Drug Chart for Pharmacology Final

Drug Chart for Pharmacol ogy Fi nal By: Ben Lawner As always, continually in rev ision.  CLASS/DRUG Anti mycobacterial Isoni azi d MECH Derivative of pyrido xine. Most potent, not admin alone. Inhibits enzy me involved in synth of mycolic acid. Assembly into outer laer of mycobacteria. Mycolic acids responsible for acid-fastness of mycobacteria; characteristic is lost following isoniazid exposure SPECTRUM Mycobacterium kansasii at high concentrations Mycobacterium TB KINETICS Orally b ioavailab le Absorption decreased by food or alu minu m containing antacids Enters body fluids and CSF Tx intracellular bacterial Dose reduced in chronic liver disease Glo m filtration Accum w/decreased renal fxn Toxic metabolite Well absorbed PO Widely distributed Enters CSF (Use for meningeal TB) Metabolized in liver Meningococcal prophylaxis Excreted in b ile, NOTE/ RES Fatal hepatoxcity Peripheral neuropathy Interactions with alcohol Vitamin B6 deficiency Resistance by: Altered target Excessive enzyme p roduced No cross resistance with other antitubercular agents Optic neurit is Hypersensitivty Potentiate phenytoin Anti mycobacterial/ Rifampin Inhibits transcription in bacteria. Inhi bits DNA dependent RNA polymerase Specific fo r prokaryotes Intra and extra cellu lar mycobacteriu m M. tuberculosis M. leprae M. aviu m Resistance develops: Alteration in target protein Decreased permeab ility Can induce hepatic microsomal en zy mes (caution with INH co ad ministration) CYP 450 interactions 1 feces, urine Some gram + act ivity Turn secretions orange-red Can stain contact lenses Jaundice Cx with protease inhi bitors (Saquinavir) due to fatalities Anti mycobacterial/ Rifabutin Anti mycobacteria/ Pyrazinami de Derivative of above Bactericidal More active against M. avium M. tuberculosis Used PO in combination with INH / rifampin Pro-drug- must be hydrolyzed to active compound Enters CSF, macrophages, lysosomes Enters CSF Metabolized Renal tubular secretion Glo merular filtration Resistance due to lack of pyrazinamidase or deceased permeab ility Anti mycobacterial / Myambutol Mechanism unclear. Used in co mbo with other agents, similar mechanis mt M. tuberculosis M. kansasii Optic neurit is Decreased visual acuity Disturbances in color vision Hyperuricemia Alternati ve TB agents / Aminosalycilic aci d Ethionami de Co mpetitive inhibitor of PA BA, similar to sulfonamide, inhib its PABA Folate antimetabolite Second line, unclear mechanis m . May inhibit synthesis of mycolic acids. M. tuberculosis M. tuberculosis Cycl oserine Inhibits cell wall synth M. tuberculosis PO Enters CSF Metabolized, inhibits INH Excreted in u rine PO Optic neurit is GI d isturbances Hepatotoxicity Peripheral neuropathies Peripheral neuropathies, CNS 2 Enters CSF Metabolized and enters urine Dose adjust in CRF CHEMOTHERAPY OF LEPROSY Daps one Rifampin Clofazi mine Must treat with 3 drugs to avoid resistance PABA antagonist, antimetabolite. Inhibits folic acid synthesis. Inhibits bacterial temp late function. disturbances, and seizures. Use limited to t x of resistant strains Daps one M. leprae PCP M. leprae M. aviu m FIRST LINE: Clarithro mycin Ethambutol Rifabutin Used for systemic and topical infect ions DOC systemic fungal infection Broad antifungal spectrum Produced synergy with flucytosene Candida alb icans Coccidiodes Cryptococcus Aspergillus Paracoccidiodes Blastomycoses Chro moblastomycosis Candidiasis Well absorbed PO Excreted in u rine Well absorbed PO Does not enter CNS SECOND LINE: Amikacin Ciproflo xacin Excreted in u rine and bile Clofazi mine Peripheral neuropathy Hemolytic anemia Methemoglobinemia Skin discoloration Eosinophilic enterit is TREATMENT OF ATYPICAL MYCOB ACTERIUM. Anti fung al/ Amphotericin B (Fungazone) Most common is M. aviu m. Affects immunocomp ro mised patients. Polyene macrolide antibiotic Binds to ergosterol and disrupts membrane function. Fungicidal. Disrupts membranes. Resistance is relatively uncommon but can occur due to decreased ergosterol composition. Low chemotherapeutic index. Flucytosine Antimetabolite. Converted within fungal cells into 5FU Synergy with Amph-B because Dose reduced in CRF Reversible bone marrow 3 Inhibits replication Cryptococcus with Amphotericin B Ampg B increased permeab ility Orally b ioavailav le suppression Hepatic dysfunction GI affects N/ V/ D CSF entry GLOM FILTRATION 4 Ketoconazole Imidazole derivative. Inhib its synthesis of lanosterol to ergosterol. Fungal equiv of cholesterol. Inhibiting fungal cytochrome p450 en zy mes Affects fungal memb rane permeability (Amphotericin binds to ergosterole already formed) Specific fo r fungi. Additive effect with flucytosine Azoles given in co mbo with flucytosine. Histoplasmosis Nonmen igeal coccidio mycosis Blastomycosis Does NOT enter CSF Only given orally Acidic conditions enhance bioavailability Undergoes extensive hepatic metabolism Excreted i n B ILE CYP 450 interaction Inhibit adrenal and gonadal steroidal synthesis Will inhibit effects of Amphotericin B Impaired by acids, food, and cimetid ine GI d isturbances Allerg ies Endocrine effects Half life decreased by agents that decrease p450 activity. (Rifamp in, phenytoin, phenobarbitol) Toxicity of phenytoin, cyclosporine, terfenadine, and astemizole are potentiated by inhibit ion of p450 systems. Potentiates toxicity of phenytoin, terfenadine, astemizole N/ V Candida Dermato mycosis Penetrates bone, lung, and skin. Useful for t x o f histoplasmosis in these areas. Fluconazole (Diflucan) Prevents the production of ergosterol identically to ketoconazole. Cryptococcus neoformans Candidemia Mucosal candidiasis Given orally or IV Excellent oral bioavailability Enters CSF Blastomycosis Coccidiodo mycosis Histoplasmosis Eliminated in URINE Skin rashes Teratogenic Care with renal dysfunction 5 Cryptococcal meningit is in HIV Resistance limited to AIDS patients Hypersensitivity Half life decreased by Rifamp in, phenytoin, and phenobarbitol (these increase p450, thus increasing metabolism of antifungals) N/ V Edema Hypertension Itraconazole (S poranox) Similar mechanism. Decreased production and synthesis of ergosterol DOC Blastomycosis AIDS associated histoplasmosis Aspergillosis Orally Increased by food Well d istributed Does not enter CSF Candidemia Coccidiodo mycosis DOC Paracocci diodomycosis Cryptococcosis (Not men ingitis) Tricophyton Microsporum Ep idermophyton Tinea Hepatic p450 enzy mes Skin rash/HA Griseoful vin (antifungal given systemic fo r topical infections) Inhibit fungal mitosis by binding to microtubules and disturbin mitotic spindle. Concentrates in keratin producing tissues Orally b ioavailab le High fat p ro motes absorption Ineffective topically Bound to keratin ized tissue Induces cyp450 Ki dney excretion Allergy Hepatotoxicity Teratogenic H/A Nausea Do not give for patient with AIP Cx: pregnancy 6 Nystatin Polyene antibiotic. Mechanis m of act ion similar to amphotericin B. Limited to topical therapy of candida Candidiasis (oral) Poor oral bioavailability Emp loyed orally (swish and swallow) for: Oral candidiasis Intestinal candidiasis Eliminated in feces Topically applied Adverse effects include N/ V/D Miconazole and other agents Clotri mazole Econazole Mechanism of action and kinetics similar to ketoconazole- Inhibits synthesis of ergosterol. Disruption of fungal membrane stability. Autonomic receptors and agents TARGET TISS UE EYE LENTICULA R RESPONSE AQUEOUS HUM OR SYMPATHETIC / PARAS YMPATHETIC Sympathetic: Contracts radial muscle of iris and produces mydriasis Parasympathetic: Contracts circular muscle of eye and produces constriction Sympathetic: Relaxes ciliary muscle- acco mmodates for near vision Parasympathetic: Contracts ciliary muscle for near v ision S: Facilitate secretion of aqueous humor by ciliary epitheliu m. Increased IOP. P: Contraction of ciliary muscle exerts pressure on trabecular meshwork. Opens its pores, increases outflow fro m canal of schlemm. Decreased IOP S: + chronotrope P: - chronotrope S: Increased arrythmias P: No effect S: Increased force of contraction, + inotropy P: No effect S: Vasodilation, vasocontrsiction at high stimulat ion, beta stimu lation usually predominates P: No effect RECEPTOR TYPES A1 (S) M3 (P) B (S) M3 (P) B M3 B1 > B2 M2 B1>B2 B1>B2 B2 HEART (SA node) HEART (ECTOPIC PACEMAKERS) HEART (CONTRA CTILIT Y) SKIN, SPLANCHNIC VESSELS 7 ENDOTHELIUM BRONCHIA L SMOOTH MUSCLE GI SMOOTH M USCLE SMOOTH MUSCLE SPHINCTERS SECRETION MYENTERIC PLEXUS BLADDER WA LL GU SPHINCTER UTERUS PENIS, SEM VESICLES PILOERECTOR SM OOTH MUSCLE THERMOREGULA TORY SW EAT APOCRINE (STRESS) SW EAT GLA NDS LIVER FAT CELLS KIDNEY KIDNEY S: No effect P: Vasodilation med iated by NO, activates the guanylyl cyclase. Inhibits CA ++ release fro m ER. No cholinerg ic innervation S: Bronchodilation P: Bronchoconstriction S: Relaxes, decreased motility and tone, alpha effect may involve pre-synaptic inhibition of Ach release P: Contracts: Increased mot ility and tone S: Contracts P: Relaxes S: No effect P: Increases S: No effect P: Stimu lates S: Relaxes, less pressure P: Contracts, more pressure S: Contracts P: Relaxes S: Relaxes Contracts P: No effect S: Ejacu lation P: Erection S: Contracts P: No effect S: Increases P: No effect S: Increases P: No effect S: Gluconeogenesis, glycogenolysis P: No effect S: LIPOLYSIS S: RENIN RELEASE (Vasoconstriction) S: DILATION OF RENAL ARTERIES (Maintains perfusion during shock states) M3 (P) B2 M3 A2, B2 (S) M3 (P) A1 M3 M3 M1 B2 M3 A1 M3 B2 A A M A M (S YMP) A B2, A B3 B1 D1 8 Cholinergic Agonists Five types of muscarin ic receptors have been identified. For class purposes, M1 M 2 and M3 are considered  M1 and M3 linked to IP3/ DA G cascade  Production of IP3 and DA G leads to release of intracellular Ca++ which can stimulate or inhib it enzy mes  M1 receptors are found in the myenteric p lexus and gastric parietal cells  M3 receptors are found in glands, smooth muscle and endothelium  M2 receptors are in heart and s mooth muscle  Nicotin ic receptors are lin ked to a depolarizing ion channel  -Found in CNS, autonomic ganglia, adrenal medulla  -Ach and nicotinic agonists stimulate nicotin ic receptors Nicotin ic receptors of autonomic ganglia are selectively blocked by GANGLIONIC b lockers (reviewed in cholinergic antagonist section) Nicotin ic receptors at NMJ are selectively b locked by tubocurarine and other ndmb’s. DIRECT ACTING CHOLINERGIC A GONISTS  -Consits of esters of choline  -Alkaloids 1. More resistant to hydrolysis from A CHe than ACh DRUG/ CLASS General cholinergic agonists MECHANIS M Stimu lation of muscarin ic and nicotinic receptors of via indirect mechanis m SPECTRUM/ US E KINETICS GENERA L OVER VIEW OF SYSTEMS: CLINICAL RESPIRATORY SYSTEM : Bronchoconstriction, caution with asthmatics GI: Increases secretion and motor activity via stimu lation of muscarin ic agents. N/ V, belching, diarrhea GU: Pro mote voiding of u rine by stimulat ing detrussor muscle and relaxing trigone sphincter muscles of bladder SECRETORY GLANDS: Stimu late activity of sweat glands, lacrimal glands, Nasopharyngeal glands. Miosis, and contraction of ciliary Does not cross BBB Used in intraocular sx muscle. Produces accommodation for near v ision. Intraocular solution Quaternary amine Acetylcholine, cholinergic agonist Stim of cholinergic receptors 9 Methacholine No nicotinic affin ity, muscarin ic stimulat ion available Diagnosis of bronchial hyperactivity. Inhalation + d x by hyperreactivity of airway, excessive bronchial constriction Ocular Carbachol (Mi ostat) Bethanecol Resistant to ACHe hydrolysis, cholinergic agonist. +++ Activity at cholinergic and nicotin ic receptors Resistant to ACHe hydrolysis. Increases tone and intestinal motility. PURE MUSCARINIC A GONIST. Profound C/ V effects. LOCAL USE IN EYE Produce miosis Expu lsion of urine via detrusor contraction and relaxation of trigone sphincter. Used to promote bladder emptying in postoperative NONOBSTRUCTIVE urinary retention. Oral SQ Contraindicated in : Asthmatics Hyperthyroidism Coronary insufficiency Acid-pepsin disease Precip itates atrial fib rillation in hyperthyroid patients. SE: Bronchospasm Sweating Salivation Flushing Parasympathomimetic effects SE: Profuse sweating Profuse salivation Pilocarpine Alkaloid that posseses muscarin ic activity. Tertiary amine. Long acting Produces rapid miosis. Opens trabecular meshwork to decrease IOP Emergency IOP lowering in acute angle glaucoma Crosses BBB Topical for glauco ma Oral fo r xerostomia associated with head and neck radiat ion t x +Saliva Smokin’ Nicotine Ganglionic stimulant and ganglionic blocker. Init ial Acute: + HR 10 INDIRECT ACTING CHOLINERGIC AGONIS TS Tensilon (Edorphonium) Physostigmine (Antilirium) effects are to stimu late + BP ganglia. Prolonges use +Intestinal tone and motility desensitizes nicotinic receptor and produces blockade. Co mplicated mechanism. Actions of Ach released fro m autonomic and somatic nerve endings is terminated via en zy matic destruction. ACHE hydrolyzes Ach to choline and acetate. All indirect acting cholinerg ic agonists inhibit ACHe and increas e duration of action of endogenous ACH. Produce cholinergic activ ity at all cholinergic receptors (nicotinic and muscarinic) Few therapeutic applications, used as insecticides. Binds to active site on ACHe Dx of myasthenia gravis. Short lived Patients with M G respond to and blocks access of drug Tensilon within 5 acetylcholine. Bond is ionic Tx of myasthenia gravis IV inject ion minutes. (They have antibodies and short lives. 10-20 minute which reduce the functional effect. Assess effectiveness of M G nicotinic receptors.) treatment: -If ACHe inhibitors are Caution- may provoke excessively admin istered, then cholinergic crisis they can mimic disease symptoms. In this case, admin of Tensilon will have no effect or worsen weakness. Form covalent bond with Tx g laucoma 2 hour duration of action High doses produce ACHe. Resistant to cleavage. convulsions and skeletal Alkaloid and tertiary amine. Lower IOP muscle paralysis. Local applicat ion produces (Pilocarp ine more effective) miosis. Direct n icotinic Also used to antagonize the agonism at NMJ. + Intestinal and bladder motility neuromuscular blockers, non depolarizing Formerly used to tx overdoses of drugs with anticholinergic effects like atropine. Synthetic ACHe inhibitor. Quaternary amine. Tx myasthenia gravis Tx postoperative ileus Tx atony of bladder 2 hour duration of action SE: Nausea Salivation Flushing Hypotension Neostigmine 11 IRREV ERS IB LE ACHe INHIB ITORS Isofl urophate Mal athi on May be useful in antagonizing Used as antidote for competit ivive effects of non depolarizing neuromuscular blockers like neuromuscular blockade tubocurarine. Co mmonly called organophosphates, these drugs irreversibly inhibit A CHe in t wo steps. The OP covalently phosphorylyzes the enzy me’s active site. Hydro lysis may take 100’s of hours. In the second step, known as aging, on of the oxygen -phosphorus bonds is broken, further strengthening the phosphorus -enzyme bond. Once the inhib itor enzy me co mp lex has aged, pralido xime cannot regenerate ACHe. Pralido xime is used to tx OP poisoning. OP Tx of glauco ma Last for a week OP Lipid soluble, rapid ly absorbed. Convertd to active compounds in insects and fish. Converted to inactive compounds in mammals. OP Dangeous use- not publicly Not detoxified in available. vertebrates Direct acting muscarinic agents produce predictable signs of muscarin ic excess. S/s include nausea, vomiting, d iarrhea, saliv ation, and sweating. Sympto ms blocked by atropine. Nicotine is the only direct acting nicotin ic agent that causes poisoning. Ingestion of large doses causes + CNS stimulation which can lead to coma and convulsions. Tx wit valiu m. Neuro muscular b lockade not responsive to treatment. Cholinesterase inhibitors: OP pesticide overdoses must be treated and recognized promptly. S/S resemb les muscarinic excess. Therapy is aggressive and includes parenteral atropine (large doses sufficient enough to produce atropinization as evid enced by pupillary d ilation and abatement of parasympathetic symptoms. Pralido xime t x used to regenerate ACHe. Parathi on A WORD ABOUT TOXICITY OF CHOLINOMIMETICS Cholinergic antagonists DRUG/ CLASS Muscurinic antagonists MECHANIS M Co mpetitively antagonizes the effects of cholinergic agonists at SPECTRUM/ US E CNS: sedative efec. Scopolamine possesses more KINETICS Cross conjunctival memb ranes Cross BBB CLINICAL Not all tissues have same sensitivity, not easy to 12 muscarin ic receptors. Blockade by a small dose of atropine can be overcome by increasing agonist concentration. Select ive for muscarinic receptors. Undetectable actions at nicotinic receptors. Affinity for M1 M2 M3 No affinity for nicotinic cns effects like dro wsiness Tremor of parkinson’s disease reduced. High doses can cause excitement, agitat ion, co ma. EYE: Pupillary constriction is inhibited. Mydriasis. (Unopossed of sympathetic activity). Measurement of accommodation for near vision. May precipitate acute glaucoma. (Measurement of refract ive effor without interference by accommodation.) CVS: Low doses result in bradycardia. Low doses block presynaptic receptors on vagus nerve. Ach release decreased. CV response is not dramatic. Tachycardia. Non innervated muscarin ic receptors in endothelial cells release NO and pro mote vasodilation. RESP: Smooth muscle and secretory glands of airway recive muscarin ic innervation. Bronchodilation and reduction of secretion can be detected in normal individuals. Reduce laryngospasm. GI: Marked reduction of salivary secretion. Gastric Well d istributed Reach levels in 30 min to 1 hr ½ life o f 2 hours Not well absorbed from gut ADVERS E EFFECTS : Using atropine to treat peptic ulcer disease will produce side effects like d ry mouth, blurred vision, urinary retentsion. Side effects are hot flushed skin, deliriu m, elevated body temperature. Dry as a bone, mad as a hatter…. Effects of OD may last a week. Infants and kids particularly susceptible to hyperthermic effects. In past physostigmine was used, but currently is considered more dangerous than symptomatic management. CONTRAINDICATIONS: Glauco ma, elderly males with prostatic hyperplasia titrate Effects on eye persist Free fro m side effects Gastric acid secretion is least sensitive, not used to decrease acid secretion. Individual agents for t x of parkinson’s disease: Benztropi ne (Cogentin) Biperiden Orphenadrine Procyclid ine Trihexypheni dil (Artane) Diphenhydramine Anti muscurinic drugs are more effecti ve against tremor than akinesa or rigi dity. Taken in co mb ination with drugs that enhance dopaminergic activity. Tertiary amines. Cross BBB. Used CNS. Drugs to know in bold. Also treat EPS effects. Motion sickness: Scopolami ne Taken by inject ion or PO. Most effective taken prior to onset. Transdermal patch 13 secretion reduced less effectively. Motility of muscle is affected fro m stomach to colon. Walls of v iscera are relaxed. GU: Relax smooth muscle of ureters and bladder, slows voiding. Useful in t x of spasm reduced by mild inflammat ion. Urinary retention in men with BPH SWEAT: Suppresses thermoregulatory sweat glands. Little effect on body temperature. Ord inary doses may cause “atropine fever” withdrawn. Mydriasis and cycloplegia: Atropine Scopolami ne Ho matropine Cyclopentolate Tropicamide Preventon of respiratory secretion and laryngospasm fro m inhalation anesthetics: Atropine Scopolami ne Not irritating to airway. Increases chance of post operative urinary retention and intestinal hypomobility Treat ment of asthma and COPD Atrovent (Ipatropi um) Target bronchodilator tissue locally. Peptic ulcer t x Largerly replaced by h2 receptor antagonists. Gastric acid secretions are least senbsitive. Doses employed will blur vision, dry mouth, and cause urinary hesitancy. Will slow 14 gastric emptying time. Erratically aborbed Methscopol amine Urinary and GI disorderd. Used to tx overactive bladder and GI d isease Flavo xate Oxybutynin Bentyl Atropine Used to counteract peripheral and central effects of muscarinic excess following OP to xicity / exposure. Push atropine 1-2 mg q 5-15 until signs of effect appear. As much as 1 g m per day. Repeat large doses many times. Resynthesis of receptors is required due to covalent bonding. Continue pushing. 15 Ganglionic blockers MECHANISM/PHYSIO: Antagonize effects of Ach at parasympathetic and sympathetic ganglia. Effects are diffuse because they block all autonomic outflow. Lack of select ivity. Prevent reflex adjustment of ANS. What you see is what you get. If you have a cholinergic, beta agonist, or whatever, it will p roduce its direct effect WITHOUT reflex adjustment. Nicotinic receptor susceptible to both depolarizing and non depolarizing blockade. Nicotine and even Ach at high concentrations can produce non depolarizing blockade. Too much agonist. No repolarizat ion. Impossible to control and never used clinically. Clincally effective ganglionic blockers are non depolarizing competit ive antagonists at nicotinic receptor. NO INTRINSIC ACTIVITY. ORGAN S YSTEM EFFETCS : Organ system effects dependent upon DOMINA NT innervation. Ganglionic blockade will remove more of the relatively dominant ANS system. So, ganglionic b locker ad min effects in vascular system will p roduce parasympathetic effects, for examp le. PLUS, no reflex co mpensation!!!!!!! CNS: Mecamy lamine enters CNS and produces sedation, choreiform movements, and men tal aberrations. Antagonize central effects of nicotine. EYE: Ciliary muscle is primarily innervated by parasymptathetc. Ganglionic blockade induces cycloplegia with loss of accommodation. Moderate dilation. CVS: Parasympathetic tone dominates in the SA node. Ganglionic b lockers will produce moderate tachycardia. Blood vessels chiefly innervated by sympathetic fibers. Orthostatic hypotension will occur. GI TRACT: Parasy mpathetic system dominates. Ganglionic blockers cause marked constipation. Reduction of secretion is not sufficient to effectively t reat peptic ulcer d isease. GENITOURINARY S YSTEM: Ganglionic blockade causes urinary hesitancy and precipitate urinary retention. Impair erection and ejaculation. Mecamylamine Hexamethonium: Ganglionic blocker RESPONS E TO AUTONOMIC: Drugs that act at postganglionic receptors are not blocked by ganglionic blockers. NE would raise blood pressure that was decreased by hexamethonium. Responses may be exaggerated or reversed with ganglionic blockade. NE elevates blood pressure via vasoconstrictor effects. No rmally, this would elicit reflexive vagal HR slowing. In presence of ganglionic blockade, this reflexive bradycardia would NOT occur. Important historically as the first clinically utilized ganglionic b lockers. Effectiv e antihypertensive. Important because it allows pharmacologists to write fiendishly difficult test questions. 16 Mecamylamine Ganglionic blocker Neuro muscular blockers Depolarizing and non depolarizing Currently the only ganglion ic blocker available in the US. Used to control BP in hypertensive emergencies or to produce controlled hypotension to produce a bloodless surgical field in neurosurery. Rapid onset, short acting agents such as nitroprusside have gradually replaced ganglionic b lockade. In itial control of blood pressure in patients with acute dissecting aortic aneurysm. Block sy mpathetic reflexes and reduce rate of rise of BP at site of tear. Block cholinergic Normal function: Blockade of normal endplate function: neurotransmission between motor TUB OCURARINE: nerve endings and nicotinic skeletal Arrival at action potential PROTOTYPICAL NON muscle receptors. Used during sx to results in influ x of Ca and DEPOLARIZING NMB, USE A CHe induce paralysis. Achievement of release of Ach. Binding of 2 INHIBITORS TO ANTA GONIZE. adequate muscle relaxat ion for s x mo lecules or Ach to receptors requirements on a2 subunits of the nicotinic SUCCYNYLCHOLINE: receptor results in ion channel PROTOTYPICAL opening. Resultant DEPOLARIZING MB . A CTION IS movements of Na and K ions DEPENDENT UPON DIFFUSION are associated with AWAY FROM ENDPLATE. 2 ACH depolarization of endplate MOLECULES END TO END. memb rane. Small INDUCE PHASES OF BLOCKA DE depolarization results in AND PREVENT OTHER permeab ility and endplate STIM ULUS FROM CAUSING potential return ing to normal DEPOLA RIZATION. without impulse propagation to rest of muscle. Co mpetitive antagonism. Prevent Large depolarization produces access of Ach to nicotinic receptor and muscle contraction. prevent depolarization. Referred to ACHesterase removes Ach. non depolarizing blockers. Fast response Blockade can also occur through excess agonist induced depolarizat ion. (Excess nicotine or Ach amp lified with ACHe inhib ition.) Whopping high doses of agonist will cause depolarizing blockade. All nondepolarizing blockers contain 2 Ach molecu les concealed within one or two types of bulky and rig id ring 17 structures. Poorly lipid soluble and do not cross BBB. Ad ministered IV. Highly ionized and do not cross memb ranes. Limited volu me distribution. Co mpetit ive antagonist of nicotinic receptor at NMJ. Small doses compete with AcH at nicotin ic receptors. ACHE inhibitors can be used to antagonize the NDMBs like Neostigmine Physostigmine Endrophonium At higher doses, some drugs enter pore of the ion channel to cause blockade. DEPOLARIZING B LOCKADE: Not an antagonist. Succynylcholine. Two ACH mo lecules linked end to end. Given IV, exh ibits comp lete diaphragmatic paralysis. Ext remely brief duration of action. Rapid ly metabolized by acetylcholinesterase, an enzyme of p lasma and liver. No plasma cholinesterase at motor. Su x binds at NMJ with much greater affinity with ACH. PHAS E 1: Depolarizing block. Acts like A CH. Effect is much longer. Binds to and occupies receptor, depolarization occurs. Receptor cannot fire again. PHAS E II: Desensitizing block. A CH binding endplate resulting in 18 depolarization. Fast event. The cell reploarizes fast due to potassium current. With SUX on board, repolarizat ion does not recur. At some point, processes within cell will co me into play. Time constant is long. After several minutes, partial repolarization still occurs with sux still bound to receptor. ADRENERGIC DR UGS Types of receptors and their function, review A1 Found in vascular smooth muscle where agonist binding causes vasoconstriction. Stim of A1 receptors causes the G protein to activate the phospholipase C cascade. Sequestered intracellular Ca is released and smooth muscle contracts. Found primarily on post ganglionic sympathetic nerve terminals where agonist binding serves to block NE release. Found in vascular smooth muscle where agonist binding also mediates vasoconstriction. Stim by A2 receptors activates inhibitory G protein resulting in a decrease of CAMP levels. Open K channels, close Ca channels. B1 primarily found in heart. + Chronotrope and + Inotropic effects. (Rate and contractility as well as CO increased) Primarily in s mooth muscle in lungs and vasculature. B2 agonism causes bronchial dilation and vasodilation. Found in fat tissue, promotes lipolysis Found in kidney. At normal doses, D1 receptors are activated and maintain renal perfusion. Higher doses cause activation of alpha and beta like effects. A2 B1 B2 B3 D1 ADRENERGIC A GONIST DRUG TA BLE CLASS/DRUG Adrenergic Agonist, catecholaminegic MECHANISM CV: Vascular s mooth muscle tone in blood vessels is dominated by sympathetic nervous system. Adrenergic effects have profound S/S CLINICA L 19 effects effects on vascular tone.D1 receptors promote vasodilation of renal splanchnic and coronary arteries. HRT: Direct effects on heart are mediated through B1 receptors whose activation results in increased Ca influ x, both in pacemaker activ ity and contractility. Pacemaker activ ity increased in purkinje fibers. Direct effects can be demonstrated in pts with ganglionic blockade, where vagal reflex activ ity is not in play. W/O vagal response, effects on heart rate may be dominated by a reflex response to BP changes. BP: A purse alpha agonists increased PAR and decreases venous capacitance, which increases BP. (Phenylephrine). CO does not dimin ish proportionate to reduction of heart rate due to increased venous return increasing stroke volume. Use of a pure alpha agonist in a hypotensive patient probably would not evoke reflex slowing of heart because BP is turning to normal. A purse BETA agonist (isoproterenol) increased HR, contractility, and CO. Decreased SVR by systemic vasodilation. Diastolic BP reduced while systolic BP is maintained or slightly inceased. EYE: Radial papillary dilator muscle of iris contains a1 receptors whose activation cause mydriasis. Alpha agonists increase outflow of aqueous humor fro m eye and beta ANTAGONISTS decrease production of aqueous humor. Useful for treat ment of glaucoma. RESPIRATORY TRACT: BV in upper resp tract contain a1 receptors. Activation produces decongestion. Bronchial smooth muscle contains B2 receptors whose activation produce bronchial dilation. GI: Relaxat ion of gastrointestinal smooth muscle mediated by A2 and B2 agonists. Alpha 2 agonists decrease muscle activity indirectly by presynaptically reducing ACH release. Beta 2 agonists hyperpolarize smooth muscle cells and promote relaxation. A2 mediated response is more significant 20 pharmacologically. Focus on alpha 2. GU: Pregnant uterus contracts in response to a1 agonists and relaxes in response to B2 agaonists. B2 agonists useful in t x of premature labor (terbutaline). B2 receptors of bladder wall med iate relaxat ion. Ejacu lation depends upon a1 receptor activation in ductus deferens and prostate. Bladder base, urethral sphincte, and prostate contain a1 receptors which med iate urinary incontinence. EXOCRINE: Respond to alpha agonists with increase sweat production. META BOLIC: B3 receptor binding stims lipolysis. Sympaho mimeti drugs in liver stimulate g lycogenolysis and gluconeoenesis primarily through B2 receptors although A receptors may play a role. ENDOCRINE: Catacholamines stim glucagons release through B2 activation and block insulin release through A2 activation. B1 activates rennin. CNS: Dependent upon ability to cross BBB. Effects range fro m nervousness to impending disaster. Catecholamines cross barrier extremely poorly. Adrenergic agonists may mimic presentation of anxiety. 21 Adrenergic agonist, epinephrine Poseses significant agonist activity at A1, A2, B1, and B2 receptors. Stimulates all that is sympathetic. Potent vasoconstrictor and cardiac stimu lant. HR increase + inotrope + chronotrope + CO +Myocardial o xygen demand + vasodilation in skeletal muscle vessels + systolic BP + bronchodilation + glucagons release + mean blood pressure + hyperglycemia + increases FFA (via beta 3) + diversion of b lood fro m skeletal muscle + RAA system Metabolized by MAO/COMT and has short IV half life Given IM or SC, epinephrine is longer acting due to slower absorption and local vasoconstriction Still utilizd in temporary emergency dept of comp lete heart block. Proarrhythmogenic Mostly alpha one and beta 2 agonists. Activation of a1 will increase peripheral resistance. Activation of B2 causes vasodilation. Net effect is that of dominant vasodilation. Drop in diastolic BP? DOC anaphylaxis, B1 and B2 make it specific for Ig E mediated vasodilation Most common agent for local vasoconstruction given during local anesthesia, examp le suturing face With norepinepherine, rise in BP due to systemic vasocontriction. No compensatory (little) B activ it B2 vasodilation seems to offset the constrictor effect and thus produces a mean b lood pressure decrease. Marginal substrate for COMT and resistant to MAO. Half life increased to approx 2 hours. Acute treatment of asthma. Replaced by selective B2 agents. Adrenergic agonist, norepinehperine Adrenergic agonist, isproterenol Possesses activity at all receptors but is selective for alpha over beta. B1 activity equal to or probably less than epinephrine. More of an alpha agonist. Synthetic catecholamine. Strong agonist at B1 and B2 receptors with virtually no alpha effect. + vasoconstriction + HR +Ch ronotrope +Inotrope 22 Adrenergic agonist, dopamine Endogenous catecholamine. Binds to D1 and D2. D2 receptors are presynaptic in ANS- not clin ically significant. D1 are in the renal vasculature where they cause vasodilation. When doses are increased, you get alpha and beta receptors. + renal blood flow at normal concentrations + HR + Force of contraction Temporary emergency management of complete heart b lock. Metabolized by MAO and COMT. Admin IV Therapeutic use is tx of shock Use of cardiogenic shock or fo r renal perfusion. Maintain renal perfusion Adrenergic agonist, B1 Dobutamine Selective for B1 in the heart. Relat ively more inotropic than chronotropic effects. + CO + inotrope Given IV Metabolized by MAO Metabolized of COMT Tx of cadiac deco mpensation or patients with acute CHF or M I Heart not pumping, increase inotropy. DOES NOT INCREASEM MYOCA RDIAL OXYGEN DEMAND Resistanct to COMT No resistance to MAO Longer half life Penetrates BBB Will increase BP (no opposed B stim) Local anesthesia Chronic orthostatic hypotension tx Elicits reflexive brady C Past, use as tx for P.A.T. (atrial tachycarda) Decrease of side effects during opiate withdrawal. Therapeutic effect due to availability of catecholamines within the CNS Alpha agonists (A1), phenylephrine A1 agonist 100 fo ld less potent than epi. Sufficient doses produce a1 activ ity. Nasal decongestion Mydriasis Treat orthostasis Alpha one agonist, Methoxamne A1 selective Nasal decongestion` Alpha 2 agonist, Clonidine Adrenergic agonist, A2 agonist, selective. Presynaptic agonist effects would decrease endogenous release of NE. It does happen, but mechanism is believed to be the binding of A2 receptors in brain stem. Centrally acting. Decreases total centeral sympathetic outflow. CENTRA L/CLONIDINE. Effective in decreasing blood pressure A2 agonists (Me too) Reduction of BP at the source of sympathetic drive 23 Alpha 2, Guanabenz Guanfacne Adrenergic agonist, B2 Albuterol Adrenergic agonist, B2, Terbutaline Adrenergic agonist, B2, Ritodrine Mis. Adrenergic agonist Ephedrine Selective B2 agonist. Retain so me weak B1 act ivity. + HR + Bronchodilation + Tocolysis (stop contractions) +Bronchodilation Reduction of contractions +HR +BP +PVR Insomnia +CO +BP +Decongestion +BP +HR +Reflexive brady C? +Appetite suppression + CO is a dose dependent effect + NE release +arryth mia +decongestion +anorexia Relatively selective B2 agonism. Ad min oral, Sub-Q, inhalation Selective B2 agonist. Used as tocolytic Yutopar- uterus on par… Natural alkalo id. Acts primarily by causing the release of stored catecholamines. Direct adrenergic activ ity. High oral bioavailability. First orally active sympathomimet ic. Used for t x of asthma via B2 mediated dilation of bronchial s mooth muscle. Given by inhalat ion route Long term t x of COPD Patentally in t x of status asthmaticus Premature labor Control contractions, delay premature labor Cross BBB Long duration of action Misc adrenergic agonist, Pseudoephedrine Misc adrenergic agonist, Amphetamine Phenmetramine Methylphenidate Pemoline One of 4 ephedrine stereoisomers. Less potent than ephedrine. Sudafed. CNS stimu lants but all have strong sympathomimetic effects EXCEPT M ETHYLPHENIDATE (RITA LIN). X BBB and are long acting. Often abused. CNS stimulated due to release of dopamine/NE. Ritalin b locks uptake of dopamine and is slightly more selective. These increase availability of NE… therapeutic effects can be similar to anti-depressants. Contraindicated in MAOIs. If MAOI is inhibited in the pre -synaptic terminal, it will lead to increase in sympathomimet ic effects. Massive cytoplasmic buildup of NE with concominantly ad min istered MAOI… hypertensive crisis, etc. Misc. adrenergic agonist, phenylpropanalomine Misc adrenergic agonist, Tyramine Misc adrenergic Orally act ive, indirect acting sympathomimet ic. Resemb les ephedrine in spectrum and potency but does not seem to produce the same degree of CNS stimulat ion. Availab le OTC. Has been associated with CVA , hypertensive crisis Tyramine is not a drug but rather an indirect acting sympathomimet ic found in various fermented foods and beverages. Slight sypathomimetic effects under normal conditions. Local anesthetic that produces both CNS stimulation and With MAOIs, may cause hypertensive crisis. Massive NE release +BP Obvious 24 agonist, Cocaine peripheral sy mpathetic stimu lation. CNS stimu lation is due to blockade of dopamine reuptake. +HR +CNS Proconvulsant Proarryth mogenic Misc adrenergic agonist, TCA’s Exert ion of antidepressant effects through blockade of norepinepherine and / or serotonin in CNS. Blockade of NE uptake causs indirect sympathomimet ic effects A word about adverse effects: Sy mpathomimetic d rug effects are extensions of their receptor affects in the CV and CNS. Marked elevation of BP can cause cerebral hemorrhage and PE. B1 agonists can cause dysrhythmias. ADRENERGIC ANTA GONISTS THE B IG ALPHA PICTURE -Alpha receptor antagonism may be reversible o r non reversible -So me are nonselective -Major pharmaco logical effect is to lower blood pressure thus eliciting a reflex tachycardia -Ateriolar and venous tone is determined by A receptors on smooth muscle -A agonists lower peripheral resistance and blood pressure -Epinepherine will LOW ER blood pressure in the presence of an a1 antagonist because B2 -mediated vasodilation will cause vasodilation -Phenomenon called, epinepherine reversal -Cause Orthostatic hypotention -Miosis and nasal stuffiness as SE -Will decrease resistance to flow of urine -ANTA GONISM OF A LPHA TWO RECEPTORS IS W HAT CAUSES THE REFLEX TA CH- More norepinepherine is available to bind cardiac B1 receptors THE PICTUR E OF B ETA-ANTAGONIS M -Extremely important -Useful in lowering blood pressure -Select ive for B1 o r B2, or some can be non selective -Mechanism of lowered BP is due to a decrease in cardiac output -Reduced BP may elicit a reflex alpha-1 mediated increase in vascular tone -NO POSTURA L HYPOTENSION because alpha ones are not blocked -Reduction of card iac workload -Post MI prophylaxis or therapy 25 -Used for angina (reduce myocardial o xygen demand) -B2 b lockade in asthmatics may be dangerous -Reduce intraocular pressure due to reduced aq humor production -May be associated with increases in cholesterol -HDL and LDL rad ios reduced. The ratio of good to bad cholesterol is lo wered. Clinically, the ratio is given as LDL to HDL. Higher numbers are therefore prognostic of increased risk for CAD/ CHD -Local anesthetic effects -Membrane stabilizing GEN ERAL S UMMARY OF B ETA B LOCKADE EFFECTS: Decreased HR Decreased CO Decreased sympathetic activity Decreased cardiac arrythmias Some have local anesthetic activity Clin ically useful for management of hypertension WARNINGS: -Made several points about beta blockers an diabetics. Diabetics having an insulin shock crisis depend on sympathetic response to alert themselves to a hypoglycemic state. Beta blockers may mask tachycardia and therefore exacerbate hypoglycemic ep isodes -Contraind icated in patients with severe obstructive pulmonary diseases (COPD/asthma) -Caution with rapid withdrawal. Persons can be sensitized to beta blockers. Rapid withdrawal may cause exaggerated responses to circulat ing catecholamines. Ex: Pat ients with angina who are rapidly withdrawn fro m beta blocker therapy may experience worsening of sympto ms -B blockers can interact with Ca++ channel blockers an cause severe hypotension -B blockers can cause cardiac conduction abnormalities -May mask symptoms of developing hyperthyroidism DRUG/ CLASS Phenoxybenzami ne, al pha antag onist, non-selective MECHANIS M Irreversib le alpha one antagonism Covalently binds a1 and a2 receptors. Long duration of action Elicits reflexive tachycardia partially augmented by S/S Emergence of therapeutic effects CLINICAL Pheochromocytoma: Tu mor in the adrenal medulla that releases XS catecholamines. Causes hypertension, tachycardia, and arrythmias Used in preoperative period SE Postural hypotension Tachycardia (reflex) Nasal stuffiness Inhibition of ejaculat ion 26 blockade of presynaptic a2 receptors. (Increase in NE) WILL PRODUCE EPI REVERSA L -Causes unopposed B2 med iated vasodilation Raynaud’s: Phenoxybenzamine will reverse alpha med iated vasoconstriction Autonomic hyperreflexia: May be used to diminish this post CVA syndrome Tx hypertension BPH- prostatic hyperplasia Prazosin (Mini press) Terazosin (Hytrin) Doxazosin (Cardura) Selective al pha one antag onists Selective a1 antagonism. W ill lover blood pressure through a1 med iated effects. No reflex tachycardia. Lack of activity at presynaptic alpha two receptors. Lowered BP Postural hypotension- less likely with chronic administration Well tolerated Dizziness, lack of energy Nasal congestion Headache Yohi mbe, selective a2 antag onist Propanolol, Nonselecti ve beta antagonist A2 antagonism B1 and B2 b lockade. Has local anesthetic activity. Low oral bioavailability and half life of 3-5 hours. Possible augmenting of sexual function Emergence of clinical results like lowered BP, normalized heart rhythm. No major clin ical use Tx hypertension Can be given with diuret ic Can be given with vasodilator Tx supraventricular arrythmias Chronic angina pectoris Increases long term survival post-MI Slows ventricular response rates May reduce size of evolv ing myocardial infarction SE: Bronchoconstriction Not effective when given acutely for migraines 27 Tx open angle glauco mareduces ciliary body production of aq humor but has systemic effects Hyperthyroidism management May reduce systemic man ifestations of anxiety Tx HTN Tx Angine Tx open angle glauco ma May prolong post MI survival Systemic absorption fro m topical applicat ion may occur. Caution in asthmatics Caution with CHF Pindol ol, nonselective beta bl ocker Nonselective beta blockade. Has weak intrinsic sympathomimet ic activ ity. Has local anesthetic activity. Reduces HR Reduces CO May be preferred in insulin dependent diabetics. Faster recovery fro m hypoglycemic episodes Less likely to produce plasma alterations in lipids Tx migraine Tx hypertension May improve long term M I survival Extremely hydrophilic Prolongs survival post MI Tx hypertension Tx angina Used in critical care settings when rapid lowering of BP is Contraindicated in asthmatics Nadol ol, l ongest acting beta bl ocker Ti mol ol (TIMOPTIC), Nonselective beta bl ocker Nonselective beta blockade. Long half life. No anesthetic activity. Nonselective beta blockade. Lacks local anesthestic effects. Metoprolol (LOPRESSOR), a selective beta antagonist Possesses local anesthetic effects. B1 blockade. Half life of three to four hours No local anesthetic effects. B1 blockade. Reduce HR Reduce CO Lower BP Reduce HR Reduce CO Bradycardia Atenolol (TENORMIN) Selective beta antagonist Simu lar profile o f SE to other beta blockers Es molol (BREVIB LOCK) Selective beta antagonist BREVI-short acting beta (1) blocker. No local anesthetic Reduce HR Reduce CO SE profile improved due to BREVI, or short, half life. 28 effect. Metyrosine Blocks synthesis or release of catecholamines. Blocks tyrosine hydroxylase, the rate limit ing step of NE synthesis Blocks reuptake of NE, EPI, and serotonin into vesicles. MAO destroys the monoamines in the cytoplasm. Decreased NE release Blocks release of NE fro m sympathetic nerve terminal. Displaces NE fro m storage vesicles. Admin IV of value. Metabolized rap idly by erythrocytes Tx: Pheochro mocytomatumor of adrenal g lands Reserpine Gradual BP reduction Reduce HR Slow onset OBSOLETE HTN treat ment New NE must be synthesized Guanethi dine Gradual HR reduction Gradual BP reduction Rarely used HTN Tx ANTIVIRAL DRUGS: CLASS/DRUG Anti respiratory viral infections, Amantadi ne and Rimantadi ne MECH Inhibit rep licat ion of in fluenza A, genes bl ock viral membrane matrix protient M2 , a membrane ion channel SPECTRUM Prophylaxis of influenze Anti-respiratory viral infection Ri bavirin Activer versus wide spectrum of DNA and RNA Inhi biti on of viral mRNA synth RSV in infants / kids Influenza A and B Hep A KINETICS Well absorbed Amantadine enters CNSuseful for mg mt of parkinsons Orally b ioavailab le Orally Inhalation for RSV Parent compound and mets excreted in urine IV / PO / topically Enters CSF Underoes partial metabolism into inactive compound CLINICA L SE due to CNS disturbances Emb ryotoxic and teratogenitc Cx pregnancy, teratogenesis Antiherpes virus agents Acycl ovir Acyclovir activated in cell by v iral and host protein kinases. Inhi bits viral DNA polymerase. Less active vs. host enzyme HSV-1 HSV encephalit is VZV CM V prophylaxis H/A Nausea Vo mit ing Diarrhea Renal dysfunction 29 Antiherpes virus agents Ganciclovir Activated following phosphorylation by viral and cellular kinases into g triphosphate. Inhi bits DNA polymerase. Inhi bits DNA synthesis CM V ret initis Acyclovir resistant HSV CM V prophylaxis in transplant patients Eliminated into urine RENAL TUBULA R SECRETION GLOM FILTRATION Accumulated during renal failure IV Enters CSF Renal tubular secretion Glo merular filtration Carcinogenic Emb ryotoxic Teratogenic Neutropenia Thrombocytopenia Nausea, headache Nephrotoxic Nausea Fever Anemia Electrolyte disturbances GI/ CNS/hepatotoxicity Famciclovir Foscarnet Vi darabi ne Prodrug, converted to penciclovir Inhi biti on of RNA and DNA pol ymerasis Reverse transcriptase inhibitor NOT A PURINE OR PYRIDINE DERIVA TIVE- possible test question No therapeutic HIV use Analogue of adenosine, converted to triphosphate. Therefore inhi bits viral DNA synthesis Acute herpes zoster CM V ret initis in immunocomp ro mised host Orally b ioavailab le IV Well d istributed Renal tubular secretion Glo merular filtration IV infusion Systemic infection CSF entering Topically for HSV keratoconjunctivitis Eliminated in urine Topically HSV encephalit is HSV keratit is Neonatal HSV (II) Varicella zoster in immunosuppressed Topical HSV keratit is Topical HSV keratoconjunctivitis Opthalmic viral infections HSV 1 HSV 2 Varicella zoster CM V induced retinit is HSV1 HSV2 Trifluri dine (Viroptic) Pyrimid ine analogue. Converted into triphosphate. Inhi bit viral DNA synth and replication. Penciclovir Ci dofovir Guanosine nucleosde derivative, converted to triphosphate. Inhi bi ts DNA pol merase, inhi bits DNA synthesis Cytosine nucleotide analogue, converted to triphosphate. Inhi bits DNA synthesis. Topically Inflammation Pruritus Edema of eyelids Local in flammatory effects Well tolerated Renal to xicity Metabolic acidosis AIDS TREATMENT 30 -Loss of CMI -HIV worldwide -Immunosuppression -Increased chance of opportunistic infections -Retrovirus -RNA template that uses RT via reverse transcriptate -AKA DNA poly merase*** -Treat ment currently consists of a comb ination -Recall that current standard of care is 2 RT d rugs and a protease inhibitor -2 NRTI plus PI 2 NRTA plus NNRTI 1 NRTA plus 1 NNRTI p lus 1 PI DRUG/CLA SS Nucleoside RT inhib itors Zi dovudine (Retrovir) MECHANISM Pyrimid ine analogue, RT inhi bitor. Limits reverse transcriptase. A mainstay in RT inhib itor therapy. Converted into ddATP. Integrated into growing viral DNA chain. Inhi bits RT, viral DNA synthesis, and viral replication Used in combo with AZT. DdCTP converted, incorporated into growing chain. RT i nhi bitor Converted to d4TTp. Inhi bits RT. Inhi bi ts viral DNA synthesis and viral replication Inhi bits viral DNA synthesis by li miting reverse transcri ptase. SPECTRUM HIV KINETICS Oral Crosses BBB Eliminated in urine Oral SE/CLINICA L Bone marrow to xicity Leukopenia H/A, seizures Pancreatitis Peripheral neuropathy Do not use for first choice Less myelosuppresion Pancreatitis Peripheral neuropathy Di danosine (Vi dex) HIV Zalcitabi ne HIV Oral Stavudine (Zerit) HIV Oral Peripheral neuropathy Tx: advanced HIV Lami vudine (Epi vir, 3TC) HIV Chronic Hep-B infections Oral Pancreatitis in pediatric patients 31 HIV PROTEASE INHIBITORS were developed to reduce toxicity w ith use of nucleoside RT inhibitors. Retard rap id development of resistance. The HIV protease is an asparate proteinase vital for viral rep licat ion. Several HIV protease inhibitors have received approval for ma nagement of HIV one infection. Co mmonly emp loyed together with zidovudine and lamivudine. Saquinavir Inhibit cleavage of HIV Oral GI, H/A, thro mbocytopenia, Ritonavir polypeptide precursors that hyperbilirubinemia, renal Nelfinavir generate structural proteins damage. Indinavir and enzymes of virus. Amprenavir Protease inhi bitor Do not use with rifampin Non nucleoside reverse transcriptase inhibitors. Noncompetitively inhib it HIV-1 RT. Lack bone marro w to xicity associated with NRTIs and are not cross resistant with the NRTIs. Nevirapine (Viramune) RT inhib ition. Inhib it viral HIV Oral Hepatotoxicity, fatal DNA synthesis. Actually bind Enter CNS H/A to enzyme Breast, milk, fetus Fever Excreted in u rine Rash Increase T cell counts Decrease viral load Delaviri dine (Rescriptor) Increase effectivenesds of HIV Oral Rash AZT, dll. NNRTI. Extensively metabolized Nausea Excreted in feces and urine H/A Dizziness Efavirenz (Susti va) Decreases viral load HIV Oral H/A Increase T cell counts Enters CNS Dizziness NNRTI Lack of concentration Interferon Natural g lycoproteins that HIV IV Bone marrow depression reduce viral infect ions. Synth Kaposi’s sarcoma Enters CNS Fever with reco mb inant DNA IFN-a used clin ically Lethargy technology. Block viral RNA HPV Hypersensitivity translati on, promoting viral Chronic hepatitis B and C CHF mRNA and tRNA degredati on. ANTI-W ORM Y, A NT-HELMINTHS “GUESS METRONDIAZOLE” DRUG/CLA SS Mebendazole, Vermo x MECHANISM Inhibits microtubule synthesis SPECTRUM Whipworm (trichuris) KINETICS PO SE Tetarogenic 32 in parasite, inhibits glucose uptake Pyrantel pamoate (Antiminth) Induces paralysis through activation of nicotinic receptors. Depolarizing muscle blocker Inhibits microtubule polymeriation Pinwo rm (Enterobius) Hookworm (Necator) Roundworm (Ascaris) Roundworm Pinwo rm Hookworms Strongyloidiasis Cutaneous larva migrans Theadworm Trich inosis, early stages Onchocerciasis (river blindness) Scabies Active against micro filariae Cx pregnancy Emb ryotoxic PO GI Thiabendazole (M intezol PO GI CNS to xicity Ivermectin Inhibits hyperpolarization by activating GABA receptors in nematode. Praziquantel Induces paralysis by enhancing calcium permeab ility. Schistosomiasis Cysticercosis Niclosamide Inhibits ATP production by inhibit ing ADP phosphorylation Cestodes ALSO praziquantel Contra in pregnancy Contra in pts taking antianxiety agents, benzodiazepines (allosterically agonize GA BA) Contraindicated during pregnancy and nursing. Tx for ocular cystercercosis (contraindicated!!!!) GI upsets Not useful against the ova, laxat ive must be given prior to treatment to purge the bowel ANTIPR OTOZOALS Classified as mixed, lu minal, or systemic dependent upon therapeutically effective site of action Disease may be asympto matic or produce mild to severe dysentery Therapy treats acute illness and carrier state. Metrondiazole is lu minal and systemic (mixed) DRUG/CLA SS Metrondiazole, Flagyl, M ixed anti-protozoal. MECHANISM Electron acceptor. Produces cytotoxins that inhibits SPECTRUM Entamoeba histolytica Giardia lamb lia KINETICS Oral Widely distributed SE/CLINICA L GI Neuro problems 33 cellu lar proteins and DNA. Induces cell death. Trichonomas vaginalis Bacteroides fragilis Clostridiu m dificile Amoebiasis Dilo xan ide furonate, a lu minal amoebicide Centers virtually all flu ids (CSF, saliva, seminal, vaginal) Excreted in liver PO Hydrolized in intestive to dilo xan ide Disulfiram reactions Contra in pregnancy and young children Caution in hepatic dysfunction GI Farting Allerg ic rxns Paro mo mycin, a lu minal amoebicide Chloroquine, systemic ameb icide and anti-malaria (erythrocytic) Aminoglycoside antibiotic. Induces cell membrane leakarge Prevention and tx o f amebic liver abcess. Given in co mbo with lu minal agenst. Inhibit protein synthesis. Inhibits plasmodial heme polymerase. Damages parasitic membranes. Inhib its parasitic DNA synthesis. PLAS MODIAL HEME POLYMERAS E INHIB ITION FOR MALARIA Entamoeba histolytica Only active against lu minal form of E. histolytica IM in jection Concentrates in erythrocytes CV to x Lifecycle of p lasmodiu m: An infected mosquito injects sporozoites into circulation. They travel to liver. Tissue schizonts are produced. ERYc’s are invaded. Liver is site of exo-erythrocytic infection. Plas modiam v ivax, ovale cause secondary erythrocytic stage. (Infect liver) Resistance does develop due to decreased accumulation Retinal d mg GI d isturbances Radical cure of p. v ivax and o. ovale. If pt treated with chloroquine, some parasites can persist in Malaria Entamoeba histolytica P. falciparu m P. vivax P. malariae P. ovale BLOOD SCHIZONTICIDE DOC for erythrocytic form for: P. falciparu m P. vivax Used for prophylaxis Primaquine, exoerythrocytic anti-malarial) Efffect ive only against exoerythrocytic state. Used in combo with b lood schizonticide. P. vivax P. falcipariu m Effective against gemetocytic forms of all species. 34 Quinine, blood schionticide Inhibits DNA synthesis ONLY ONE TX FOR EXO ERYTHROCYTIC FORM ! Radical cure of P. vivax P. ovale Used for resistant strains of malaria. PO in co mbo with Fansidar (Sulfado xine and pyrimethamine) Plas modiu m P. falciparu m P. malariae T. gondii (with sulfado xine) liver if primaquine is not given to combat latent phase. Traverses placenta N/ V/vertigo/tinnitus Cinchonism Fetotoxic Not generally used as a first line agent GI, dizziness, hallucination, depression Megaloblastic anemia Reversed with leucovorin (folinic acid / THF) Mefloquine, blood schizonticide Pyrimethamine, a b lood schizonticide Damages parasitic memb ranes Inhibits DHFR, inhibits fo lic acid, antimetabolite Elim in feces Absorbed from GI tract ANTI TRYPA NOSOM E DRUGS DRUG/CLA SS Melarsoprol MECHANISM Interaction with sulfhydryl groups, inhibits parasite enzy me activity. SPECTRUM First line for advanced CNS trypanosomiasis T. rhodesiense T. gambiense (meningoencephalitis) AFRICA N SLEEPING T. rhodesiense T. brucei gamb iense AFRICA N SLEEPING PCP Leishmaniasis (second line) T. cru zi (Chagas) KINETICS IV Enters CSF SE/CLINICA L CNS Hypersensitivity GI Pentamidine Isethionate Interaction with parasitic DNA, interferes with DNA/ RNA protein synthesis Nifurtamo x Generation of to xic intracellular o xygen radicals IM Aerosol Accumulates in liver, kidney Eliminated in urine unchanged Oral Renal dysfunction Hypotension Dizziness Hypersensitivity GI d isturbances Peripheral neuropathly 35 Suramin En zy me inhibit ion Decreased energy metabolis m T. rhodesiense T. gambiense AFRICA N SLEEPING Useful prior to men ingoencephaliis PROPHYLA XIS IV Accum. in liver and kidney Vo mit ing, shock, urit icaria, neuro problems. Know which drugs active against Chagas Know which drugs active against meningoenchapalitic forms OTHER ANTIPROTOZOA L A GENTS DRUG/CLA SS Sodiu m stibogluconate, anti against LEISHMANIA SIS MECHANISM SPECTRUM Leishmaniasis KINETICS Parenteral ad min SE/CLINICA L Pain at injection GI Renal and hepatic function monitoring Co mbo with sulfadiazine. Leucovorin can limit folate deficiency in host HA/dizziness Vo mit ing Psychosis Skin pig mentation Contraindicated with primaquine Pyrimethamine, active against Toxop lasmosis Metrondiazole, anti Giard ia Quinacrine Antifolate Toxop lasmosis Interaction of phospohlipids. Inhibits phospholipase A2. Giardiasis Tapeworm Malaria Leishmaniasis PO Accumulation in liver 36