxazepam to ↓ risk of alcohol withdrawal seizures), skeletal muscle spasms, spasticity from degenerative disorders. SE: dependence, tolerance, amnesia, strong interaction w/ alcohol, drowsiness, confusion, avoid during pregnancy. Benzodiazepine antagonist Flumazenil: GABA receptor antagonist that reverses effects of benzodiazepines, IV, rapid onset, short duration, half-life: 1h. SEROTONIN (5HT1A) AGONIST Buspirone: chronic treatment of generalized anxiety disorders (GAD), slow onset, not effective for short-term, no anticonvulsant or muscle-relaxant properties, low frequency of SE (headache, dizziness, nervousness, nausea), dependance is unlikely. ANTIDEPRESSANTS SSRIs: escitalopram, paroxetine, SNRI: venlafaxine, duloxetine. Given in combination with low dose of benzodiazepines, ↓dependance than benzodiazepines, first- line treatment of GAD. BARBITURATES potentiate GABA action by prolonging duration of Cl- channel opening, block excitatory glutamate, replaced by benzodiazepines because barbiturates cause tolerance, dependence, and withdrawal symptoms. PK: oral, metabolism in liver, excretion in urine, cross placenta. Long-acting (1-2days): phenobarbital; short-acting (3-8h): pentobarbital, secobarbital, amobarbital; ultra-short-acting (20min): thiopental. Actions: low dose-sedation, high dose-anesthesia, respiratory depression. Therapy: hypnosis, sedation, anticonvulsant, anesthesia. SE: addictive, enzyme induction, drowsiness, nausea, vertigo, tremors. OTHER HYPNOTICS Zolpidem: binds to omega-1 subtype which is a-unit of the GABAa receptor complex, no anticonvulsant or muscle-relaxing properties, minimal rebound insomnia, little tolerance, few withdrawal effects. PK: lingual spray, rapid onset of action, short half-life: 2-3h. SE: nightmares, agitation, anterograde amnesia, headache. Zaleplon: similar to zolpidem but causes less SE, oral, half-life: 1h. Eszopiclone: BZ1 receptor, oral, peak effect: 1h, half-life: 6h, therapy: insomnia for up to 6 months, SE: unpleasant taste, dry mouth, peripheral edema, anxiety. Ramelteon: agonist at M1 and MT2 melatonin receptors, promote sleep, minimal abuse, no dependence or withdrawal effects, okay for long term use. 15. Stimulants of CNS Psychomotor stimulants: Methylxanthines: Theophylline (tea), Theobromine (cocoa), Caffeine (coffee products, tea, cola drinks). Actions: decrease in fatigue, increase mental alertness. Tolerance can develop rapidly (CNS). Positive inotropic effects on heart, mild diuretic action, stimulate secretion of gastric acid. Therapeutic use: relax smooth muscles of bronchioles. PK: orally, cross the placenta and secreted in breast milk, metabolized in liver and excreted in urine. SE: insomnia, anxiety, agitation. At high doses emesis and convulsions. Lethal dose arrhythmias. Nicotine: active ingredient of tobacco. Not used therapeutically. Mechanism of action: at low dose ganglionic stimulation (increase BP, HR, increase motility), at high dose ganglionic blockade (decrease BP and activity of GIT). Actions: liposoluble, cross BBB, improves attention, learning, reaction time. High doses central respiratory paralysis and severe hypotenion. PK: cross placenta, metabolism in lung and liver, urinary excretion. Tolerance rapid. SE: irritability, tremors, intestinal cramps, diarrhea, withdrawal sy. Varenicline: partial agonist at neuronal nicotinic acetylcholine receptors in CNS. Less euphoric than nicotine. Useful for smoking cessation in pt with nicotine withdrawal sy. Cocaine: Highly addictive. Blockade of reuptake of norepinephrine, serotonin and dopamine into presynaptic membrane. Potentiate and prolon their actions. Amphetamine: sympathethic amine. Metamphetamine is a derivative. Mechanism of action: release intracellular stores of catecholamines and inhibits monoamine oxidase (MAO). Increase alertness, decrease fatigue, depressed appetite, insomnia. Therapeutic use: (Psychological and physiological dependence limit therapeutic use). Attention defecit hyperactivity disorder, narcolepsy. PK: completely absorbed by GIT, metabolized by liver, excreted in urine. SE: vertigo, hypertension, insomnia, confusion, potential for addiction, nausea, diarrhea. Methylphenidate: Dopamine and norepinephrine transport inhibitor, increase both norepinephrine and dopamine in synaptic space. Therapeutic use: Attention defecit hyperactivity disorder, narcolepsy. PK: oral. SE: abdominal pain, nausea, anorexia, insomnia, fever, nervousness. 16. Antiepileptics Epilepsy is a disorder manifested by repeated seizures which result from paroxysmal uncontrolled discharges of neurons. There are two main types Focal: involve only part of the brain (simple partial-patient doesn’t lose consciousness, complex partial: altered consciousness). Generalized: involve both hemispheres of the brain (tonic-clonic, absence, myoclonic, clonic, atonic). General SE: nausea, vomiting, sedation, ataxia, rash, hyponatremia, weight gain, teratogenicity, osteoporosis. Carbamazepine: blocks Na+ channels, therapy: focal seizure, tonic-clonic seizures, trigeminal neuralgia, bipolar disorder, SE: ataxia, hyponatremia, fatigue, don’t use for absence seizures. Eslicarbazepine: blocks Na+ channels, SE: somnolence, diplopia, dizziness. Ethosuximide: blocks Ca2+ channels, therapy: absence seizure. Ezogabine: opens K+ channels, SE: urinary retention, QT interval prolongation, blue skin discoloration, retinal problems. Felbamate: block Na+ and Ca2+ channels, potentiate GABA, therapy: lennox-gastaut syndrome, SE: aplastic anemia, hepatic failure. Gabapentin: analog of GABA, unknown mechanism of action, therapy: focal seizures, postherpetic neuralgia, crosses BBB. Lacosamide: in vitro, blocks Na+ channels and binds to collapsing response mediator protein2, IV, therapy: focal seizures, SE: headache, dizziness, fatigue. Lamotrigine: block Na+ and Ca2+ channels, therapy: focal, generalized, and absence seizures, lennox-gastaut syndrome, SE: rash. Levetiracetam: high affinity for synaptic vesicle protein, therapy: myoclonic and tonic-clonic seizures. Oxcarbazepine: blocks Na+ channels. Perampanel: blocks AMPA glutamate receptors. Phenytoin: blocks Na+ channels, therapy: focal and tonic-clonic seizures, status epilepticus, SE: gingival hyperplasia, nystagmus, ataxia, slurred speech. Pregabalin: block Ca2+ channels, therapy: focal seizures, diabetic peripheral neuropathy, fibromyalgia, SE: weight gain, peripheral edema. Rufinamide: acta at Na+ channels, unknown mechanism, therapy: lennox-gastaut syndrome, drug interactions: inhibited by valproate, induced by carbamazepine, SE: shorten QT intervals. Tiagabine: block GABA uptake. Valproic acid, divalproex: block Na+ channels and GABA transaminase, therapy: absences, myoclonic, tonic-clonic seizures, SE: nausea, vomiting, abdominal pain, weight gain, hepatotoxicity, alopecia. Vigabatrin: irreversible inhibitor of GABA-T, SE: vision loss. Zonisamide: block Na+ and Ca2+ channels, therapy: focal epilepsy, SE: kidney stones, oligohidrosis. BENZODIAZEPINES bind to GABA inhibitory receptors to reduce firing rate, only for emergency. Diazepam-acute epileptic attack, Lorazepam-same as diazepam but more effective, Clonazepam-absences, myoclonic seizures, long acting, very effective. 17. Antiparkinsonics Parkinsonism is a degenerative disease of CNS, characterised by hypokinesia, muscle rigidity, tremor, and postural lability. It’s linked to destruction of dopaminergic neurons in the substantia nigra and a reduction of dopamine actions in the corpus striatum. Levodopa: metabolic precursor of dopamine, drug of first choice, converted to dopamine so it ↑ synthesis of dopamine, effective in first few years of treatment, decline in response during the 3rd-5th year of therapy, crosses BBB, must be administered with carbidopa (without it levodopa is decarboxylated to dopamine in the periphery→nausea, vomiting, cardiac arrhythmias, hypotension). Carbidopa: dopamine decarboxylase inhibitor, ↑ availability of levodopa in CNS, PK: absorbed from small intestine, short half-life (1-2h), SE: peripheral effects (anorexia, nausea, vomiting, tachycardia, hypotension, mydriasis), CN effects (mood changes, psychosis, dyskinesia. Drug interactions: vitamin B6 ↓ effectiveness, MAOIs produce hypertensive crisis, antipsychotic drugs are contraindicated. Amantadine: ↑ dopamine release, block cholinergic rec, inhibit NMDA, less efficacy than levodopa, fewer SE, tolerance. MAO-B INHIBITORS Selegiline: inhibits MAO-B, ↑dopamine by decreasing its metabolism, selegiline+levodopa=enhanced action, reduced required dose, SE: loses selectivity at high doses, insomnia, hypertension. Rasagiline:5x more potent, not metabolized to amphetamine- like substance. COMT INHIBITORS Entacapone, tolcapone (longer duration of action): reversibly inhibit COMT, prolong half-life of L-dopa, PK: oral, absorption not influenced by food, bound to plasma albumin, elimination by feces/urine. SE: postural hypotension, nausea, diarrhea, dyskinesia, hallucinations, fulminating hepatic necrosis (only tolcapone). DOPAMINE RECEPTOR AGONISTS delay motor complications, delay need to start L-dopa, less risk of dyskinesia, SE: hallucinations, confusion, nausea, hypotension Bromocriptine: ergot derivative, SE: pulmonary fibrosis. Apomorphine (IV), pramipexole, ropinirole (oral), rotigotine (transdermal patch): nonergot, don’t cause fibrosis. ANTIMUSCARINICS Benztropine, trihexyphenidyl, procyclidine: block cholinergic receptors, SE: mood changes, xerostomia, visual problems, contraindicated in patients with glaucoma, pyloric stenosis, prostatic hyperplasia. 18. Analgesics and antipyretic drugs Made up by 2 main categories NSAIDs and Acetaminophen. NSAIDS act by inhibiting synthesis of prostaglandins (PG) and cyclo-oxygenase (COX). Prostaglandins’ role in inflammation: release PGE2 (bronchodilation, vasodilation, ↓gastric acid secretion, ↑gastric mucus secretion, sensation on pain, ↑body temp), PGD2 (vasodilation, inhibit platelet aggregation), TXA2 (enhances platelet aggregation), PGF2a, PGI2. (Extra info, probably not necessary: arachidonic acid is primary precursor, PG synthesis by COX pathway: production of PG, TX and prostacyclines, COX 1-physiological production of prostanoids, COX 2-elevated production of prostanoids at inflammation site; Lipoxygenase pathway: production of leukotriens). NSAIDS have antipyretic, analgesic, and anti-inflammatory properties. Inhibit COX→↓PG synthesis (inhibition of COX1= prevention of cardiovascular events and most SE, inh. of COX2=anti- inflammatory and analgesic action). 5 classes include derivates of: salicylic acid (aspirin, diflunisal, salsalate), propionic acid (ibuprofen, ketoprofen, fenoprofen, naproxen, oxaprozin), acetic acid (diclofenac, etodolac, ketorolac, indomethacin, tolmetin), enolic acid (meloxicam, piroxicam), fenamates (mefenamic, meclofenamate) and selective COX-2 inhibitor celecoxib. General PK: oral, highly bound to plasma proteins, eliminated via urine. ASPIRIN: irreversible inhibitor of COX-1, Actions: anti-inflammatory (↓PG synthesis), analgesic action (for mild/moderate pain, ↓PGE2=↓sensation of pain), antipyretic action (↓PGE2=↓body temp). Therapy: anti-inflammatory and analgesic use (osteoarthritis, gout, RA, headache, arthralgia, myalgia; opiods+NSAIDS=treat pain caused by malignancy), antipyretic use (fever-aspirin, ibuprofen, naproxen), CV use (aspirin ↓risk of CV events by inhibiting COX1 production of TXA2 ex. MI), salicylic acid used topically to treat acne, calluses, warts. PK: deacetylated to salicylate, salicylates cross BBB and placenta, half-life: 3.5h at 4g/day, cleared by kidney, excreted by urine. General SE for most NSAIDs: GI (dyspepsia, bleeding, pain; caused by inhibition of COX1→reduction of beneficial properties of PGI2, PGE2, PGF2a), ↑risk of bleeding and bleeding time (antiplatelet effect; caused by inhibition of TXA2 formation), kidney problems (retention of Na+ and water, renal isufficiency/failure, hyperkalemia), ↑risk of CV events (all NSAIDs except aspirin), toxicity (mild form: nausea, vomiting, hyperventilation, headache, dizziness, tinnitus; severe form: hallucinations, convulsions, coma, death). Contraindications of aspirin: should be avoided in