All Drugs - For Review

PHARMACOLOGY REVIEWER
Class Drug Indication Mechanism Cardiovascular drugs Activation of alpha2 receptors in CNS --> decrease NE release --> decrease TPR, cardiac output, renin activity Adverse effects Salt and water retention, severe rebound hypertension, sedation, dry mouth Salt and water retention, sedation, positive Coombs test, hemolytic anemia, hepatitis --> fulminant hepatic failure Sympathetic and parasympathetic blockade (decrease in cardiac contractility and output, increase in heart rate, postural hypotension, dry mouth, mydriasis, urinary retention, constipation, severe sexual dysfunction) Depression Orthostatic hypotension, sexual dysfunction (retrograde ejaculation) First-dose syncope Notes
Alpha2-selective agonists
Clonidine
Hypertension
CNS+ (enters CNS)
Methyldopa
Hypertension
Activation of alpha2 receptors in CNS --> decrease vascular resistance
CNS+
Ganglion blockers
Hexamethonium, trimethaphan Postganglionic neuron blockers Alpha1-selective antagonists Reserpine
Hypertension (obsolete) Hypertension
Nicotinic blockers that act in the ganglia -> block the predominant tone of the arterioles (sympathetic) and the heart (parasympathetic) --> lowers blood pressure, increases heart rate Deplete adrenergic nerve terminal of NE stores Deplete and block release of nerve terminal NE stores Alpha1-selective antagonist --> decrease vascular resistance
CNS+; adjunct to other agents
Guanethidine Prazosin, terazosin
Hypertension Hypertension Hypertension, angina prophylaxis, arrhythmia prophylaxis after MI, supraventricular tachycardias, hypertrophic cardiomyopathy, migraine, tremor, thyroid storm, thyrotoxicosis
CNSDecrease TG and LDL; increase HDL
Beta-blockers
Propranolol
Nonselective cardiac beta blockade --> reduction in cAMP --> reduction of both sodium and calcium currents and suppression of abnormal pacemakers --> reduce heart rate, cardiac output; reduce renin secretion
Sleep disturbances, sedation, sexual dysfunction, bradycardia, AV block, asthma (bronchoconstriction)
Slightly elevated LDL and TG; reduced HDL 1 |czida
Carvedilol Esmolol Chronic heart failure Acute arrhythmias (AV nodal arrhythmias, etc.) Combined beta and alpha blockade Very short-acting beta blockade; slows AV conduction --> increased PR interval Release of nitric oxide --> stimulates guanylyl cyclase --> increases cGMP --> smooth muscle relaxation --> decrease vascular resistance (afterload) Prodrug --> minoxidil sulfate --> opens K+ channels --> hyperpolarizes/relaxes smooth muscle cells --> reduce TPR (afterload), reflex increase of heart rate, cardiac output, renin activity; acts by unknown mechanism to reverse effects of testosterone in patients with androgenic alopecia Release of nitric oxide (from molecule itself) --> stimulates guanylyl cyclase --> increases cGMP --> smooth muscle relaxation in arterioles and venules --> decreases preload and afterload Opens K+ channels --> hyperpolarizes/relaxes smooth muscle cells; reduces insulin release Block voltage-gated "L-type" calcium channels (smooth muscle) --> reduce intracellular calcium and muscle contractility --> decrease vascular resistance (afterload) Block voltage-gated "L-type" calcium channels (cardiac/smooth muscle) --> reduce intracellular calcium and muscle contractility; slows AV conduction, reduce TPR Others: labetalol Administered IV Salt and water retention, marked reflex tachycardia, lupus-like syndrome (lacking renal effects)
Hydralazine
Hypertension, heart failure
Vasodilators Minoxidil
Hypertension, topically for baldness
Marked salt and water retention, very marked tachycardia, hirsutism/hypertrichosis, pericardial effusion
Nitroprusside
Diazoxide
Hypertensive emergencies, acute CHF Hypertensive emergencies, hypoglycemia due to insulin-producing tumors
Cyanide toxicity Hypotension, hyperglycemia, salt and water retention
Calcium channel blockers
Nifedipine
Verapamil
Hypertension, angina, Prinzmetal's angina Hypertension, angina prophylaxis, coronary vasospasm, AV nodal arrhythmias, arrhythmias involving calciumdependent cardiac tissue
Constipation, edema, nausea, flushing, dizziness CHF, AV blockade, sinus node depression, constipation, edema, nausea, flushing, dizziness, meningeal vasodilation (headache)
Also used in migraine, preterm labor, stroke, and Raynaud's syndrome
2 |czida
Hypertension, angina prophylaxis, AV nodal arrhythmias, arrhythmias involving calciumdependent cardiac tissue Block voltage-gated "L-type" calcium channels (cardiac/smooth muscle) --> reduce intracellular calcium and muscle contractility; AV conduction velocity decreased --> increased PR interval, effective refractory period increased; Block voltage-gated "L-type" calcium channels (cardiac/smooth muscle) --> reduce intracellular calcium and muscle contractility; conduction velocity decreased, effective refractory period increased
Diltiazem
Constipation, edema, nausea, flushing, dizziness
Nimodipine
Hemorrhagic stroke
ACE inhibitors
Captopril, enalapril Angiotensin II receptor blockers Losartan
Hypertension, CHF
Inhibit ACE --> reduced AT II (decreased afterload) and aldosterone (decreased preload) --> increased K+, compensatory increase in renin and AT I; inhibit degradation of bradykinin --> increase in bradykinin; decreased TPR (afterload)
Hypertension, CHF
Competitively inhibit AT II at its AT1 receptor site
Nitrates Nitroglycerin Angina, acute CHF, Prinzmetal's angina
Denitration within smooth muscle cells --> release of NO --> stimulates guanylyl cyclase --> increases cGMP --> smooth muscle relaxation, venodilation
Cough, renal damage in patients with bilateral renovascular disease, renal damage in the fetus, hyperkalemia Renal damage in patients with preexisting renal vascular disease, renal damage in the fetus, hyperkalemia Reflex tachycardia, orthostatic hypotension, meningeal vasodilation (throbbing headache), tolerance especially with skin patches
Renal-protective in diabetic kidney (decrease effect of AT II on efferent arteriolar tone); less effective in blacks and older patients; others: benazepril
Interaction with sildenafil (Viagra); others: isosorbide dinitrate, isosorbide mononitrate (metabolite of dinitrate)
3 |czida
Treatment of cyanide poisoning: (1) immediate amyl nitrite, (2) IV sodium nitrite, (3) IV sodium thiosulfate; nitrite converts ferrous iron in Hb to ferric form -> methemoglobinemia (higher affinity for CN than iron in cytochrome oxidase) --> thiosulfate converts cyanomethemoglobin to thiocyanate (excreted) and methemoglobin; also relaxes smooth muscle and produces venodilation
Nitrites
Amyl nitrite, sodium nitrite Cyanide poisoning
Methemoglobinemia, orthostatic hypotension
Cardiac glycosides CHF, rapid atrial (fibrillation, flutter, paroxysmal tachycardia) or AV nodal arrhythmias
Digoxin
Inhibit Na+/K+ ATPase --> increases intracellular sodium --> increases Na+/Ca2+ exchange --> increased intracellular Ca2+ stored in sarcoplasmic reticulum --> release leads to greater contractile force; slows AV conduction in AV nodal arrhythmias, accelerates ventricular repolarization (shortened QT) Inhibit the cotransport of sodium, potassium, and chloride in ascending loop of Henle --> sodium chloride diuresis (hypertonic loss; decreases preload); increased calcium excretion Combines with and blocks intracellular aldosterone receptor in late distal tubule and collecting tubule --> reduces expression of genes controlling synthesis of sodium ion channels and Na+/K+ ATPase
Loop diuretics Furosemide
Hypertension, CHF, ascites, acute pulmonary edema, severe hypercalcemia
Arrhythmias (extrasystoles, tachycardia, fibrillation), nausea, vomiting, diarrhea Hypokalemic metabolic alkalosis due to potassium wasting and excretion of protons, hypovolemia, ototoxicity, sulfonamide allergy (furosemide)
Must be administered by inhalation Quinidine, verapamil reduce clearance of digoxin; digoxin effects inhibited by extracellular K+ and Mg2+, facilitated by extracellular Ca2+; primarily dependent on renal clearance; half life 1.6 days; digoxin antibodies useful for digoxin poisoning
Others: ethacrynic acid, bumetanide Others: amiloride and triamterene (potassiumsparing, but not aldosterone antagonists)
Potassium-sparing diuretics Spironolactone
CHF; potassium wasting with loop or thiazide diuretics; aldosteronism
Hyperkalemic metabolic acidosis, gynecomastia and anti-androgenic effects
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Inhibit sodium chloride transport in the early segment of the distal convoluted tubule --> sodium chloride diuresis (and increased calcium reabsoprtion) --> decreased blood volume (preload) and peripheral resistance; chronic administration --> PCT reabsorption of water and solutes --> reduced free water clearance in patients with diabetes insipidus Inhibition of carbonic anhydrase in the brush border and intracellular carbonic anhydrase in the PCT cells --> bicarbonate diuresis, block formation of bicarbonate required for aqueous humor secretion by the ciliary body --> lower intraocular pressure in glaucoma Freely filtered at glomerulus but poorly reabsorbed from the tubule --> "holds" water via osmotic effect; can also reduce intracranial and intraocular pressure by osmotically extracting water from the tissue into the blood Activation of adenylyl cyclase --> increased cAMP --> insertion of additional water channels into luminal membrane of collecting tubule --> water reabsorption
Thiazide diuretics Hypertension, CHF, chronic renal calcium stone formation, Hydrochlorothiazide diabetes insipidus
Sodium diuresis with hyponatremia, potassium wasting (hypokalemia), thrombocytopenia, gout, hyperglycemia, hyperlipidemia, cholestasis, sulfonamide allergy Drowsiness, paresthesias, hyperchloremic metabolic acidosis, precipitation of calcium salts and formation of renal stones due to alkalinization of the urine, potassium wasting
Carbonic anhydrase inhibitors Glaucoma; acute mountain (high-altitude) sickness Maintaining high urine flow, acute glaucoma, reducing intracranial pressure in neurologic conditions
Acetazolamide
May increase LDL and TG; lower HDL; other thiazides: indapamide, metolazone Alkalinization of urine -> ammonium ion converted to ammonia gas --> rapidly reabsorbed --> encephalopathy in patients with liver problems
Osmotic diuretics Mannitol ADH agonists ADH, desmopressin
Hyponatremia and pulmonary edema, headache, nausea, vomiting
Pituitary diabetes insipidus
ADH antagonists
Demeclocycline Lithium Dobutamine
SIADH
Inhibit actions of ADH Discussed below; inhibit actions of ADH Discussed below Increase heart rate, contractility; specific activation of renal dopaminergic
Hyponatremia with large water load Bone and teeth abnormalities in children younger than 8 years Nephrogenic diabetes insipidus Increases renal blood flow more than 5 |czida
Acute heart failure Acute heart failure
Beta1-selective agonists Dopamine
receptors; dose-dependent vasoconstriction and activation of alphaadrenergic receptors Increase cAMP by inhibiting its breakdown by phosphodiesterase --> increase in cardiac intracellular calcium -> increase cardiac output; also cause vasodilation Cinchonism (GI distress, headache, vertigo, blurred vision, tinnitus), cardiac depression (prolonged QT and QRS), diarrhea, autoimmune hemolytic anemia (immune complex); torsade de pointes dobutamine
Phosphodiesterase inhibitors Amrinone Acute heart failure
Class IA antiarrhythmics
Quinidine
Atrial and ventricular arrhythmias
Procainamide Disopyramide
Atrial and ventricular arrhythmias
Block I(Na) --> slow conduction velocity in atria, Purkinje fibers, and ventricular cells; block I(K) --> increase action potential duration and effective refractory period; increased QRS (phase 0) and QT (phase 3) Block I(Na) --> slow conduction velocity in atria, Purkinje fibers, and ventricular cells; block I(K) --> increase action potential duration and effective refractory period; increased QRS and QT; converted to Nacetyl procainamide (class III activity) --> slow acetylators more likely to experience procainamide toxicity Selectively affects ischemic or depolarized Purkinje and ventricular tissue; blocks both activated and inactivated channels; reduces action potential duration; little effect on normal cardiac cells --> little effect on EKG High oral availability; electrophysiologic properties similar to lidocaine Depress sodium current --> slow conduction velocity in atrial and
Hypotension, lupus-like syndrome; torsade de pointes
Reduces clearance of digoxin; hyperkalemia exacerbates cardiac toxicity; treatment of overdose with sodium lactate (arrhythmias) and pressor sympathomimetics (hypotension) Hyperkalemia exacerbates cardiac toxicity; treatment of overdose with sodium lactate (for arrhythmias) and pressor sympathomimetics (for hypotension) Hyperkalemia increases cardiac toxicity; less likely than quinidine or flecainide to cause or exacerbate ventricular arrhythmias
Class IB antiarrhythmics Lidocaine Mexiletine, tocainide Class IC antiarrhythmics Flecainide
Acute ventricular arrhythmias, digoxininduced arrhythmias Acute ventricular arrhythmias Refractory ventricular tachycardia, certain
Allergy (usually rashes but may extend to anaphylaxis), CNS (tremors, twitching, dizziness, visual disturbances) Tocainide: agranulocytosis Proarrhythmic effect
Hyperkalemia increases cardiac toxicity 6 |czida
intractable supraventricular arrhythmias Class II antiarrhythmics Discussed above Blockade of potassium channels responsible for repolarization of action potential --> prolongation of action potential duration, increased effective refractory period; increased QT Blockade of potassium channels responsible for repolarization of action potential --> prolongation of action potential duration, increased effective refractory period; increased QT ventricular cells; no effect on ventricular action potential duration or QT interval, increase QRS
Class III antiarrhythmics
Sotalol
Arrhythmias
Torsade de pointes, sinus bradycardia, asthma
Ibutilide Class IV antiarrhythmics Discussed above
Atrial flutter and fibrillation
Torsade de pointes
Miscellaneous antiarrhythmics
Amiodarone
Arrhythmias resistant to other drugs
Adenosine Potassium ion
Magnesium ion
AV nodal arrhythmias Digitalis toxicity Digitalis toxicity, some cases of torsade de pointes
Blocks sodium, calcium, and potassium channels and beta adrenoreceptors Slows conduction in AV node (high doses) probably by hyperpolarizing the tissue and reducing calcium current Flushing, hypotension Depresses ectopic pacemakers
Microcrystalline deposits in the cornea and skin, bluegray skin discoloration, thyroid dysfunction, paresthesias, tremor, pulmonary fibrosis
Extremely long half-life -> requires many days to achieve steady-state levels, even with loading doses Short duration of action (15 s) --> IV bolus
Histamine H1 antagonists
Diphenhydramine (first-generation)
Drugs with important actions on smooth muscle IgE-mediated allergies Competitive antagonists at the H1 (hay fever, urticaria, receptor; more effective if given before atopic dermatitis); histamine release occurs; antimuscarinic motion sickness; actions, alpha-blocking actions
Sedation; antimuscarinic effects (dry mouth, blurred vision, tachycardia); orthostatic hypotension;
Ineffective in asthma; others effective in motion sickness (dimenhydrinate, 7 |czida
chemotherapy-induced vomiting; OTC sleep aids, Meniere disease Cyclizine, meclizine Promethazine Chlorpheniramine (prototype), fexofenadine (second-generation) Terfenadine, astemizole, loratadine Motion sickness, vertigo Motion sickness, antiemetic IgE-mediated allergies (hay fever, urticaria, atopic dermatitis) IgE-mediated allergies (hay fever, urticaria, atopic dermatitis) Same as diphenhydramine Same as diphenhydramine excitement in children cyclizine, meclizine, promethazine)
Less sedating Marked sedation
Same as diphenhydramine
Same as diphenhydramine
Histamine H2 antagonists
Cimetidine, ranitidine, famotidine, nizatidine
Peptic ulcer disease, Zollinger-Ellison syndrome, GERD Acute migraine and cluster headache attacks Carcinoid tumor Carcinoid tumor Vomiting associated with cancer chemotherapy (most effective treatment) Hyperprolactinemia and parkinsonism
Blockade of histamine H2 receptors --> reduction of gastric acid secretion
Sedation Arrhythmias (long QT) when combined with azole antifungal drugs, erythromycin Inhibits hepatic drugmetabolizing enzymes (primarily cimetidine), cimetidine: gynecomastia and other feminizing effects in men Chest discomfort, mild tingling Toxicities of alpha blockade
Ineffective in asthma Withdrawn from US market; little or no sedation
Serotonin 5-HT1D agonists
Sumatriptan Ketanserin
Serotonin antagonists
Cyproheptadine
5-HT1D agonist Competitive 5-HT2 antagonist; also has alpha-blocking effects Competitive 5-HT2 antagonist; also H1 blocking effects Selective 5-HT3 receptor blockers; central antiemetic action in area postrema of the medulla Potent dopamine agonists; alpha adrenoceptor and 5-HT2 antagonist
Serotonin is involved in mood, sexuality, anxiety, sleep
Ondansetron Ergot alkaloids Bromocriptine
Diarrhea, headache GI upset
8 |czida
Selectively stimulates uterine smooth muscle; alpha adrenoceptor and dopamine agonist; partial 5-HT2 antagonist Stimulates uterine smooth muscle; alpha adrenoceptor and dopamine agonist; partial 5-HT2 antagonist Severe prolonged vasoconstriction (ischemia, gangrene), GI upset, marked uterine contractions Severe prolonged vasoconstriction (ischemia, gangrene), GI upset, marked uterine contractions cardiac, retroperitoneal, and pleuropulmonary fibrosis
Ergonovine
Obstetric bleeding
Ergotamine
Migraine, obstetric bleeding
Methysergide PGE2 (dinoprostone)
Migraine prophylaxis Ripen cervix at term; abortion in second trimester
Prostaglandins PGF2-alpha
PGE1 (misoprostol, alprostadil) Prostacyclin PGI2 (epoprostenol) Leukotriene inhibitors Zafirlukast, montelukast Zileuton
Ripen cervix at term; abortion in second trimester Abortion with mifepristone (RU 486) or methotrexate; maintain PDA; PUD prevention in patients on NSAIDs; impotence
Serotonin antagonist/partial agonist Activation of cell surface receptors coupled by G proteins to adenylyl cyclase or the phosphatidylinositol cascade Activation of cell surface receptors coupled by G proteins to adenylyl cyclase or the phosphatidylinositol cascade --> increases cardiac output, constricts bronchial smooth muscle, initiates uterine contractions, and causes contraction of gastrointestinal longitudinal muscle
Nausea, vomiting, diarrhea
Vaginal suppository
Nausea, vomiting, diarrhea
Latanoprost, a PGF2alpha derivative, used in glaucoma (increase outflow of aqueous humor)
Inhibitory effect on cAMP --> decreases acid secretion in stomach Activation of cell surface receptors coupled by G proteins to adenylyl cyclase or the phosphatidylinositol cascade --> potent inhibitor of platelet aggregation Churg-Strauss syndrome (rare) Elevation of liver enzymes
Should not be given to pregnant women or to women attempting to conceive
Exercise- and antigeninduced bronchospasm; aspirin allergy Exercise- and antigen-
Inhibitors at the LTD4 and LTE4 receptors Selecitve inhibitor of 5-lipoxygenase
Not recommended for acute episodes of asthma
9 |czida
induced bronchospasm; aspirin allergy Inhibit production of arachidonic acid by phospholipases; inhibit synthesis of COX2; inhibit release of mediators by mast cells Inhibit production of arachidonic acid by phospholipases; inhibit synthesis of COX2; inhibit release of mediators by mast cells Inhibit production of arachidonic acid by phospholipases; inhibit synthesis of COX2; inhibit release of mediators by mast cells Others: budesonide, dexamethasone, flunisolide, fluticasone, mometasone
Prednisone Corticosteroids Hydrocortisone
Moderate to severe asthma
Adrenal suppression, oral candidiasis (inhalers)
Moderate to severe asthma
Adrenal suppression, oral candidiasis (inhalers)
Beclomethasone
Moderate to severe asthma, allergy
Oral candidiasis (inhalers) Diversion of arachidonic acid to leukotriene synthesis in aspirin allergy (more common with nasal polyps [triad asthma])
COX inhibitors Aspirin Celecoxib, rofecoxib Terbutaline, albuterol, metaproterenol Fever, inflammation, pain Fever, inflammation, pain
Discussed below; nonselective, irreversible inhibition of COX-1 and COX2; permanent inhibition of thromboxane synthesis in platelets Selective COX-2 inhibitors Beta2 agonist --> stimulates adenylyl cyclase --> increases cAMP in smooth muscle cells --> bronchodilation more than cardiac stimulation Beta 2 agonist --> stimulates adenylyl cyclase --> increases cAMP in smooth muscle cells --> bronchodilation more than cardiac stimulation
Beta2-selective agonists
Asthma (acute bronchospasm)
Skeletal muscle tremor; tachycardia; tolerance
Inhaled; shorter-acting; no use in treating allergic rhinitis
Salmeterol, formoterol
Asthma (prophylaxis)
Skeletal muscle tremor; tachycardia
Methylxanthines
Theophylline
Asthma
Inhibit phosphodiesterase --> increase cAMP --> bronchodilation; block adenosine receptors --> bronchodilation; stimulate diaphragm muscle activity
GI distress (nausea, anorexia), tremor, insomnia, nervousness, headache
Inhaled; long-acting (> 12 h) Inhibits metabolism of theophylline: cimetidine, erythromycin, allopurinol; promote metabolism: rifampin, barbiturates, alcohol, 10 |czida
tobacco, marijuana
Muscarinic antagonists Ipratropium Cromolyn and nedocromil Asthma; COPD
Competitively blocks muscarinic receptors in airways, prevents bronchoconstriction mediated by vagal discharge Cough, wheezing, and irritation of airway when given by aerosol, gastroenteritis in some patients
Cromolyn and nedocromil
Asthma/allergy prophylaxis (especially in children)
Decrease in release of mediators (leukotrienes, prostaglandins and histamine) from mast cells
Of no value in treating an acute asthma attack
Magnesium hydroxide Antacids Aluminum hydroxide
PUD
PUD
Sucralfate
Sucralfate (aluminum sucrose sulfate)
PUD
Drugs used in gastrointestinal disorders Antacid; reacts with protons in the lumen of the gut Antacid; reacts with protons in the lumen of the gut; may also stimulate the protective functions of the gastric mucosa Small, poorly soluble molecule that polymerizes in the acid environment of the stomach --> polymer binds to injured tissue --> forms protective coating over ulcer beds
Strong laxative effect Calcium carbonate (gastric antacid) is also constipating Must be taken four times daily; low gastric pH required --> incompatible with H2 blockers and antacids Used with bismuth, tetracycline, and metronidazole or a course of amoxicillin plus clarithromycin to eradicate H. pylori
Constipating
Low toxicity
Proton pump inhibitors Omeprazole Drugs that promote upper GI motility Metoclopramide
Zollinger-Ellison syndrome, GERD, nonNSAID-induced peptic ulcers (H. pylori) Gastroparesis; emesis following surgical anesthesia, emesis induced by cancer
Inibit H+/K+ ATPase located in the luminal membrane of gastric parietal cells Acetylcholine facilitator and dopamine receptor antagonist in the enteric nervous system
Hypergastrinemia; carcinoid tumors in rats; low toxicity in humans Induction of parkinsonism and other extrapyramidal effects
11 |czida
chemotherapy 5-HT4 agonist in the enteric nervous system --> increase release of Ach from motor neurons that innervate GI smooth muscle --> increase GI motility and lower esophageal sphincter tone
Cisapride Ondansetron, granisetron, dolasetron Metoclopramide, dexamethasone, some H1 antihistamines, several phenothiazines, dronabinol
Gastroparesis, GERD Nausea and vomiting after general anesthesia and in patients receiving cancer chemotherapy
Long QT syndrome, fatal arrhythmias
Limited availability due to adverse effects
5-HT3 inhibitors in chemoreceptor trigger zone
Drugs with antiemetic actions
Pancreatic enzyme replacements Pancrelipase Castor oil, cascara, senna Saline cathartics, psyllium Dioctyl sodium sulfosuccinate (docusate) Mineral oil, glycerin Bisacodyl Steatorrhea Pancreatic lipase obtained from pigs Benign melanotic pigmentation of the colon (melanosis coli)
90% of an administered dose destroyed in stomach unless pH raised by antacids or drugs that reduce acid secretion
Constipation Constipation
Irritant action on the bowel wall Bulk-forming action on the stool that evokes reflex contraction of the bowel Softening action on hard or impacted stools Lubricating action that eases passage of stool through the rectum Stimulant laxative: activates neural plexuses in intrinsic nervous system
Laxatives
Constipation Constipation Constipation
Mild cramping, rashes, nausea
Abdominal cramps, atonic colon with prolonged use
Others: phenolphthalein 12 |czida
Synthetic disaccharide (galactose plus fructose) metabolized by colonic bacteria --> low molecular weight acids that trap ammonia that diffuses into the colon from the blood by converting it to ammonium ion (not reabsorbed); also retains water and stimulates colonic peristalsis
Lactulose
Portal-systemic encephalopathy, constipation
Cramps, diarrhea, flatulence, electrolyte disturbances Difenoxin is the active metabolite of diphenoxylate; cross blood-brain barrier poorly --> low CNS effects
Antidiarrheal agents Diphenoxylate and loperamide Drugs that inhibit the Chenodiol formation of gallstones Ursodiol Diarrhea Inhibit formation of cholesterol gallstones Inhibit formation of cholesterol gallstones Meperidine analogs with very weak analgesic effects Reduce secretion of bile acids by the liver Unknown mechanism Endocrine drugs Acts on somatotropes to produce a rapid increase in plasma growth hormone levels Activates Gi protein --> decreases cAMP -> inhibits release of growth hormone, thyrotropin, glucagon, insulin, and gastrin Stimulates secretion of both ACTH and beta-endorphin from the pituitary; increases synthesis of proopiomelanocortin from anterior pituitary Stimulates secretion of TSH from pituitary Diagnosis and treatment of hypogonadal states Stimulate gonadotropin release when given in pulsatile doses (resembling
Growth hormonereleasing hormone Octreotide (synthetic somatostatin) Hypothalamic hormones Corticotropinreleasing hormone Thyrotropinreleasing hormone Gonadotropinreleasing hormone
Determine cause of GH deficiency Acromegaly, carcinoid, gastrinoma, glucagonoma, and other endocrine tumors
Diagnosis of abnormal ACTH secretion
Tripeptide: Glu-His-Pro
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physiologic cycling); steady dosing causes a marked inhibition of gonadotropin release Suppress gonadotropin secretion in prostatic carcinoma or other gonadal steroid-sensitive tumors, endometriosis, or precocious puberty Infertility GnRH analog; stimulate gonadotropin release when given in pulsatile doses (resembling physiologic cycling); steady dosing causes a marked inhibition of gonadotropin release GnRH antagonist Inhibits prolactin release Discussed above; inhibits prolactin release Growth hormone acts at liver and other tissues to increase secretion of insulinlike growth factor I (somatomedin C; peptide that circulates bound to carrier protein); IGF-1 acts in hypothalamus to increase secretion of somatostatin --> decrease GH release (negative feedback) Made up of two subunits (unique beta subunit) --> increases iodine uptake and production of thyroid hormones in thyroid cells ACTH analog, stimulates adrenal cortex Made up of two subunits (unique beta subunit) --> stimulates gametogenesis and follicle development in women and spermatogenesis in men FSH-like activity (stimulates gametogenesis and follicle development in women and spermatogenesis in men) Made up of two subunits (unique beta subunit) --> major stimulant of gonadal 14 |czida
Leuprolide Ganirelix Dopamine Bromocriptine
Bone pain, gynecomastia, hematuria, impotence, testicular atrophy Only nonpeptide hypothalamic hormone
Hyperprolactinemia
Growth hormone (somatotropin), somatropin, somatrem
GH deficiency in children and adults Distinguish primary from secondary hypothyroidism Diagnosis of abnormal corticosteroid production
Anterior pituitary hormones
Thyroid-stimulating hormone (TSH) Cosyntropin
Follicle-stimulating hormone (FSH)
Urofollitropin Luteinizing hormone (LH)
Infertility
steroid production; regulates follicular development and ovulation in women LH-like activity (major stimulant of gonadal steroid production; regulates follicular development and ovulation in women) FSH plus LH activity Effective stimulant of uterine contraction; causes contraction of smooth muscle in the myoepithelial cells of the mammary gland Selective agonist of V2 receptors (increases synthesis or insertion of water channels by a cAMP-dependent mechanism --> increase in water permeability in the collecting tubules of the kidney --> water reabsorption) Binds to receptors in the nucleus that control expression of genes responsible for many metabolic process --> proteins include Na+/K+ ATPase, specific contractile proteins in smooth muscle and the heart, enzymes involved in lipid metabolism, developmental components in the brain, etc. Binds to receptors in the nucleus that control expression of genes responsible for many metabolic process --> proteins include Na+/K+ ATPase, specific contractile proteins in smooth muscle and the heart, enzymes involved in lipid metabolism, developmental components in the brain, etc.
Human chorionic gonadotropin Menotropins
Infertility Infertility
Oxytocin Posterior pituitary hormones
Induce or reinforce labor, stimulate milk let-down
Desmopressin
Pituitary diabetes insipidus
Thyroid hormones
T4 (synthetic levothyroxine)
Hypothyroidism
Thyrotoxicosis
Form of choice for most cases; TSH levels suppressed --> thyroid gland inactive --> low 131I uptake
T3 (liothyronine)
Hypothyroidism
Thyrotoxicosis
T3 vs. T4: about ten times more potent, faster-acting but has a shorter half-life and is more expensive
15 |czida
Concentrated in thyroid --> inhibit the oxidative processes (mediated by thyroid peroxidase) required for iodination of tyrosyl groups and coupling of DIT and MIT; PTU inhibits 5'-deiodinase, methimazole does not Inhibit organification (iodination of tyrosine) and thyroid hormone release; decrease size and vascularity of hyperplastic thyroid gland Taken up and concentrated in the thyroid --> dose large enough to severely damage the gland can be given without endangering other tissues --> can produce permanent cure of thyrotoxicosis Iodinated radiocontrast media; effectively suppresses conversion of T4 to T3 via 5'deiodinase in liver, kidney, and other peripheral tissues Propranolol also inhibits 5'-deiodinase Enter the cell --> bind to cytosolic receptors --> transport into nucleus --> steroid-receptor complex alters gene expression by binding to glucocorticoid response elements or mineralocorticoidspecific elements; metabolic effects: gluconeogenesis, glycogen deposition in hepatocytes, muscle protein catabolism, insulin secretion, lipolysis/lipogenesis; osteoporosis (--> should receive supplemental calcium); immunosuppression (lymphotoxic), antiinflammatory Skin rash (common); severe immune reactions (rare): vasculitis, hypoprothrombinemia, agranulocytosis
Thioamides (propylthiouracil and methimazole)
Antithyroid drugs
Iodide salts and iodine
Hyperthyroidism Thyroid storm (severe thyrotoxicosis); preparation for surgical resection of hyperactive thyroid
Slow onset since synthesis, not release, is inhibited Onset occurs rapidly (within 2-7 days), though effects are transient (several weeks)
Radioactive iodine (131I)
Thyrotoxicosis
Should not be used in pregnant or nursing women
Ipodate Beta-blockers (propranolol)
Thyrotoxicosis Thyrotoxicosis Addison's disease; lifethreatening shock, infection or trauma; inflammatory or immunologic disorders, dermatitis (allergic, eczematous, seborrheic), hematopoietic cancers, neurologic disorders, chemotherapy-induced vomiting, hypercalcemia, mountain sickness
Glucocorticoids
Cortisol (hydrocortisone)
Adrenal suppression (from ACTH suppression; Addison-like crisis with abrupt cessation of longterm use), metabolic effects (growth inhibition, diabetes, muscle wasting, osteoporosis), salt retention, psychosis
Glucocorticoids aggravate PUD; decrease in blood glucose stimulates release; fluorinated corticosteroids best absorbed from scrotum, scalp, and face compared to arms, legs, and trunk
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Adrenal suppression (from ACTH suppression), metabolic effects (growth inhibition, diabetes, muscle wasting, fat redistribution, osteoporosis), salt retention, psychosis See cortisol toxicity
Prednisone, prednisolone, dexamethasone, triamcinolone Betamethasone Beclomethasone
Congenital adrenal hyperplasia and above indications for cortisol Hastens fetal lung maturation Discussed above Replacement therapy after adrenalectomy Cushing's syndrome Discussed above Adrenal carcinoma, hirsutism, breast cancer Steroid-producing adrenocortical cancer Diagnostic tests of adrenal function
Synthetic glucocorticoids with the same action as cortisol Glucocorticoid with low degree of protein binding Mineralocorticoid (synthesis of sodium ion channels and Na+/K+ ATPase) with significant glucocorticoid activity Inhibitor at glucocorticoid receptors as well as progesterone receptors Antifungal drug; inhibits the P450 enzymes necessary for the synthesis of all steroids (e.g., testosterone) Blocks conversion of cholesterol to pregnenolone and also inhibits synthesis of all hormonal active steroids Inhibits normal synthesis of cortisol, but not that of cortisol precursors
Mineralocorticoids
Fludrocortisone Mifepristone (RU 486) Spironolactone
Long duration of action
Corticosteroid antagonists
Ketoconazole
Aminoglutethimide Metyrapone
Ovarian hormones Primary hypogonadism in young females; hormone replacement therapy; component of oral contraceptives
Estrogens
Growth of genital structures during childhood; secondary sexual characteristics and growth spurt of puberty; metabolic effects: modifies serum protein levels and reduces bone resorption, enhances coagulability, increases plasma triglycerides; constant low level prevents LH surge; increases HDL, reduces LDL; suppresses FSH
Premature closure of epiphyses in hypogonadal girls; increased risk of endometrial cancer in HRT (prevented by use of a progestin); nausea, breast tenderness, migraines, thromboembolic events, gallbladder disease, hypertriglyceridemia, hypertension
Others: estradiol, ethinyl estradiol, mestranol; estrogen in HRT: reduces hot flushes, sweating, atrophic vaginitis; less urinary urgency, incontinence, frequency; less risk of osteoporosis; less death in coronary artery disease; may cause 17 |czida
mood depression
Progestins
Component of oral or implantable contraceptives; HRT; produce anovulation and amenorrhea in women with dysmenorrhea, endometriosis, or bleeding disorders
Cause development of secretory tissue in the breast and maturation of the uterine endometrium; affect carbohydrate metabolism and stimulate fat deposition; arrests proliferative phase and inhibits LH and midcycle LH surge; high doses suppress FSH; progestin implants containing levonorgestrel believed to inhibit sperm transport and embryo implantation
Weight gain, hair growth, acne, and decreased HDL
Oral contraceptives containing both estrogen and progestin Postcoital contraceptives
Oral contraceptives
Mifepristone (RU 486)
Selective estrogen receptor modulators Tamoxifen
Postcoital contraceptive Hormone-responsive breast cancers, after breast cancer surgery in patients with estrogendependent tumors
See estrogens and progestins; act by a negative feedback inhibition of hypothalamic and pituitary function --> suppression of gonadotropin secretion and ovulation Progesterone antagonist, partial agonist; when administered before the LH surge, they inhibit ovulation; also affect implantation and possibly fertilization Acts as an antagonist to prevent receptor activation by endogenous estrogens; acts as an agonist at endometrial receptors --> hyperplasia, increased risk for endometrial cancer
May increase risk of breast and cervical cancer
Others: progesterone, medroxyprogesterone, levonorgestrel, norethindrone, norgestimate, desogestrel Oral contraceptives render cervical mucus hostile to sperm and decrease tubal motility; decrease incidence of ovarian and endometrial cancer, iron deficiency anemia, and PID Given as a single oral dose followed by a prostaglandin E or F analog Prevents osteoporosis in women who are taking the drug for breast cancer
Hot flushes, increased risk of venous thrombosis, depression, dizziness, thrombocytopenia
18 |czida
Partial agonist effects on bone and increases serum HDL; antagonist effects in breast tissue, reduces incidence of breast cancer in high-risk women; no estrogenic Hot flushes, increased risk of venous thrombosis effects on endometrial tissue Selectively blocks estrogen receptors in the hypothalamus --> reduces negative feedback and increases FSH and LH output from pituitary via GnRH --> stimulates ovulation Associated with infertility, ectopic pregnancy, and vaginal adenosis/adenocarcinoma in daughters of women treated with high doses Estrogen agonist activity (synthetic during pregnancy nonsteroidal estrogen)
Raloxifene
Prevention of osteoporosis in postmenopausal women Induce ovulation in anovulatory women who wish to become pregnant
Clomiphene
Estrogen and progesterone agonists, antagonists, and synthesis inhibitors
Diethylstilbestrol Mifepristone (RU 486)
No longer used commonly
Discussed above Weak partial agonist that binds to progestin, androgen, and glucocorticoid receptors in cells (blocks progesterone stimulation of uterus in endometriosis) and to steroid transport proteins in the blood; also inhibits several P450 enzymes involved in gonadal steroid synthesis Inhibitors of aromatase, the enzyme required for estrogen synthesis Androgens enter cells and bind to cytosolic receptors; hormone-receptor complex enters nucleus and modulates expression of certain genes: normal development of male fetus and infant, male changes at puberty, secondary sex characteristics, male-pattern baldness; Nausea, diarrhea, hot flushes, bone and back pain, dyspnea, peripheral edema Virilization in females; feminization in men with excessive doses due to feedback inhibition of pituitary and conversion to estrogens (decreased spermatogenesis, sexual
Danazol
Endometriosis, fibrocystic disease of the breast
Anastrozole
Breast cancer Replacement therapy in hypogonadism (impotence, decreased libido); stimulate RBC production in certain anemias; weight gain in patients with wasting
Androgens
Testosterone
Others: oxandrolone, nandrolone, stanozolol; increased libido, sebaceous gland secretion (acne) 19 |czida
syndromes anabolic actions (increased muscle size and strength, increased RBC production, maintain bone density) dysfunction); behavioral effects (hostility, aggression ["roid rage"]); cholestatic jaundice, elevation of liver enzymes, possibly hepatocellular carcinoma
Flutamide
Prostate carcinoma
Cyproterone Antiandrogens Spironolactone Leuprolide
Hirsutism Hirsutism Discussed above Benign prostatic hyperplasia, prevent hair loss in men (lower dose)
Nonsteroidal competitive antagonists at androgen receptors; decrease action of endogenous hormones in prostate carcinoma Act as competitive antagonists at androgen receptors; decrease action of endogenous hormones in prostate carcinoma; also has progestational activity that provides negative feedback to the pituitary Discussed above; potassium-sparing diuretic; also inhibits androgen receptors 5-alpha-reductase inhibitor --> inhibits conversion of testosterone to dihydrotestosterone Estrogen in contraceptive acts in liver to increase production of sex hormone binding globulin --> reduces concentration of free androgen in blood Activation of insulin receptor (tyrosine kinase) --> autophosphorylation and phosphorylation of a variety of intracellular proteins; liver: increases glycogen, GLUT 2 glucose transport insertion in cell walls, synthesis of pyruvate kinase, PFK, glucokinase, decreases protein catabolism; muscle:
Gynecomastia, hot flushes, hepatic dysfunction
Finasteride
Combined oral contraceptives Ketoconazole
Hirsutism Discussed above
Insulin Diabetes mellitus, diabetic ketoacidosis
Insulin
Hypoglycemia from excessive insulin effect; immunologic toxic effects from development of antibodies
Ultra rapid and very short action (lispro), rapid onset and short action (regular), intermediate onset and action (NPH, lente), slow onset and long action (ultralente), ultra-long20 |czida
glycogen and protein synthesis, insertion of GLUT 4 transporters; adipose: plasma lipoprotein lipase activation, triglyceride storage, GLUT 4, reduces intracellular lipolysis acting (glargine)
Insulin secretagogues (sulfonylureas) Glyburide, glipizide, glimepride Insulin secretagogues (meglitinides) Type 2 diabetes mellitus Type 2 diabetes mellitus (taken before meals for postprandial glucose control)
Stimulate release of endogenous insulin; sulfonylureas close K+ channels --> depolarization --> insulin release Also promotes insulin release by binding to K+ channels in pancreatic B cell membranes Act by an unknown mechanism to reduce postprandial and fasting glucose levels in patients with type 2 diabetes (may increase glucose uptake by muscle and adipose tissue and decrease hepatic gluconeogenesis and glucose output) Stimulate peroxisome proliferatoractivated receptor-gamma nuclear receptor --> transcription of genes involved in carbohydrate and lipid metabolism --> increase target tissue sensitivity to insulin, inhibit hepatic gluconeogenesis Carbohydrate analogs that act within the intestine to inhibit alpha-glucosidase, an enzyme necessary for the conversion of complex starches, oligosaccharides, and disaccharides to monosaccharides that can be absorbed
Relatively uncommon: hypoglycemia, rash (occasionally), allergy, transient leukopenia (agranulocytosis), SIADH (chlorpropamide)
Repaglinide
Not effective in patients who lack functional beta cells; others: tolbutamide, chlorpropamide, acetohexamide, tolazamide Rapid onset and short duration of action compared to sulfonylureas
Biguanides Metformin Type 2 diabetes mellitus
GI distress (nausea, diarrhea), lactic acidosis, inhibits vitamin B12 absorption
Effects do not depend on functional islet cells
Thiazolidinediones Rosiglitazone, pioglitazone
Type 2 diabetes mellitus
Edema, mild anemia
Alpha-glucosidase inhibitors Acarbose, miglitol
Postprandial hyperglycemia in type 2 diabetes mellitus
Flatulence, diarrhea, and abdominal pain
Treatment of hypoglycemia with oral glucose (dextrose), not sucrose 21 |czida
Severe hypoglycemia in diabetics; x-ray studies of bowel or abdomen when reduction of motility is necessary; management of severe beta blocker overdose Acts on G-protein coupled receptors located in heart, smooth muscle, and liver --> stimulate adenylyl cyclase --> increases intracellular cAMP --> increases heart rate, contraction, hepatic glycogenolysis and gluconeogenesis, lipolysis, and relaxation of smooth muscle (gut) Acts on membrane G protein-coupled receptors --> increase cAMP in bone and the renal tubule --> increase resorption of bone, increase renal reabsorption of calcium, excretion of phosphate --> increases blood calcium and decreases phosphate; increases active vitamin D formation; increase net bone formation at low doses (physiologic levels)
Hyperglycemic drugs
Glucagon
Decrease in blood glucose stimulates release
Parathyroid hormone
Drugs affecting bone mineral homeostasis Vitamin D
Postmenopausal osteoporosis (using low doses of a PTH analog) Treatment of deficiency states: chronic renal failure, intestinal osteodystrophy, nutritional rickets, postmenopausal osteoporosis
Calcitonin Estrogens and SERMs
Bisphosphonates
Paget's disease, hypercalcemia, osteoporosis Postmenopausal bone loss Osteoporosis (postmenopausal, glucocorticoid-induced),
Increased intestinal calcium and phosphorus absorption, decreased renal excretion, and net increase in blood levels; increases bone resorption of calcium Decreases bone resorption and serum calcium and phosphate by osteoclast inhibition; increases renal reabsorption of calcium; bone formation not impaired initially, but ultimately reduced; contained in parafollicular cells (C cells) of thyroid May involve inhibition of PTH-stimulated bone resorption Reduce both the resorption and the formation of bone by an action on the basic hydroxyapatite crystal structure
Salmon calcitonin most often used because of longer half-life and greater potency
Esophageal ulceration
Alendronate, etidronate, pamidronate, risedronate 22 |czida
Paget's disease Acute toxicity (usually caused by ingestion of rat poison): GI and neurologic symptoms; chronic toxicity (fluorosis): ectopic bone formation, exostoses, chalky deposits on teeth Serious toxicity: thrombocytopenia, hemorrhage, hepatic and renal damage
Fluoride
Plicamycin (mithramycin)
Dental caries Paget's disease, testicular cancer, serious hypercalcemia (shortAntibiotic used to reduce serum calcium term treatment) and bone resorption
Appropriate concentrations in drinking water and as a dentifrice have a welldocumented ability to reduce dental caries; chronic exposure, especially in high concentrations, may increase new bone synthesis
Not used commonly
Iron Drugs used in anemias
Vitamin B12
Folic acid
Drugs with important actions on blood, inflammation, and gout Most common in children due to ingestion of supplements: necrotizing gastroenteritis, shock, metabolic acidosis, coma, Essential metallic component of heme; an death; chronic toxicity with important fraction is bound to transferrin frequent transfusions, hemochromatosis, inherited (transport protein) and ferritin (storage abnormality in absorption protein) Iron deficiency anemia Absorbed from GI tract in the presence of intrinsic factor --> cofactor in transfer of one-carbon units (necessary for DNA synthesis) --> stored in liver (enough to last 5 years) --> deficiency manifests first Pernicious anemia and anemia caused by gastric as anemia; also, development of neurologic defects No significant toxicity resection Anemia due to folic acid Absorbed from GI tract --> only modest deficiency; anemia in amounts stored in body --> decreased vitamin B12 deficiency intake followed by anemia in a few (but not neurologic months (folic acid necessary for normal defects) DNA synthesis) None
Should not be given in hemolytic anemia because iron stores are elevated; treatment of acute iron intoxication: deferoxamine; treatment of chronic toxicity: phlebotomy Essential for two reactions: conversion of methylmalonyl-CoA to succinyl-CoA and conversion of homocysteine to methionine Folic acid --> tetrahydrofolate by dihydrofolate reductase; important in the dTMP cycle 23 |czida
Anemias associated with renal failure, other anemias (aplastic Erythropoietin anemia) Recovery of neutrophils after cancer chemotherapy, primary and secondary neutropenia, aplastic anemia Filgrastim (G-CSF) Recovery of neutrophils after cancer chemotherapy, primary and secondary Sargramostim, (GM- neutropenia, aplastic anemia CSF) Patients with previous thrombocytopenia after cycle of cancer Oprelvekin (IL-11) and thrombopoietin chemotherapy Activates specific receptors on erythroid progenitors in bone marrow --> stimulates production of RBCs and increases release from marrow Minimal, usually results from excessive increase in hematocrit
Hematopoietic growth factors
Stimulate the production and function of neutrophils; mobilize hematopoietic stem cells (increased concentration in peripheral blood)
Minimal; sometimes bone pain
Stimulate the production and function of neutrophils and other myeloid and megakaryocyte progenitors Stimulate growth of primitive megakaryocytic progenitors and increase the number of peripheral platelets Binds to and activates endogenous antithrombin III --> heparin-ATIII complex combines with and inactivates thrombin and several other factors, especially factor X; rapid onset, active in vitro, parenteral; protamine sulfate forms inactive complex with heparin --> antidote for overdose Inhibit epoxide reductase (converts vitamin K to active form) --> interfere with normal posttranslational modification of clotting factors in the liver (vitamin K dependent) (factors II, VII, IX, and X); delayed onset because activated factors still operational, not active in vitro, oral
Fever, arthralgias, capillary damage with edema
Fatigue, headache, dizziness, fluid retention
Anticoagulants
Heparin
Used for immediate anticoagulation: deep vein thrombosis, pulmonary embolism, myocardial infarction
Coumarin anticoagulants (warfarin)
Chronic anticoagulation (e.g., in patients with atrial fibrillation to prevent thrombi)
Bleeding, thrombocytopenia, thrombosis, osteoporosis (prolonged use) Bleeding; increased clearance with P450inducing drugs (barbiturates, carbamazepine, phenytoin); reduced clearance with P450-inhibiting drugs (amiodarone, cimetidine,
Action of heparin monitored by activated partial thromboplastin time (aPTT or PTT); does not cross placenta; administered IV or SQ Slow reversal with vitamin K; rapid reversal with fresh or frozen plasma containing clotting factors; effect monitored by prothrombin time; administered PO 24 |czida
disulfiram); crosses placenta --> birth defects
Aspirin and other NSAIDs
Prevent further infarcts in those with previous MI; may reduce incidence of first MI; prevent transient ischemic attacks, ischemic stroke, and other thrombotic events
Antiplatelet drugs
Dipyridamole Prevent transient ischemic attacks, ischemic strokes, MI, prevent thrombosis in those with recent coronary artery stent Prevent restenosis after coronary angioplasty, used in acute coronary syndromes Emergency treatment of coronary artery thrombosis, ischemic stroke, multiple pulmonary emboli Emergency treatment of coronary artery thrombosis, multiple
Discussed below; inhibit thromboxane synthesis by blocking cyclooxygenase; thromboxane A2 is a potent stimulator of platelet aggregation; irreversible GI and CNS effects inhibition with aspirin (several days) Increases cAMP by inhibiting cyclic nucleotide phosphodiesterase --> inhibits thromboxane A2 production in platelets -> inhibits platelet aggregation
Increase bleeding time
Inhibitors of ADP receptors (ticlopidine, clopidogrel) Glycoprotein IIb/IIIa receptor inhibitors (abciximab, tirofiban, eptifibatide)
Irreversible inhibition of the ADPreceptor --> inhibition of ADP-mediated pathway involved in binding of platelets to fibrinogen and to each other
Ticlopidine: bleeding, leukopenia, agranulocytosis
Reversibly inhibits the binding of fibrin and other ligands to the IIb/IIIa receptor (involved in platelet cross-linking)
Bleeding, thrombocytopenia (chronic use)
Thrombolytic agents
Alteplase, reteplase
Directly converts fibrin-bound plasminogen to plasmin; not allergenic (compared to streptokinase)
Bleeding
Must rule out cerebral hemorrhage
Urokinase
Directly converts plasminogen to plasmin
Bleeding 25 |czida
pulmonary emboli Emergency treatment of coronary artery thrombosis, multiple pulmonary emboli, deep vein thrombosis
Streptokinase
Anistreplase
Drugs used in bleeding disorders
Vitamin K Clotting factors
Antiplasmin agents (aminocaproic acid)
Emergency treatment of coronary artery thrombosis, multiple pulmonary emboli Deficiency of vitamin K (common in newborns and older individuals with abnormalities in fat absorption); reverse warfarin Hemophilia (factors VIII and IX) Acute bleeding episodes in hemophiliacs and others with bleeding disorders
Forms a complex with endogenous plasminogen --> complex catalyzes rapid conversion of plasminogen to plasmin Anisoylated plasminogen-streptokinase activator complex is a prodrug; as anisoyl group is hydrolyzed in vivo, streptokinaseactivated plasminogen is released --> converts endogenous plasminogen to plasmin
Bleeding, allergic reactions
Bleeding
Aids in posttranslational modification of clotting factors in the liver (factors II, VII, IX, and X) Clotting factors Infection and immunologic reactions
Resins Cholestyramine, colestipol HMG-CoA reductase inhibitors Lovastatin, simvastatin, atorvastatin
Hypercholesterolemia; used to reduce pruritus in patients with cholestasis and bile salt accumulation
Inhibit fibrinolysis by inhibiting plasminogen activation Bile acid-binding resins prevent absorption of dietary cholesterol and reduce reabsorption of bile acids secreted by liver --> divert hepatic cholesterol to synthesis of new bile acids --> reduces available cholesterol --> modest reduction of LDL Competitively inhibit mevalonate synthesis by HMG-CoA reductase (essential for cholesterol biosynthesis in liver) --> liver compensates by increasing
Hypercholesterolemia
Bloating, constipation, unpleasant gritty taste; impaired absorption of vitamins, drugs Mild elevations of serum aminotransferases; increase in creatine kinase, severe muscle pain,
Interfere with absorption of certain reductase inhibitors Others: pravastatin, cerivastatin, fluvastatin; metabolized by P450; teratogenic; severe 26 |czida
LDL receptors --> increased clearance of IDL and LDL from the blood rhabdomyolysis myopathy when coadministered with niacin, gemfibrozil
Niacin Niacin (nicotinic acid) Familial hypercholesterolemia, hypercholesterolemia
Fibric acid derivatives
Gemfibrozil, fenofibrate, clofibrate
Hypertriglyceridemia
Directly reduces the secretion of VLDL from the liver and inhibits hepatic synthesis of apolipoproteins or cholesterol --> decreased LDL; increased clearance of VLDL by lipoprotein lipase in the periphery --> decreased triglycerides; may increase HDL Ligands for PPAR-alpha protein (regulates transcription of genes involved in lipid metabolism) --> increased activity of lipoprotein lipase and enhanced clearance of triglyceride-rich lipoproteins (VLDL); may be small decrease in LDL and small increase in HDL
Cutaneous flushing, dosedependent nausea and abdominal discomfort, pruritus and other skin conditions, elevation of liver enzymes, hepatotoxicity may occur, hyperuricemia
NSAIDs
Aspirin
Others (ibuprofen, indomethacin, naproxen, etc.)
Antiplatelet effects (low dose), antipyretic and analgesic effects (intermediate dose), antiinflammatory effect (high dose) Mild to moderate pain, especially pain of inflammation (rheumatoid arthritis, gout); dysmenorrhea (naproxen, ibuprofen); patent ductus arteriosus (indomethacin)
Irreversibly inhibit COX-1 and COX-2 --> decrease prostaglandin and thromboxane synthesis
Nausea, skin rashes (gemfibrozil), increased risk for cholesterol gallstones Gastric upset, ulceration, bleeding; renal effects (acute failure; interstitial nephritis; reduced renin --> reduced aldosterone --> hyperkalemia; inhibit uric acid excretion --> hyperuricemia)
Reye's syndrome in children with viral infections; zero-order elimination at high concentrations
Reversibly inhibit COX-1 and COX-2 --> decrease prostaglandin and thromboxane synthesis
GI disturbance, renal damage, bone marrow depression (indomethacin)
Phenylbutazone --> aplastic anemia, agranulocytosis
27 |czida
Selectively inhibit COX-2 (expressed in inflammatory cells) NSAID with antiinflammatory and analgesic properties Reduced gastric effects, hypersensitivity (celecoxib is a sulfonamide)
Celecoxib, rofecoxib Ketorolac
Inflammatory disorders Short-term management of postoperative pain
Methotrexate
Sulfasalazine
Rheumatoid arthritis unresponsive to other agents, anticancer Rheumatoid arthritis unresponsive to other agents, inflammatory bowel disease
Disease-modifying, slow-acting antirheumatic drugs
Rheumatoid arthritis unresponsive to other Hydroxychloroquine agents, antimalarial Rheumatoid arthritis unresponsive to other agents, chelating agent (lead, copper, mercury) Rheumatoid arthritis unresponsive to other agents
Discussed below; probably acts by reducing the numbers of immune cells available to maintain the inflammatory response Not fully understood; main metabolites: 5-aminosalicylic acid (active in IBD), sulfapyridine (active in rheumatoid arthritis) May interfere with activity of T lymphocytes, decrease leukocyte chemotaxis, stabilize lysosomal membranes, interfere with DNA and RNA synthesis, and trap free radicals
Nausea, mucosal ulcers, hematotoxicity, teratogenicity Rash, GI disturbance, dizziness, headache, leukopenia
May develop folate deficiency by blocking dihydrofolate reductase (converts dihydrofolate back into active tetrahydrofolate)
Penicillamine Organic gold compounds (auranofin)
Leflunomide Infliximab, etanercept
Rheumatoid arthritis unresponsive to other agents Rheumatoid arthritis unresponsive to other
Anti-inflammatory effects similar to hydroxychloroquine; chelating agent Alter activity of macrophages and suppress leukocyte activity (lysosomal enzymes, phagocytosis, mediator release) Inhibits dihydroorotate dehydrogenase (enzyme required by activated lymphocytes for synthesis of pyrimidines needed for RNA synthesis) --> cell cycle arrest Bind to and prevent action of TNF-alpha (plays a key role in chronic inflammation)
Rash, GI disturbance, ototoxicity, myopathy, peripheral neuropathy Many adverse effects: proteinuria, dermatitis, GI disturbance, hematologic abnormalities (aplastic anemia) Many adverse effects: diarrhea, dermatitis, hematologic abnormalities (aplastic anemia)
Gold poisoning treated with dimercaprol
Teratogen, hepatotoxicity, GI disturbance, skin reactions Infliximab: upper respiratory infection; 28 |czida
agents, Crohn's disease (infliximab) Same indications as intermediate-dose aspirin (substitute in children with viral infections, aspirin hypersensitivity) Discussed above Acute gout attacks (and also prophylaxis), Mediterranean fever etanercept: injection site reactions
Acetaminophen Acetaminophen Indomethacin
Unclear; weak COX inhibitor in peripheral tissues; may be a more effective inhibitor of prostaglandin synthesis in the CNS --> analgesic, antipyretic Selective inhibitor of microtubule assembly, reduces leukocyte migration and phagocytosis
Very dangerous hepatotoxin when taken in overdose; renal tubular cell injury Severe liver and kidney damage, GI disutrbance (diarrhea)
Overdose treated with N-acetylcysteine
Colchicine
Drugs used in gout
Uricosuric agents (probenecid, sulfinpyrazone)
Chronic gout (withheld 12 weeks after an acute episode)
Allopurinol
Chronic gout (withheld 12 weeks after an acute episode), cancer chemotherapy
Weak acids that compete with uric acid for reabsorption by weak acid transport mechanism in proximal tubule Converted to oxipurinol (alloxanthine) by xanthine oxidase (enzyme that converts hypoxanthine to xanthine to uric acid); allopurinol and oxipurinol are irreversible suicide inhibitors of this enzyme Chemotherapeutic drugs Bactericidal; inhibit cell wall synthesis: bind to penicillin-binding proteins in bacterial cytoplasmic membrane --> inhibit transpeptidase enzymes (cross link cell wall) --> activate autolytic enzymes -> cause lesions in cell wall
May precipitate acute attack of gouty arthritis, allergenicity (sulfonamide)
At low doses, may compete with uric acid for secretion by proximal tubule --> may elevate serum uric acid Inhibits metabolism of mercaptopurine and azathioprine (depend on xanthine oxidase for elimination)
May precipitate acute attack of gouty arthritis, GI upset, granulomatous hepatitis, rash, fever
Penicillins
Penicillin G (IM)
Penicillin V (oral)
Common strep, meningococci, grampositive bacilli, spirochetes Oropharyngeal infections, pneumococcal pneumonia
Allergy (urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, anaphylaxis), hypersensitivity vasculitis syndrome
Pregnancy OK
Same as penicillin G
Nausea, diarrhea, allergy
Pregnancy OK 29 |czida
Methicillin, nafcillin, oxacillin, dicloxacillin Known or suspected staphylococcal infections Same as penicillin G; penicillinase resistant Nephritis (methicillin), neutropenia (nafcillin), allergy
Ampicillin, amoxicillin Piperacillin, ticarcillin, carbenicillin First-generation (cefazolin [parenteral], cephalexin [oral]) Second-generation (cefotetan, cefoxitin) Cephalosporins Second-generation (cefuroxime, cefaclor) Third-generation (cefoperazone, cefotaxime, ceftazidime, ceftriaxone)
Similar to penicillin G, plus infections due to enterococci, Listeria monocytogenes, E. coli, P. mirabilis, H. influenzae, Moraxella catarrhalis
Same as penicillin G
Allergy; ampicillin: maculopapular skin rash, nausea, diarrhea, pseudomembranous colitis
Pregnancy OK When used in combination with inhibitors of penicillinase (clavulanic acid, etc.), antibacteria activity is enhanced; pregnancy OK; bacterial endocarditis prophylaxis in dental surgery for patients with valve disease
P. aeruginosa
Gram-positive cocci, P. mirabilis, E. coli, K. pneumoniae
Same as penicillin G Bactericidal; bind to PBPs on bacterial cell membranes to inhibit bacterial cell wall synthesis by mechanisms similar to penicillins; less susceptible to penicillinases
Hypersensitivity reactions Allergy (skin rashes to anaphylactic shock) < penicillins, phlebitis after IV administration Allergy; cefotetan: hypoprothrombinemia, disulfiram-like reactions with ethanol
Pregnancy OK May increase nephrotoxicity of aminoglycosides; pregnancy OK May increase nephrotoxicity of aminoglycosides; pregnancy OK May increase nephrotoxicity of aminoglycosides; pregnancy OK May increase nephrotoxicity of aminoglycosides; cefoperazone and ceftazidime (pseudomonas), 30 |czida
Bacteroides fragilis
Same as first-generation cephalosporins
H. influenzae, Moraxella catarrhalis Enterobacter, providencia, Serratia marcescens, betalactamase-producing strains of H. influenzae and neisseria
Allergy
Allergy; cefoperazone: hypoprothrombinemia, disulfiram-like reactions with ethanol
ceftizoxime (B. fragilis), ceftriaxone (parenteral; gonorrhea, acute otitis media), cefixime (oral; gonorrhea); pregnancy OK Gram-positive activity of first-generation agents and gram-negative spectrum of thirdgeneration
Fourth-generation (cefipime)
Aztreonam
Klebsiella, pseudomonas, serratia
Same as first-generation cephalosporins Monobactam that is resistant to betalactamases produced by certain gramnegative rods (klebsiella, pseudomonas, serratia); inhibitor of cell wall synthesis, binds to PBP3
Allergy GI upset with possible superinfection, vertigo and headache, hepatotoxicity (rare)
May increase nephrotoxicity of aminoglycosides
Other beta-lactam drugs
Imipenem, meropenem
Enterobacter (drug of choice), gram-positive cocci, gram-negative rods, anaerobes
Beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) Other inhibitors of cell wall synthesis Vancomycin
Plasmid encoded betalactamases (gonococci, streptococci, E. coli, H. influenzae) Serious infections caused by drug-resistant grampositive organisms (MRSA, penicillin-
Carbapenems with low susceptibility to beta-lactamases Used in fixed combinations with certain hydrolyzable penicillins; clavulanic acid covalently reacts with bacterial penicillinase --> inhibits the enzyme that cleaves the beta-lactam ring of penicillins, such as amoxicillin and ticarcillin; sulbactam used with parenteral ampicillin Bactericidal; binds to D-Ala-D-Ala terminal of nascent peptidoglycan side chain --> inhibits transglycosylation --> interferes with cross linking
GI distress, skin rash, CNS toxicity at high levels (confusion, encephalopathy, seizures)
No activity against grampositive bacteria or anaerobes Given in combination with cilastatin (limits imipenem's toxicity by blocking renal dipeptidase --> minimizes accumulation of nephrotoxic metabolites)
Chills, fever, phlebitis, ototoxicity, nephrotoxicity, diffuse flushing ("red man syndrome") with rapid
Pregnancy OK; bacterial endocarditis prophylaxis in high-risk penicillinallergic patients 31 |czida
resistant pneumococci, and C. difficile) Interferes with a late stage in cell wall synthesis in gram-positive organisms Antimetabolite that blocks incorporation of D-Ala into the side chain of the peptidoglycan infusion
Bacitracin
Cycloserine
Chloramphenicol
Inhibitors of bacterial protein synthesis
Macrolides (erythromycin, azithromycin, clarithromycin)
Gram-positive organisms Tuberculosis caused by organisms resistant to first-line antituberculous drugs Backup drug for severe Salmonella infections and pneumococcal and meningococcal meningitis in betalactam-sensitive persons; rickettsial disease; Bacteroides fragilis Mycoplasma, corynebacterium, Chlamydia pneumoniae, Chlamydia trachomatis, Legionella pneumophila, Ureaplasma urealyticum, B. pertussis, grampositive cocci; azithromycin: H. influenzae, M. catarrhalis, neisseria; clarithromycin: prophylaxis and treatment of M. avium complex and as a component of drug regimens for H. pylori
Nephrotoxicity --> limited to topical use
Neurotoxicity (tremors, seizures, psychosis) GI disturbance (direct irritation, superinfection), bone marrow (inhibits red cell maturation), aplastic anemia (rare), gray baby syndrome (cyanosis, cardiovascular collapse)
Bacteriostatic; bind to bacterial 50S ribosomal subunit --> indirectly inhibits transpeptidation by blocking binding of aminoacyl moiety of charged tRNA to acceptor site (inhibits peptidyl transferase)
Inhibits metabolism of several drugs: phenytoin, coumarins, tolbutamide
Bacteriostatic; large, cyclic, lactone-ring structure; bind to bacterial 50S ribosomal subunit --> block translocation of peptidyl-tRNA from acceptor site to donor site
GI irritation (common), skin rashes, eosinophilia, cholestasis (erythromycin)
Inhibits cytochrome P450 --> increased plasma levels of anticoagulants, carbamazepine, cisapride, digoxin, theophylline; pregnancy OK (except clarithromycin --> fetal toxicity in primates); prophylaxis of endocarditis in valvular disease patients with penicillin allergy
32 |czida
Severe infections due to certain anaerobes (bacteroides), backup drug against grampositive cocci, prophylaxis of endocarditis in valvular disease patients with penicillin allergy; Pneumocystis carinii, Toxoplasma gondii
Clindamycin (lincomycin, clindamycin)
Bacteriostatic; bind to bacterial 50S ribosomal subunit --> block translocation of peptidyl-tRNA from acceptor site to donor site
GI irritation, skin rashes, neutropenia, hepatic dysfunction, possible superinfections (C. difficile pseudomembranous colitis) Tetracycline (GI ulcers caused by Helicobacter pylori), doxycycline (Lyme disease, chloroquine-resistant malaria, amebiasis), minocycline (meningococcal carrier state), demeclocycline (ADH-secreting tumors); no pregnancy (fatal liver toxicity in pregnant women with large IV dose) Increase plasma levels of many drugs: cisapride, cyclosporine, diazepam, nonnucleoside reverse transcriptase inhibitors, warfarin
Tetracyclines
Drug of choice: mycoplasma pneumoniae (in adults), chlamydia, rickettsia, vibrios; alternative drug: syphilis, chronic bronchitis prophylaxis, leptospirosis, acne
Bacteriostatic; bind to 30S ribosomal subunit; blocks binding of amino acidcharged tRNA to acceptor site; demeclocycline inhibits renal actions of ADH; doxycycline is fecally eliminated; divalent cations (milk, antacids, iron) inhibit absorption in gut
GI disturbance (mild nausea and diarrhea to severe colitis), irregularities in bone growth, permanent yellowish mottling of teeth in children that fluoresces with a Wood's lamp, liver and renal toxicity, photosensitivity (UV light), vestibular toxicity
Streptogramins (quinupristindalfopristin)
Linezolid
Penicillin-resistant pneumococci, MRSA, VRSA, resistant Enterococcus faecium Many drug-resistant gram-positive cocci, including strains resistant to beta-lactams and vancomycin
Bactericidal; bind to 50S ribosomal subunit, constricting exit channel on the ribosome; tRNA synthetase activity is inhibited Bacteriostatic; binds to a unique site on the 50S subunit, inhibiting initiation by blocking formation of tRNA-ribosomemRNA ternary complex
Pain and an arthralgiamyalgia syndrome with IV administration
33 |czida
Gentamicin, neomycin, tobramycin, amikacin, streptomycin Serious infections caused by aerobic gram-negative bacteria (E. coli, enterobacter, klebsiella, proteus, pseudomonas, serratia) Bactericidal; penetrate cell envelope (oxygen-dependent transport) --> bind to 30S subunit --> inhibit protein synthesis (block formation of initiation complex, cause misreading of code on mRNA template, inhibit translocation) Ototoxicity, nephrotoxicity (myeloid bodies in PCT cells; tubular damage --> ARF, proteinuria), augment neuromuscular blockade, skin reactions, teratogen Hypersensitivity (skin rashes, fever), GI (nausea, vomiting, diarrhea), hematotoxicity (rare), granulomatous hepatitis, nephrotoxicity, hemolytic anemia in neonate (do not give in pregnancy) Streptomycin (TB, plague, tularemia), netilmicin (organisms resistant to other aminoglycosides) Competition with warfarin and methotrexate for plasma protein binding --> increase plasma levels of these drugs; displace bilirubin from plasma proteins --> kernicterus in neonate
Aminoglycosides
Sulfonamides
Antifolate drugs
Trimethoprimsulfamethoxazole
Gram-positive, gramnegative, chlamydia, nocardia, simple UTIs/ulcerative colitis/rheumatoid arthritis (oral), ocular infections/burns (topical) Complicated UTIs; respiratory, ear, and sinus infections due to H. influenzae and M. catarrhalis; Aeromonas hydrophila, pneumocystis pneumonia, P. falciparum; many gram positives (except Streptococcus), many gram negatives (except anaerobes and Pseudomonas) Infections of urogenital and GI tracts (gonococci, E. coli, K. pneumoniae, C. jejuni, enterobacter, P. aeruginosa, salmonella, shigella)
Bacteriostatic; antimetabolites of PABA, competitively inhibit dihydropteroate synthase --> inhibit folic acid synthesis
Trimethoprim: selective inhibitor of bacterial dihydrofolate reductase --> prevents formation of active tetrahydro form of folic acid; concentrated in the urine Bactericidal; interfere with bacterial DNA synthesis by inhibiting topoisomerase II (DNA gyrase) and topoisomerase IV (block relaxation of supercoiled DNA, interfere with separation of replicated chromosomal DNA during cell division)
See sulfonamides toxicity; trimethoprim: megaloblastic anemia, leukopenia, granulocytopenia
Fluoroquinolones Ciprofloxacin, levofloxacin, ofloxacin
GI distress (most common), skin rashes, headache, seizures, dizziness, insomnia, abnormal LFTs, phototoxicity, tendonitis
Trimethoprimsulfamethoxazole is bactericidal; for recurrent UTIs, if a specific inciting event is known (e.g., sexual intercourse), TMP-SMX can be administered after the event instead of daily prophylaxis Ciprofloxacin and ofloxacin (alternative to third-generation cephalosporins in gonorrhea), ofloxacin (chlamydia), levofloxacin (community-acquired 34 |czida
pneumonia); no pregnancy (arthropathy in children)
Isoniazid
Tuberculosis, TB prophylaxis
Inhibition of enzymes required for the synthesis of mycolic acids and mycobacterial cell walls
Neurotoxic effects (common; peripheral neuritis, restlessness, muscle twitching, insomnia) alleviated by pyridoxine, hepatitis
Drugs for tuberculosis
Rifampin
Tuberculosis, leprosy, TB prophylaxis; drug of choice for chronic carriers of N. meningitidis, S. aureus, and H. influenzae
Bactericidal; inhibits DNA-dependent RNA polymerase in M. tuberculosis and many other microorganisms
Ethambutol Pyrazinamide
Tuberculosis Tuberculosis
Inhibits arabinosyl transferases involved in synthesis of arabinogalactan (component of mycobacterial cell wall) Bacteriostatic; mechanism not known Bactericidal; penetrate cell envelope (oxygen-dependent transport) --> bind to 30S subunit --> inhibit protein synthesis (block formation of initiation complex, cause misreading of code on mRNA template, inhibit translocation) May involve inhibition of folic acid synthesis
Light chain proteinuria, skin rashes, thrombocytopenia, nephritis, liver dysfunction, induces cytochrome P450 enzymes Dose-dependent visual disturbances (decreased visual acuity, red-green color blindness, optic neuritis) Nongouty polyarthralgia, hyperuricemia, hepatitis
Recent positive TB test with no signs of disease --> isoniazid alone for 6 to 12 months; inhibits P450 Activates P450 --> enhances elimination of the following: anticonvulsants, contraceptive steroids, cyclosporine, ketoconazole, methadone, warfarin
Streptomycin Drugs for leprosy Sulfones (dapsone)
Life-threatening tuberculous disease
Leprosy
Ototoxicity, nephrotoxicity, neuromuscular blockade (rare), skin reactions GI irritation, fever, skin rashes, methemoglobinemia,
Others: kanamycin
35 |czida
hemolytic anemia Infusion-related: fever, chills, muscle spasms, vomiting, shock-like fall in BP; dose-limiting: decreased GFR, renal tubular acidosis
Amphotericin B
Flucytosine
Systemic mycoses (aspergillus, C. albicans, cryptococcus, histoplasma, mucor) Antifungal treatment in combination with amphotericin B: Cryptococcus neoformans, systemic candidal infections Backup drug for systemic infections caused by certain blastomyces, coccidioides, histoplasma Drug of choice: esophageal and oropharyngeal candidiasis and most infections of coccidioides; cryptococcal meningitis Drug of choice: systemic infections due to blastomyces and sporothrix and for subcutaneous chromoblastomycosis Wider spectrum than itraconazole
Fungicidal; bind to ergosterol (specific to fungal cell membranes) --> cause formation of artificial pores
Administered IV
Accumulated in fungal cells by membrane permease and converted by cytosine deaminase to 5-FU (inhibitor of thymidylate synthase)
Reversible bone marrow depression, alopecia, and liver dysfunction Inhibits P450 --> increase plasma levels of anticoagulants, cyclosporine, oral hypoglycemics, phenytoin
Drugs for systemic fungal infections
Ketoconazole
Interfere with fungal cell membrane permeability by inhibiting synthesis of ergosterol
Vomiting, diarrhea, rash, hepatotoxicity
Fluconazole
Interfere with fungal cell membrane permeability by inhibiting synthesis of ergosterol
Vomiting, diarrhea, rash, hepatotoxicity
Administered PO
Itraconazole
Voriconazole
Interfere with fungal cell membrane permeability by inhibiting synthesis of ergosterol Interfere with fungal cell membrane permeability by inhibiting synthesis of ergosterol
Vomiting, diarrhea, rash, hepatotoxicity Vomiting, diarrhea, rash, hepatotoxicity 36 |czida
Interferes with microtubule function in dermatophytes; may also inhibit synthesis and polymerization of nucleic acids Fungicidal; inhibits a fungal enzyme, squalene epoxidase --> accumulation of toxic levels of squalene --> interferes with ergosterol synthesis Discussed above Disrupts fungal membranes by binding to ergosterol Interfere with fungal cell membrane permeability by inhibiting synthesis of ergosterol Headaches, mental confusion, GI irritation, photosensitivity, changes in liver function
Systemic drugs for superficial fungal infections
Griseofulvin
Severe dermatophytoses of the skin, hair, and nails
Terbinafine Azoles Nystatin Topical drugs for superficial fungal infections Miconazole, clotrimazole Haloprogin, tolnaftate, undecylenic acid
Onychomycosis Dermatophytes Local candida infections, GI fungi
GI upsets, rash, headache, taste disturbances
Acyclovir
Topical antifungal agents Topical antifungal agents (dermatophyte infections) Drug of choice: mucocutaneous and genital herpes lesions, prophylaxis in immunocompromised, varicella-zoster virus
Azole compounds
Nonazole compounds Guanosine analog --> activated to form acyclovir triphosphate (competitive substrate for DNA polymerase) --> incorporation into viral DNA --> chain termination Prodrug converted to penciclovir by firstpass metabolism in the liver --> activation by viral thymidine kinase --> inhibits DNA polymerase (no chain termination)
GI distress, headache
Antiherpes drugs
Famciclovir
Orally in genital herpes and for herpes zoster Prophylaxis and treatment of cytomegalovirus infections, herpes Prophylaxis and treatment of cytomegalovirus infections (drug of
Foscarnet
Inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase Guanosine analog --> triphosphorylated -> inhibits DNA polymerases of CMV and HSV (no chain termination)
Well tolerated Nephrotoxicity (hypocalcemia), genitourinary ulceration, CNS effects (headache, hallucinations, seizures) Leukopenia, neutropenia, thrombocytopenia, renal toxicity 37 |czida
Ganciclovir
choice) CMV retinitis, mucocutaneous HSV infections, genital warts HIV (most frequently used NRTI in HAART), HIV prophylaxis
Cidofovir
Zidovudine (ZDV; formerly AZT)
Inhibits DNA polymerases of HSV, CMV, adenovirus, and papillomavirus Phosphorylation by host cell kinases --> thymidine analog --> inhibits reverse transcriptase of HIV-1 and HIV-2 and causes chain termination in viral DNA
Nephrotoxicity Bone marrow suppression -> anemia, neutropenia, thrombocytopenia Pancreatitis (more frequently in alcoholics and those with hypertriglyceridemia), sensorimotor neuropathy Sensorimotor neuropathy Usually mild (GI distress, headache, insomnia, fatigue) Peripheral neuropathy Severe hypersensitivity reactions Hypersensitivity reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) CNS dysfunction, skin rash, elevations of plasma cholesterol Nausea, diarrhea, thrombocytopenia, hyperbilirubinemia, and nephrolithiasis GI irritation, bitter taste GI distress, headache, neutropenia 38 |czida
Nucleoside reverse transcriptase inhibitors
Didanosine (ddI) Zalcitabine (ddC)
Lamivudine (3TC) Stavudine (d4T)
Abacavir
HIV (used in HAART) HIV (used in HAART) HIV (used in HAART), HBV (used with interferon alpha) HIV (used in HAART) HIV (used in combinations with ZDV and 3TC)
Similar to ZDV Similar to ZDV
Similar to ZDV Similar to ZDV
Similar to ZDV
Nonnucleoside reverse transcriptase inhibitors
Nevirapine
Efavirenz
HIV, prevention of HIV vertical transmission HIV (shown to be effective when used with two NRTIs)
Bind to a site on reverse transcriptase different from NRTI binding site Bind to a site on reverse transcriptase different from NRTI binding site Inhibits HIV-1 protease (cleaves viral precursor proteins, critical to production of mature infectious virions) Similar to indinavir Similar to indinavir
Protease inhibitors
Indinavir Ritonavir Saquinavir
HIV (used most often with two NRTIs) HIV HIV
Nelfinavir HIV HIV (effective when used with two NRTIs) Similar to indinavir Diarrhea Skin rash, in some cases leading to Stevens-Johnson syndrome
Amprenavir
Amantadine
Rimantadine Oseltamivir, zanamivir Miscellaneous antiviral agents Interferons
Ribavirin Idoxuridine, cytarabine, trifluorothymidine
Similar to indinavir Inhibit the first steps in replication of the influenza A and rubella viruses (viral adsorption, penetration, uncapping); also Influenza A virus binds to protein in surface coat of virus to infection and prophylaxis prevent fusion Inhibit the first steps in replication of the Influenza A virus influenza A and rubella viruses (viral infection and prophylaxis adsorption, penetration, uncapping) Decrease the time to Inhibitors of neuraminidase produced by alleviation of influenza influenza A and B --> impede viral spread symptoms Glycoproteins produced in human leukocytes (alpha), fibroblasts (beta), and Chronic hepatitis A and B immune cells (gamma) --> affect viral RNA infections, Kaposi's and DNA synthesis, block peptide chain sarcoma, papillomatosis, initiation, degrade terminal nucleotides of genital warts (topical) tRNA, activate Rnase Respiratory syncytial virus bronchiolitis (aerosol), wide range of RNA and DNA viruses: Not known; inhibits guanosine Lassa fever and other triphosphate formation --> prevents viral hemorrhagic fevers capping of viral mRNA; can block RNA(IV), hepatitis C dependent RNA polymerases Herpes simplex eye infections
CNS effects: dizziness, ataxia, slurred speech, insomnia, nervousness Less CNS effects than amantadine
Use catiously in patients with epilepsy or psychosis
Neutropenia, GI irritation, fatigue, myalgia, mental confusion, reversible cardiomyopathy
Trifluorothymidine: thymidine analog
Aerosol: conjunctival or bronchial irritation; systemic: myelosuppression Marked systemic toxicity (bone marrow, hepatic, renal) --> topical use
Teratogen
Topical drugs
39 |czida
Bacteroides, clostridia (drug of choice for pseudomembranous colitis due to C. difficile), anaerobic or mixed intra-abdominal infections, brain abscess, Gardnerella vaginalis, component of H. pylori therapy, trichomoniasis and giardiasis (drug of choice), intestinal amebiasis, amebic hepatic abscess Impetigo caused by staphylococci, betahemolytic streptococci (topical)
Miscellaneous antimicrobial agents
Metronidazole
Undergoes a reductive bioactivation of its nitro group by ferredoxin (present in anaerobic parasites) to form reactive cytotoxic products that interfere with nucleic acid synthesis Acts on gram-positive cocci and inhibits protein synthesis by specifically binding to isoleucyl-tRNA synthetase Bactericidal against gram-negative bacteria; interact with a specific lipopolysaccharide component of the outer cell membrane --> distorts membrane lipid structure --> increased permeability to polar molecules --> marked changes in cell metabolism
GI irritation (diarrhea), headache, dizziness, rash, dark coloration of urine
Mupirocin
Local itching and burning
Polymyxins
Topical therapy of resistant gram-negative infections (including enterobacter, pseudomonas)
Urinary antiseptics Nitrofurantoin
Many urinary tract pathogens (not proteus or pseudomonas) Acute attacks of nonfalciparum and sensitive falciparum malaria
Drugs for malaria Chloroquine
Rapidly excreted in the urine and acts there to suppress bacteriuria Prevent polymerization of heme into hemozoin (accumulation of heme is toxic); selective toxicity due to energydependent carrier mechanism in parasitized cells
Neurotoxicity, acute renal tubular necrosis GI irritation, skin rashes, phototoxicity, neuropathies, hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, pulmonary fibrosis
GI irritation, skin rash, headaches 40 |czida
Cinchonism (GI distress, headache, vertigo, blurred vision, tinnitus), Blackwater fever (rare; intravascular hemolysis) Less toxic than quinine; GI distress, skin rash, headache, dizziness Well tolerated; GI distress, pruritus, headaches, methemoglobinemia, hemolytic anemia
Quinine
Mefloquine
P. falciparum resistant to chloroquine P. falciparum, P. vivax prophylaxis and treatment (drug of choice)
Complexes with dsDNA to prevent strand separation --> block DNA replication and transcription
Chemically related to quinine; mechanism not known Forms quinoline-quinone metabolites --> electron-transferring redox compounds that act as cellular oxidants Converted in gut to diloxanide freebase form (active amebicide)
Primaquine Antifolate drugs Diloxanide furoate
Emetines Drugs for amebiasis Iodoquinol Metronidazole
Paromomycin
Drugs for pneumocystis and toxoplasmosis
Pentamidine Trimethoprimsulfamethoxazole Antifolate drugs
Eradicate liver stages of P. vivax and P. ovale Discussed above Asymptomatic amebiasis, mild intestinal disease Backup drugs for severe intestinal or hepatic amebiasis in hospitalized patients Alternative drug for mildto-severe intestinal infections Discussed above Second-line luminal amebicide, cryptosporidiosis Pneumocystis in HIV patient allergic or resistant to trimethoprimsulfamethoxazole, trypanosomiasis Discussed above Discussed above
GI symptoms GI distress, muscle weakness, cardiovascular (arrhythmias, CHF)
Inhibit protein synthesis by blocking ribosomal movement along mRNA
Luminal amebicide
GI effects
Unknown; may involve inhibition of glycolysis or interference with nucleic acid metabolism of protozoans and fungi
GI effects Respiratory stimulation followed by depression, hypotension (peripheral vasodilation), hypoglycemia, anemia, neutropenia, hepatitis, pancreatitis
41 |czida
Mild to moderate pneumocystis pneumonia Discussed above Drug of choice in African sleeping sickness Drug of choice in American trypanosomiasis, mucocutaneous leishmaniasis Drug of choice for early hemolymphatic stages of African trypanosomiasis Leishmania Alternative for larva migrans, ascariasis, infections caused by roundworms, whipworms, hookworms, pinworms, threadworms; Microsporidia (drug of choice) Inhibits mitochondrial electron transport and probably folate metabolism Rash, cough, nausea, vomiting, diarrhea, fever, abnormal LFTs
Atovaquone Pentamidine Melarsoprol Drugs for trypanosomiasis Nifurtimox
Inhibits enzyme sulfhydryl groups
Reactive encephalopathy
Inhibits parasite-unique enzyme trypanothione reductase
Allergies, GI irritation, CNS effects Skin rashes, GI distress, neurologic complications
Drugs for leishmaniasis
Suramin Sodium stibogluconate
Inhibition of glycolysis or effects on nucleic acid metabolism --> kills parasite
Albendazole Drugs that act against nematodes
Unclear; blocks glucose uptake in both larval and adult parasites --> decreased ATP --> parasite immobilization
Diethylcarbamazine
Drug of choice for filariasis; alternative for onchocerciasis (used with suramin)
Ivermectin
Drug of choice for onchocerciasis, strongyloidiasis
Immobilizes microfilariae by an unknown mechanism --> susceptible to host defenses Intensifies GABA-mediated neurotransmission in nematodes (does not cross blood-brain barrier --> selective toxicity) --> immobilization of parasites --> removal by reticuloendothelial system
Few during short course of therapy Headache, malaise, weakness, anorexia; reaction to proteins released by dying filariae (fever, rash, ocular damage, joint and muscle pain, lymphangitis) Mazzotti reactions (fever, headache, dizziness, rashes, pruritus, tachycardia, hypotension, pain in joints, muscles, lymph glands)
Mazzotti reaction in onchocerciasis (described adverse effects plus hypotension, pyrexia, respiratory distress, prostration)
42 |czida
Drug of choice for pinworm and whipworm infections, roundworm (with pyrantel pamoate), combined infections with ascarids and hookworm; trichinosis Alternative drug for ascariasis One of two drugs of choice (with mebendazole) for infections due to hookworm, pinworm, roundworm
Mebendazole
Piperazine
Selectively inhibiting microtubule synthesis and glucose uptake in nematodes GI irritation Paralyzes ascaris by acting as an agonist at GABA receptors --> expelled by normal Mild GI irritation (most peristalsis common)
Contraindicated in patients with seizure disorders
Pyrantel pamoate
Levamisole
Thiabendazole
Drugs that act against trematodes
Praziquantel
Adjunctive therapy with 5-FU in colorectal cancer Drug of choice for visceral forms of larva migrans; strongyloidiasis, cutaneous larva migrans, threadworm Drug of choice in schistosomiasis, clonorchiasis, paragonimiasis, flukes, cestodes, cysticercosis Drug of choice for fascioliasis (sheep liver fluke) Schistosoma haematobium (cause of
Stimulate nicotinic receptors present at neuromuscular junctions of nematodes -> muscle contraction --> depolarizationMinor (GI distress, induced paralysis headache, weakness) Stimulates maturation and proliferation of T cells in patients with impaired immune function; also antiparasitic (same mechanism as pyrantel pamoate) GI irritation, headache, dizziness, leukopenia, hematuria, allergic reactions (intrahepatic cholestasis) Similar action as mebendazole Increases membrane permeability to calcium --> marked contraction initially --> paralysis of tremeatode muscles --> vacuolization and parasite death
Bithionol Metrifonate
Unknown Converted in the body to the cholinesterase inhibitor dichlorvos
Headache, dizziness, malaise Nausea and vomiting, diarrhea and abdominal cramps, dizziness, headache, phototoxicity Excess cholinergic stimulation 43 |czida
bilharziasis) Oxamniquine Drugs that act against cestodes (tapeworms) Schistosoma mansoni One of two drugs of choice (with praziquantel) for cestodes Chronic lymphocytic leukemia Non-Hodgkin's lymphoma (in COP), multiple myeloma, lymphoblastic leukemias, breast (in CMF), ovarian, lung, and cervical cancers, mycosis fungoides, and neuroblastoma Dizziness Not effective in cysticercosis or hydatid disease caused by Echinococcus granulosus
Niclosamide
Chlorambucil
Uncouples oxidative phosphorylation or by activating ATPases Slow-acting; alkylate nucleophilic groups on DNA bases --> cross-linking, abnormal base pairing, strand breakage
GI distress, headache, rash, fever
Myelosuppression
Nitrogen mustards
Cyclophosphamide
Alkylate nucleophilic groups on DNA bases --> cross-linking, abnormal base pairing, strand breakage --> inhibit proliferation of lymphocytes (B cells > T cells) Alkylate nucleophilic groups on DNA bases --> cross-linking, abnormal base pairing, strand breakage Alkylate nucleophilic groups on DNA bases --> cross-linking, abnormal base pairing, strand breakage; high lipophilicity facilitates CNS entry
Alkylating agents
Mechlorethamine
Hodgkin's disease (in MOPP)
GI distress, myelosuppression, alopecia, secondary leukemia, transitional cell carcinoma, hemorrhagic cystitis GI distress, myelosuppression, alopecia, secondary leukemia GI distress, myelosuppression, CNS dysfunction GI distress, mild hematotoxicity, neurotoxic (peripheral neuritis), ototoxicity (acoustic nerve damage), hypomagnesemia --> hypocalcemia, nephrotoxic Myelosuppressant, GI irritation, CNS dysfunction, peripheral neuropathy, skin
Nitrogen mustards
Nitrogen mustards
Carmustine, lomustine
Adjuncts in treatment of brain tumors
Nitrosureas
Cisplatin (Platinol), carboplatin
Testicular carcinoma (in PVB and PEB), and cancers of bladder, lung, and ovary Hodgkin's disease (in MOPP)
Procarbazine
Alkylate nucleophilic groups on DNA bases --> cross-linking, abnormal base pairing, strand breakage Reactive agent that forms hydrogen peroxide --> generates free radicals that cause DNA strand scission
44 |czida
reactions, secondary leukemia Alkylate nucleophilic groups on DNA bases --> cross-linking, abnormal base pairing, strand breakage Alkylate nucleophilic groups on DNA bases --> cross-linking, abnormal base pairing, strand breakage Substrate for and inhibitor of dihydrofolate reductase --> decreased synthesis of thymidylate, purine nucleotides, and amino acids Purine antimetabolites activated by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) -> toxic nucleotides that inhibit several enzymes involved in purine metabolism Pyrimidine antimetabolite activated by kinases to AraCTP --> inhibits DNA polymerases; specific for S phase Biotransformed to 5-fluoro-2'deoxyuridine-5'-monophosphate (5FdUMP) --> inhibits thymidylate synthase --> "thymineless death" Adrenal insufficiency, bone marrow suppression, pulmonary fibrosis, skin pigmentation Alopecia, skin rash, GI distress, myelosuppression, phototoxicity, flu-like syndrome Bone marrow suppression, toxic effects on skin and GI mucosa (mucositis), folate deficiency, liver disease (fatty change, fibrosis)
Busulfan
CML
Alkylsulfonates
Dacarbazine
Methotrexate
Hodgkin's disease (in ABVD) Choriocarcinoma, acute leukemias, nonHodgkin's and cutaneous T cell lymphomas, breast cancer (in CMF)
"Leucovorin rescue": reduce toxic effects by administration of folinic acid (leucovorin)
Antimetabolites
Mercaptopurine (6MP), thioguanine (6-TG)
Acute leukemias (maintenance), CML
Bone marrow suppression GI irritation, myelosuppression GI distress, myelosuppression, alopecia, dermatitis, stomatitis
Cytarabine (Ara-C)
Fluorouracil (5-FU)
Plant alkaloids Vincristine (Oncovin)
Acute leukemias Bladder, breast (in CMF), colon, head and neck, liver, and ovarian cancers; skin cancers (topically) Hodgkin's disease (in MOPP), lymphomas (in COP), used in acute leukemias, Wilms' tumor, CNS tumors, sarcomas, choriocarcinoma
Spindle poisons --> prevent assembly of tubulin dimers into microtubules; act primarily in M phase
Neurotoxicity
Vinca alkaloid; chemotherapeutic agent not associated with development of bone marrow suppression 45 |czida
Hodgkin's disease (in ABVD), lymphomas, neuroblastoma, testicular carcinoma (in PVB), Kaposi's sarcoma Used in combination regimens for lung (small cell), prostate, and testicular carcinoma (in PEB)
Vinblastine
Etoposide, teniposide
Spindle poisons --> prevent assembly of tubulin dimers into microtubules; act primarily in M phase Increases degradation of DNA, possibly via interaction with topoisomerase II, and also inhibits mitochondrial electron transport; most active in late S and early G2 phase
GI distress, alopecia, bone marrow suppression
Vinca alkaloid
Advanced breast and Paclitaxel, docetaxel ovarian cancers Hodgkin's disease (in ABVD), lymphomas, myelomas, sarcomas, and breast (in CAF), endometrial, lung, ovarian, and thyroid Doxorubicin carcinomas (Adriamycin) Daunorubicin Acute leukemias Antibiotics
Spindle poisons --> prevent microtubule disassembly into tubulin monomers
GI irritants, alopecia, bone marrow suppression, stomatitis, erythema Paclitaxel: neutropenia, thrombocytopenia, hepatotoxicity, bronchospasm, peripheral neuropathy; docetaxel: neurotoxicity, bone marrow depression
Podophyllotoxins
Taxanes
Intercalate between base pairs, inhibit topoisomerase II, generate free radicals, block synthesis of RNA and DNA, and cause strand scission Same as doxorubicin
Bleomycin Dactinomycin
Hodgkin's disease, testicular cancer (in PVB and PEB), lymphomas, squamous cell cancer Melanoma, Wilms' tumor
Mixture of glycopeptides --> generates free radicals which bind to DNA, cause strand breaks, and inhibit DNA synthesis Binds to dsDNA and inhibits DNAdependent RNA synthesis
Bone marrow suppression, GI distress, severe alopecia, cardiotoxicity (EKG abnormalities, cardiomyopathy, CHF) Same as doxorubicin Pulmonary dysfunction (pneumonitis, fibrosis), hypersensitivity (chills, fever, anaphylaxis), mucocutaneous reactions (alopecia, blisters, hyperkeratosis) Bone marrow suppression, skin reactions, GI irritation
Other anthracyclines: idarubicin (used in AML)
Does not cause bone marrow suppression
46 |czida
Used in combination regimens for adenocarcinomas of the cervix, stomach, pancreas, breast, and lung Acute and chronic lymphocytic leukemia, Hodgkin's disease (in MOPP), lymphomas (in COP) Severe myelosuppression, toxic to heart, liver (hepatotoxicity), lung (acute bronchospasm, interstitial pneumonitis), and kidney
Mitomycin
Metabolized by liver enzymes to form an alkylating agent which cross-links DNA
Glucocorticoids (prednisone)
Discussed above; inhibit proliferation of lymphocytes (T cells > B cells) Fluoxymesterone (an androgenic steroid; used in advanced breast cancer), estrogenic steroids (diethylstilbestrol; used in prostatic carcinoma)
Hormonal anticancer agents
Sex hormones (estrogens, progestins, androgens) Sex hormone antagonists (tamoxifen, flutamide) GnRH analogs (leuprolide) Aromatase inhibitors (anastrozole)
Hormone-dependent cancers
Change the hormone balance in some hormone-dependent cancers
Discussed above Discussed above
Asparaginase Miscellaneous anticancer agents Mitoxantrone Alpha-interferon
Discussed above T cell auxotrophic cancers (leukemias and lymphomas) that require asparagine for growth Used in combination regimens for refractory acute leukemia and in breast carcinoma Number of neoplasms including hairy cell
Depletes serum asparagine
Hypersensitivity reactions, acute pancreatitis, bleeding
Probably acts via alkylation of DNA bases Interferons are endogenous glycoproteins with antineoplastic, immunosuppressive,
Myelosuppression, GI effects, cardiac arrhythmias Myelosuppression, neurologic dysfunction 47 |czida
leukemia, early CML, T cell lymphomas Rituximab Low-grade lymphomas and antiviral actions Monoclonal antibody to a surface protein in non-Hodgkin's lymphoma cells Monoclonal antibody to a surface protein in breast cancers that overexpress the HER2 protein Binds to cyclophilin --> complex inhibits calcineurin (regulates ability of nuclear factor of activated T cells [NF-AT] to translocate to nucleus and increase production of cytokines); inhibits early stages of T-cell differentiation Binds to FK-binding protein --> complex inhibits calcineurin (regulates ability of nuclear factor of activated T cells [NF-AT] to translocate to nucleus and increase production of cytokines) Binds to FK-binding protein --> inhibits response of T cells to cytokines without affecting cytokine production; also inhibits B cell proliferation, antibody production, and mononuclear cell responses to colony-stimulating factors Converted into mycophenolic acid --> inhibits inosine monophosphate dehydrogenase (enzyme in de novo pathway of purine synthesis) --> suppresses both B and T lymphocyte activation Prodrug transformed to the antimetabolite mercaptopurine --> inhibits enzymes involved in purine metabolism --> inhibits proliferation of lymphocytes (T cells > B cells) Hypersensitivity, myelosuppression Cardiac dysfunction, including CHF
Trastuzumab Corticosteroids
Breast cancer Discussed above Prevent rejection in organ transplantation, graft-versus-host in bone marrow transplantation, immune diseases
Cyclosporine
Renal dysfunction after several weeks to months, hypertension, neurotoxicity
Less likely to cause bone marrow suppression than cytotoxic agents
Tacrolimus Immunosuppressive agents Sirolimus
Liver and kidney transplant recipients
Renal dysfunction, hypertension, neurotoxicity
Kidney and heart transplantation
Hyperlipidemia, hematopoietic cell toxicity
Mycophenolate mofetil
Azathioprine
Kidney, liver, and heart transplants Autoimmune diseases (SLE, rheumatoid arthritis), immunosuppression in renal homografts
GI effects
Bone marrow suppression, cancer 48 |czida
Autoimmune diseases (including hemolytic anemia), antibodyinduced red cell aplasia, bone marrow transplants Discussed above Discussed above Some forms of leprosy reactions, immunologic diseases (SLE), anticancer drug, aphthous ulcers and wasting syndrome in AIDS Used prior to bone marrow transplantation to prevent GVH, maintenance following bone marrow, heart, and renal transplantation Prevention of hemolytic disease of the newborn
Cyclophosphamide Etanercept Leflunomide
Prodrug transformed to alkylating agent -> cytotoxic to proliferating lymphoid cells (greater effect on B cells than T cells)
Pancytopenia, GI distress, hemorrhagic cystitis, alopecia
Discussed above
Thalidomide
Antibodies as immunosuppressants
Lymphocyte immune globulin Rh (D) immune globulin
Muromonab-CD3
Renal homograft rejection crisis
Daclizumab Infliximab Immunomodulating agents
Renal transplants (not for acute rejection) Discussed above
Immunosuppressant actions that appear to be due to suppression of TNF production Also known as antithymocyte globulin; usually produced in horses by immunization against human thymus cells; binds to T cells involved in antigen recognition --> initiates their destruction by serum complement Human IgG preparation that contains antibodies against red cell Rh (D) antigens Binds to CD3 antigen on surface of human thymocytes and mature T cells --> blocks killing action of cytotoxic T cells, probably interferes with other T cell functions Highly specific monoclonal antibody that binds to alpha subunit of IL-2 receptor expressed on T cells --> prevents activation by IL-2 Recombinant IL-2 --> promotes production of cytotoxic T cells and activates natural killer cells Discussed above
Teratogenic effects (phocomelia)
Hypersensitivity reactions (serum sickness, anaphylaxis)
Fever, chills, dyspnea, pulmonary edema
Equivalent to placebo
Aldesleukin Alpha-interferon Beta-interferon
Renal cell carcinoma Discussed above Relapsing multiple
49 |czida
Increasing synthesis of TNF --> immuneenhancing actions Live attenuated strain of Mycobacterium Immunization against TB, bovis; efficacy may be due to activation of macrophages --> enhancement of immunostimulant in superficial bladder cancer immune response Protein hormone from thymus gland --> stimulate maturation of pre-T cells and promotes formation of T cells from DiGeorge's syndrome ordinary lymphoid stem cells (thymic aplasia) Drugs that act in the central nervous system Anxiety states, alcohol withdrawal, sleep disorders (flurazepam, temazepam, triazolam), anesthesia and muscle Receptor forms part of a GABA(A) spasticity (diazepam), receptor chloride ion channel macromolecular complex --> binding psychotic agitation, facilitates inhibitory actions of GABA via chronic epilepsy (clonazepam), grand mal increased chloride conductance (cell hyperpolarization); lorazepam and seizures and status oxazepam conjugated with glucuronide epilepticus (diazepam), (phase II drug metabolism reaction); panic disorders and depression (alprazolam) suppress REM sleep Benzodiazepine Reverses CNS effects of benzodiazepines overdose Depress neuronal activity in the midbrain reticular formation --> facilitate and prolong inhibitory effects of GABA and glycine; increase duration of GABAAnesthesia, mediated chloride ion channel opening; anticonvulsant (phenobarbital; grand interact with site on chloride ion channel mal and partial seizures), different from benzodiazepine and GABA anxiety receptors; suppress REM sleep sclerosis Chronic granulomatous disease
Gamma-interferon
Discussed above
Bacille CalmetteGuerin (BCG)
Contraindicated in HIV+ patients
Thymosin
Benzodiazepines
Diazepam Benzodiazepine receptor antagonist Flumazenil
Psychomotor dysfunction, additive CNS depression, delirium and confusion in elderly with overuse
Others: chlordiazepoxide (ethanol withdrawal), temazepam, alprazolam, clonazepam, flurazepam, lorazepam and oxazepam (do not require phase I metabolism), triazolam, midazolam (anesthesic; retrograde amnesia when given IV)
Barbiturates Phenobarbital, pentobarbital, thiopental
CNS depression, overdose (severe respiratory and cardiovascular depression), induce P450 system, addiction
May decrease the effect of drugs metabolized by P450 system (activates P450); contraindicated in acute intermittent porphyria (induce deltaALA synthetase) 50 |czida
Anxiety states (generalized anxiety disorders in patients with past history of substance abuse) Interacts with 5-HT1A subclass of brain serotonin receptors as a partial agonist; precise mechanism of anxiolytic effect unknown; no sedation, muscle relaxation, or anticonvulsant effects (contrast with benzodiazepines) Appear to exert CNS effects via interaction with certain benzodiazepine receptors Calcium channel blockade similar to ethosuximide (below); also causes neuronal membrane hyperpolarization (possibly by enhancing K+ channel permeability)
Other sedativehypnotic drugs
Buspirone
Zolpidem, zaleplon
Anxiety states, insomnia (short-term treatment) Generalized tonic-clonic, partial, absence, myoclonic seizures, bipolar affective disorder
Low frequency of side effects Nightmares, agitation, headache, GI upset, dizziness, daytime drowsiness GI distress, hepatotoxicity (rare but possibly fatal), inhibition of drug metabolism, teratogen
Slow onset of action No anticonvulsant or muscle relaxing properties
Carboxylic acids Valproic acid
Hydantoins Generalized tonic-clonic and partial seizures, bipolar affective disorder
Phenytoin Succinimides Ethosuximide Tricyclics Carbamazepine
Carbamates Felbamate
Absence seizures Generalized tonic-clonic and partial seizures, bipolar affective disorder, trigeminal neuralgia Partial seizures; myoclonic seizures (adjunct); epileptic encephalopathy (Lennox-Gastaut
Block voltage-gated sodium channels in neuronal membranes (rate-dependent) -> prolongation of inactivated state of Na+ channel and refractory period of neuron Inhibits low-threshold (T-type) Ca2+ currents (especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge)
Nystagmus, diplopia, ataxia, sedation, gingival hyperplasia, hirsutism, anemias, enzyme induction, teratogen
Activates P450; inhibits intestinal conjugase (converts polyglutamates to monoglutamates for absorption in jejunum) -> folate deficiency; zero-order elimination
Same as phenytoin
GI distress, lethargy, headache Diplopia, ataxia, hepatic drug-metabolizing enzyme induction, blood dyscrasias, teratogen
Activates P450; others: oxcarbazepine
Mechanism not known
Aplastic anemia, hepatotoxicity 51 |czida
syndrome) Pain of neuropathic origin, migraine, generalized tonic-clonic and partial seizures (refractory), bipolar affective disorder Generalized tonic-clonic and partial seizures (alternative agent); myoclonic seizures in children
GABA derivatives Gabapentin
Structural analog of GABA; interacts with different receptor site on chloride channels --> increased duration of chloride channel opening
Sedation, behavioral changes in children, movement disorders, leukopenia
Phenyltriazine Lamotrigine
Inhaled anesthetics (volatile liquids)
Halothane
General anesthesia
Diethylether Inhaled anesthetics (gas) Nitrous oxide Intravenous anesthetics (barbiturates) Thiopental
General anesthesia Weak anesthetic (must be combined with other agents for major surger); analgesic for minor surgery
Same as phenytoin Respiratory depressants; decrease arterial blood pressure (depress cardiac output, peripheral vasodilation); relax skeletal and smooth muscle; some analgesia; relatively low blood-gas partition coefficient; high anesthetic potential (low minimum alveolar concentration) Produces analgesia, amnesia, unconsciousness, and muscle relaxation, while permitting adequate oxygenation without cardiovascular or respiratory depression
Sedation, ataxia, lifethreatening skin disorders, hematotoxicity Others: enflurane, desflurane, isoflurane, methoxyflurane, sevoflurane; augment neuromuscular blockade of nondepolarizing muscle relaxants Flammability, disagreeable odor, high blood-gas partition coefficient
Malignant hyperthermia (treated with dantrolene); arrhythmias (sensitizes heart to catecholamines)
Induction of anesthesia, short surgical procedures
Low anesthetic potential (high minimum alveolar concentration); low blood-gas partition coefficient High lipid solubility --> rapid entry into brain --> surgical anesthesia in one circulation time (< 1 minute) --> redistributed to skeletal muscle and skin --> redistributed to adipose tissue (long-
Minimal cardiovascular depression
52 |czida
term reservoir due to lipid solubility)
IV anesthetics (opioids) Morphine, fentanyl IV anesthetics (phenols) Propofol IV anesthetics (benzodiazepines)
Midazolam
IV anesthetics (dissociative agent) Ketamine
Anesthesia regimens with other CNS depressants (nitrous oxide, benzodiazepines) Component of balanced anesthesia (inhalation + IV), anesthesia in outpatient surgery Adjunct to inhaled anesthetics and IV opioids Dissociative anesthesia (patient remains conscious with marked catatonia, analgesia, and amnesia)
Discussed below
Respiratory depression (reversed with naloxone)
Anesthesia at a rate similar to barbiturates, recovery more rapid Onset slower than thiopental, longer duration Antagonist of glutamic acid --> blocking action at NMDA receptor; increases muscle tone, stimulates cardiovascular function Nonionized drug crosses lipid cell membrane --> blocks voltage-dependent sodium channels (ionized form of drug is more effective blocking entity) --> prevents depolarization of membrane --> block conduction of action potential; procaine is a short duration ester local anesthetic; lidocaine is a mediumduration amide and an antiarrhythmic Nonopiate antitussive related to local anesthetics; may be preferred in patients who cannot receive opiate drugs
Marked hypotension Postoperative respiratory depression Emergence reactions (disorientation, excitation, hallucination) during recovery from anesthesia Emergence reactions can be reduced by preoperative benzodiazepines Others: tetracaine (longduration ester local anesthetic), cocaine (medium duration ester and an uptake blocker), bupivacaine (longduration amide); augment neuromuscular blockade
Local anesthetics Procaine, lidocaine Minor surgical procedures
CNS effects, cardiovascular effects (arrhythmias, vasodilation [except cocaine])
Benzonatate
Cough suppression
53 |czida
Respiratory paralysis; tubocurarine: blocks autonomic ganglia (tubocurarine), causes histamine release (tubocurarine; hypotension, bronchospasm, excessive bronchial and salivary secretions) Respiratory paralysis, stimulation of autonomic ganglia and cardiac muscarinic receptors, muscle pain, hyperkalemia, increased intraocular pressure Blockade reversed with cholinesterase inhibitors (neostigmine, pyridostigmine); others: pancuronium (IV; eliminated by renal excretion), atracurium, vecuronium, rocuronium Paralysis increased by cholinesterase inhibitors during phase I, usually reversible in phase II; others: decamethonium
Neuromuscular blocking drugs
Tubocurarine
Facilitate surgery or artificial ventilation
Succinylcholine
Facilitate surgery or artificial ventilation
Diazepam
Discussed above
Spasmolytic drugs Baclofen
Dantrolene
Muscle spasticity (neurologic or muscle end plate disease) Muscle spasticity (neurologic or muscle end plate disease); malignant hyperthermia (neuroleptic malignant syndrome, general anesthesia)
Nondepolarizing type: prevent action of Ach at the skeletal muscle end plate (surmountable blockade) Depolarizing type: act like nicotinic agonists --> depolarize neuromuscular end plate --> continuous depolarization results in muscle relaxation (after initial fasciculations) and paralysis (phase I) --> gradual repolarization with resistance to depolarization (phase II) Receptor forms part of a GABA(A) receptor chloride ion channel macromolecular complex --> binding facilitates inhibitory actions of GABA via increased chloride conductance (cell hyperpolarization) --> reduce tonic output of primary spinal motoneurons GABA(B) agonist --> GABA(B) receptors coupled to G proteins --> either open potassium channels or close calcium channels --> reduce tonic output of primary spinal motoneurons
Less sedation than diazepam Malignant hyperthermia can be triggered by general anesthesia protocols that include succinylcholine or tubocurarine 54 |czida
Acts in skeletal muscle cell to reduce release of activator calcium from the sarcoplasmic reticulum
Muscle weakness, hepatotoxicity (chronic use), less sedation than baclofen
Muscle spasticity (neurologic or muscle end plate disease) Related to clonidine --> reinforces both presynaptic and postsynaptic inhibition in the cord --> reduce tonic output of primary spinal motoneurons Believed to act in brain stem or spinal cord by interfering with polysynaptic reflexes that maintain skeletal muscle tone Central inhibitor of cholinesterase --> increases acetylcholine at central synapses, including those in hippocampus, believed to be involved in Alzheimer's disease Metabolic precursor of dopamine --> transported into CNS --> converted to dopamine in the brain (much of the dose converted to dopamine in the periphery -> peripheral side effects); amino acids (from dietary protein) may compete with L-dopa and reduce its brain uptake; pyridoxine (cofactor for decarboxylation of L-dopa) can reduce therapeutic effect by stimulating conversion in the periphery
Tizanidine
Drowsiness and hypotension
Cyclobenzaprine Drugs used in Alzheimer's disease Tacrine
Acute spasm due to muscle injury
Marked sedative and antimuscarinic actions
Alzheimer's disease
Drugs used in Parkinson's disease
Levodopa (L-dopa)
Parkinson's disease
Bromocriptine, pergolide Pramipexole, ropinirole
Parkinson's disease Parkinson's disease (firstline drugs)
Discussed above; ergot derivatives; partial agonists at certain dopamine D2 receptors in the brain
Dopamine receptor agonists
Anorexia, nausea, vomiting (stimulation of emetic center), postural hypotension, tachycardia, dyskinesias, behavioral effects Anorexia, nausea, vomiting (stimulation of emetic center), postural hypotension, arrhythmias, dyskinesias, behavioral effects Dyskinesias, postural hypotension, lassitude, sleepiness, fatigue
Coadministering carbidopa enhances effects of levodopa (DOPA decarboxylase inhibitor that does not cross blood-brain barrier)
Amantadine
Parkinson's disease
Discussed above; enhances dopaminergic Behavioral effects, neurotransmission by unknown dermatologic reactions mechanisms (may involve increasing (livedo reticularis), GI 55 |czida
synthesis or release of dopamine or inhibition or reuptake); also muscarinic blocking actions effects, urinary retention, postural hypotension, peripheral edema Meperidine + selegiline = agitation, delirium, and death; "serotonin syndrome" in patients taking selective serotonin reuptake inhibitors
Selegiline
Parkinson's disease
Entacapone, tolcapone Propranolol
Parkinson's disease Tremor Huntington's disease, Tourette's syndrome
Selective inhibitor of MAO type B (which metabolizes dopamine in preference to norepinephrine and serotonin) --> may increase brain dopamine levels Inhibitors of catechol-Omethyltransferase (COMT; converts levodopa to 3-O-methyldopa); increased plasma levels of 3OMD associated with poor response to levodopa Discussed above Antipsychotic agents that block dopamine receptors Pimozide: dopamine D2 receptor blocker; mecamylamine: ganglion blocking drug that enters the CNS Discussed above; chelating agent which removes excess copper
Insomnia, mood changes, dyskinesias, GI distress, hypotension
Dyskinesias, GI distress, postural hypotension; acute hepatic failure (tolcapone) Excessive secretion of prolactin --> amenorrhea, galactorrhea, and infertility
Haloperidol Drugs used in other movement disorders Pimozide, mecamylamine
Tourette's syndrome
Penicillamine
Wilson's disease
Antipsychotics (phenothiazines)
Chlorpromazine, thioridazine, fluphenazine, prochlorperazine (antiemetic)
Schizophrenia (positive symptoms), antiemetic actions (except thioridazine), antipruritics and sedatives
D2 and H1 receptor blockade; antipsychotic effects attributable to D2 blockade; fluphenazine available in injectable long-acting preparation useful in chronic management of schizophrenia
GI distress, myasthenia, optic neuropathy, blood dyscrasias Parkinson-like syndrome (bradykinesia, rigidity, tremor), tardive dyskinesias, muscarinic receptor blockade, postural hypotension (alpha blockade), depress hypothalamus, neuroleptic malignant syndrome, sedation, visual impairment (thioridazine), seizures
Neuroleptic malignant syndrome (characterized by fever, muscular rigidity, altered mental status, and autonomic dysfunction) 56 |czida
Antipsychotics (thioxanthenes) Antipsychotics (butyrophenones) Schizophrenia (positive symptoms) Schizophrenia (positive symptoms) D2 and H1 receptor blockade; antipsychotic effects attributable to D2 blockade
Thiothixene Haloperidol
See chlorpromazine toxicity See chlorpromazine toxicity See chlorpromazine toxicity; agranulocytosis See chlorpromazine toxicity Others: loxapine, olanzapine, pimozide, quetiapine, sertindole
Antipsychotics (heterocyclics)
Clozapine Molindone
Risperidone
Discussed above; D2 receptor blockade D4 receptor blockade; more effective against negative symptoms than Schizophrenia traditional antipsychotic agents Tourette's syndrome D2 receptor blockade Blocks dopamine and serotonin receptors; more effective against Schizophrenia (refractory negative symptoms than traditional to other drugs) antipsychotic agents Not well-defined; inhibits recycling of neuronal membrane phosphoinositides involved in generation of IP3 and DAG (important in amine neurotransmission); low therapeutic index --> serum level monitoring necessary; sodium depletion (dietary restriction, diuretics) --> Bipolar affective disorder promotes lithium reabsorption in PCT
Drugs used in bipolar (manic-depressive) disorder
Lithium
Tremor, weight gain, hypothyroidism, gastric distress, mild cognitive impairment (sedation), reversible nephrogenic diabetes insipidus, congenital cardiac anomalies (Ebstein's malformations)
Tricyclic antidepressants Amitriptyline, imipramine, desipramine Amoxapine, bupropion, maprotiline, trazodone
Major depressive disorders, bipolar affective disorders, acute panic attacks, phobic disorders, enuresis, chronic pain states Major depressive disorders, nicotine dependence (bupropion)
Heterocyclic antidepressants (second generation)
Inhibit reuptake mechanisms (transporters) responsible for termination of synaptic actions of both NE and 5-HT in the brain --> potentiation of neurotransmitter actions at postsynaptic receptors Some drugs inhibit reuptake of NE (maprotiline); others have more action on serotonin reuptake (trazodone); bupropion has unknown mechanism of
Excessive sedation (desipramine is least sedating), atropine-like effects, orthostatic hypotension (alpha receptor blockade), tremor and paresthesias, weight gain See amitriptyline toxicity; amoxapine: akathisia, parkinsonism, and amenorrhea-galactorrhea
Alternate drugs for bipolar affective disorder: carbamazepine, clonazepam, gabapentin, valproic acid "Three Cs" (coma, convulsions [seizures], cardiotoxicity [arrhythmias]) in overdose (treat acidosis with sodium bicarbonate); additive depression of CNS with other central depressants Amoxapine is most dangerous in overdose (avoid in suicidal patients) 57 |czida
action (may exert antidepressant effect by blocking neuronal uptake of dopamine) Venlafaxine: potent inhibitor of both NE and 5-HT transporters; mirtazapine: increases amine release from nerve endings by antagonism of presynaptic alpha2 adrenoceptors involved in feedback inhibition syndrome (dopamine blockade); trazodone: priapism, sedation
Heterocyclic antidepressants (third generation)
Mirtazapine, nefazodone, venlafaxine
Major depressive disorders
See amitriptyline toxicity
Selective serotonin reuptake inhibitors Major depressive disorders, obsessivecompulsive disorders, panic attacks, social phobias, bulimia, premenstrual syndrome, alcohol dependence
Fluoxetine
Highly selective action on the 5-HT transporter (inhibitor of neuronal reuptake) Increase brain amine levels by interfering with their metabolism in the nerve endings (inhibit A and B forms of MAO; A form responsible for antidepressant effects) --> increase in vesicular stores of NE and serotonin --> increased amine release when neuronal activity causes discharge of vesicles
Monoamine oxidase inhibitors Major depressive disorders
Phenelzine
Nausea, headache, anxiety, agitation, insomnia, weight loss, sexual dysfunction, extrapyramidal effects Orthostatic hypotension, weight gain, ejaculatory delay, hypertensive reactions in response to indirectly acting sympathomimetics (e.g., tyramine from diet), hyperthermia, CNS stimulation
Nefazodone and venlafaxine inhibit cytochrome P450 isozymes Inhibits hepatic cytochrome P450 isozymes; serotonin syndrome with drugs that enhance serotonergic function (severe muscle rigidity, myoclonus, hyperthermia, cardiovascular instability, marked CNS stimulatory effects); useful in overweight patients (associated with weight loss); others: sertraline, citalopram, paroxetine Therapeutic effect usually not observed for 2-3 weeks; involved in serotonin syndrome when taken with SSRIs; others: tranylcypromine, isocarboxazid 58 |czida
Tolerance (except to miosis and constipation), dependence, decreased urine output, constipation, nausea and vomiting, pruritus and flushing (histamine); coma with marked respiratory depression and hypotension, miosis; meperidine: mydriasis, hyperpyrexic coma (with MAO inhibitors), serotonin syndrome Others: meperidine, fentanyl, and levorphanol (strong agonists --> more abuse potential); codeine, oxycodone, and hydrocodone (moderate agonists), propoxyphene (weak agonist); additive CNS depression with ethanol, sedativehypnotics, anesthetics, antipsychotics, TCAs, and antihistamines
Opioid analgesics Analgesia, acute pulmonary edema, anesthesia
Morphine
Methadone Opioid antitussives Opioid antidiarrheal drugs Codeine, hydrocodone, dextromethorphan Diphenoxylate
Opioid withdrawal states; maintenance programs for addicts
Mu and delta receptors contribute to analgesia at both spinal and supraspinal levels (enkephalin release --> inhibits ascending pain impulses; direct activation of spinal cord opiate receptors --> inhibit release of substance P and other pain mediators --> inhibit ascending pain impulses), respiratory depression, and physical dependence, sedation, miosis, and increased smooth muscle tone (constipation, biliary spasm); kappa receptors contribute to spinal analgesia, sedation, dysphoria See morphine mechanism; suppresses heroin withdrawal symptoms, has longer duration of action, orally effective, and causes less euphoria, drowsiness, and depression than heroin
See morphine toxicity Dextromethorphan has no other significant opiate activity in the See morphine toxicity (except dextromethorphan) CNS Others: loperamide, See morphine toxicity meperidine Others: nalbuphine, butorphanol (parenteral and intranasal); can Sedation, respiratory precipitate a withdrawal depression, tolerance, syndrome in opiate dependence (less than full addicts agonists) Sedation, respiratory depression, tolerance, dependence (less than full agonists) 59 |czida
Cough suppression Diarrhea
See morphine mechanism See morphine mechanism; meperidine analog
Opioid mixed agonist-antagonists Pentazocine Opioid partial agonists Buprenorphine Analgesia Analgesia
Kappa agonists with weak mu receptor antagonist activity; sigma agonist (mediates dysphoria, psychotomimetic effects)
Binds strongly to mu receptors (resistant to naloxone reversal)
Short duration of action (1-2 hours); can precipitate a withdrawal syndrome in opiate addicts
Opioid antagonists Naloxone, naltrexone Acute opioid overdose Pure opioid receptor (mu, kappa, delta) antagonists Autonomic drugs Blocks uptake of choline and slows synthesis of Ach Prevents storage, depletes Ach Prevents release of Ach Blocks synthesis of NE (inhibits tyrosine hydroxylase) Discussed above Discussed above Discussed below
Few other effects at doses which produce antagonism of agonist effects
Drugs affecting cholinergic nerve terminals Drugs affecting noradrenergic nerve terminals
Hemicholinium Vesamicol Botulinum toxin Alphamethyltyrosine (metyrosine) Reserpine Guanethidine Cocaine
Direct-acting cholinomimetic agonists
Bethanechol
Postoperative and neurogenic ileus and urinary retention
Activates bowel and bladder smooth muscle; muscarinic
Carbachol Pilocarpine
Glaucoma Chronic open-angle glaucoma
Activates pupillary sphincter and ciliary muscles of eye; muscarinic and nicotinic Activates pupillary sphincter and ciliary muscles of eye; muscarinic
Muscarinic toxicity (CNS stimulation, miosis, spasm of accomodation, bronchoconstriction, increased GI and GU smooth muscle activity, increased secretory activity, vasodilation, reflex tachycardia) See muscarinic toxicity; nicotinic toxicity (CNS stimulation, ganglionic stimulation, neuromuscular end plate depolarization --> fasciculations and paralysis) See muscarinic toxicity
In endothelium, muscarinic agonists activate phospholipase C (via Gq) --> increase IP3 and DAG --> intracellular calcium --> activate nitric oxide synthase --> NO --> activate guanylate cyclase --> cGMP --> vasodilatation
60 |czida
Cevimeline Dry mouth in Sjogren's syndrome Postoperative and neurogenic ileus and urinary retention; myasthenia gravis; reversal of neuromuscular blockade Myasthenia gravis; reversal of neuromuscular blockade Increases salivation; muscarinic Bind to cholinesterase --> undergo prompt hydrolysis --> alcohol portion of molecule released --> acidic portion released much more slowly --> prevent binding and hydrolysis of acetylcholine -> amplifies endogenous Ach; muscarinic and nicotinic See muscarinic toxicity DUMBELS: diarrhea, urination, miosis, bronchoconstriction, excitation (skeletal muscle and CNS), lacrimation, salivation and sweating
Neostigmine Indirect-acting cholinomimetic agonists
Carbamic acid esters (carbamates) Carbamic acid esters (carbamates) Also used to distinguish between myasthenic crisis and cholinergic crisis in patients with myasthenia gravis Carbamic acid esters (carbamates) Phosphoric acid esters (organophosphates)
Pyridostigmine
Same as neostigmine
See neostigmine toxicity
Edrophonium Physostigmine Echothiophate
Diagnosis of myasthenia gravis Glaucoma Glaucoma
Short-acting cholinomimetic Same as neostigmine Same as neostigmine
See neostigmine toxicity See neostigmine toxicity See neostigmine toxicity Antimuscarinic toxicity: "atropine fever" (hyperthermia from blockade of thermoregulatory sweating), reduced sweating, salivation, lacrimation; urinary retention, acute angleclosure glaucoma, constipation, blurred vision, CNS toxicity (sedation, amnesia, delirium, hallucinations); "atropine flush"
Muscarinic antagonists Act like competitive (surmountable) pharmacologic antagonists; receptors: M1 ("neural"; enteric nervous system, gastric paracrine cells), M2 ("cardiac"; heart), M3 ("glandular"; smooth muscle)
Benztropine, trihexyphenidyl, biperiden
Parkinson's disease
"Dry as a bone, red as a beet, mad as a hatter" 61 |czida
Act like competitive (surmountable) pharmacologic antagonists; administered as a skin patch to provide sustained low blood levels that will not cause significant side effects in most patients Act like competitive (surmountable) pharmacologic antagonists; full doses of atropine block cardiac M2 receptors --> tachycardia; small doses activate receptors in the vagal nucleus --> bradycardia Act like competitive (surmountable) pharmacologic antagonists M1-selective muscarinic blocker --> blocks vagally mediated gastric acid secretion
Scopolamine
Motion sickness (most effective drug for prevention)
See antimuscarinic toxicity (mydriasis, cycloplegia)
Atropine, homatropine, cyclopentolate, tropicamide Ipratropium
Produce mydriasis and cycloplegia Cause bronchodilation in asthma and COPD
See antimuscarinic toxicity See antimuscarinic toxicity Available in Europe but not the USA
Pirenzepine
Glycopyrrolate, dicyclomine Methscopolamine Oxybutynin, tolterodine
Peptic ulcer disease Reduce transient hypermotility in GI tract; transient cystitis, postoperative bladder spasms, or incontinence Reduce transient hypermotility in GI tract Transient cystitis, postoperative bladder spasms, or incontinence
See antimuscarinic toxicity
Act like competitive (surmountable) pharmacologic antagonists Act like competitive (surmountable) pharmacologic antagonists Act like competitive (surmountable) pharmacologic antagonists
See antimuscarinic toxicity See antimuscarinic toxicity
Nicotinic antagonists
Mecamylamine
Nicotine addiction, Tourette's syndrome
Ganglion blocking drug; act like competitive pharmacologic antagonists
See antimuscarinic toxicity Sympathetic and parasympathetic blockade (decrease in cardiac contractility and output, increase in heart rate, postural hypotension, dry mouth, mydriasis, urinary retention, constipation, severe sexual dysfunction)
Others: hexamethonium and trimethaphan were used for hypertension -> abandoned due to adverse effects
62 |czida
Discussed above; nondepolarizing neuromuscular blocking drugs; competitive block of Ach at the end plate nicotinic receptor --> flaccid paralysis; tubocurarine blocks autonomic ganglia Discussed above; act like nicotine agonists and depolarize the neuromuscular end plate --> continuous depolarization results in muscle relaxation and paralysis (after transient muscle fasciculations primarily involving chest and abdomen) Molecules contain oxime group (high affinity for phosphorus in organophosphate insecticides) --> bind inhibitor and displace cholinesterase (AChE reactivating agent) Hydrophilic hormone directly actvates adrenoreceptors (alpha1, alpha2, beta1, beta2); at low doses --> increases heart rate (beta1), mean arterial pressure unchanged (alpha1, beta2 opposition); vasoconstriction and "decongestion" in trabecular area --> easier drainage of aqueous humor in glaucoma; increases muscle glycogenolysis --> glucose-1phosphate --> glucose-6-phosphate --> glycolysis --> increase serum lactate
Tubocurarine
Complete skeletal muscle relaxation in surgery
Respiratory paralysis
Succinylcholine Cholinesterase regenerators Pralidoxime
Complete skeletal muscle relaxation in surgery
Respiratory paralysis, postoperative muscle pain
Shorter-acting drugs: pancuronium, atracurium, vecuronium Succinylcholine (also mivacurium) rapidly eliminated by cholinesterase --> prolonged apnea may occur in patients with genetically determined abnormal variant
Treat patients exposed to insecticides (parathion)
Sympathomimetics (general agonists) Epinephrine
Anaphylaxis, open-angle glaucoma, asthma, to cause vasoconstriction
Amphetamine, tyramine, methylphenidate (amphetamine derivative)
Narcolepsy, obesity, attention deficit disorder, hyperkinetic syndrome
Increases intraneuronal levels of norepinephrine --> release of norepinephrine from adrenergic neurons --> vasoconstriction
Excessive vasoconstriction, cardiac arrhythmias, myocardial infarction, pulmonary edema or hemorrhage Mild to severe CNS toxicity (nervousness, anorexia, insomnia --> anxiety, aggressiveness, paranoid behavior, convulsions); raise BP and cardiac oxygen requirements; urinary
Others: methamphetamine and dextroamphetamine (drugs of abuse); urine acidification (ammonium chloride, ascorbic acid) hastens 63 |czida
retention elimination
Ephedrine, pseudoephedrine
Cocaine
Asthma (obsolete), urinary incontinence, vasoconstriction in hypotension To cause vasoconstriction and local anesthesia
Sympathomimetics (alpha1, alpha2, beta1) To cause vasoconstriction in hypotension To cause mydriasis, vasoconstriction, decongestion
Norepinephrine Sympathomimetics (alpha1 > alpha2)
Phenylephrine
Indirect mechanisms: release of norepinephrine from adrenergic neurons -> vasoconstriction, decongestion of nasal passages (allergic rhinitis) Inhibit reuptake of catecholamines by nerve terminals --> increase synaptic activity of released transmitter Selective adrenoceptor agonist; alpha1: Gq protein --> IP3 and DAG --> calcium release in smooth muscle cells --> vasoconstriction (increase preload and afterload); alpha2: inhibition of adenylyl cyclase via Gi protein; beta1: stimulate adenylyl cyclase via Gs --> increase in cAMP --> increase heart rate (increase SA node conductance of calcium) See norepinephrine, alpha1 --> vasoconstriction, mydriasis without cycloplegia
See amphetamine toxicity Cardiac arrhythmias or infarction and convulsions; drug of abuse
Excessive vasoconstriction, cardiac arrhythmias, myocardial infarction, pulmonary edema or hemorrhage
Hypertension Apraclonidine and brimonidine for glaucoma; can counteract opiate withdrawal syndrome in opiate addicts
Sympathomimetics (alpha2 > alpha1) Clonidine Hypertension Discussed above; see norepinephrine, alpha2
Sympathomimetics (beta1 = beta2) Isoproterenol Asthma, AV block (rare)
See norepinephrine, beta receptors; increase heart rate, contractility, causes vasodilation (decrease in blood pressure); bronchodilation
Salt and water retention, severe rebound hypertension, sedation, dry mouth Tachycardia, cardiac arrhythmias, excessive vasoconstriction, myocardial infarction, pulmonary edema or hemorrhage
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Sympathomimetics (beta1 > beta2) Dobutamine Shock, heart failure Asthma (acute bronchospasm), suppress premature labor (terbutaline, ritodrine) See norepinephrine, beta receptors; also stimulates alpha1 receptors Discussed above; beta2 receptors --> stimulates adenylyl cyclase --> increases cAMP in smooth muscle cells --> bronchodilation more than cardiac stimulation, uterine relaxation Discussed above; D1 receptors: activate adenylyl cyclase in neurons and vascular smooth muscle; D2 receptors: brain Binds covalently to the alpha receptor --> irreversible blockade --> vasodilatation; also has serotonin receptor-blocking effects and H1 antihistamine effects Sinus tachycardia, serious arrhythmias Skeletal muscle tremor; tachycardia; CNS stimulation (anxiety, restlessness, convulsions); tolerance Inhaled; shorter-acting; no use in treating allergic rhinitis; others: salmeterol, albuterol, metaproterenol, ritodrine
Sympathomimetics (beta2 > beta1) Terbutaline Sympathomimetics (dopamine agonist) Alpha-blockers (nonselective) Phenoxybenzamine Alpha-blockers (alpha1-selective)
Dopamine
Prazosin, terazosin, doxazosin
Beta-blockers (nonselective)
Propranolol
Timolol Nadolol Carvedilol
Shock, heart failure Presurgical management of pheochromocytoma, carcinoid tumor, mastocytosis Hypertension, urinary hesitancy and prevention of urinary retention in men with prostatic hyperplasia Hypertension, angina prophylaxis, arrhythmia prophylaxis after MI, supraventricular tachycardias, hypertrophic cardiomyopathy, migraine, tremor, thyroid storm, thyrotoxicosis Hypertension, arrhythmia prophylaxis after MI, glaucoma Angina pectoris CHF
Orthostatic hypotension, reflex tachycardia
Others: phentolamine (reversible blockade)
Discussed above; reversible alpha1selective antagonist --> decrease vascular First-dose syncope resistance
Decrease TG and LDL; increase HDL
Discussed above; nonselective cardiac beta blockade --> reduction in cAMP --> reduction of both sodium and calcium currents and suppression of abnormal pacemakers --> reduce heart rate, cardiac output; reduce renin secretion See propranolol; acts on ciliary process to inhibit production of aqueous humor in glaucoma See propranolol Discussed above; two isomers: alpha blocker and nonselective beta-blocker
Sleep disturbances, sedation, sexual dysfunction, bradycardia, AV block, asthma (bronchoconstriction)
Slightly elevated LDL and TG; reduced HDL
See propranolol toxicity See propranolol toxicity; less CNS toxicity
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Chronic hypertension and hypertensive emergencies, block side effects of CNS stimulants (e.g., methamphetamine) Hypertension, arrhythmia prophylaxis after MI Supraventricular tachycardias (AV nodal arrhythmias, etc.)
Labetalol Metoprolol, Beta-blockers (beta1- atenolol selective) Esmolol
Blocks both alpha and beta adrenoceptors Selective beta1 receptor blockers --> decrease cardiac output, heart rate, renin secretion (to a lesser extent) Discussed above; very short-acting beta blockade; slows AV conduction --> increased PR interval Miscellaneous Large doses decrease mucous viscosity and increase mucous membrane hydration --> facilitate expectoration of sputum
Bradycardia, AV blockade, CHF
Others: acebutolol; does not exacerbate asthma
IV
Expectorants Guaifenesin Sinusitis, bronchitis
Vaccines
Measles-mumpsrubella (MMR) Haemophilus influenzae type b
Hepatitis A virus Hepatitis B virus
Primary administration (12-15 months); booster shot before entry into school (4-6 years) or middle school (11-12 years) Ages 2 months and 4 months Given 2-4 weeks prior to travel to endemic areas; household contacts; IV drug users First dose (birth), second dose (2 months), third
Live attenuated (egg-based) vaccines available as single-antigen preparations or in combination Contains type b capsular polysaccharide; not egg-based
Contraindications: anaphylactic reactions following egg ingestion, pregnancy, congenital immunodeficiency syndromes; recent immune globulin injection (interferes with patient's immune response)
Inactivated virus Inactivated viral antigen, recombinant Hypersensitivity reactions to yeasts (HBsAg produced 66 |czida
dose (6-18 months) Egg-based vaccine; inactivated virus or viral components; in elderly, 30-40% effective in preventing influenza (70-90% in young adults), 80% effective in preventing death in yeast by plasmid gene insertion)
Influenza virus
Annually for the elderly, those with chronic disease, and other high risk individuals
Diphtheria-tetanusacellular pertussis (DTaP) Varicella Pneumococcal conjugate vaccine Oral polio vaccine (Sabin) Inactivated polio vaccine
Shots at 2, 4, and 6 months of age; booster given at 15-18 months and at 4-6 years; tetanus toxoid booster given at 14-16 years, or before entering college At or after 12 months Ages 2-23 months
Toxoids
Contraindications: anaphylactic reactions following egg ingestion If tetanus immunization incomplete, toxoid for clean minor wounds, toxoid and Ig for dirty wounds; if complete immunization, toxoid for clean minor wounds (if last booster > 10 years ago), toxoid for dirty wounds (if last booster > 5 years ago); else, no treatment
Both intestinal and bodily immunity (lifelong); oral administration Four doses: ages 2 months, 4 months, 6-18 months, and 4-6 years
Contraindicated in HIV+ patients
Bodily immunity Contraindications: anaphylactic reactions following egg ingestion Dermatologic (dry skin and mucous membranes, pruritus, alopecia), muscle and joint pain, lipid abnormalities (hypertriglyceridemia), 67 |czida
Yellow fever
Egg-based vaccine
Vitamins Isotretinoin Severe cystic acne Vitamin A derivative
teratogen
Vitamin B12 Vitamin D Vitamin K Male contraceptives Gossypol Coal tar Miscellaneous topical treatments Salicylic acid
Discussed above Discussed above Discussed above Obtain from cottonseed; acts by impairing the seminiferous epithelium and sperm production; does not affect secretion of testosterone Topical preparation Keratolytic agent when applied topically; believed to work by solubilizing components of the stratum corneum --> desquamation of keratotic debris
Male contraception Psoriasis, seborrheic dermatitis
Dermatophyte infections
68 |czida

All Drugs - For Review

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PHARMACOLOGY REVIEWER

CNS+ (enters CNS)

Activation of alpha2 receptors in CNS --> decrease vascular resistance

Hexamethonium, trimethaphan Postganglionic neuron blockers Alpha1-selective antagonists Reserpine

Hypertension (obsolete) Hypertension

CNS+; adjunct to other agents

Guanethidine Prazosin, terazosin

CNSDecrease TG and LDL; increase HDL

Sleep disturbances, sedation, sexual dysfunction, bradycardia, AV block, asthma (bronchoconstriction)

Slightly elevated LDL and TG; reduced HDL 1 |czida

Hypertension, heart failure

Hypertension, topically for baldness

Cyanide toxicity Hypotension, hyperglycemia, salt and water retention

Calcium channel blockers

Also used in migraine, preterm labor, stroke, and Raynaud's syndrome

Also used in migraine, preterm labor, stroke, and Raynaud's syndrome

Constipation, edema, nausea, flushing, dizziness

Also used in migraine, preterm labor, stroke, and Raynaud's syndrome

Captopril, enalapril Angiotensin II receptor blockers Losartan

Competitively inhibit AT II at its AT1 receptor site

Nitrates Nitroglycerin Angina, acute CHF, Prinzmetal's angina

Amyl nitrite, sodium nitrite Cyanide poisoning

Methemoglobinemia, orthostatic hypotension

Loop diuretics Furosemide

Hypertension, CHF, ascites, acute pulmonary edema, severe hypercalcemia

Potassium-sparing diuretics Spironolactone

CHF; potassium wasting with loop or thiazide diuretics; aldosteronism

Hyperkalemic metabolic acidosis, gynecomastia and anti-androgenic effects

Osmotic diuretics Mannitol ADH agonists ADH, desmopressin

Hyponatremia and pulmonary edema, headache, nausea, vomiting

Pituitary diabetes insipidus

Demeclocycline Lithium Dobutamine

Acute heart failure Acute heart failure

Beta1-selective agonists Dopamine

Phosphodiesterase inhibitors Amrinone Acute heart failure

Atrial and ventricular arrhythmias

Atrial and ventricular arrhythmias

Hypotension, lupus-like syndrome; torsade de pointes

Class IB antiarrhythmics Lidocaine Mexiletine, tocainide Class IC antiarrhythmics Flecainide

Hyperkalemia increases cardiac toxicity 6 |czida

Class III antiarrhythmics

Torsade de pointes, sinus bradycardia, asthma

Ibutilide Class IV antiarrhythmics Discussed above

Atrial flutter and fibrillation

Arrhythmias resistant to other drugs

Adenosine Potassium ion

Ineffective in asthma; others effective in motion sickness (dimenhydrinate, 7 |czida

Less sedating Marked sedation

Cimetidine, ranitidine, famotidine, nizatidine

Blockade of histamine H2 receptors --> reduction of gastric acid secretion

Ineffective in asthma Withdrawn from US market; little or no sedation

Serotonin 5-HT1D agonists

Serotonin is involved in mood, sexuality, anxiety, sleep

Ondansetron Ergot alkaloids Bromocriptine

Diarrhea, headache GI upset

Migraine, obstetric bleeding

Methysergide PGE2 (dinoprostone)

Migraine prophylaxis Ripen cervix at term; abortion in second trimester

Nausea, vomiting, diarrhea

Nausea, vomiting, diarrhea

Latanoprost, a PGF2alpha derivative, used in glaucoma (increase outflow of aqueous humor)

Should not be given to pregnant women or to women attempting to conceive