PHARMACOLOGY NURSING

PHARMACOLOGY NURSING What are the major functions of the α1 receptor? - Increase vascular smooth muscle contraction, increase pupillary dilator muscle contraction (mydriasis), increase intestinal and bladder sphincter muscle contraction What are the major functions of the α2 receptor? - Decrease sympathetic outflow, decrease insulin release, decrease lipolysis, increase platelet aggregation, decrease aqueous humor production What are the major functions of the β1 receptor? - Increase heart rate, increase contractility, increase renin release, increase lipolysis What are the major functions of the β2 receptor? - Vasodilation, bronchodilation, increase lipolysis, increase insulin release, decrease uterine tone (tocolysis), ciliary muscle relaxation, increase aqueous humor production What are the major functions of the M1 receptor? - CNS, enteric nervous system What are the major functions of the M2 receptor? - Decrease heart rate and contractility of atria What are the major functions of the M3 receptor? - Increase exocrine gland secretions (e.g., lacrimal, salivary, gastric acid), increase gut peristalsis, increase bladder contraction, increase bronchoconstriction, pupillary sphincter muscle contraction (miosis), ciliary muscle contraction (accommodation) What are the major functions of the D1 receptor? - Relaxes renal vascular smooth muscle What are the major functions of the D2 receptor? - Modulates transmitter release, especially in the brain What are the major functions of the H1 receptor? - Increase nasal and bronchial mucus production, increase vascular permeability, contraction of bronchioles, pruritis, pain What are the major functions of the H2 receptor? - Increase gastric acid secretion What are the major functions of the V1 receptor? - Increase vascular smooth muscle contraction What are the major functions of the V2 receptor? - Increase H2O permeability and reabsorption in collecting tubules of kidney (V2 is found in the "2" kidneys) What receptors are associate with Gq? - H1, α1, V1, M1, and M3 What receptors are associated with Gs? - H2, B1, B2, V2, D1 What receptors are associated with Gi? - M2, α2, D2 Bethanechol - -Direct cholinergic agonist -Activates bowel and bladder smooth muscle -Used in postoperative and neurogenic ileus -Resistant to AChE Carbachol - -Direct cholinergic agonist -Carbon copy of acetylcholine -Constricts pupils and relieves intraocular pressure in glaucoma Methacholine - -Direct cholinergic agonist -Stimulates muscarinic receptors in airways when inhaled -Used as a challenge test for diagnosis of asthma Pilocarpine - -Direct cholinergic agonist -Contracts ciliary muscle of eye (open angle glaucoma), contracts pupillary sphincter (closed angle glaucoma) -Potent stimulator of sweat, tears and saliva -AChE resistant Donepezil - -Anticholinesterse - increases ACh -Alzheimer disease Galantamine - -Anticholinesterse - increases ACh -Alzheimer disease Rivastigmine - -Anticholinesterse - increases ACh -Alzheimer disease Edrophonium - -Anticholinesterse - increases ACh -Historically used to diagnose myasthenia gravis (MG is now diagnosed by anti-AChR Ab test. Neostigmine - -Anticholinesterse - increases ACh -Used in postoperative and neurogenic ileus and urinary retention, myasthenia gravis, and postoperative reversal of neuromuscular junction blockade Physostigmine - -Anticholinesterse - increases ACh -Used in anticholinergic toxicity -Crosses the blood-brain barrier (CNS) Pyridostigmine - -Anticholinesterse - increases ACh -Increases muscle strength -Used in myasthenia gravis (long acting) -Does not penetrate CNS Atropine - -Muscarinic antagonist -Used in bradycardia and for ophthalmic applications -Also used as antidote for cholinesterase inhibitor poisoning -Actions include increase pupil dilation, cycloplegia, decreased airway secretions, decreased acid secretions, decreased gut motility, decreased bladder urgency in cystitis -Toxicity: increased body temp (due to decreased sweating), rapid pulse, dry mouth, dry and flushed skin, cycloplegia, constipation, disorientation; -Can cause acute angle-closure glaucoma in elderly (due to mydriasis), urinary retention in men with prostatic hyperplasia, and hyperthermia in infants -See also homatropine and tropicamide Benztropine - -Muscarinic antagonist -Works in CNS -Used in Parkinson disease and acute dystonia Glycopyrrolate - -Muscarinic antagonist -Parental use: preoperative use to reduce airway secretions -Oral use: drooling, peptic ulcer Hyoscyamine - -Muscarinic antagonist -Antispasmodics for IBS Dicyclomide - -Muscarinic antagonist -Antispasmodics for IBS Ipratropium - -Muscarinic antagonist -Used in COPD and asthma Tiotropium - -Muscarinic antagonist -Used in COPD and asthma Oxybutynin - -Muscarinic antagonist -Reduced bladder spasms and urge urinary incontinence Solifenacin - -Muscarinic antagonist -Reduced bladder spasms and urge urinary incontinence Tolterodine - -Muscarinic antagonist -Reduced bladder spasms and urge urinary incontinence Scopalamine - -Muscarinic antagonist -Motion sickness Tetrodotoxin - -Poisoning can result from ingestion of poorly prepared puffer fish (exotic sushi) -Highly potent toxin that binds fast voltage-gated Na+ channels in cardiac and nerve tissue, preventing depolarization - blocks action potential without changing resting potential (same mechanism as Lidocaine) -Causes nausea, diarrhea, paresthesias, weakness, dizziness, loss of reflexes. -Treatment is primarily supportive. Ciguatoxin - -Consumption of reef fish (e.g. barracuda, snapper, eel...) -Causes ciguatera fish poisoning. -Opens Na+ channels causing depolarization. Symptoms easily confused with cholinergic poisoning. -Temperature-related dysesthesia (e.g., "cold feels hot; hot feels cold") is regarded as a specific finding of ciguatera. -Treatment is primarily supportive. Scombroid poisoning - -Caused by consumption of dark-meat fish (e.g., bonito, mackerel, mahi-mahi, tuna) improperly stored at warm temperature. -Bacterial histidine decarboxylase converts histidine to histamine. Histamine is not degraded by cooking. -Acute-onset burning sensation of the mouth, flushing of face, erythema, urticaria, pruritus, headache. May cause anaphylaxis-like presentation (i.e., bronchospasm, angioedema, hypotension). -Frequently misdiagnosed as allergy to fish. -Treat supportively with antihistamines; if needed, antianaphylactics (e.g., bronchodilators, epinephrine). Albuterol - -β2 β1 direct agonist -Acute asthma Salmterol - -β2 β1 direct agonist -Long term asthma or COPD control Dobutamine - -β1 β2, α direct agonist -Uses: heart failure (HF) (inotropic chronotropic), cardiac stress testing. Dopamine - -D1 = D2 β α direct agonist -Uses: unstable bradycardia, HF, shock; inotropic and chronotropic α effects predominate at high doses. Epinephrine - -β α direct agonist -Uses: anaphylaxis, asthma, open-angle glaucoma; α effects predominate at high doses. Significantly stronger effect at β2-receptor than norepinephrine. Isoprterenol - -β1 = β2 direct agonist -Uses: electrophysiologic evaluation of tachyarrhythmias. Can worsen ischemia Norepinephrine - -α1 α2 β1 direct agonist -Hypotension (butrenal perfusion). Significantly weaker effect at β2-receptor than epinephrine. Phenylephrine - -α1 α2 direct agonist -Uses: hypotension (vasoconstrictor), ocular procedures (mydriatic), rhinitis (decongestant) Amphetamine - -Indirect general sympathetic agonist -reuptake inhibitor; also releases stored catecholamines -Narcolepsy, obesity, ADHD. Cocaine - -Indirect general sympathetic agonist -Reuptake inhibitor -Causes vasoconstriction and local anesthesia. -Never give β-blockers if cocaine intoxication is suspected (can lead to unopposed α1 activation and extreme hypertension). Ephedrine - -Indirect general sympathetic agonist -Releases stored catecholamines -Nasal decongestion, urinary incontinence, hypotension. Norepinephrine vs. isoproterenol - -Norepinephrine increases systolic and diastolic pressures as a result of α1-mediated vasoconstriction causing increased in mean arterial pressure and reflex bradycardia. -However, isoproterenol (no longer commonly used) has little α effect but causes β2-mediated vasodilation, resulting in decreased mean arterial pressure and increased heart rate through β1 and reflex activity. Clonidine - -α2-agonist -Uses: hypertensive urgency (limited situations); does not decrease renal blood flow; ADHD, Tourette syndrome -Toxicity: CNS depression, bradycardia, hypotension, respiratory depression, miosis α-methyldopa - -α2-agonist -Used for hypertension in pregnancy -Toxicity: Direct Coombs ⊕ hemolysis, SLE-like syndrome Phenoxybenzamine - -Nonselective α-blocker -Irreversible -Used preoperatively for pheochromocytoma to prevent catecholamine (hypertensive) crisis -Toxicity: orthostatic hypotension, reflex tachycardia Phentolamine - -Nonselective α-blocker -Give to patients on MAO inhibitors who eat tyramine containing foods -Toxicity: orthostatic hypotension, reflex tachycardia Prazosin - -Selective α1-blocker -Uses: urinary symptoms of BPH; PSTD -Hypertension -Toxicity: 1st-dose orthostatic hypotension, dizziness, headache Terazosin - -Selective α1-blocker -Uses: urinary symptoms of BPH; -Hypertension -Toxicity: 1st-dose orthostatic hypotension, dizziness, headache Doxazosin - -Selective α1-blocker -Uses: urinary symptoms of BPH; -Hypertension -Toxicity: 1st-dose orthostatic hypotension, dizziness, headache Tamsulosin - -Selective α1-blocker -Uses: urinary symptoms of BPH; -Toxicity: 1st-dose orthostatic hypotension, dizziness, headache Mirtazapine - -Selective α2-blocker -Used in depression -Toxicity: sedation, increased serum cholesterol, increased appetite α-blockade of epinephrine vs. phenylephrine - Shown in the picture are the effects of an α-blocker (e.g., phentolamine) on blood pressure responses to epinephrine and phenylephrine. The epinephrine response exhibits reversal of the mean blood pressure change, from a net increase (the α response) to a net decrease (the β2 response). The response to phenylephrine is suppressed but not reversed because phenylephrine is a "pure" α-agonist without β action. Effects of β-blockers - -Angina pectoris—decrease heart rate and contractility, resulting in decrease O2 consumption -MI—β-blockers (metoprolol, carvedilol, and bisoprolol) mortality -SVT (metoprolol, esmolol)—decrease AV conduction velocity (class II antiarrhythmic) -Hypertension—decrease cardiac output, decrease renin secretion (due to β1-receptor blockade on JGA cells) -HF—decrease mortality in chronic HF -Glaucoma (timolol)—decrease secretion of aqueous humor Nonselective β-blockers - -Nadolol, pindolol (partial agonist), propranolol, timolol -Mostly go from N to Z β1-selective antagonist - -acebutolol (partial agonist), atenolol, betaxolol, esmolol, metoprolol -Mostly go from A to M Nonselective α- and β-antagonists - -Carvedilol, labetalol Nebevolol - -Combines cardiac-selective β1-adrenergic blockade with stimulation of β3-receptors, which activate nitric oxide synthase in the vasculature Toxicity of β-blockers - -Impotence, cardiovascular adverse effects (bradycardia, AV block, HF), CNS adverse effects (seizures, sedation, sleep alterations), dyslipidemia (metoprolol), and asthma/COPD exacerbations -Avoid in cocaine users due to risk of unopposed α-adrenergic receptor agonist activity -Despite theoretical concern of masking hypoglycemia in diabetics, benefits likely outweigh risks; not contraindicated Acetaminophen toxicity antidote - N-acetylcysteine (replenishes glutathione) AChE inhibitor/organophosphate toxicity antidote - Atropine pralidoxime Amphetamines toxicity antidote - NH4Cl (acidify urine) Antimuscarinic, anticholinergic agents toxicity antidote - Physostigmine salicylate, control hyperthermia Benzodiasepines toxicity antidote - Flumazenil β-blocker toxicity antidote - Glucagon Carbon monoxide toxicity antidote - 100% O2, hyperbaric O2 Penicillamine Cyanide toxicity antidote - Nitrite + thiosulfate, hydroxocobalamin Digitalis toxicity antidote - Anti-dig Fab fragments Heparine toxicity antidote - Protamine sulfate Iron toxicity antidote - Deferoxamine, deferasirox Lead toxicity antidote - EDTA, dimercaprol, succimer, penicillamine Mercury, arsenic, gold toxicity antidote - Dimercaprol (BAL), succimer Copper, arsenic, gold toxicity antidote - Penicillamine Methanol, ethylene glycol (antifreeze) toxicity antidote - Fomepizole ethanol, dialysis Methemoglobin toxicity antidote - Methylene blue, vitamin C Opioids toxicity antidote - Naloxone, naltrexone Salicylates toxicity antidote - NaHCO3 (alkalinize urine), dialysis TCAs toxicity antidote - NaHCO3 (plasma alkalinization) tPA, streptokinase, urokinase toxicity antidote - Aminocaproic acid Warfarin toxicity antidote - Vitamin K (delayed effect), fresh frozen plasma (immediate) Drugs that cause coronary vasospasm - Cocaine, sumatriptan, ergot alkaloids Drugs that cause cutaneous flushing - Vancomycin, Adenosine, Niacin, Ca2+ channel blockers (VANC) Drugs that cause dilated cardiomyopathy - Anthracyclines (e.g., doxorubicin, daunorubicin); prevent with dexrazoxane Drugs that cause Torsades de pointes - Class III (e.g., sotalol) and class IA (e.g., quinidine) antiarrhythmics, macrolide antibiotics, antipsychotics, TCAs Drugs that cause adrenocortical insufficiency - HPA suppression 2° to glucocorticoid withdrawal Drugs that cause hot flashes - Tamoxifen, clomiphene Drugs that cause hyperglycemia - Tacrolimus, Protease inhibitors, Niacin, HCTZ, Corticosteroids Drugs that cause hypothyroidism - Lithium, amiodarone, sulfonamides Drugs that cause acute cholestatic hepatitis, jaundice - Erythromycin Drugs that cause diarrhea - Metformin, Erythromycin, Colchicine, Orlistat, Acarbose Drugs that cause focal to massive hepatic necrosis - Halothane, Amanita phalloides (death cap mushroom), Valproic acid, Acetaminophen Drugs that cause hepatitis - Rifampin, isoniazid, pyrazinamide, statins, fibrates Drugs that cause pancreatitis - Didanosine, Corticosteroids, Alcohol, Valproicacid, Azathioprine, Diuretics (furosemide, HCTZ) Drugs that cause pseudomembranous colitis - Clindamycin, ampicillin, cephalosporins Drugs that cause agranulocytosis - Ganciclovir, Clozapine, Carbamazepine, Colchicine, Methimazole, Propylthiouracil Drugs that cause aplastic anemia - Carbamazepine, Methimazole, NSAIDs, Benzene, Chloramphenicol, Propylthiouracil Drugs that cause direct Coombs- positive hemolytic anemia - Methyldopa, penicillin Drugs that cause gray baby syndrome - Chloramphenicol Drugs that cause hemolysis in G6PD deficiency - Isoniazid, Sulfonamides, Dapsone, Primaquine, Aspirin, Ibuprofen, Nitrofurantoin Drugs that cause thrombocytopenia - Heparin Drugs that cause thrombotic complications - OCPs, hormone replacement therapy Drugs that cause gingival hyperplasia - Phenytoin, Ca2+ channel blockers, cyclosporine Drugs that cause gout - Pyrazinamide, Thiazides, Furosemide, Niacin, Cyclosporine Drugs that cause myopathy - Fibrates, niacin, colchicine, hydroxychloroquine, interferon-α, penicillamine, statins, glucocorticoids Drugs that cause osteoporosis - Corticosteroids, heparin Drugs that cause photosensitivity - Sulfonamides, Amiodarone, Tetracyclines, 5-FU Drugs that cause Stevens-Johnson syndrome - Anti-epileptic drugs (especially lamotrigine), allopurinol, sulfa drugs, penicillin Drugs that cause SLE-like syndrome - Sulfa drugs, Hydralazine, Isoniazid, Procainamide, Phenytoin, Etanercept Drugs that cause teeth discoloration - Tetracyclines (TETra=bad TEeTh) Drugs that cause tendonitis, tendon rupture, and cartilage damage - Fluoroquinolones Drugs that cause cinchonism (symptoms are tinnitus and slight deafness, photophobia and other visual disturbances, mental dullness, depression, confusion, headache, and nausea) - Quinidine, quinine Drugs that cause Parkinson-like syndrome - Antipsychotics, Reserpine, Metoclopramide Drugs that cause seizures - Isoniazid (vitamin B6 deficiency), Bupropion, Imipenem/cilastatin, Enflurane Drugs that cause tardive dyskinesia - Antipsychotics, metoclopramide Drugs that cause diabetes insipidus - Lithium, demeclocycline Drugs that cause fanconi syndrome - Expired tetracycline Drugs that cause hemorrhagic cystitis - Cyclophosphamide, ifosfamide Drugs that cause interstitial nephritis - Methicillin, NSAIDs, furosemide Drugs that cause SIADH - Carbamazepine, Cyclophosphamide, SSRIs Drugs that cause dry cough - ACE inhibitors Drugs that cause pulmonary fibrosis - Bleomycin, amiodarone, methotrexate, busulfan Drugs that cause antimuscarinic reaction - Atropine, TCAs, H1-blockers, antipsychotics Drugs that cause disulfiram-like reaction - Metronidazole, certain cephalosporins, griseofulvin, procarbazine, 1st-generation sulfonylureas Drugs that cause nephrotoxicity/ototoxicity - Aminoglycosides, vancomycin, loop diuretics, cisplatin. Cisplatin toxicity may respond to amifostine. Cytochrome P-450 inducers - Chronic alcohol use, St. John's wort, Phenytoin Phenobarbital, Nevirapine, Rifampin, Griseofulvin, Carbamazepine Cytochrome P-450 substrates - Anti-epileptics, Theophylline, Warfarin OCPs Cytochrome P-450 inhibitors - Acute alcohol abuse, Ritonavir, Amiodarone, Cimetidine, Ketoconazole, Sulfonamides, Isoniazid (INH), Grapefruit juice, Quinidine, Macrolides, (except azithromycin) Sulfa drugs - Probenecid, Furosemide, Acetazolamide, Celecoxib, Thiazides, Sulfonamide antibiotics, Sulfasalazine, Sulfonylureas. Patients with sulfa allergies may develop fever, urinary tract infection, Stevens- Johnson syndrome, hemolytic anemia, thrombocytopenia, agranulocytosis, and urticaria (hives). Symptoms range from mild to life threatening. -azole - Ergosterol synthesis inhibitor -bendazole - Antiparasitic/antihelmintic -cillin - Peptidoglycan synthesis inhibitor -cycline - Protein synthesis inhibitor -ivir - Neuraminidase inhibitor -navir - Protease inhibitor -ovir - DNA polymerase inhibitor -thromycin - Macrolide antibiotic -ane - Inhalational general anesthetic -azine - Typical antipsychotic -barbital - Barbiturate -caine - Local anesthetic -etine - SSRI -ipramine, -triptyline - TCA -triptan - 5-HT1B/1D agonists -zepam, -zolam - Benzodiazepine -chol - Cholinergic agonist -curium, -curonium - Nondepolarizing paralytic -olol - β-blocker -stigmine - AChE inhibitor -terol - β2-agonist -zosin - α1-antagonist -afil - PDE-5 inhibitor -dipine - Dihydropyridine CCB -pril - ACE inhibitor -sartan - Angiotensin-II receptor blocker -statin - HMG-CoA reductase inhibitor -dronate - Bisphosphonate -glitazone - PPAR-γ activator -prazole - Proton pump inhibitor -prost - Prostaglandin analog -tidine - H2-antagonist -tropin - Pituitary hormone -ximab - Chimeric monoclonal Ab -zumab - Humanized monoclonal Ab Penicillin G, V - -Prototype β-lactam antibiotics -G=IV or IM; V=Oral administration -Bind penicillin-binding proteins (transpeptidases). -Block transpeptidase cross-linking of peptidoglycan in cell wall. Activate autolytic enzymes. -Mostly used for gram-positive organisms (S. pneumoniae, S. pyogenes, Actinomyces). Also used for gram-negative cocci (mainly N. meningitidis) and spirochetes (namely T. pallidum). Bactericidal for gram-positive cocci, gram-positive rods, gram-negative cocci, and spirochetes. -Penicillinase in bacteria (a type of β-lactamase) cleaves β-lactam ring. -Toxicity: hypersensitivity reactions, hemolytic anemia Amoxicillin, ampicillin (aminopenicillins) - -Penicillinase-sensitive penicillins -Same mechanism as penicillin (inhibits peptidoglycan cross-linking) with wider spectrum; -Penicillinase sensitive (ombine with clavulanic acid to protect against destruction by β-lactamase) -Use: extended-spectrum penicillin—H. influenzae, H. pylori, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, enterococci. -Toxicity: Hypersensitivity reactions; rash; pseudomembranous colitis. -Resistance: penicillinase in bacteria (a type of β-lactamase) cleaves β-lactam ring. Dicloxacillin, nafcillin, oxacillin - -Penicillinase-resistant penicillins Same mechanism as penicillin (inhibits peptidoglycan cross-linking) -Narrow spectrum; -Penicillinase resistant because bulky R group blocks access of β-lactamase to β-lactam ring. -Use with S. aureus (except MRSA; resistant because of altered penicillin-binding protein target site). -Toxicity: Hypersensitivity reactions, interstitial nephritis. Piperacillin, ticarcillin - -Antipseudomonals -Same mechanism as penicillin (inhibits peptidoglycan cross-linking); extended spectrum -Use: Pseudomonas spp. and gram-negative rods; susceptible to penicillinase; use with β-lactamase inhibitors. -Toxicity: hypersensitivity reactions β-lactamase inhibitors - -Clavulanic Acid, Sulbactam, Tazobactam -Often added to penicillin antibiotics to protect the antibiotic from destruction by β-lactamase (penicillinase). Mechanism of action of cephalosporins - -β-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases. Bactericidal. -Organisms typically not covered by cephalosporins are LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, and Enterococci. Exception: ceftaroline covers MRSA. 1st generation cephalosporins - Cefazolin, cephalexin Use: Gram- positive cocci, Proteus mirabilis, E. coli, Klebsiella pneumoniae. Cefazolin used prior to surgery to prevent S. aureus wound infections 2nd generation cephalosporins - -Cefoxitin, cefaclor, cefuroxime -Use: gram-positive cocci, Haemophilus influenzae, Enterobacter aerogenes, Neisseria spp., Proteus mirabilis, E. coli, Klebsiella pneumoniae, Serratia marcescens. 3rd generation cephalosporins - -Ceftriaxone, cefotaxime, ceftazidime) -Use: serious gram-negative infections resistant to other β-lactams. Ceftriaxone—meningitis, gonorrhea, disseminated lyme disease; ceftazidime—Pseudomonas 4th generation cephalosporins - -Cefepime -Use: gram-negative organisms, with activity against Pseudomonas and gram-positive organisms. 5th generation cephalosporins - -Ceftaroline -Use: broad gram-positive and gram-negative organism coverage, including MRSA; does not cover Pseudomonas. Cephalosporin toxicity - -Hypersensitivity reactions, autoimmune hemolytic anemia, disulfiram-like reaction, vitamin K deficiency. -Exhibit cross-reactivity with penicillins. -Increased nephrotoxicity of aminoglycosides. Mechanism of resistance of cephalosporins - Structural change in penicillin-binding proteins (transpeptidases) Carbapenems - -Imipenem, meropenem, ertapenem, doripenem -Imipenem is a broad-spectrum, β-lactamase- resistant carbapenem. Always administered with cilastatin (inhibitor of renal dehydropeptidase I) to decrease inactivation of drug in renal tubules -Use: gram-positive cocci, gram-negative rods, and anaerobes. Wide spectrum, but significant side effects limit use to life-threatening infections or after other drugs have failed. Meropenem has arisk of seizures and is stable to dehydropeptidase I -Toxicity: GI distress, skin rash, and CNS toxicity (seizures) at high plasma levels Aztreonam - -Monobactam -Less susceptible to β-lactamases. Prevents peptidoglycan cross-linking by binding to penicillin- binding protein 3. -Synergistic with aminoglycosides. No cross-allergenicity with penicillins. -Gram-negative rods only—no activity against gram-positives or anaerobes. For penicillin-allergic patients and those with renal insufficiency who cannot tolerate aminoglycosides. -Usually nontoxic; occasional GI upset. Vancomycin - -Inhibits cell wall peptidoglycan formation by binding D-ala D-ala portion of cell wall precursors. Bactericidal. Not susceptible to β-lactamases. -Gram-positive bugs only—serious, multidrug-resistant organisms, including MRSA, S. epidermidis, sensitive Enteroccocus species, and Clostridium difficile (oral dose for pseudomembranous colitis). -Well tolerated in general—but NOT trouble free. Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse flushing—red man syndrome (can largely prevent by pretreatment with antihistamines and slow infusion rate). -Resistance occurs in bacteria via amino acid modification of D-ala D-ala to D-ala D-lac. "Pay back 2 D-alas (dollars) for vandalizing (vancomycin)." Aminoglycosides - -Gentamicin, neomycin, amikacin, tobramycin, streptomycin -Bactericidal; irreversible inhibition of initiation complex through binding of the 30S subunit. Can cause misreading of mRNA. Also block translocation. Require O2 for uptake; therefore ineffective against anaerobes. -Severe gram-negative rod infections. Synergistic with β-lactam antibiotics. -Neomycin for bowel surgery. -Toxicity: Nephrotoxicity, Neuromuscular blockade, Ototoxicity (especially when used with loop diuretics). Teratogen. -Resistance: Bacterial transferase enzymes inactivate the drug by acetylation, phosphorylation, or adenylation. Tetracyclines - -Tetracycline, doxycycline, minocycline -Bacteriostatic; bind to 30S and prevent attachment of aminoacyl-tRNA; limited CNS penetration. Doxycycline is fecally eliminated and can be used in patients with renal failure. Do not take tetracyclines with milk (Ca2+), antacids (Ca2+ or Mg2+), or iron-containing preparations because divalent cations inhibit drugs' absorption in the gut. -Clinical use: Borrelia burgdorferi, M. pneumoniae. Drugs' ability to accumulate intracellularly makes them very effective against Rickettsia and Chlamydia. Also used to treat acne. -Toxicity: GI distress, discoloration of teeth and inhibition of bone growth in children, photosensitivity. Contraindicated in pregnancy. -Resistance: decrease uptake or increased efflux out of bacterial cells by plasmid-encoded transport pumps. Chloramphenicol - -Blocks peptidyltransferase at 50S ribosomal subunit. -Bacteriostatic. -Use: Meningitis (Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae) and Rocky Mountain spotted fever (Rickettsia rickettsii). Limited use owing to toxicities but often still used in developing countries because of low cost. -Toxicity: anemia (dose dependent), aplastic anemia (dose independent), gray baby syndrome (in premature infants because they lack liver UDP-glucuronyl transferase). -Resistance: plasmid-encoded acetyltransferase inactivates the drug. Clindamycin - -Blocks peptide transfer (translocation) at 50S ribosomal subunit. Bacteriostatic. -Anaerobic infections (e.g., Bacteroides spp., Clostridium perfringens) in aspiration pneumonia, lung abscesses, and oral infections. Also effective against invasive group A streptococcal infection. -Treats anaerobic infections above the diaphragm vs. metronidazole (anaerobic infections below diaphragm) -Toxicity: pseudomembranous colitis (C. difficile -overgrowth), fever, diarrhea Linezolid - -Oxazolidinone -Inhibit protein synthesis by binding to 50S subunit and preventing formation of the initiation complex. -Gram-positive species including MRSA and VRE. -Toxicity: Bone marrow suppression (especially thrombocytopenia), peripheral neuropathy, serotonin syndrome. -Resistance: Point mutation of ribosomal RNA. Macrolides - -Azithromycin, clarithromycin, erythromycin -Inhibit protein synthesis by blocking translocation ("macroslides"); bind to the 23S rRNA of the 50S ribosomal subunit. Bacteriostatic. -Atypical pneumonias (Mycoplasma, Chlamydia, Legionella), STIs (Chlamydia), gram-positive cocci (streptococcal infections in patients allergic to penicillin), and B. pertussis. Toxicity: MACRO: Gastrointestinal Motility issues, Arrhythmia caused by prolonged QT interval, acute Cholestatic hepatitis, Rash, eOsinophilia. Increases serum concentration of theophyllines, oral anticoagulants. Clarithromycin and erythromycin inhibit cytochrome P-450. Resistance: methylation of 23S rRNA-binding site prevents binding of drug. Trimethoprim - -Inhibits bacterial dihydrofolate reductase. Bacteriostatic. -Used in combination with sulfonamides (trimethoprim-sulfamethoxazole [TMP- SMX]), causing sequential block of folate synthesis. Combination used for UTIs, Shigella, Salmonella, Pneumocystis jirovecii pneumonia treatment and prophylaxis, toxoplasmosis prophylaxis. -Toxicity: megaloblastic anemia, leukopenia, granulocytopenia. (May alleviate with supplemental folinic acid). TMP Treats Marrow Poorly. Sulfonamides - -Sulfamethoxazole (SMX), sulfisoxazole, sulfadiazine -Inhibit folate synthesis. Para-aminobenzoic acid (PABA) antimetabolites inhibit dihydropteroate synthase. Bacteriostatic (bactericidal when combined with trimethoprim). (Dapsone, used to treat lepromatous leprosy, is a closely related drug that also inhibits folate synthesis.) -Gram-positives, gram-negatives, Nocardia, Chlamydia. Triple sulfas or SMX for simple UTI. -Toxicity: Hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity (tubulointerstitial nephritis), photosensitivity, kernicterus in infants, displace other drugs from albumin (e.g., warfarin). -Resistance: Altered enzyme (bacterial dihydropteroate synthase), decreased uptake, or increased PABA synthesis. Fluoroquinolones - -Ciprofloxacin, norfloxacin, levofloxacin, ofloxacin, moxifloxacin, gemifloxacin, enoxacin. -Inhibit prokaryotic enzymes topoisomerase II (DNA gyrase) and topoisomerase IV. Bactericidal. Must not be taken with antacids. -Gram-negative rods of urinary and GI tracts (including Pseudomonas), Neisseria, some gram-positive organisms. Toxicity: GI upset, superinfections, skin rashes, headache, dizziness. Less commonly, can cause leg cramps and myalgias. -Contraindicated in pregnant women, nursing mothers, and children 18 years old due to possible damage to cartilage. Some may prolong QT interval. May cause tendonitis or tendon rupture in people 60 years old and in patients taking prednisone. -Resistance: chromosome-encoded mutation in DNA gyrase, plasmid-mediated resistance, efflux pumps. Daptomycin - -Lipopeptide that disrupts cell membrane of gram-positive cocci. -S. aureus skin infections (especially MRSA), bacteremia, endocarditis, VRE. Not used for pneumonia (avidly binds to and is inactivated by surfactant) -Toxicity: myopathy, rhabdomyolysis. Metronidazole - -Forms toxic free radical metabolites in the bacterial cell that damage DNA. Bactericidal, antiprotozoal. -Treats Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, Anaerobes (Bacteroides, C. difficile). Used with a proton pump inhibitor and clarithromycin for "triple therapy" against H. Pylori. -Treats anaerobic infection below the diaphragm vs. clindamycin (anaerobic infections above diaphragm). Toxicity: Disulfiram-like reaction (severe flushing, tachycardia, hypotension) with alcohol; headache, metallic taste. What is the prophylaxis for M. tuberculosis? - Isoniazid What is the treatment for M. tuberculosis? - Rifampin, isoniazid, pyrazinamide, ethambutol (RIPE) What is the prophylaxis for M. avium-intracellulare? - Azithromycin, rifabutin What is the treatment for M. avium-intracellulare? - More drug resistant than M. tuberculosis. Azithromycin or clarithromycin + ethambutol. Can add rifabutin or ciprofloxacin. What is the prophylaxis for M. leprae? - None What is the treatment for M. leprae? - Long-term treatment with dapsone and rifampin for tuberculoid form. Add clofazimine for lepromatous form. Rifamycins - -Rifampin, rifabutin -Inhibit DNA-dependent RNA polymerase -Mycobacterium tuberculosis; delay resistance to dapsone when used for leprosy. Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with Haemophilus influenzae type B. -Toxicity: minor hepatotoxicity and drug interactions (cytochrome P-450); orange body fluids (nonhazardous side effect). Rifabutin favored over rifampin in patients with HIV infection due to less cytochrome P-450 stimulation. -Resistance: mutations reduce drug binding to RNA polymerase. Monotherapy rapidly leads to resistance. Isoniazid - -Decrease synthesis of mycolic acids. Bacterial catalase- peroxidase (encoded by KatG) needed to convert INH to active metabolite. -Use in Mycobacterium tuberculosis. The only agent used as solo prophylaxis against TB. -Toxicity: Neurotoxicity, hepatotoxicity. Pyridoxine (vitamin B6) can prevent neurotoxicity. -Resistance: mutations leading to underexpression of KatG. Pyrazinamide - -Mechanism uncertain. Pyrazinamide is a prodrug that is converted to the active compound pyrazinoic acid. -Use: Mycobacterium tuberculosis. -Toxicity: Hyperuricemia, hepatotoxicity. Ethambutol - -Reduces carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase. -Use: Mycobacterium tuberculosis. -Toxicity: optic neuropathy (red-green color blindness). High risk for endocarditis and undergoing surgical or dental procedures - Amoxicillin Exposure to gonorrhea - Ceftriaxone History of recurrent UTIs - TMP-SMX Exposure to meningococcal infection - Ceftriaxone, ciproflaxacin, or rifampin Pregnant woman carrying group B strep - Penicillin G Prevention of gonococcal conjunctivitis in newborn - Erythromycin ointment Prevention of postsurgical infection due to S. aureus - Cefazolin Prophylaxis of strep pharyngitis in child with prior rheumatic fever - Benzanthine penicillin G or or penicillin V Exposure to syphili - Benzanthine penicillin G Prophylaxis in HIV patients - Treatment of MRSA - Vancomycin, daptomycin, linezolid, tigecycline, ceftaroline Treatment of Vancomycin-resistant enterococci (VRE) - Linezolid and streptogramins (quinupristin, dalfopristin). Treatment of multidrug-resistant P. aeruginosa, multidrug-resistant Acinetobacter baumannii - Polymyxins B and E (colistin). Antifungal therapy (general overview) - Amphotericin B MoA - -Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes. -Amphotericin "tears" holes in the fungal membrane by forming pores Aphotericin B clinical use - -Serious, systemic mycoses. Cryptococcus (amphotericin B with/without flucytosine for cryptococcal meningitis), Blastomyces, Coccidioides, Histoplasma, Candida, Mucor. -Intrathecally for fungal meningitis. -Supplement K+ and Mg2+ because of altered renal tubule permeability Amphotericin B toxicity - Fever/chills ("shake and bake"), hypotension, nephrotoxicity, arrhythmias, anemia, IV phlebitis ("amphoterrible"). Hydration nephrotoxicity. Liposomal amphotericin toxicity. Nystatin MoA - Same as amphotericin B. Topical use only as too toxic for systemic use. Nystatin clinical use - "Swish and swallow" for oral candidiasis (thrush); topical for diaper rash or vaginal candidiasis. Flucytosine MoA - Inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil by cytosine deaminase. Flucytosine clinical use - Systemic fungal infections (especially meningitis caused by Cryptococcus) in combination with amphotericin B. Flucytosine toxicity - Bone marrow suppression. Name the -azoles - Clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole. Azoles MoA - Inhibit fungal sterol (ergosterol) synthesis by inhibiting the cytochrome P-450 enzyme that converts lanosterol to ergosterol. Azoles clinical use - Local and less serious systemic mycoses. Fluconazole for chronic suppression of cryptococcal meningitis in AIDS patients and candidal infections of all types. Itraconazole for Blastomyces, Coccidioides, Histoplasma. Clotrimazole and miconazole for topical fungal infections. Azoles toxicity - Testosterone synthesis inhibition (gynecomastia, especially with ketoconazole), liver dysfunction (inhibits cytochrome P-450). Terbinafine MoA - Inhibits the fungal enzyme squalene epoxidase. Terbinafine clinical use - Dermatophytoses (especially onychomycosis—fungal infection of finger or toe nails). Terbinafine toxicity - GI upset, headaches, hepatotoxicity, taste disturbance. Name the echinocandins - Anidulafungin, caspofungin, micafungin Echinocandins MoA - Inhibit cell wall synthesis by inhibiting synthesis of β-glucan. Echinocandins clinical - Invasive aspergillosis, Candida. Echinocandins - GI upset, flushing (by histamine release). Griseofulvin - Interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing tissues (e.g., nails). Oral treatment of superficial infections; inhibits growth of dermatophytes (tinea, ringworm). Teratogenic, carcinogenic, confusion, headaches, cytochrome P-450 and warfarin metabolism. Toxoplasmosis therapy - Pyrimethamine Trypanosoma brucei therapy - Suramin and melarsoprol T. cruzi therapy - Nifurtimox Leishmaniasis therapy - Sodium stibogluconate Anti-mite/louse therapy - -Permethrin (blocks Na+ channels neurotoxicity), malathion (acetylcholinesterase inhibitor), lindane (blocks GABA channels neurotoxicity). -Used to treat scabies (Sarcoptes scabiei) and lice (Pediculus and Pthirus). Chloroquine MoA - Blocks detoxification of heme into hemozoin. Heme accumulates and is toxic to plasmodia Chloroquine clinical use - Treatment of plasmodial species other than P. falciparum (frequency of resistance in P. falciparum is too high). Resistance due to membrane pump that intracellular concentration of drug. Treat P. falciparum with artemether/lumefantrine or atovaquone/proguanil. For life-threatening malaria, use quinidine in U.S. (quinine elsewhere) or artesunate. Choroquine toxicty - Retinopathy; pruritus (especially in dark-skinned individuals). Antihelminthic therapy drug regimen - Mebendazole, pyrantel pamoate, ivermectin, diethylcarbamazine, praziquantel. Antiviral therapy general - Oseltamivir, zanamivir MoA - Inhibit influenza neuraminidase and decrease release of progeny virus. Oseltamivir, zanamivir clinical use - Treatment and prevention of both influenza A and B. Acyclovir, famciclovir, valacyclovir MoA - Guanosine analogs. Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells few adverse effects. Triphosphate formed by cellular enzymes. Preferentially inhibit viral DNA polymerase by chain termination. Acyclovir, famciclovir, valacyclovir clinical use - -HSV and VZV. Weak activity against EBV. No activity against CMV. Used for HSV- induced mucocutaneous and genital lesions as well as for encephalitis. Prophylaxis in immunocompromised patients. No effect on latent forms of HSV and VZV. Valacyclovir, a prodrug of acyclovir, has better oral bioavailability. -For herpes zoster, use famciclovir. Acyclovir, famciclovir, valacyclovir toxicity - Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated. Mutated viral thymidine kinase. Acyclovir, famciclovir, valacyclovir mechanism of resistance - Mutated viral thymidine kinase. Ganciclovir MoA - 5′-monophosphate formed by a CMV viral kinase. Guanosine analog. Triphosphate formed by cellular kinases. Preferentially inhibits viral DNA polymerase. Preferentially inhibit viral DNA polymerase by chain termination. Ganciclovir clinical use - CMV, especially in immunocompromised patients. Valganciclovir, a prodrug of ganciclovir, has better oral bioavailability. Ganciclovir toxicity - Leukopenia, neutropenia, thrombocytopenia, renal toxicity. More toxic to host enzymes than acyclovir. Ganciclovir mechanism of resistance - Mutated viral kinase. Foscarnet MoA - Viral DNA/RNA polymerase inhibitor and HIV reverse transcriptase inhibitor. Binds to pyrophosphate-binding site of enzyme. Does not require activation by viral kinase. Foscarnet = pyrofosphate analog. Foscarnet clinical use - CMV retinitis in immunocompromised patients when ganciclovir fails; acyclovir-resistant HSV. Foscarnet toxicity - Nephrotoxicity, electrolyte abnormalities (hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, hypomagnesemia) can lead to seizures. Foscarnet mechanism of resistance - Mutated DNA polymerase. Cidofovir MoA - Preferentially inhibits viral DNA polymerase. Does not require phosphorylation by viral kinase. Cidofovir clinical use - CMV retinitis in immunocompromised patients; acyclovir-resistant HSV. Cidofovir toxicity - Long half-life. Nephrotoxicity (coadminister with probenecid and IV saline to toxicity). HIV therapy - -Highly active antiretroviral therapy (HAART): often initiated at the time of HIV diagnosis. -Strongest indication for patients presenting with AIDS-defining illness, low CD4+ cell counts ( 500 cells/mm3), or high viral load. -Regimen consists of 3 drugs to prevent resistance: 2 NRTIs and 1 of the following: NNRTI or protease inhibitor or integrase inhibitor. List the protease inhibitors - Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Ritonavir Saquinavir Protease inhibitor mechanism - -Assembly of virions depends on HIV-1 protease (pol gene), which cleaves the polypeptide products of HIV mRNA into their functional parts. Thus, protease inhibitors prevent maturation of new viruses. -Ritonavir can "boost" other drug concentrations by inhibiting cytochrome P-450. -All protease inhibitors end in -navir. Navir (never) tease a protease. Protease inhibitor toxicity - -Hyperglycemia, GI intolerance (nausea, diarrhea), lipodystrophy. -Nephropathy, hematuria (indinavir). -Rifampin (a potent CYP/UGT inducer) contraindicated with protease inhibitors because it can decrease protease inhibitor concentration. List the NRTIs - Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (ZDV, formerly AZT) NRTI mechanism of action - -Competitively inhibit nucleotide binding to reverse transcriptase and terminate the DNA chain (lack a 3′ OH group). Tenofovir is a nucleoTide; the others are nucleosides and need to be phosphorylated to be active. -ZDV is used for general prophylaxis and during pregnancy to risk of fetal transmission. NNRTIs - Delavirdine Efavirenz Nevirapine NNRTIs MoA - Bind to reverse transcriptase at site different from NRTIs. Do not require phosphorylation to be active or compete with nucleotides. NNRTIs toxicity - Rash and hepatotoxicity are common to all NNRTIs. Vivid dreams and CNS symptoms are common with efavirenz. Delavirdine and efavirenz are contraindicated in pregnancy. Raltegravir MoA - -Integrase inhibitors -Inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase. Raltegavir toxicity - Increased creatine kinase Enfuvirtide MoA - Binds gp41, inhibiting viral entry Enfuvirtide toxicity - Skin reaction at injection sites Maraviroc MoA - Binds CCR-5 on surface of T-cells/monocytes, inhibiting interaction with gp120 Interferons MoA - Glycoproteins normally synthesized by virus-infected cells, exhibiting a wide range of antiviral and antitumoral properties. Interferons clinical use - IFN-α: chronic hepatitis B and C, Kaposi sarcoma, hairy cell leukemia, condyloma acuminatum, renal cell carcinoma, malignant melanoma. IFN-β: multiple sclerosis. IFN-γ: chronic granulomatous disease. Interferons toxicity - Neutropenia, myopathy. Ribavirin MoA - Inhibits synthesis of guanine nucleotides by competitively inhibiting inosine monophosphate dehydrogenase. Ribavirin clinical use - Chronic HCV, also used in RSV (palivizumab preferred in children) Ribavirin toxicity - Hemolytic anemia; severe teratogen. Simeprevir MoA - HCV protease inhibitor; prevents viral replication Simeprevir clinical use - -Chronic HCV in combination with ribavirin and peginterferon alfa. -Do not use as monotherapy. Simeprevir toxicity - Photosensitivity reactions, rash Sofosbuvir MoA - Inhibits HCV RNA-dependent RNA polymerase acting as a chain terminator. Sofosbuvir clinical use - -Chronic HCV in combination with ribavirin, +/- peginterferon alfa. -Do not use as monotherapy. Sobosbuvir toxicity - Fatigue, headache, nausea Goals of infection control techniques - Goals include the reduction of pathogenic organism counts to safe levels (disinfection) and the inactivation of self-propagating biological entities (sterilization). Describing autoclaving - Pressurized steam at 120°C. May be sporicidal. Describe the mechanism of alcohols as an infection control technique - Denature proteins and disrupt cell membranes. Not sporicidal. Describe the mechanism of chlorhexidine as an infection control technique - Denatures proteins and disrupts cell membranes. Not sporicidal. Describe the mechanism of hydrogen peroxide as an infection control technique - Free radical oxidation. Sporicidal. Describe the mechanism of iodine and iodophors as an infection control technique - Halogenation of DNA, RNA, and proteins. May be sporicidal Antibiotics to avoid during pregnancy - -Sulfonamides -Aminoglycosides -Fluoroquinolones -Clarithromycin -Tetracyclines -Ribavirin (antiviral) -Griseofulvin (antifungal) -Chloramphenicol (SAFe Children Take Really Good Care) Adverse effect of sulfonamides during pregnancy - Kernicterus Adverse effect of aminoglycosides during pregnancy - Ototoxicity Adverse effect of fluorquinolones during pregnancy - Cartilage damage Adverse effect of clarithromycin during pregnancy - Embryotoxic Adverse effect of tetracyclines during pregnancy - Discolored teeth, inhibition of bone growth Adverse effect of ribavirin during pregnancy - Teratogenic Adverse effect of griseofulvin during pregnancy - Teratogenic Adverse effect of chloramphenicol during pregnancy - Gray baby syndrome (vomiting, ashen gray color of the skin, limp body tone, hypotension, cyanosis of lips and skin, hypothermia, cardiovascular collapse, within 2-9 days of birth-especially premature) Cyclosporine MoA - Calcineurin inhibitor; binds cyclophilin. Blocks T-cell activation by preventing IL-2 transcription. Cyclosporine clinical use - Transplant rejection prophylaxis, psoriasis, rheumatoid arthritis Cyclosporine toxicity - Nephrotoxicity, hypertension, hyperlipidemia, neurotoxicity, gingival hyperplasia, hirsutism. Tacrolimus MoA - -Calcineurin inhibitor; binds FK506 binding protein (FKBP). -Blocks T-cell activation by preventing IL-2 transcription. Tacrolimus clinical use - Transplant rejection prophylaxis Tacrolimus toxicity - Similar to cyclosporine, risk of diabetes and neurotoxicity; no gingival hyperplasia or hirsutism. Sirolimus (Rapamycin) MoA - -mTOR inhibitor; binds FKBP. -Blocks T-cell activation and B-cell differentiation by preventing response to IL-2. Sirolimus (Rapamycin) clinical use - -Kidney transplant rejection prophylaxis. -Synergistic with cyclosporine. -Also used in drug- eluting stents Sirolimus (Rapamycin) toxicity - Anemia, thrombocytopenia, leukopenia, insulin resistance, hyperlipidemia; not nephrotoxic (kidney "sir-vives") Daclizumab, basiliximab MoA - Monoclonal antibodies; block IL-2R. Daclizumab, basiliximab clinical use - Kidney transplant rejection prophylaxis Daclizumab, basiliximab toxicity - Edema, HTN, tremor Azathioprine MoA - Antimetabolite precursor of 6-mercaptopurine. Inhibits lymphocyte proliferation by blocking nucleotide synthesis. Azathioprine clinical use - Transplant rejection prophylaxis, rheumatoid arthritis, Crohn disease, glomerulonephritis, other autoimmune conditions. Azathioprine toxicity - -Leukopenia, anemia, thrombocytopenia. -6-MP degraded by xanthine oxidase; toxicity by allopurinol. Glucocorticoids MoA - Inhibit NF-κB. Suppress both B- and T-cell function by transcription of many cytokines. Glucocorticoids clinical use - Transplant rejection prophylaxis (immunosuppression), many autoimmune disorders, inflammation Glucocorticoids toxicity - -Hyperglycemia, osteoporosis, central obesity, muscle breakdown, psychosis, acne, hypertension, cataracts, avascular necrosis. -Can cause iatrogenic Cushing syndrome. Immunosuppression targets image - Clinical use of aldesleukin (IL-2) - Renal cell carcinoma, metastatic melanoma Clinical use of epoetin alfa (erythropoietin) - Anemias (especially in renal failure) Clinical use of filgrastim (G-CSF) - Recovery of bone marrow Clinical use of sargramostim (GM-CSF) - Recovery of bone marrow Clinical use of IFN-α - Chronic hepatitis B and C, Kaposi sarcoma, malignant melanoma Clinical use of IFN-β - Multiple sclerosis Clinical use of IFN-γ - Chronic granulomatous disease Clinical use of romiplostim, eltrombopag - Thrombocytopenia Clinical use of oprelvekin (IL-11) - Thrombocytopenia Alemtuzumab target - CD52 Alemtuzumab clinical use - CLL "Alymtuzumab"—chronic lymphocytic leukemia Bevacizumab target - VEGF Bevacizumab clinical use - Colorectal cancer, renal cell carcinoma Cetuximab target - EGFR Cetuximab clinical use - Stage IV colorectal cancer, head and neck cancer Rituximab target - CD20 Rituximab clinical use - B-cell non-Hodgkin lymphoma, CLL, RA, ITP Trastuzumab target - HER2/neu (Can't 'trust' HER) Trastuzumab clinical use - Breast cancer Adalimumab, infliximab target - Soluble TNF-α Etanercept is a decoy TNF-α receptor and not a monoclonal antibody Adalimumab, infliximab clinical use - IBD, rheumatoid arthritis, ankylosing spondylitis, psoriasis Eculizumab target - Complement protein C5 Eculizumab clinical use - Paroxysmal nocturnal hemoglobinuria Natalizumab target - α4-integrin α4-integrin: WBC adhesion Risk of PML in patients with JC virus Natalizumab clinical use - Multiple sclerosis, Crohn disease Abciximab target - Platelet glycoproteins IIb/IIIa IIb times IIIa equals "absiximab" Abciximab clinical use - Antiplatelet agent for prevention of ischemic complications in patients undergoing percutaneous coronary intervention Denosumab target - RANKL Denosumab clinical use - Osteoperosis; inhibits osteoclast maturation (mimics osteoprotegerin) Digoxin immune Fab target - Digoxin Digoxin immune Fab clinical use - Antidote for digoxin toxicity Omalizumab target - IgE Omalizumab clinical use - Allergic asthma, prevents IgE binding to FcεRI Palivizumab target - RSV F protein ("VI" for VIrus) Palivizumab clinical use - RSV prophylaxis for high risk infants Ranibizumab, bevacizumab target - VEGF Ranibizumab, bevacizumab clinical use - Neovascular age-related macular degeneration Primary (essential) hypertension therapy - Thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), dihydropyridine Ca2+ channel blockers. Hypertension with heart failure therapy - -Diuretics, ACE inhibitors/ARBs, β-blockers (compensated HF), aldosterone antagonists. -β-blockers must be used cautiously in decompensated HF and are contraindicated in cardiogenic shock. Hypertension with diabetes mellitus - ACE inhibitors/ARBs, Ca2+ channel blockers, thiazide diuretics, β-blockers. ACE inhibitors/ARBs are protective against diabetic nephropathy. Hypertension in pregnancy - Hydralazine, lebetalol, methyldopa, nifedipine List the dihydropyridine calcium channel blockers - Amlodipine, clevidipine, nicardipine, nifedipine, nimodipine -Act on vascular smooth muscle List the non-dihydropyridine calcium channel blockers - diltiazem, verapamil -Act on the heart Calcium channel blockers mechanism - -Block voltage-dependent L-type calcium channels of cardiac and smooth muscle to decrease muscle contractility. -Vascular smooth muscle—amlodipine = nifedipine diltiazem verapamil. -Heart—verapamil diltiazem amlodipine = nifedipine (verapamil = ventricle). Dihydropyridine calcium channel blockers clinical use - HTN, angina (including Prinzmetal), Raynaud phenomenon. **NOT nimodipine which is used for subarachnoid hemorrhage to prevent cerebral vasospasm) Nimodipine clinical use - Used in subarachnoid hemorrhage to prevent cerebral vasospasm) Clevidipine clinical use - HTN urgency or emergency Non-dihydropyridine calcium channel blockers clinical use - HTN, angina, atrial fib/flutter Calcium channel blocker toxicity - Cardiac depression, AV block (non-dihydropyridines), peripheral edema, flushing, dizziness, hyperprolactinemia (verapamil), constipation, gingival hyperplasia. Hydralazine mechanism - Increase cGMP causing smooth muscle relaxation. Vasodilates arterioles veins; afterload reduction. Hydralazine clinical use - -Severe HTN (particularly acute), HF (with organic nitrate). -Safe to use in pregnancy. -Frequently coadministered with a β-blocker to prevent reflex tachycardia. Hydralazine toxicity - Compensatory tachycardia (contraindicated in angina/CAD), fluid retention, headache, angina. Lupus-like syndrome!!!! What drugs can be used in a hypertensive emergency? - Clevidipine, fenoldopam, labetalol, nicardipine, nitroprusside Nitroprusside - Short acting; increase cGMP via direct release of NO. Can cause cyanide toxicity (releases cyanide) Fenoldopam - -Dopamine D1 receptor agonist—coronary, peripheral, renal, and splanchnic vasodilation. -Decrease BP, increase natriuresis. List the nitrates - Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate Nitrate mechanism of action - Vasodilate by increasing NO in vascular smooth muscle thereby increasing cGMP and smooth muscle relaxation. Dilate veins arteries. Reduces preload Nitrate clinical use - Angina, acute coronary syndrome, pulmonary edema Nitrate toxicity - Reflex tachycardia (treat with β-blockers), 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 - tachycardia, dizziness, headache upon reexposure. Goal of antianginal therapy - Goal is reduction of myocardial O2 consumption (MVO2) by decreasing 1 or more of the determinants of MVO2: end-diastolic volume, BP, HR, contractility. What effect do nitrates have on EDV? - Decreases What effect do nitrates have on BP? - Decreases What effect do nitrates have on contractility? - None What effect do nitrates have on HR? - Increase (reflex response) What effect do nitrates have on ejection time? - Decrease What effect do nitrates have on MVO2? - Decreased What effect do β-blockers have on EDV? - None or decrease What effect do β-blockers have on BP? - Decrease What effect do β-blockers have on contractility? - Decrease What effect do β-blockers have on HR? - Decrease What effect do β-blockers have on ejection time? - Increase What effect do β-blockers have on MVO2? - Decrease What effect does nitrates + β-blockers have on EDV? - No effect or decrease What effect does nitrates + β-blockers have on BP? - Decrease What effect does nitrates + β-blockers have on contractility? - Little/no effect What effect does nitrates + β-blockers have on HR? - No effect or decreased What effect does nitrates + β-blockers have on ejection time? - little/no effect What effect does nitrates + β-blockers have on MVO2 - Double decrease Antianginal therapy summary table - Lipid lowering agents summary table - Lipid lowering agents summary schematic - List the HMG-CoA reductase inhibitors - Lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin HMG-CoA reductase effect on lipid levels - LDL Δ: big time triple decrease!!! HDL Δ: increase TG Δ: decrease HMG-CoA reductase mechanism of action - Inhibit conversion of HMG- CoA to mevalonate, a cholesterol precursor; Decreased mortality in CAD patients HMG-CoA reductase side effects/problems - Hepatotoxicity ( LFTs), myopathy (esp. when used with fibrates or niacin) List the bile acid resins - Cholestyramine, colestipol, colesevelam Bile acid resins effect on lipid levels - LDL Δ: double decrease HDL Δ: slight increase TG Δ: slight increase Bile acid resin mechanism - Prevents intestinal absorption of bile acids; liver must use cholesterol to make more Bile acid resin side effects/problems - GI upset, decrease absorption of other drugs and fat-soluble vitamins What effect does ezetimibe have on lipid levels? - LDL Δ: double decrease HDL Δ: none TG Δ: none Ezetimibe mechanism of action - Prevents cholesterol absorption at the small intestine brush border Ezetimibe side effects/problems - Rare increase in LFTs, diarrhea List the fibrates - gemfibrozil, clofibrate, bezafibrate, fenofibrate Fibrate effect on lipid levels - LDL Δ: down HDL Δ: up TG Δ: TRIPLE DOWN!!! Fibrates mechanism of action - -Upregulate LPL causing increase in TG clearance. -Activates PPAR-α to induce HDL synthesis Fibrates side effects/problems - Myopathy (increase risk with statins), cholesterol gallstones Niacin effect on lipid levels - LDL Δ: double down HDL Δ: double up TG Δ: down Niacin mechanism - -Inhibits lipolysis (hormone sensitive lipase) in adipose tissue; -Reduces hepatic VLDL synthesis Niacin side effects/problems - Red, flushed face, which is decreased by NSAIDs or long term use; hyperglycemia, hyperuricemia (gout) Digoxin mechanism - Direct inhibition of Na+/K+ ATPase causing indirect inhibition of Na+/Ca2+ exchanger. Increased [Ca2+]i creates positive inotropy. Stimulates vagus nerve to increase HR. Digoxin clinical use - HF (increased contractility), atrial fibrillation (decrease conduction at AV node and depression of the SA node) Digoxin toxicity - -Cholinergic—nausea, vomiting, diarrhea, blurry yellow vision (think van Gogh), arrhythmias, AV block. -Can lead to hyperkalemia, which indicates poor prognosis. Factors predisposing to digoxin toxicity - Renal failure (decreased excretion), hypokalemia (permissive for digoxin binding at K+-binding site on Na+/K+ ATPase), verapamil, amiodarone, quinidine (digoxin clearance; displaces digoxin from tissue-binding sites). Antidote - Slowly normalize K+, cardiac pacer, anti-digoxin Fab, Mg2+ General mechanism of sodium channel blockers (class I antiarrhythmic) - -Slow or block conduction (especially in depolarized cells). -Decrease slope of phase 0 depolarization. -Are state dependent - selectively depress tissue that is frequently depolarized (e.g., tachycardia) List the class IA sodium channel blockers - Quinidine, procainamide, disopyramide, Class IA sodium channel blockers effect on action potential - -Decreases slope of phase 0 -Increase action potential duration -Increase effective refractory period -Increased QT interval Class IA sodium channel blocker mechanism - Increase action potential duration, increase effective refractory period in ventricular action potential, and increase QT Class IA sodium channel blocker clinical use - Both atrial and ventricular arrhythmias, especially re-entrant and ectopic SVT and VT Class IA sodium channel blocker toxicity - Cinchonism (headache, tinnitus with quinidine), reversible SLE like syndrome (procainamide), heart failure (disopyramide), thrombocytopenia, torsades de pointes due to increased QT Procainamide toxicity - SLE like syndrome (reversible) Quinidine toxicity - Cinchonism (headache, tinnitus) Disopyramide toxicity - Heart failure List the class IB sodium channel blockers - Lidocaine, mexiletine Phenytoin can also fall into this category Class IB sodium channel blockers effect on action potential - -Decreases AP duration -Decreases slope of phase 0 Class IB sodium channel blockers mechanism - Decrease AP duration. Preferentially affect ischemic or depolarized Purkinje and ventricular tissue. Class IB sodium channel blockers clinical use - Acute ventricular arrhythmias (especially post- MI), digitalis-induced arrhythmias. (IB is Best post-MI) Class IB sodium channel blockers toxicity - CNS stimulation/depression, CV depression List the class IC sodium channel blockers - Flecainide, propafenone Class IC sodium channel blockers effect on action potential curve - -Minimal effect on action potential duration -Decreases slope of phase 0 Class IC sodium channel blockers mechanism - -Significantly prolongs ERP in AV node and accessory bypass tracts. No effect on ERP in Purkinje and ventricular tissue. -Minimal effect on AP duration Class IC sodium channel blockers clinical use - SVTs, including atrial fibrillation. Only as a last resort in refractory VT. Class IC sodium channel blockers toxicity - -Proarrhythmic, especially post-MI (DO NOT USE POST MI!) -Contraindicated in structural and ischemic heart disease List the key β-blockers (class II antiarrhythmics) - Metoprolol, propranolol, esmolol, atenolol, timolol, carvedilol β-blockers (class II antiarrhythmics) mechanism - -Decrease SA and AV nodal activity by decreasing cAMP, and decreasing Ca2+ currents. Suppress abnormal pacemakers by decreasing slope of phase 4. -AV node particularly sensitive - increase PR interval. Esmolol very short acting What is the shortest acting β-blocker - Esmolol β-blockers (class II antiarrhythmics) clinical use - SVT, ventricular rate control for atrial fibrillation and atrial flutter β-blockers (class II antiarrhythmics) toxicity - Impotence, exacerbation of COPD and asthma, cardiovascular effects (bradycardia, AV block, HF), CNS effects (sedation, sleep alterations). May mask the signs of hypoglycemia. β-blockers cause unopposed α1-agonism if given alone for pheochromocytoma or cocaine toxicity. Metoprolol side effects - Dyslipidemia Propranolol side effects - May exacerbate vasospasm in Prinzmetal angina β-blockers overdose treatment - Saline, atropine, glucagon β-blockers effect on the pacemaker cell action potential curve - -Decreased slope of phase 4 depolarization -Prolonged repolarization (at AV node) -Increased PR interval List the potassium channel blockers (class III antiarhythmics) - Amiodarone, ibutilide, dofetilide, sotalol Potassium channel blockers mechanism - Increase AP duration, increase ERP, increase QT interval Potassium channel blockers clinical use - Atrial fibrillation, atrial flutter; ventricular tachycardia (amiodarone, sotalol) Amiodarone toxicity - Pulmonary fibrosis, hepatotoxicity, hypothyroidism/hyperthyroidism, act as hapten (corneal deposits, blue/gray skin deposits resulting in photodermatitis), neurologic effects, constipation, CV effects (bradycardia, heart block, HF) Sotalol toxicity - Torsades de pointes, excessive β blockade. Ibutilide toxicity - Torsades de pointes Potassium channel blockers effect on action potential curve - -No change in slope of phase 0 -Greatly increased action potential duration -Greatly increased ERP and QT interval List the calcium channel blockers (class IV antiarrhythmics) - Verapamil, diltiazem Calcium channel blockers effect on the pacemaker cell action potential curve - -Slow rise of AP (decrease conduction velocity) -Increased ERP -Increased PR interval -Prolonged repolarization (at AV node) Calcium channel blockers (class IV antiarrhythmics) mechanism - -Decrease conduction velocity -Increase ERP and PR interval Calcium channel blockers (class IV antiarrhythmics) clinical use - Prevention of nodal arrhythmias (e.g. SVT), rate control in atrial fibrillation Calcium channel blockers (class IV antiarrhythmics) toxicity - Constipation, flushing, edema, CV effects (HF, AV block, sinus node depression) Adenosine - -Antiarrhythmic -Increase K+ out of cells hyperpolarizing the cell and increasing intracellular Ca2+. -Drug of choice in diagnosing/abolishing supraventricular tachycardia. Very short acting (~ 15 sec). Effects blunted by theophylline and caffeine (both are adenosine receptor antagonists). What are the adverse effects of adenosine? - Adverse effects include flushing, hypotension, chest pain, sense of impending doom, bronchospasm. Mg2+ - Effective in torsades de pointes and digoxin toxicity Treatment strategy with type 1 DM - Low-carb diet and insulin replacement Treatment strategy with type 2 DM - Dietary modification and exercise for weight loss; oral agents, non-insulin injectables, insulin replacement Treatment strategy for gestational DM - Dietary modification, exercise, insulin replacement if lifestyle changes fail Name the rapid acting insulins - Aspart, glulisine, lispro Rapid acting insulin mechanism - -Binds insulin receptor (tyrosine kinase activity) -Liver: increase glucose stored as glycogen -Muscle: increase glycogen, protein synthesis; increase K+ uptake -Fat: increase TG storage Rapid acting insulin clinical use - Type 1 DM, type 2 DM, GDM (postprandial glucose control) Rapid acting insulin toxicity - Hypoglycemia, rare hypersensitivity reaction Short acting insulin (regular) mechanism - -Binds insulin receptor (tyrosine kinase activity) -Liver: increase glucose stored as glycogen -Muscle: increase glycogen, protein synthesis; increase K+ uptake -Fat: increase TG storage Short acting insulin clinical use - Type 1 DM, type 2 DM, GDM, DKA (IV), hyperkalemia (+ glucose), stress hyperglycemia. Intermediate acting insulin (NPH) clinical use - Type 1 DM, type 2 DM, GDM Name the long acting insulins - Detemir, Glargine Long acting insulin clinical use - Type 1 DM, type 2 DM, GDM (basal glucose control) Metformin mechanism - -Exact mechanism unknown. -D