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NB: SE = side effect C/I = contraindication There are graphics in FA that have not been included in this document
Participants: Eddie Ahn, Tala Al-Talib, Mona Bahouth, Richie Bryson, Sarah Bui, Niloo Ghassemzadeh, Nidhi Goel, Jen Han, Kyle Hatten, Ashley Huber, Anita Katikineni, Jessica Lue, Thom Reznik, Justin Waltrous, Felicia Washington, Melissa Wisner, Danielle York, Zombor Zoltani
Erythromycin, Clindamycin, Sulfamethoxazole, Trimethoprim, Tetracyclines, Chloramphenicol ("We're ECSTaTiC about bacteriostatics") Vancomycin, Fluoroquinolones, Penicillin, Aminoglycosides, Cephalosporins, Metronidazole ("Very Finely Proficient At Cell Murder") 1. Bind penicillin-binding proteins -Prototype -lactam antibiotics 2. Block transpeptidase cross-linking of cell wall -Not penicillinase resistant 3. Activate autolytic enzymes -SE: hypersensitivity reactions, hemolytic anemia -Same as penicillin -Narrow spectrum -Penicillinase-resistant -Penicillinase resistant because of bulkier R group -SE: hypersensitivity reactions; methicillin - interstitial nephritis -Penicillinase-sensitive -Also combine with clavulanic acid (penicillinase inhibitor) to enhance spectrum. -amOxicillin has greater Oral bioavailability than ampicillin -SE: hypersensitivity reactions; ampicillin rash; pseudomembranous colitis
-Bactericidal for gram-positive cocci, gram-positive rods, gram-negative cocci, and spirochetes.
Penicillinase-resistant -S. aureus (except MRSA; resistant penicillins because of altered pencillinMethicillin binding protein target site) Nafcillin ("Use naf (nafcillin) for staph") Dicloxacillin Aminopenicillins Ampicillin Amoxicillin -Extended spectrum penicillin: certain gram-positive bacteria and gram-negative rods (Haemophilus influenzae, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, enterococci) (Coverage: ampicillin/amoxicillin HELPS kill enterococci) -Pseudomonas spp. and gram-negative rods
Cephalosporins
--lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases
-Bactericidal -SE: -hypersensitivity reactions -cross-hypersensitivity with penicillins occurs in 5-10% of patients - nephrotoxicity of aminoglycosides -disulfiram-like reaction with ethanol (in cephalosporins with a methylthiotetrazole group, e.g. cefamandole)
-Gram-positive cocci, Proteus mirabilis, E. coli, Klebsiella pneumoniae (PEcK) -Gram-positive cocci, Haemophilus influenzae, Enterobacter aerogenes, Neisseria spp., Proteus mirabilis, E. coli, Klebsiella pneumoniae, Serratia marcescens (HEN PEcKS) -Serious gram-negative infections resistant to other -lactams -Meningitis (most penetrate the blood-brain barrier) -Examples -ceftazidime for Pseudomonas -ceftriaxone for gonorrhea - activity against Pseudomonas and gram-positive organisms
Aztreonam
-Gram-negative rods: -A monobactam resistant to -lactamases Klebsiella spp. -Inhibits cell wall synthesis (binds to PBP3) Pseudomonas spp. Serratia spp. -No activity against gram-positives or anaerobes. -Use for penicillin-allergic patients and those with renal insufficiency who cannot tolerate aminoglycosides -Gram-positive cocci, gram-negative rods, and anaerobes. -Drug of choice for Enterobacter -Imipenem is a broad-spectrum, -lactamase-resistant carbapenem
-Synergistic with aminoglycosides -No cross-allergenicity with penicillins -No cross-sensitivity with penicillins or cephalosporins -SE: usually nontoxic; occasional GI upset
-Always administered with cilastatin (inhibitor of renal dihydropeptidase I) to inactivation in renal tubules (With imipenem, "the kill is LASTIN' with ciLASTATIN") -The significant side effects limit use to life-threatening infections, or after other drugs have failed. Meropenem, however, has a reduced risk of seizures and is stable to dihydropeptidase I. -SE: GI distress, skin rash, and CNS toxicity (seizures) at high plasma levels. -Bactericidal -Resistance occurs with amino acid change of D-ala D-ala to D-ala D-lac -SE: Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse flushing - "red man syndrome" (can largely prevent by pretreatment with antihistamines and slow infusion rate). (Well tolerated in general - does NOT have many problems)
Vancomycin
-Used for serious, gram-positive multidrug-resistant organisms, including S. aureus and Clostridium difficile (pseudomembranous colitis)
-Inhibits cell wall mucopeptide formation by binding D-ala D-ala portion of cell wall precursors
-Severe gram-negative rod Aminoglycosides infections Gentamicin, -Synergistic with -lactam Neomycin, antibiotics Amikacin, -Neomycin for bowel surgery Tobramycin, Streptomycin ("Mean" GNATS canNOT kill anaerobes) Tetracyclines Tetracycline, Doxycycline, Demeclocycline, Minocycline
-Bactericidal -AminO2glycosides require O2 for uptake; therefore ineffective against anaerobes -SE: Nephrotoxicity (esp. when used with cephalosporins), Ototoxicity (esp. when used with loop diuretics), Teratogen -Bacteriostatic -Limited CNS penetration -Doxycycline is fecally eliminated and can be used in patients with renal failure -Demeclocycline - ADH antagonist; acts as a Diuretic in SIADH -Must NOT take with milk, antacids, or iron-containing preparations because divalent cations inhibit its absorption in the gut -SE: GI distress, discoloration of teeth and inhibition of bone growth in children, photosensitivity -C/I: pregnancy -Bacteriostatic -SE: GI discomfort (most common cause of noncompliance), acute cholestatic hepatitis, eosinophilia, skin rashes. Increases serum concentration of theophyllines, oral anticoagulants. -Bacteriostatic -Conservative use owing to toxicities -SE: anemia (dose dependent), aplastic anemia (dose independent), gray baby syndrome (in premature infants because they lack liver UDP-glucuronyl transferase) -Bacteriostatic -SE: pseudomembranous colitis (C. difficile overgrowth), fever, diarrhea
Vibrio cholerae, Acne, Chlamydia, -Bind to 30S and prevent attachment of aminoacyl-tRNA Ureaplasma Urealyticum, Mycoplasma pneumoniae, Tularemia, H. pylori, Borrelia burgdorferi (Lyme disease), Rickettsia (VACCUUM THe BedRoom)
-URIs, pneumonias, STDs gram-positive cocci (streptococcal infections in patients allergic to penicillin), Mycoplasma, Legionella, Chlamydia, Neisseria -Meningitis (Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae)
-Inhibit protein synthesis by blocking translocation -Bind to the 23S rRNA of the 50S ribosomal subunit
Chloramphenicol
Clindamycin
-Treat anaerobic infections (e.g. Bacteroides fragilis, Clostridium perfringens) -Treats anaerobes above the diaphragm
-Gram-positive, gram-negative, Nocardia, Chlamydia -Use triple sulfas or SMX for simple UTI
-Bacteriostatic -SE: hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity (tubulointerstitial nephritis), photosensitivity, kernicterus in infants, displace other drugs from albumin (e.g. warfarin) -Bacteriostatic -SE: Megaloblastic anemia, leukopenia, granulocytopenia. (May alleviate with supplemental folic acid) ( Trimethoprim = TMP : "Treats Marrow Poorly )
-Used in combination with sulfonamides (trimethoprimsulfamethoxazole (TMP-SMX)), causing sequential block of folate synthesis. -Combination used for recurrent UTIs, Shigella, Salmonella, Pneumocystis jiroveci pneumonia
-Patients who do not tolerate sulfa drugs should not be given sulfonamides or other sulfa drugs, such as sulfasalazine, sulfonylureas, thiazide diuretics, acetazolamide, or furosemide -Gram-negative rods of urinary and GI tracts (including Pseudomonas), Neisseria, some gram-positive organisms -Inhibit DNA gyrase (topoisomerase II) -Bactericidal -Must not be taken with antacids -SE: GI upset, superinfections, skin rashes, headache, dizziness. In adults, tendonitis and tendon rupture. In kids, leg cramps and myalgias -C/I: pregnant women, and in children because animal studies show damage to cartilage (FluoroquinoLONES hurt attachment to your BONES)
Fluoroquinolones Ciprofloxacin, Norfloxacin, Ofloxacin, Sparfloxacin, Moxifloxacin, Gatifloxacin, Enoxacin, (fluoroquinolones), Nalidixic acid (a quinolone) Metronidazole
-Antiprotozoal. Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, Anaerobes (Bacteroides, Clostridium). -Used with bismuth and amoxicillin (or tetracycline) for "triple therapy" against H. pylori (GET GAP on the Metro!) -Treats anaerobes below the diaphragm
-Bind to cell membranes of bacteria and disrupt their osmotic properties -Polymyxins are cationic, basic proteins that act like detergents ('MYXins MIX up membranes)
Antimycobacterial drugs M. tuberculosis M. avium-intracellulare M. leprae Anti-TB drugs Streptomycin, Pyrazinamide, Isoniazid (INH), Rifampin, Ethambutol (INH-SPIRE (inspire)) Cycloserine (2nd-line therapy) Isoniazid (INH) -Mycobacterium tuberculosis -The only agent used as solo prophylaxis against TB
Isoniazid Isoniazid, rifampin, ethambutol, pyrazinamide Azithromycin Azithromycin, rifampin, ethambutol, streptomycin N/A Dapsone, rifampin, clofazimine -important SE of ethambutol is optic neuropathy (red-green color blindness). -for other drugs, hepatotoxicity
-Different INH half-lives in fast vs slow acetylators. -SE: Hemolysis if G6PD deficient, neurotoxicity, hepatotoxicity, SLE-like syndrome. Pyridoxine (vitamin B6) can prevent neurotoxicity. (INH Injures Neurons and Hepatocytes) -SE: Minor hepatotoxicity and drug interactions (P450); orange body fluids (nonhazardous side effect). (Rifampin's 4 R's: RNA polymerase inhibitor Revs up microsomal P450 Red/orange body fluids Rapid resistance if used alone)
Rifampin
-Mycobacterium tuberculosis -Delays resistance to dapsone when used for leprosy -Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with Haemophilus influenzae type B
Resistance mechanisms Penicillins / cephalosporins for various antibiotics Aminoglycosides Vancomycin Chloramphenicol Macrolides Tetracycline Sulfonamides Quinolones Meningococcal infection Nonsurgical antimicrobial prophylaxis Gonorrhea Syphilis History of recurrent UTIs Pneumocystis jiroveci pneumonia Endocarditis with surgical or dental procedures Treatment of highly resistant bacteria MRSA VRE
-lactamase cleavage of -lactam ring, or altered PBP in case of MRSA Modification via acetylation, adenylation, or phosphorylation Terminal D-ala of cell wall component replaced with D-lac; affinity Modification via acetylation Methylation of rRNA near erythromycin's ribosome-binding site uptake or transport out of cell Altered enzyme (bacterial dihydropteroate synthetase), uptake, or PABA synthesis Altered gyrase or reduced uptake Rifampin (drug of choice), minocycline Ceftriaxone Benzathine penicillin G TMP-SMX TMP-SMX (drug of choice), aerosolized pentamidine Penicillins Vancomycin Linezolid and streptogramins (quinupristin / dalfopristin)
CLASS/NAME Amphotericin B
CLINICAL USE -Used for wide spectrum of systemic mycoses. -Cryptococcus, Blastomyces, Coccidioides, Aspergillus, Histoplasma, Candida, Mucor (systemic mycoses). -Intrathecally for fungal meningitis; does not cross blood brain barrier. "Swish and swallow" for oral candidiasis (thrush); topical for diaper rash or vaginal candidiasis. -Systemic mycoses. -Fluconazole for cryptococcal meningitis in AIDS patients (because it can cross the blood-brain barrier) and candidal infections of all types (i.e., yeast infections). -Ketoconazole for Blastomyces, Coccidioides, Histoplasma, Candida albicans ; hypercortisolism. -Clotrimazole and miconazole for topical fungal infections. -Used in systemic fungal infections (e.g., Candida, Cryptococcus ) in combination with amphotericin B. -Invasive aspergillosis -Used to treat dermatophytoses (especially onychomycosis) -Oral treatment of superficial infections; inhibits growth of dermatophytes (tinea, ringworm).
ANTIFUNGAL THERAPY (p 184) MECHANISM -Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes
SIDE EFFECTS / MISC -SE: Fever/chills ("shake and bake"), hypotension, nephrotoxicity, arrhythmias, anemia, IV phlebitis ("amphoterrible"). Hydration reduces nephrotoxicity. Liposomal amphotericin reduces toxicity. -Misc. notes: Amphotericin "tears" holes in the fungal membrane by forming pores.
Nystatin
-SE: Hormone synthesis inhibition (gynecomastia), liver dysfunction (inhibits cytochrome P-450), fever, chills.
Flucytosine
Caspofungin Terbinafine
-Inhibits cell wall synthesis. -Inhibits the fungal enzyme squalene epoxidase. -Interferes with microtubule function; disrupts mitosis -Deposits in keratin-containing tissues (e.g., nails).
Griseofulvin
CLASS/NAME Amantadine
ANTIVIRAL THERAPY (pp 185-187) MECHANISM -Blocks viral penetration / uncoating (M2 protein); -May buffer pH of endosome. -Also causes the release of dopamine from intact nerve terminals. ("A man to dine" takes off his coat)
SIDE EFFECTS / MISC -Mechanism of resistance: Mutated M2 protein. 90% of all influenza A strains are resistant to amantidine, so not used. -Amantadine blocks influenza A and rubellA and causes problems with the cerebellA -SE: Ataxia, dizziness, slurred speech. -Rimantidine is a derivative of amantadine with fewer CNS side effects. Does not cross the blood-brain barrier
Rimantidine Zanamivir Oseltamivir Ribavirin Acyclovir -Both influenza A and B -RSV, chronic hepatitis C -HSV, VZV, EBV -HSV induced mucocutaneous and genital lesions, and encephalitis -Prophylaxis in immunocompromised pts. -For herpes zoster- use related agent famciclovir. -No effect on latent forms of HSV and VZV. -CMV, especially in immunocompromised. -Inhibit influenza neuraminidase, decreasing the release of progeny virus. -Inhibits synthesis of guanine nucleotides by competitively inhibiting IMP dehydrogenase. -Monophosphorylated by HSV/VZV thymidine kinase. -Triphosphate formed by cellular enzymes. -Preferentially inhibits viral DNA polymerase by chain termination.
-SE: Hemolytic anemia. Severe teratogen. -Mechanism of resistance: Lack of thymidine kinase. -SE: Generally well tolerated
Ganciclovir
-5`-monophosphate formed by CMV viral kinase or HSV/VZV thyrmidine kinase. -Triphosphate formed by cellular kinases. -Preferentially inhibits viral DNA polymerase. -Viral DNA polymerase inhibitor that binds to the pyrophosphate binding site of enzyme -Does not require activation by viral kinase. (FOScarnet=pyroFOSphate analog) -Glycoproteins from human leukocytes that block various stage of viral RNA and DNA synthesis -Induce ribonuclease that degrades viral mRNA.
-Mechanism of resistance: Mutated CMV DNA polymerase or lack of viral kinase. -SE: Leukopenia, neutropenia, thrombocytopenia, renal toxicity. More toxic to host enzymes than acyclovir. -Mechanism of resistance: Mutated DNA polymerase -SE: Nephrotoxicity -SE: Neutropenia.
Foscarnet
-CMV retinitis in immunocompromised patients when ganciclovir fails. -Acyclovir resistant HSV. -IFN- : chronic hepatitis B, C, Karposi's sarcoma -IFN- : MS -IFN- : NADPH oxidase deficiency.
Interferons
-HIV Protease Inhibitors Saqunavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir -all end in -navir (NAVIR (never) TEASE a proTEASE) -HIV Reverse -HAART (highly active Transcriptase antiretroviral therapy) usually a Inhibitors protease inhibitor + RT inhibitor. Initiated when patients Nucleosides have low CD4 (<500) or high Zidovudine (ZDV viral load. formerly AZT), -ZDV is used for general Didanosine (ddI), prophylaxis and during Zalcitabine (ddC), pregnancy to reduce risk of Stavidine (d4T), fetal transmission. Lamivudine (3TC), Abacavir Non-Nucleosides Nevirapine, Efavirenz, Delaviridine. (Never Ever Deliver nucleosides) Fusion Inhibitors Enfuvirtide
HIV THERAPY -Inhibit assembly of new virus by blocking protease in progeny virions.
-Preferentially inhibit reverse transcriptase of HIV. -Prevent incorporation of DNA copy of viral genome into host DNA.
-SE: -Bone marrow suppression (neutropenia, anemia) (give GM-CSF + Erythropoetin to reduce marrow suppression) -Peripheral neuropathy -Nucleosides: lactic acidosis -Non-nucleosides: rash -ZDV: megaloblastic anemia.
-HIV -In patients with persistent viral replication in spite of antiretroviral therapy. -Use in combo with other drugs.
-Bind viral gp41 subunit; inhibit conformational change required for fusion with CD4 cells. -Therefore block entry and subsequent replication.
-SE: -Hypersensitivity reactions -Reactions at subcutaneous injection site - risk of bacterial pneumonia
CLASS/NAME
CLINICAL USE
IMMUNOLOGY (pp 204-205) MECHANISM -Binds to cyclophilins -The resulting complex blocks the differentiation and activation of T cells by inhibiting calcineurin, preventing the production of IL-2 and its receptor
SIDE EFFECTS / MISC -SE: -predisposes patients to viral infections and lymphoma -nephrotoxic (preventable with mannitol diuresis)
Immunosuppressants Cyclosporine -Suppresses organ rejection after transplantation -Selected autoimmune disorders
Tacrolimus (FK506)
-Potent immunosuppressive used -Similar to cyclosporine in organ transplant recipients -Binds to FK-binding protein, inhibiting secretion of IL-2 and other cytokines -Kidney transplantation -Autoimmune disorders (including glomerulonephritis and hemolytic anemia) -Antimetabolite precursor of 6-mercatopurine that interferes with the metabolism and synthesis of nucleic acids. Toxic to proliferating lymphocytes.
Azathioprine
-SE: -Bone marrow suppression -Active metabolite mercaptopurine is metabolized by xanthine oxidase; thus, toxic effects may be by allopurinol -SE: Cytokine release syndrome, hypersensitivity reaction
Muromonab-CD3 (OKT3)
-Immunosuppression after kidney -Monoclonal Ab that binds to CD3 (epsilon transplantation chain) on the surface of T cells. Blocks cell interaction with CD3 protein responsible for T cell signal transduction. -Immunosuppression after kidney -Binds to mTOR (molecular target of transplantation in combo with rapamycin). cyclosporine and corticosteroids -Inhibits T cell proliferation in response to IL-2 -Inhibits de novo guanine synthesis and blocks lymphocyte production. -Monoclonal Ab with high affinity for the IL-2 receptor on activated T cells.
Sirolimus (rapamycin)
-Renal cell carcinoma -Metastatic melanoma Erythropoietin (epoetin) -Anemias (esp in renal failure) Filgrastim -Recovery of bone marrow (granulocyte colonystimulating factor) Sargramostim (granulocytemacrophage colonystimulating factor) -interferon -Recovery of bone marrow
-Hepatitis B and C -Kaposi's sarcoma -Leukemias Malignant melanoma -Multiple sclerosis -Chronic granulomatous disease -Thrombocytopenia -Thrombocytopenia
CLINICAL USE
Direct agonists Bethanechol -Postoperative and neurogenic ileus and urinary retention -Glaucoma -Pupilary contraction - Intraocular pressure -Potent stimulator of sweat, tears, saliva -Emergency treatment for open and narrow glaucoma -Contracts ciliary muscle of eye (open angle), pupillary sphincter (narrow angle) -Challenge test to diagnose asthma -Direct cholinergic agonist -Activates Bowel and Bladder smooth muscle -Direct cholinergic agonist (muscarinic and nicotinic agonist) Direct cholinergic agonist -Resistant to AchE (Pile on the sweat and tears) -Resistant to AChE (Beth Anne, call (bethanechol) me if you want to activate your bowels and bladder)
Carbachol
Pilocarpine
Methacholine
Indirect agonists (anticholinesterases) Neostigmine -Postoperative and neurogenic ileus and urinary retention -Myasthenia gravis -Reversal of neuromuscular junction blockade (postop) -Myasthenia gravis (long acting) -(Indirect agonist (anticholinesterase)) = - endogenous Ach -No CNS penetration (NEO CNS = NO CNS) -Shorter acting than pyridostigmine
Pyridostigmine
- endogenous Ach therefore increases strength -No CNS penetration - endogenous Ach - endogenous Ach -Crosses the BBB to CNS - endogenous Ach
-Long acting
-Diagnosis of myasthenia gravis -Glaucoma (b/c crosses BBB) -Atropine overdose -Glaucoma
Cholinesterase inhibitor -Causes: Parathion and other organophosphates. Irreversible inhibitors. -Symptoms: (DUMBBELSS) poisoning -Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Excitation skeletal muscle and CNS; Lacrimation, Sweating, Salivation (also abdominal cramping) -Antidote: Atropine (muscarinic antagonist) plus pralidoxime (chemical antagonist used to regenerate active cholinesterase)
Muscarinic antagonists Atropine, Homatropine, Tropicamide Benztropine Scopolamine Ipratropium Methoscopolamine, Oxybutynin, Glycopyrrolate Pirenzepine, Propantheline Glaucoma drugs Epinephrine
-Produce mydriasis and cycloplegia -Parkinson's disease (PARK my BENZ) -Motion sickness -Asthma, COPD -Reduce urgency in mild cystitis and reduces bladder spasms -Peptic ulcer treatment
-Gastrointestinal
-Glaucoma
--agonist - aqueous humor synthesis due to vasoconstriction --agonist - aqueous humor synthesis --blockers - aqueous humor synthesis -Diuretic - aqueous humor secretion due to HCO3 (via inhibition of carbonic anhydrase) -Cholinomimetics - outflow of aqueous humor -Contract ciliary muscle and opens trabecular meshwork -Use pilocarpine in emergencies -Very effective at opening the canal of Schlemm -Prostaglandin - outflow of aqueous humor
-SE: Mydriasis; stinging -C/I: Do not use in closed angle glaucoma -No pupillary or vision changes -No pupillary or vision changes
-Glaucoma -Glaucoma
-Glaucoma
-Glaucoma
-Glaucoma
Atropine
(Blocks DUMBBELLS) -Eye: -pupil dilation, cycloplegia -Airway - secretions -Stomach - acid secretions -Gut - motility -Bladder - urgency in cystitis -Ganglionic blocker - used in experimental models to prevent vagal reflex responses to changes in blood pressure (e.g. prevents reflex bradycardia caused by NE)
Muscarinic antagonist
-SE: - body temp, rapid pulse, dry mouth, dry flushed skin, cycloplegia, constipation, disorientation -(Hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter) -Acute angle-closure glaucoma in elderly -Urinary retention in men with prostatic hypertrophy -Hyperthermia in infants
Hexamethonium
Nicotinic antagonist
Sympathomimetics
(DIRECT, INDIRECT, SYMPATHOPLEGICS)
Direct sympathomimetics Epinephrine NE Isoproterenol Dopamine Dobutamine Phenylephrine -Anaphylaxis, glaucoma (open angle), asthma, hypotension -Hypotension (but renal perfusion) -AV block (rare) -Shock ( renal perfusion), heart failure -Shock, heart failure, cardiac stress testing -Pupillary dilation, vasoconstriction, nasal decongestion -Albuterol for acute asthma -Terbutaline reduces premature uterine contractions -Reduces premature uterine contractions 1, 2, 1, 2, low doses selective for 1 1, 2 > 1 1 = 2 D1 = D2 > > 1 > 2 1 > 2
Albuterol, Terbutaline Ritodrine Indirect sympathomimetics Amphetamine Ephedrine Cocaine Sympathoplegics Clonidine, -methyldopa Selective 2-agonists Metaproterenol, Albuterol, Salmeterol, Terbutaline
2 > 1
-Narcolepsy, obesity, attention deficit disorder -Nasal decongestion, urinary incontinence, hypotension -Causes vasoconstriction and local anesthesia -Hypertension, especially with renal disease (no in blood flow to kidney)
-Indirect general agonist, releases stored catecholamines -Indirect general agonist, releases stored catecholamines -Indirect general agonist, uptake inhibitor -Centrally acting 2-agonist, central adrenergic outflow 2-agonist MAST: Metaproterenol, Albuterol, Salmeterol, Terbutaline
-blockers
(NONSELECTIVE, 1 SELECTIVE, 2 SELECTIVE)
-Pheochromocytoma (use phenoxybenzamine before removing tumor, since high levels of released catecholamines will not be able to overcome blockage) -Hypertension, urinary retention in BPH
Nonselective -blocker
1-selective Prazosin, Terazosin, Doxazosin 2-selective Mirtazapine -blockers Propranolol, Metoprolol, Atenolol, Nadolol, Timolol, Pindolol, Esmolol, Labetalol
1 selective -blocker
-Depression
2 selective -blocker
-Hypertension cardiac output, renin secretion -Angina pectoris heart rate and contractility, resulting in O2 consumption -MI -blockers mortality -SVT (propranolol, esmolol) AV conduction velocity (class II antiarrhythmic) -CHF Slows progression of chronic failure -Glaucoma (timolol) secretion of aqueous humor
-Nonselective antagonists (1 = 2) propranolol, timolol, nadolol, pindolol, and labetalol -1-selective antagonists (1 > 2) Acebutolol (partial agonist), Betaxolol, Esmolol (short acting), Atenolol, Metoprolol (A BEAM of 1-blockers) -Nonselective - and - antagonists carvedilol, labetalol -Partial -agonists acebutolol, pindolol
-SE: -impotence -exacerbation of asthma -cardiovascular adverse effects (bradycardia, AV block, CHF) -CNS adverse effects (sedation, sleep alterations) -use with caution in diabetics
CARDIOVASCULAR (pp 266-272) MECHANISM -Thiazide diuretic (prevents NaCl resorption in early DCT) -Loop diuretic (blocks NKCC channel in TALH) -Sympathoplegic
SIDE EFFECTS / MISC -SE: Hypokalemia, mild hyperlipidemia, hyperuricemia, lassitude, hypercalcemia, hyperglycemia -SE: Potassium wasting, metabolic alkalosis, hypotension, ototoxicity -SE: Dry mouth, sedation, severe rebound HTN -SE: Sedation, positive Coomb's test -SE: Severe orthostatic hypotension, blurred vision, constipation, sexual dysfunction -SE: Sedation, depression, nasal stuffiness, diarrhea -SE: Orthostatic and exercise hypotension, sexual dysfunction, diarrhea -SE: 1st dose orthostatic hypotension, dizziness, headache -SE: Impotence, flushing, Cardiovascular effects (bradycardia, CHF, AV block), CNS effects (sedation, sleep alterations)
-Hypertension
Clonidine
-Hypertension
Methyldopa
-Hypertension
-Sympathoplegic
Hexamethonium
-Hypertension
-Sympathoplegic
Reserpine
-Hypertension
-Sympathoplegic
Guanethidine
-Hypertension
-Sympathoplegic
Prazosin
-Hypertension
-Sympathoplegic
Blockers
-Hypertension
-Sympathoplegic
Hydralazine
-Severe hypertension -CHF -First-line therapy for HTN in pregnancy, with methyldopa
-Vasodilator - cGMP smooth muscle relaxation. -Vasodilates arterioles > veins; afterload
-SE: Nausea, headache, lupus-like syndrome, reflex tachycardia, angina, salt/fluid retention. -C/I: angina/CAD -Use with blockers to prevent reflex tachycardia, diuretic to block salt retention -SE: Hypertrichosis, pericardial effusion, reflex tachycardia, angina, salt retention -Use with blockers to prevent reflex tachycardia, diuretic to block salt retention -SE: Dizziness, nausea, flushing, constipation (verapamil), AV Block (verapamil), cardiac depression, peripheral edema
Minoxidil
-Severe hypertension
-Vasodilator -K+ channel opener - hyperpolarizes and relaxes vascular smooth muscle
-Vasodilator -Block voltage-dependent L-type Ca channels of cardiac and smooth muscle and thereby reduce muscle contractility -Vascular smooth muscle: Nifed > Dilt > Verap -Heart: Verap > Dilt > Nifed -Vasodilator -Short acting; cGMP via direct release of NO -Vasodilator -K+ channel opener - hyperpolarizes and relaxes vascular smooth muscle -ACE Inhibitor
Nitroprusside
-Hypertension -Malignant HTN (see below) -Hypertension -Malignant HTN (see below)
-SE: Cyanide toxicity (releases CN) -SE: HypER*glycemia (reduces insulin release), hypotension *Annotate your FA- this is on the errata list -SE: Hyperkalemia, cough, angioedema, taste changes, hypotension, pregnancy problems (fetal renal damage), rash, renin -SE: Fetal renal toxicity, hyperkalemia -SE: -Tachycardia, hypotension, flushing, headache, -"Monday Disease" in industrial exposure - development of tolerance for the vasodilating action during the work week and loss of tolerance over the weekend, resulting in tachycardia, dizziness, and headache on re-exposure.
Diazoxide
-Hypertension
-Hypertension -Hypertension -Angina -Pulmonary edema -Also used as an aphrodesiac and erection enhancer
Angiotensin II Receptor Inhibitor (ARB) -Vasodilate by releasing nitric oxide in smooth muscle, causing in cGMP and smooth muscle relaxation. -Vasodilates veins >> arteries; preload
-Vasodilator -Short acting; cGMP via direct release of NO -Vasodilator -Dopamine D1 receptor agonist - relaxes renal vasuclar smooth muscle -Vasodilator -K+ channel opener - hyperpolarizes and relaxes vascular smooth muscle
Diazoxide
Malignant HTN
-SE: HypER*glycemia (reduces insulin release), hypotension *Annotate your FA- this is on the errata list
Antianginal therapy
-Goal = reduction of myocardial O2 consumption (MVO2) by decreasing 1 or more of the determinants of MVO2: end diastolic volume, blood pressure, heart rate, contractility, ejection time -Calcium channel blockers: Nifedipine is similar to Nitrates in effect; Verapamil is similar to blockers in effect. -Labetalol, pindolol, and acebutolol are partial agonists- CONTRAINDICATED in angina Nitrates (affect preload) (Reflex response) (Reflex response) Blockers (affect afterload) Nitrates + Blockers No effect or Little/No Effect Little/No Effect
-Inhibits lipolysis in adipose tissue; reduces hepatic VLDL secretion into circulation -Prevent intestinal reabsorption of bile acids; liver must use cholesterol to make more -Prevent cholesterol reabsorption at small intestine brush border -Upregulate LPL TG clearance
-SE: red, flushed face, which is reduced by aspirin or long-term use -SE: pts hate it (tastes bad and causes GI discomfort), absorption of fat-soluble vitamins -SE: rare, LFTs
Bile acid resins Cholestyramine Colestipol Cholesterol absorption blockers Ezetimibe "Fibrates" Gemfibrozil Clofibrate Bezafibrate Fenofibrate Cardiac glycosides Digoxin
slightly
slightly
--
--
-CHF (increase contractility) -Atrial fibrillation (conduction at AV node and depression of SA node)
-Direct inhibition of Na/K ATPase leads to indirect inhibition of Na/Ca exchanger/antiport [Ca] positive inotropy
-Misc: 75% bioavailability 20-40% protein bound t1/2 = 40 hrs urinary excretion -SE: -cardiac: may cause PR, QT, scooping of ST segment, T-wave inversion of ECG, arrhythmia -parasympathetic activity - nausea, vomiting, diarrhea, blurry yellow vision (think Van Gogh) - toxicity if : -Renal failure (excretion) or -Hypokalemic (potentiates drug effects) or -Quinidine (digoxin clearance; displaces drug from tissue binding) -Antidote: Slowly normalize K+, lidocaine, cardiac paper, anti-dig Fab fragments, Mg2+
-Block Na channel -Slow or block () conduction (esp in depolarized cells) - slope of phase 4 depolarization, - threshold for firing in abnormal pacemaker cells -Affect both atrial and ventricular arrhythmias, especially reentrant and ectopic supraventricular and ventricular tachycardia - AP duration - effective refractory period (ERP) - QT interval
-These are local anesthetics -Are state dependent - selectively depress tissue that is frequently depolarized, eg fast tachycardia -Hyperkalemia toxicity for all class I drugs
Class IA Quinidine Amiodarone Procainamide Disopyramide (Queen Amy Proclaims Diso's pyramid) Class IB Lidocaine Mexiletine Tocainide (I'd Buy Lidy's Mexican Tacos) Class IC Flecainide Encainide Propafenone ANTIARRHYTHMICS Beta-blockers (Class II) Propanolol Esmolol Metoprolol Atenolol Timolol
-SE: -quinidine -cinchonism (headache, tinnitus, thrombocytopenia) -torsades de pointes due to QT interval; -procainamide -reversible SLE-like syndrome
-Affect ischemic or depolarized Purkinje and ventricular tissue -Useful in acute ventricular arrhythmias (esp. post-MI) and in digitalis-induced arrhythmias
- AP duration
-SE: Local anesthetic, CNS stimulation/depression, cardiovascular depression -phenytoin can also fall into the IB category
-Useful in V-tachs that progess to VF and in intractible SVT -Usually used only as last resort in refractory tachyarrhythmias
-SE: proarrhythmic, especially post MI (contraindicated), significantly prolongs refractory period in AV node
-V-tach -SVT -Slowing ventricular rate during atrial fibrillation and atrial flutter
-cAMP, Ca currents -Suppress abnormal pacemakers by slope of phase 4 -AV node particularly sensitive: PR interval
-Esomolol is very short acting -SE: Impotence, exacerbation of asthma, cardiovascular effects (bradycardia, AV block, CHF), CNS effects (sedation, sleep alterations); May mask signs of hypoglycemia; Metoprolol can cause dyslipidemia
-Used when other antiarrhythmics - AP duration, fail - effective refractory period - QT interval -SE: torsades des pointes, excesssive block -SE: torsades des pointes -SE: new arrhythmias, hypotension -Safe to use in Wolff-Parkinson-White Syndrome -SE: -pulmonary fibrosis, corneal deposits, hepatotoxicity, skin deposits resulting in photodermatitis, neurologic effects, constipation, cardiovascular effects (bradycardia, heart block, CHF), hypothyroidism/hyperthyroidism (Remember to check PFTs, LFTs, and TFTs when using amiodarone)
ANTIARRHYTHMICS Ca2+ channel blocker (Class IV) Verapamil Diltiazem -Primarily affect AV nodal cells -Used in prevention of nodal arrhythmias (eg SVT) - conduction velocity - effective refractory period - PR interval -SE: constipation, flushing, edema, CV effects (CHF, AV block, sinus node depression), torsades de pointes (bepridil)
K+
-Drug of choice in diagnosis/abolishment of AV nodal arrhythmias -Depresses ectopic pacemakers in hypokalemia (e.g. digoxin toxicity) -Effective in torsades de pointes and digoxin toxicity
-Very short acting (~15 sec) -SE: Flushing, hypotension, chest pain
Mg+
CLASS/NAME Diabetic drugs Insulins Lispro (short-acting) Aspart (short-acting) NPH (intermediate) Lente (long-acting) Ultralente (long-acting) Sulfonylureas First generation Tolbutamide Chlorpropamide Second generation Glyburide Glimepiride Glipizide Biguanides Metformin
ENDOCRINE (pp 287-288) MECHANISM -Bind insulin receptor (tyrosine kinase activity) -Liver: glucose stored as glycogen -Muscle: glycogen & protein synthesis, K+ uptake -Fat: aids TG storage
-Stimulate release of endogenous -Close K+ channel in -cell membrane, so insulin in type 2 DM. cell depolarizes triggering of insulin -Require some islet function, so release via Ca2+ intake useless in type 1 DM.
-Exact mechanism is unknown -Possibly: gluconeogenesis glycolysis serum glucose levels. - target cell response to insulin
-Used as monotherapy in type 2 DM or combined with above agents. -Used as monotherapy in type 2 DM or combined with above agents.
-Inhibit intestinal brush-border -glucosidases -Delayed sugar hydrolysis & glucose absorption lead to postprandial hyperglycemia.
-SE: GI disturbances
Misc endocrine drugs Orlistat Sibutramine Propylthiouracil, Methimazole -Long-term obesity management (in conjunction with modified diet) -Short-term & long-term obesity management -Hyperthyroidism -Alters fat metabolism by inhibiting pancreatic lipases. -Sympathomimetic serotonin & norepinephrine reupake inhibitor. -Inhibit organification and coupling of thyroid hormone synthesis. -Propylthiouracil also peripheral conversion of T4 to T3 -Thyroxine replacement. -SE: Steatorrhea, GI discomfort, reduced absorption of fat-soluble vitamins, headache. -SE: Hypertension, tachycardia. -SE: Skin rash, agranulocytosis (rare), aplastic anemia.
-Hypothyroidism, myxedema.
-GH deficiency -Turner's syndrome -Acromegaly -Carcinoid -Gastrinoma -Glucagonoma -Stimulates labor, uterine contractions, milk let-down -Controls uterine hemorrhage -Pituitary DI (central, not nephrogenic)
Oxytocin
- the production of leukotrienes and prostaglandins by inhibiting phospholipase A2 and expression of COX-2
-SE: Iatrogenic Cushing's syndrome - buffalo hump, moon facies, truncal obesity, muscle wasting, thin skin, easy bruisability, osteoporosis, adrenocortical atrophy, peptic ulcers, diabetes (if chronic).
CLASS/NAME H2 blockers Cimetidine Ranitidine Famotidine Nizatidine (take H2 blockers before you DINE) Proton pump inhibitors Omeprazole, Lansoprazole
GASTROINTESTINAL (pp 317-318) MECHANISM -Reversible block of histamine H2 receptors causing secretion of H+ from parietal cells
SIDE EFFECTS / MISC -SE of cimetidine: -Cimetidine is a potent inhibitor of P-450 -it also has antiandrogenic effects (prolactin release, gynecomastia, impotence) -can cross BBB (confusion, dizziness, headaches) and placenta -SE of cimetidine & ranitidine: - renal excretion of creatinine -Other H2 blockers are relatively free of these effects
-Bind to ulcer base, providing physical protection, and allow HCO3- secretion to reestablish pH gradient in the mucous layer -a PGE1 analog - production and secretion of gastric mucous barrier - acid production -Block M1 receptors on ECL cells ( histamine secretion) -Block M3 receptors on parietal cells ( H+ secretion)
Misoprotol
-Prevention of NSAID-induced peptic ulcers -Maintenance of a patent ductus arteriosus. -Induction of labor
-Triple therapy for H. Pylori ulcers : Metronidazole, Amoxicillin (or Tetracycline), Bismuth. -Can also use a PPI (Please MAke Tummy Better) -SE: Diarrhea -C/I: contraindicated in women of childbearing potential (abortifacient)
Antacid use
-SE of all: -Can affect absorption, bioavailability, or urinary excretion of other drugs by altering gastric and urinary pH or by delaying gastric emptying -All cause hypokalemia -SE: Constipation and hypophosphatemia; proximal muscle weakness, osteodystrophy, seizures (Aluminimum amount of feces) -SE: Diarrhea, hyporeflexia, hypotension, cardiac arrest (Mg = Must go to the bathroom) -SE: Hypercalcemia, rebound acid ; can chelate and effectiveness of other drugs (e.g. tetracycline)
Infliximab
-Crohn's disease -Rheumatoid arthritis -Ulcerative colitis -Crohn's disease -Control vomiting postoperatively and in patients undergoing cancer chemotherapy
-A monoclonal antibody to TNF, which is a proinflammatory cytokine (INFLIXimab INFLIX pain on TNF) -A combination fo sulfapyridine (antibacterial) and mesalamine (anti-inflammatory) -Activated by colonic bacteria -5-HT3 antagonist -(Powerful central-acting antiemetic)
Sulfasalazine
-SE: Malaise, nausea, sulfonamide toxicity, reversible oligospermia -SE: Headache, constipation
(You will not vomit with ONDANSetron, so you can go ON DANCing)
Ondansetron
Metoclopramide
-Acts through 5HT receptors to ACh release at the myenteric plexus. - esophageal tone - gastric and duodenal contractility, improving transit time (including through the colon) -D2 receptor antagonist - resting tone, contractility, LES tone, motility -Does not influence colon transport time
-No longer used -SE: Serious interactions (torsades des pointes) with Erythromycin, Ketoconazole, Nefazodone, Fluconazole
-SE: - Parksonian Effects. -Restlessness, drowsiness, fatigue, depression, nausea, diarrhea. -Drug interaction with digoxin and diabetic agents -C/I: pts with small bowel obstruction
CLASS/NAME Heparin
CLINICAL USE -Immediate anticoagulation for pulmonary embolism, stroke, angina, MI, DVT -Used during pregnancy (does not cross placenta)
HEMATOLOGY AND ONCOLOGY (pp 336-340) MECHANISM SIDE EFFECTS / MISC -Catalyzes activation of antithrombin III, thrombin and Xa -Short half-life -Follow patient's PTT when on heparin -Newer low-molecular-weight heparins (enoxaparin) act more on Xa, have better bioavailability and 2-4 times longer half-life. Can be administered subcutaneously and without laboratory monitoring. Not easily reversible. -SE: -bleeding -osteoporosis -drug-drug interactions, -heparin-induced thrombocytopenia (HIT): heparin binds platelets, causing autoantibody production that destroys platelets and overactivates the remaining ones, resulting in a thrombocytopenic, hypercoagulable state. -for rapid reversal of heparinization, use protamine sulfate (positively charged molecule that acts by binding negatively charged heparin) -Hirudin derivatives
-Used as an alternative to heparin for anticoagulating patients with HIT -Chronic anticoagulant -Not used in pregnant women (because warfarin, unlike heparin, can cross the placenta)
-Interferes with normal synthesis and -carboxylation of vitamin K-dependant clotting factors (II, VII, IX, X, protein C & S) -Affects Extrinsic pathway and PT -Long half-life (The EX-PaTriot went to WAR(farin))
-Follow patient's PT/INR values when on warfarin -Metabolized by cytochrome P450 -SE: bleeding, teratogenic, skin/tissue necrosis, drug-drug interactions
Heparin vs. warfarin Structure Route of administration Site of action Onset of action Mechanism of action Duration of action
Inhibits coagulation in vitro
Heparin Large anionic polymer, acidic Parenteral (IV, SC) Blood Rapid (seconds) Activates antithrombin III, which the action of IIa (thrombin) and Xa Acute (hours Yes Protamine sulfate PTT (intrinsic pathway) No -Early MI -Early ischemic stroke -Directly or indirectly aids conversion of plasminogen to plasmin, which is the major fibrinolytic enzyme that cleaves thrombin and fibrin clots. -PT, PTT, no change in platelet count
Warfarin Small lipid-soluble molecule Oral Liver Slow, limited by half-lives of normal clotting factors Impairs the synthesis of vitamin K-dependent clotting factors II, VII, IX, and X (vitamin K antagonist) Chronic (days) No IV vitamin K and fresh frozen plasma PT/INR (extrinsic pathway) Yes (teratogenic) -SE: bleeding -C/I: Patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension -Treatment of toxicity is with aminocaproic acid, an inhibitor of fibrinolysis
Treatment of acute OD Monitoring Crosses placenta Thrombolytics Streptokinase, Urokinase, tPA (alteplase), APSAC (anistreplase)
Clopidogrel, Ticlopidine
Abciximab
-Antipyretic -Analgesic -Anti-inflammatory -Antiplatelet drug -Acute coronary syndrome -Coronary stenting - incidence or recurrence of thrombotic stroke -Acute coronary syndromes -Percutaneous transluminal coronary angioplasty
-Acetylates and irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) to prevent conversion of arachidonic acid to thromboxane A2. -Inhibit platelet aggregation by irreversibly blocking ADP receptors. -Inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa expression. -Monoclonal antibody that binds to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation.
- bleeding time. -No effect on PT, PTT. -SE: Gastric ulceration, bleeding, hyperventilation, Reye's syndrome, tinnitus (CN VIII) -SE: Neutropenia (ticlopidine)
5-Fluorouracil (5-FU)
-Leukemias -Lymphomas -Choriocarcinoma -Sarcoma -Abortion -Ectopic pregnancy -Rheumatoid arthritis -Psoriasis -Colon cancer and other solid tumors -Basal cell carcinoma (topical) -Synergy with MTX -Leukemias -Lymphomas (not CLL or Hodgkin's) -AML -Non-Hodgkin's lymphoma -Breast and ovarian carcinoma -Immunosuppressant -Brain tumors (including glioblastoma multiforme)
-S-phase-specific antimetabolite. -Folic acid analog that inhibits dihydrofolate reductase, resulting in dTMP and therefore DNA and protein synthesis.
-SE: -Myelosuppression, which is reversible with leucovorin (folinic acid) "rescue." -Macrovesicular fatty change in liver -Mucositis
-S-phase-specific anti-metabolite -Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex inhibits thmidylate synthetase, resulting in dTMP and same effects as MTX -Blocks de novo purine synthesis -Activated by HGPRATase -Inhibit DNA polymerase -Alkylating agent '-Covalently cross-link (interstrand) DNA at guanine N-7 -Alkylate DNA
-SE: -Myelosuppression (NOT reversible with leucovorin). Can "rescue" with thymidine -Photosensitivity -Metabolized by xanthine oxidase; thus toxicity with allopurinol -SE: Bone marrow, GI, liver -SE: Leukopenia, thrombocytopenia, megaloblastic anemia -Requires bioactivation in liver -SE: Myelosuppression; hemorrhagic cystitis. Hemorrhagic cystitis can be partially prevented with mesna -Requires bioactivation -Crosses blood-brain barrier CNS -SE: CNS toxicity (dizziness, ataxia)
Nitrosoureas Carmustine Lomustine Semustine Streptozocin Cisplatin, Carboplatin Busulfan Doxorubicin (adriamycin), Daunorubicine Dactinomycin (actinomycin D)
-Testicular, bladder, ovary, and lung carcinomas -CML -Part of ABVD combo for Hodgkin's and for myelomas, sarcomas, solid tumors (breast, ovary, lung) -Wilm's tumor -Ewing's sarcoma -Rhabdomyosarcoma (ACTinomycin D is used for childhood tumors (children ACT out)
-Act like alkylating agent -Alkylates DNA -Generate free radicals and noncovalently intercalate in DNA (creating breaks in DNA strand to replication) -Intercalates in DNA
-SE: Nephrotoxicity, acoustic nerve damage -SE: Pulmonary fibrosis, hyperpigmentation -SE: Cardiotoxic, myelosuppression, marked alopecia, toxic extravasation
-SE: Myelosuppression
Bleomycin
Hydroxyurea
Etoposide (VP-16)
Prednisone
Tamoxifen, Raloxifene
-Testicular cancer -Lymphoma (part of ABVD regimen for Hodgkin's) -Melanoma -CML -Sickle cell disease -Small cell carcinoma of lung and prostate -Testicular carcinoma -Most commonly used glucocorticoid in cancer therapy -CLL -Hodgkin's lymphoma (part of the MOPP regimin) -Immunosuppressant used in autoimmune disease -Breast cancer -Osteoporosis prevention
-Induces free radical formation, which causes breaks in DNA strands -Inhibits Ribonucleotide Reductase DNA Synthesis (S-phase specific) -G2-phase-specific agent -Inhibits topoisomerase II and DNA degradation -May trigger apoptosis -May even work on dividing cells
-SE: Pulmonary fibrosis, skin changes, but minimal myelosuppression -SE: Bone marrow suppression, GI upset
-SE: Cushing-like symptoms, immunosuppression, cataracts, acne, osteoporosis, hypertension, peptic ulcers, hyperglycemia, psychosis
-Estrogen receptor antagonist in breast -Agonist in bone -Block the binding of estrogen to estrogen receptor-positive cells
Trastuzumab (Herceptin)
-Monoclonal antibody against HER-2 (erb-2) -Helps kill breast cancer cells expressing HER-2 possibly through antibody-dependent cytotoxicity -Philadelphia chromosome (bcr-abl) tyrosine kinase inhibitor -M-phase specific alkaloids -Bind to tubulin and block polymerization of microtubules so mitotic spindle cannot form (Microtubules are the vines of your cells) -M-phase specific agents -Bind to tubulin and hyperstabilize polymerized microtubules so mitotic spindle cannot break down (anaphase cannot occur)
-SE: -Tamoxifen may risk of endometrial carcinoma via partial agonist effects; -Roloxifen does not cause endometrial carcinoma because it is an endometrial antagonist -"Hot flashes" -SE: Cardiotoxic
-CML -GI stromal tumors -Part of MOPP (Oncovin = vincristine) regimen for lymphoma -Wilm's tumor -Choriocarcinoma -Ovarian and breast carcinoma
-SE: Fluid retention -SE: -Vincristine : -Neurotoxicity (areflexia, peripheral neuritis), -Paralytic ileus -VinBLASTine : BLASTs Bone marrow (suppression) -SE: Myelosuppression and hypersensitivity
CLINICAL USE -Antipyretic -Analgesic -Anti-inflammatory -Indomethacin: closure of PDA -Rheumatoid and osteoarthritis
MUSCULOSKELETAL (pp 358-359) MECHANISM -Reversibly inhibit cyclooxygenase (both COX-1 & COX-2) -Block prostaglandin synthesis
SIDE EFFECTS / MISC -SE: Renal damage, aplastic anemia, GI distress, ulcers
-Reversibly inhibit specifically the cyclooxygenase (COX) isoform 2, which is found in inflammatory cells and mediates inflammation and pain -Spares COX-1, which helps maintain the gastric mucosa. Thus, should not have the corrosive effects of other NSAIDs on the GI lining. -Depolymerizes microtubules, impairing leukocyte chemotaxis & degranulation -Inhibits reabsorption of uric acid in PCT (also inhibits secretion of penicillin) -Inhibits xanthine oxidase, conversion of xanthine to uric acid.
-SE: - risk of thrombosis -Sulfa allergy. -Less toxicity to GI mucosa (lower incidence of ulcers, bleeding).
-Acute gout
Probenecid Allopurinol
-Chronic gout -Chronic gout -Also used in lymphoma & leukemia to prevent tumor lysis-associated urate nephropathy -Antipyretic -Analgesic -Lacks anti-inflammatory properties -Rheumatoid arthritis -Psoriasis -Ankylosing spondylitis. -Crohn's disease -Rheumatoid arthritis -Ankylosing spondylitis
-Do not give salicylates -SE: GI side effects, especially if given orally. (Indomethacin is less toxic, more commonly used in acute gout). -C/I: should not be used to treat an acute episode of gout -Interacts with azathioprine & 6-MP -C/I: should not be used to treat an acute episode of gout
-Reversibly inhibits cyclooxygenase, mostly in CNS. -Inactivated peripherally. -Recombinant form of human TNF receptor that binds TNF (EtanerCEPT is a TNF decoy reCEPTor) -Anti-TNF antibody (INFLIXimab INFLIX pain on TNF)
-SE: Overdose produces hepatic necrosis; acetaminophen metabolite depletes glutathione and forms toxic tissue adducts in liver. N-acetylcysteine is antidote - regenerates glutathione.
Etanercept
Infliximab
CLASS/NAME Opioid Analgesics Morphine Fentanyl Codeine Heroin Methadone Meperidine Dextromethorphan
CLINICAL USE -Pain -Cough suppression (dextromethorphan) -Diarrhea (loperamide and diphenoxylate) -Acute pulmonary edema, -Maintenance programs for addicts (methadone)
NEUROLOGY (pp 394-399) MECHANISM -Acts as agonist at opioid receptors (mu=morphine, delta= enkephalin, kappa=dynorphin) to modulate synaptic transmission
SIDE EFFECTS / MISC -SE: -Addiction, respiratory depression, constipation, miosis (pinpoint pupils), additive CNS depression with other drugs -Tolerance does not develop to miosis and constipation. -Toxicity treated with naloxone (opioid receptor antagonist).
Note: There is a table on p. 395 of First Aid 2008 detailing the specific usage of epilepsy drugs Benzodiazepines Diazepam Lorazepam Triazolam Temazepan Oxazepam Midazolam Chlordiazepoxide Alprazolam Carbamazepine -Anxiety -Spasticity -Status epilepticus (lorazepam and diazepam) -Detoxification (esp. alocohol withdraw- DTs) -Night tremors -Sleepwalking -Facilitate GABAA action by frequency of Cl- channel opening (FREnzodiazepines= FREquency) -Most have long half-lives and active metabolites -Short acting= TOM Thumb (Triazolam, Oxazepam, Midazolam) -SE: -Sedation, tolerance, dependence, addictive CNS depression effects with alcohol -Less risk of respiratory depression and coma than with barbiturates -Treat overdose with flumazenil (competitive antagonist at GABA receptor) -SE: Diplopia, ataxia, blood dyscrasis (agranulocytocic, aplastic anemia), liver toxicity, teratogenesis, induction of cytochrome P-450 -SE: -GI distress, fatigue, headache, urticaria -Stevens-Johnson syndrome -Prodrome of malaise and fever followed by rapid onset of erythematous/purpuric macules (oral, ocular, genital). Skin lesions progress to epidermal necrosis and sloughing. (EFGH- Ethosuximide, Fatigue, GI, Headache) -Facilitate GABAA action by duration of Cl- channel opening, thus neuron firing (BarbiDURATe ( DURATion)) -SE: -Sedation, tolerance, dependence -Induction of cytochrome P-450; -Addictive CNS effects with alcohol, -Respiratory or cardiovascular depression (can lead to death) -Treat overdose with symptom management (assist respiration, BP) -C/I: Porphyria
-Epilepsy
Ethosuximide
-Epilepsy
Phenytoin
-Use-dependent blockade of Na+ channels -Inhibition of glutamate release from excitatory presynaptic neuron
-SE: -Nystagmus, diplopia, ataxia, sedation, gingival hyperplasia, hirsutism, megablastic anemia, teratogenesis, SLE-like syndrome, induction of cytochrome P-450 -Chronic use produced gingival hyperplasia in children, peripheral neuropathy, hirsutism, megaloblastic anemia ( folate absorption), and malignant hyperthermia (rare) -Teratogenic (fetal hydantoin syndrome). -SE: -GI distress, tremor, weight gain -Rare but fatal hepatotoxicity (measure LFTs) -Neural tube defects in fetus (spina bifida) -C/I: Pregnancy -SE: Stevens-Johnson syndrome -SE: Sedation, ataxia. -SE: Sedation, mental dulling, kidney stones, weight loss
Valproic acid
-Epilepsy
-CNS drugs must be lipid soluble (cross blood-brain barrier) or actively transported -Drugs with solubility in blood = rapid induction and recovery times -Drugs with solubility in lipids = potency = 1/MAC (minimal alveolar concentration) -Examples: -N2O has low blood and lipid soluble, and thus fast induction and low potency -Halothane, in contrast, has lipid and blood solubility and thus slow induction and high potency -Anesthesia: myocardial depression, respiratory depression, nausea/emesis, cerebral blood flow cerebral metabolic demand -Unknown -SE: -malignant hyperthermia (rare) -halothane: hepatotoxicity -methoxyflurane: nephrotoxicity -enflurane: proconvulsant
Inhaled anesthetics Halothane Enflurane Isoflurane Sevoflurane Methoxyflurane Nitrous oxide IV anesthetics Barbituates (Thiopental) Benzodiazepines (Midazolam)
B. B. King on Opiates Proposes Foolishly -Induction of anesthesia -Short surgical procedures. -Endoscopy -used in adjunct with gaseous anesthetics and narcotics -Act as dissociative anesthetics -PCP analogs - cerebral blood flow -High potency, high lipid solubility, rapid entry into brain. -Effect terminated by redistribution from the brain. -SE: -May cause severe postoperative respiratory depression, BP, and amnesia -Treat overdose with flumazenil - cerebral blood flow -SE: -Cardiovascular stimulants -Cause disorientation, hallucination, and bad dreams
Arylcyclohexylamines (Ketamine)
-Used with other CNS depressants during general anesthesia -Rapid anesthesia induction -Short procedures
Local anesthetics Esters Procaine Cocaine Tetracaine Amides Lidocaine Mepivacaine Bupivacaine (AmIdes have 2 letter I's in the name)
-Block Na channels by binding to specific receptors on inner portion of channel. -Preferentially bind to active Na channels, so most effective in rapidly firing neurons. -3 amine local anesthetics penetrate the membrane in uncharged form, then bind to ion channels as charged form.
-Principles: -In infected (acidic) tissue, alkaline anesthetics are charged and cannot penetrate membrane effectively. Therefore, more anesthetic is needed in these cases. -Order of nerve block: - small-diameter fibers > large diameter - myelinated fibers > unmyelinated fibers - Overall, size factor predominates over myelination such that small myelinated > small unmyelinated > > large myelinated > large unmyelinated -Order of loss: - pain (first) > temperature > touch > pressure (last) -Except with cocaine, given with vasoconstrictors (epinepherine) to enhance local action bleeding, anesthesia by systemic concentration -SE: -CNS excitation, severe cardiovascular toxicity (bupivacaine), hypertension, hypotension, and arrhythmias (cocaine)
Selective for motor (vs. autonomic) nicotinic receptor -Phase 1 - prolonged depolarization -No antidote -Block potentiated by cholinesterase inhibitors -Phase 2 - repolarized but blocked -Antidote is cholinesterase inhibitors (e.g. neostigmine) -Competitive -complete with Ach for receptors -Reversal of blockade via: -Neostigmine, edrophonium, and other cholinesterase inhibitors -SE: Hypercalemia and hyperkalemia
Nondepolarizing Tubocurarine Atracurium Mivacurium Pancuronium Vecuronium Rocuronium Dantrolene -Malignant hyperthermia
-Prevents the release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle
-Malignant hyperthermia is caused by concomitant use of inhalation anesthetic (except nitrous oxide (N2O)) and succinylcholine. -Neuroleptic malignant syndrome is a toxicity of antipsychotic drugs
Parkinson's disease drugs Bromocriptine Amantadine Levodopa (with carbidopa) Selegiline (and COMT inhibitors) Antimuscarinics (BALSA) Bromocriptine Pramipexole Ropinirole Amantadine L-dopa (levodopa) with carbidopa
-Strategies to treat Parkinson's are to -Agonize dopamine receptors - dopamine -Prevent dopamine breakdown -Curb excess cholinergic activity
-Parkinsonism is due to loss of dopaminergic neurons and excess cholinergic activity -For essential or familial tremors, use -blockers
-Parkinsons
-Agonize dopamine receptors -Bromocriptine is an ergot alkaloid and partial dopamine agonist -SE: ataxia -Carbidopa is given with L-dopa in order to the bioavailability of L-dopa and limit peripheral side effects -SE: -Arrhythmias from peripheral conversion to dopamine -Long-term use dyskinesia following administration and akinesia between doses -SE: May enhance adverse effects of L-dopa
-Parkinsons - dopamine release -Antiviral (influenza A and rubella) -Parkinsonism -Carbidopa increases bioavailability of L-dopa and limits peripheral side effects - level of dopamine in the brain -L-dopa, unlike dopamine, can cross the blood brain barrier and is converted into dopamine in the CNS by dopa decarboxylase -Carbidopa is a peripheral decarboxylase inhibitor -Prevent dopamine breakdown -Selectively inhibits MAO-B, thereby the availability of dopamine. -Prevent dopamine breakdown -COMT inhibitors -Antimuscarinic - curb excess cholinergic activity -5-HT1D agonist -Causes vasoconstriction
Selegiline
-Parkinsons (is an adjunctive agent to L-dopa for Parkinson's) -Parkinsons -Improves tremor and rigidity -Little effect on bradykinesia -Acute migraine -Cluster headache attacks
" your tremor before you drive your Mercedes-BENZ" -Half-life < 2 hrs -SE: Coronary vasospasm, mild tingling, hypertensive emergencies. -C/I: patients with CAD or Prinzmetal's angina
CLINICAL USE Drug used BZD SSRIs Barbiturates BZD Buspirone MAOI Methylphenidate (Ritalin) Amphetamine MAOI Mood stabilizers: Lithium Valproic acid Carbamazepine
Depression
SSRI TCA Depression w/ insomnia Trazodone Mirtazapine OCD SSRIs Panic D/O Schizophrenia Tourette's Syndrome TCAs Buspirone Antipsychotics Antipsychotics (haloperidol)
-Schizophrenia -Psychosis -Acute mania (Haloperidol + '-azine's) -Tourette's syndrome Antipsychotics (neuroleptics) High potency Haloperidol, Trifluoperazine
-Excess dopamine effects connected with schizophrenia -DA = dopamine; DA-R = dopamine receptor
-SE: (Neurologic side effects) -Extrapyramidal system (EPS) effects: -dystonia (muscle spasm, stiffness) -akinesia (parkinsonian sx) -akathisia (restlessness) -tardive dyskinesia (stereotypic oral-facial movements due to DA-R sensitization; due to long-term antipsychotic use) -Evolution of EPS SEs: -4 h acute dystonia -4 d akinesia -4 wk akathisia -4 mo tardive dyskinesia (often irreversible) -Neuroleptic malignant syndrome: -rigidity -myoglobinuria -autonomic instability -hyperpyrexia -(treat w/ dantrolene and DA agonists) -SE: (Non-neurologic side effects) -endocrine: - DA-R antagonism hyperPRL galactorrhea -muscarinic block: dry mouth, constipation --block: hypotension -histamine-R block: sedation
Unspecified Fluphenazine
(It's not atypical for old closets to risper) Olanzapine -Schizophrenia -OCD -Anxiety -Depression -Mania -Tourette's syndrome Clozapine Lithium -Schizophrenia -Mood stabilizer for bipolar affective disorder -Blocks relapse and acute manic events -Unknown -Possibly related to inhibition of phosphoinositol cascade -SE: agranulocytosis (requires weekly WBC monitoring) -narrow therapeutic window, so requires close monitoring of serum lvls -SE: -tremor -polyuria (ADH antagonist => nephrogenic diabetes insipidus) -hypothyroidism -teratogenesis (LMNOP: Lithium side effects - Movement (tremor), Nephrogenic DI, HypOthyroidism, Pregnancy problems) -Does not cause addiction or sedation -No interaction w/ EtOH
Buspirone
ANTIDEPRESSANTS SSRIs Fluoxetine Sertraline Paroxetine Citalopram -Endogenous depression -OCD -Anorexia/bulimia -Serotonin-specific reuptake inhibitors
-It normally takes 2-3 weeks for anti-dep to have an effect -SE: (Fewer than TCAs) -GI distress -sexual dysfunction (anorgasmia) -"serotonin syndrome" w/ MAOI: hyperthermia, muscle rigidity, cardiovascular collapse -SE: -sedation (desipramine is the least sedating) --blocking effects -atropine-like (anticholinergic) side effects (tachycardia, urinary retention) -3 (amitriptyline) have more anticholinergic effects than 2 (nortriptyline) -at toxic levels, Tri-C's: Convulsions, Coma, Cardiotoxicity (arrhythmias); respiratory depression, hyperpyrexia. In elderly, confusion and hallucinations due to anticholinergic side effects (use nortriptyline)
-Major depression Tricyclic antidepressants (TCA) Imipramine Amitriptyline Desipramine Nortriptyline Clomipramine Doxepin Amoxapine
-Major depression -Bedwetting -Major depression -OCD -Atypical depression (i.e. w/ mood reactivity, sensitivity to rejection, hypersomnia) -Anxiety -Hypochondriasis
-SE: -hypertensive crisis w/ tyramine ingestion (in many foods, e.g. cheese) and -agonists -CNS stimulation -C/I: SSRIs or meperidine (prevent serotonin syndrome)
OTHER ANTIDEPRESSANTS You need Butane in your VEINs to MURder for a MAP of AlcaTRAZ. Bupropion (Wellbutrin) -Depression -Smoking cessation -Not well known - SE: -stimulant effects (tachycardia, insomnia) -headache -seizure in bulimic patients -does not cause sexual SE -SE: -stimulant effects -increased BP -sedation -nausea, constipation -SE: -sedation - appetite -weight gain -dry mouth -SE: -sedation -orthostatic hypotension -SE: -sedation -postural hypotension -nausea -priapism
Venlafaxine
Mirtazapine
-Depression
-2 antagonist ( release of NE and serotonin) -Potent 5-HT2 and 5-HT3 receptor antagonist
Maprotiline
-Depression
-Blocks NE reuptake
Trazodone
-Depression
Methylphenidate (Ritalin)
-ADHD
- presynaptic NE vesicular release (like amphetamines) -Mechanism for relief of ADHD symptoms is unknown
CLASS/NAME Mannitol
CLINICAL USE
SIDE EFFECTS / MISC -SE: pulmonary edema, dehydration -C/I: anuria, CHF (ACIDazolamide causes ACIDosis) -SE: Hyperchloremic metabolic acidosis, neuropathy, NH3 toxicity, sulfa allergy - Ca2+ excretion (Loops Lose calcium) -SE: (OH DANG!) Ototoxicity, Hypokalemia, Dehydration, Allergy (sulfa) Nephritis (interstitial), Gout
-Shock -Osmotic diuretic. -Drug overdose - tubular fluid osmolarity, -intracranial/intraocular pressure producing urine flow -Glaucoma -Urinary alkalinization -Metabolic alkalosis -Altitude sickness -Edematous states (CHF, cirrhosis, nephrotic syndrome, pulmonary edema) -Hypertension -Hypercalcemia -Diuresis in patients allergic to sulfa drugs -Carbonic anhydrase inhibitor. -Causes self-limited NaHCO3 diuresis and reduction in total-body HCO3 stores -Loop diuretic (Sulfonamide) -Inhibits cotransport system (NKCC) of thick ascending limb of loop of Henle. -Abolishes hypertonicity of medulla, preventing concentration of urine -Loop diuretic (NOT a sulfonamide) -Essentially same action as furosemide
Acetazolamide
Furosemide
Ethacrynic acid
-Phenoxyacetic acid derivative -SE: similar to furosemide, can be used in hyperuricemia, acute gout (never used to treat gout)
Hydrochlorothiazide (HCTZ)
-Thiazide diuretic -Inhibits NaCl reabsorption in the early distal tubule, reducing diluting capacity of nephron
-Ca2+ excretion -SE: (hyperGLUC) Sulfa allergy. Hypokalemic metabolic alkalosis, hyponatremia, hyperGlycemia, hyperLipidemia, hyperUricemia, hyperCalcemia. (the K+ STAys)
K+-sparing diuretics Spironolactone Eplerenone Triamterene Amiloride -Hyperaldosteronism -K+ depletion -CHF -Hyperaldosteronism -K+ depletion -CHF -Competitive aldosterone receptor antagonist in the cortical collecting tubule (CCT) -Block Na+ channels in the CCT
-Inhibit angiotensin-converting enzyme, reducing levels of angiotensin-II and preventing inactivation of bradykinin, which is a potent vasodilator
Losartan
-Renin release is due to loss of feedback inhibition -SE: (CAPTOPRIL) Cough, Angioedema, Proteinuria, Taste changes, hypOtension, Pregnancy problems (fetal renal damage), Rash, Increased renin, Lower angiotensin II. Hyperkalemia. -C/I: bilateral renal artery stenosis -It is not an ACE inhibitor and does not cause cough
CLINICAL USE
- Testosterone -----------------------> DHT (more potent) -Useful in BPH -Promotes hair growth - used to treat male pattern baldness -Prostate carcinoma -Used in the treatment of polycystic ovarian syndrome to prevent hirsutism -Used in the treatment of polycystic ovarian syndrome to prevent hirsutism -Infertility (pulsatile) -Prostate cancer (continuous use with flutamide) -Uterine fibroids -5-alpha reductase inhibitor ( conversion of testosterone to dihydrotestosterone) -Nonsteroidal competitive inhibitor of androgens at the testosterone receptor -Inhibits steroid synthesis -To prevent male-pattern hair loss, give a drug that will encourage female breast growth)
Flutamide Ketoconazole
Spironolactone
Leuprolide
-GnRH analog with -agonist properties when used in pulsatile fashion -antagonist properties when used in continuous fashion. (Leuprolide can be used in lieu of GnRH) -Inhibits cGMP phosphodiestersase, causing cGMP, smooth muscle relaxation in the corpus cavernosum, blood flow, and penile erection -Competitive inhibitor of progestins at progesterone receptors
Sildenafil, Vardenafil
-SE: headache, flushing, dyspepsia, impaired blue-green color vision. -C/I: Risk of life threatening hypotension in patients taking nitrates -SE: -heavy bleeding -GI effects (nausea, vomiting, anorexia) -abdominal pain
Mifepristone (RU-486)
Advantages -Reliable (<1% failure) -Risk of endometrial and ovarian cancer -Incidence of ectopic pregnancy -Pelvic infections -Regulation of menses -Used for relief or prevention of menopausal symptoms (eg. hot flashes, vaginal atrophy) -Osteoporosis (due to diminished estrogen levels) -Cervical dilation and uterine contraction to induce labor -Relax the uterus -Breast cancer in postmenopausal women -Treat hypogonadism and promote development of secondary sex characteristics -Stimulation of anabolism to promote recovery after burn or injury -Treat ER-positive breast cancer (exemestane) -Hypogonadism or ovarian failure -Menstrual abnormalities -HRT in postmenopausal women -Use in men with androgendependent prostate cancer
Disadvantages -Taken daily -No protection against STDs -Triglycerides -Depression, weight gain, nausea, hypertension -Hypercoagulable state -SE: -unopposed estrogen replacement therapy (ERT) the risk of endometrial cancer, so progesterone is added -possible CV risk
Dinoprostone
-PGE2 analog
-2 agonist -Aromatase inhibitor -Agonist at androgen receptors -SE: -masculinization in females -reduces intratesticular testosterone in males by inhibiting Leydig cells; leads to gonadal atrophy -premature closure of epiphyseal plates - LDL, HDL.
-SE: - risk of endometrial cancer -bleeding in postmenopausal women -clear cell adenocarcinoma of vagina in females exposed to DES in utero - risk of thrombi. '-C/I: ER-positive breast cancer
Progestins
-Partial agonist at estrogen receptors in pituitary gland -Prevents normal feedback inhibition, and release of LH and FSH from pituitary, which stimulates ovulation -Antagonist on breast tissue -Agonist on bone; reabsorption of bone
-SE: -hot flashes -ovarian enlargement, -multiple simultaneous pregnancies -visual disturbances
Tamoxifen Raloxifene
CLASS/NAME H1 Blockers 1st generation Diphenhydramine, Dimenhydrinate, Chlorpheniramine 2nd generation Loratadine, Fexofenadine, Desloratadine, Cetirizine
CLINICAL USE -Allergy -Motion sickness -Sleep aid -Allergy relief, non-sedating
-SE: Far less sedating than 1st generation because of entry into CNS
Asthma drugs Isoproterenol Albuterol Salmeterol Theophylline -Use during acute exacerbation of asthma -non-specific -agonist -Relaxes bronchial smooth muscle (2) -2 agonist -Relaxes bronchial smooth muscle (2). -2 agonist -Long acting agent for prophylaxis -Methylxanthine -Likely causes bronchodilation by inhibiting phosphodiesterase, thereby cAMP hydrolysis -Asthma -COPD -Muscarinic antagonist -Competitive block of muscarinic receptors, preventing bronchoconstriction -SE: Tremor, arrhythmia -Metabolized by P450 -Usage is limited because of narrow therapeutic index. -SE: Narrow therapeutic range (cardiotoxicity, neurotoxicity) -Also used for COPD -SE: Tachycardia (1)
Ipratropium
Cromolyn
-Asthma prophylaxis
-Prevents release of mediators from mast cells -Inhibit the synthesis of virtually all cytokines. -Inactivate NF-B, the transcription factor that induces the production of TNF-, among other inflammatory agents. -Antileukotriene -5-lipoxygenase pathway inhibitor. -Blocks conversion of arachidonic acid to leukotrienes
-Effective only for prophylaxis of asthma. Not effective during acute asthma attack. -SE: Rare
Zafirlukast Montelukast
-Especially good for aspirin-induced asthma -Especially good for aspirin-induced asthma
-Removes excess sputum but large doses necessary; does not suppress cough reflex. -Can loosen mucous plugs in CF patients -Also used as an antidote in acetaminophen overdose.