What are the major functions of the ?1 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 ?2 receptor?
Decrease sympathetic outflow, decrease insulin release, decrease lipolysis, increase platelet aggregation, decrease aqueous humor production
What are the major functions of the ?1 receptor?
Increase heart rate, increase contractility, increase renin release, increase lipolysis
What are the major functions of the ?2 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, ?1, V1, M1, and M3
What receptors are associated with Gs?
H2, B1, B2, V2, D1
What receptors are associated with Gi?
M2, ?2, 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, decrea
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 po
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 fee
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 sensat
Albuterol
-?2 > ?1 direct agonist
-Acute asthma
Salmterol
-?2 > ?1 direct agonist
-Long term asthma or COPD control
Dobutamine
-?1 > ?2, ? direct agonist
-Uses: heart failure (HF) (inotropic > chronotropic), cardiac stress testing.
Dopamine
-D1 = D2 > ? > ? direct agonist
-Uses: unstable bradycardia, HF, shock; inotropic and chronotropic ? effects predominate at high doses.
Epinephrine
-? > ? direct agonist
-Uses: anaphylaxis, asthma, open-angle glaucoma;
? effects predominate at high doses. Significantly stronger effect at ?2-receptor than norepinephrine.
Isoprterenol
-?1 = ?2 direct agonist
-Uses: electrophysiologic evaluation of tachyarrhythmias. Can worsen ischemia
Norepinephrine
-?1 > ?2 > ?1 direct agonist
-Hypotension (butrenal perfusion). Significantly weaker effect at ?2-receptor than epinephrine.
Phenylephrine
-?1 > ?2 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 ?-blockers if cocaine intoxication is
suspected (can lead to unopposed ?1 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 ?1-mediated vasoconstriction causing increased in mean arterial pressure and reflex bradycardia. -However, isoproterenol (no longer commonly used) has little ? effect but causes ?2-
Clonidine
-?2-agonist
-Uses: hypertensive urgency (limited situations); does not decrease renal blood flow; ADHD, Tourette syndrome
-Toxicity: CNS depression, bradycardia, hypotension, respiratory depression, miosis
?-methyldopa
-?2-agonist
-Used for hypertension in pregnancy
-Toxicity: Direct Coombs ? hemolysis, SLE-like syndrome
Phenoxybenzamine
-Nonselective ?-blocker
-Irreversible
-Used preoperatively for pheochromocytoma to prevent catecholamine (hypertensive) crisis
-Toxicity: orthostatic hypotension, reflex tachycardia
Phentolamine
-Nonselective ?-blocker
-Give to patients on MAO inhibitors who eat tyramine containing foods
-Toxicity: orthostatic hypotension, reflex tachycardia
Prazosin
-Selective ?1-blocker
-Uses: urinary symptoms of BPH; PSTD
-Hypertension
-Toxicity: 1st-dose orthostatic hypotension, dizziness, headache
Terazosin
-Selective ?1-blocker
-Uses: urinary symptoms of BPH;
-Hypertension
-Toxicity: 1st-dose orthostatic hypotension, dizziness, headache
Doxazosin
-Selective ?1-blocker
-Uses: urinary symptoms of BPH;
-Hypertension
-Toxicity: 1st-dose orthostatic hypotension, dizziness, headache
Tamsulosin
-Selective ?1-blocker
-Uses: urinary symptoms of BPH;
-Toxicity: 1st-dose orthostatic hypotension, dizziness, headache
Mirtazapine
-Selective ?2-blocker
-Used in depression
-Toxicity: sedation, increased serum cholesterol, increased appetite
?-blockade of epinephrine vs. phenylephrine
Shown in the picture are the effects of an ?-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 ? response) to a
Effects of ?-blockers
-Angina pectoris�decrease heart rate and contractility, resulting in decrease O2 consumption
-MI�?-blockers (metoprolol, carvedilol, and bisoprolol) mortality
-SVT (metoprolol, esmolol)�decrease AV conduction velocity (class II antiarrhythmic)
-Hypertensi
Nonselective ?-blockers
-Nadolol, pindolol (partial agonist), propranolol, timolol
-Mostly go from N to Z
?1-selective antagonist
-acebutolol (partial agonist), atenolol, betaxolol, esmolol, metoprolol
-Mostly go from A to M
Nonselective ?- and ?-antagonists
-Carvedilol, labetalol
Nebevolol
-Combines cardiac-selective ?1-adrenergic blockade with stimulation of ?3-receptors, which activate nitric oxide synthase in the vasculature
Toxicity of ?-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 ?-adrenergic rec
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
?-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-?, 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, ag
-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
?-blocker
-stigmine
AChE inhibitor
-terol
?2-agonist
-zosin
?1-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-? 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 ?-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
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 ?-lactamase)
-Use: extended-spectrum pen
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 ?-lactamase to ?-lactam ring.
-Use with S. aureus (except MRSA; resi
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 ?-lactamase inhibitors.
-Toxicity: hypersensitivity reactions
?-lactamase inhibitors
-Clavulanic Acid, Sulbactam, Tazobactam
-Often added to penicillin antibiotics to protect the antibiotic from destruction by ?-lactamase (penicillinase).
Mechanism of action of cephalosporins
-?-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: ceftarol
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 ?-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, ?-lactamase- resistant carbapenem. Always administered with cilastatin (inhibitor of renal dehydropeptidase I) to decrease inactivation of drug in renal tubules
-Use: gram-positive
Aztreonam
-Monobactam
-Less susceptible to ?-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-
Vancomycin
-Inhibits cell wall peptidoglycan formation by binding D-ala D-ala portion of cell wall precursors. Bactericidal. Not susceptible to ?-lactamases.
-Gram-positive bugs only�serious, multidrug-resistant organisms, including MRSA, S. epidermidis, sensitive E
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
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 (
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 bu
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
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,
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)
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 jir
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 lepromat
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
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 clarithr
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.
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, hepatotoxi
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
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
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 ?-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, cy
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/progu
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 pro
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
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 inh
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
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-?: chronic hepatitis B and C, Kaposi sarcoma, hairy cell leukemia, condyloma acuminatum, renal cell carcinoma, malignant melanoma.
IFN-?: multiple sclerosis.
IFN-?: 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-?B. 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-?
Chronic hepatitis B and C, Kaposi sarcoma, malignant melanoma
Clinical use of IFN-?
Multiple sclerosis
Clinical use of IFN-?
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-?
Etanercept is a decoy TNF-? 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
?4-integrin
?4-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 Fc?RI
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, ?-blockers (compensated HF), aldosterone antagonists.
-?-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, ?-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 = ve
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 ?-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 ?-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
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 ?-blockers have on EDV?
None or decrease
What effect do ?-blockers have on BP?
Decrease
What effect do ?-blockers have on contractility?
Decrease
What effect do ?-blockers have on HR?
Decrease
What effect do ?-blockers have on ejection time?
Increase
What effect do ?-blockers have on MVO2?
Decrease
What effect does nitrates + ?-blockers have on EDV?
No effect or decrease
What effect does nitrates + ?-blockers have on BP?
Decrease
What effect does nitrates + ?-blockers have on contractility?
Little/no effect
What effect does nitrates + ?-blockers have on HR?
No effect or decreased
What effect does nitrates + ?-blockers have on ejection time?
little/no effect
What effect does nitrates + ?-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 ?: big time triple decrease!!!
HDL ?: increase
TG ?: 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 ?: double decrease
HDL ?: slight increase
TG ?: 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 ?: double decrease
HDL ?: none
TG ?: 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 ?: down
HDL ?: up
TG ?: TRIPLE DOWN!!!
Fibrates mechanism of action
-Upregulate LPL causing increase in TG clearance.
-Activates PPAR-? to induce HDL synthesis
Fibrates side effects/problems
Myopathy (increase risk with statins), cholesterol gallstones
Niacin effect on lipid levels
LDL ?: double down
HDL ?: double up
TG ?: 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 ?-blockers (class II antiarrhythmics)
Metoprolol, propranolol, esmolol, atenolol, timolol, carvedilol
?-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 ?-blocker
Esmolol
?-blockers (class II antiarrhythmics) clinical use
SVT, ventricular rate control for atrial fibrillation and atrial flutter
?-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.
?-blockers cause unopposed ?1-agonism if given alone for pheochromocytoma or coc
Metoprolol side effects
Dyslipidemia
Propranolol side effects
May exacerbate vasospasm in Prinzmetal angina
?-blockers overdose treatment
Saline, atropine, glucagon
?-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 ? 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 a
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.
-Decrease gluconeogenesis, increase glycolysis, increase peripheral glucose uptake (increase insulin sensitivity).
Metformin clinical use
-Oral. First line therapy in type 2 DM, causes modest weight loss.
-Can be used in patients without islet function
Name the Sulfonylureas
First generation: Chlorpropamide, Tolbutamide
Second generation: Glimepiride, Glipizide, Glyburide
Sulfonylureas mechanism
Close K+ channel in ?-cell membrane then cell depolarizes causing insulin release via increased Ca2+ influx.
Sulfonylureas clinical use
Stimulate release of endogenous insulin in type 2 DM. Require some islet function, so useless in type 1 DM.
Sulfonylureas toxicity
Risk of hypoglycemia in renal failure.
First generation: disulfiram- like effects.
Second generation: hypoglycemia.
List the glitazones/ thiazolidinediones
Pioglitazone, rosiglitazone
Glitazones/ thiazolidinediones mechanism
Increase sensitivity in peripheral tissue. Binds to PPAR-? nuclear transcription regulator.
Glitazones/ thiazolidinediones clinical use
Used as monotherapy in type 2 DM or combined with other agents
Glitazones/ thiazolidinediones toxicity
Weight gain, edema, hepatotoxicity, HF, increased risk if fractures
List the GLP-1 analogs
Exenatide, liraglutide
GLP-1 analogs action
-Increase insulin
-Decrease glucagon release
GLP-1 analogs clinical use
Type 2 DM
GLP-1 analogs toxicity
Nausea, vomiting, pancreatitis
List the DPP-4 inhibitors
Linagliptin, saxagliptin, sitagliptin
DPP-4 inhibitors action
-Increase insulin
-Decrease glucagon release
DPP-4 inhibitors
Type 2 DM
DPP-4 inhibitors
Mild urinary or respiratory infections
Pramlintide action
-Amylin analog
-Decrease gastric emptying
-Decrease glucagon
Pramlintide clinical use
Type 1 and type 2 DM
Pramlintide toxicity
Hypoglycemia, nausea, diarrhea.
Canagliflozin action
-SGLT-2 inhibitor
-Block reabsorption of glucose in PCT
Canagliflozin clinical use
Type 2 DM
Canagliflozin toxicity
Glucosuria, UTIs, vaginal yeast infections.
?-glucosidase inhibitors
Acarbose, miglitol
?-glucosidase inhibitors action
-Inhibit intestinal brush-border ?-glucosidases.
-Delayed carbohydrate hydrolysis and glucose absorption leading to decreased postprandial hyperglycemia.
?-glucosidase inhibitors clinical use
-Used as monotherapy in type 2 diabetes or in combination with other agents
PPAR-?
Genes activated by PPAR-? regulate fatty acid storage and glucose metabolism. Activation of PPAR-? insulin sensitivity and levels of adiponectin.
Propylthiouracil, methimazole mechanism
Block thyroid peroxidase, inhibiting the oxidation of iodide and the organification (coupling) of iodine -> inhibition of thyroid hormone synthesis. Propylthiouracil also blocks 5?-deiodinase -> decreased peripheral conversion of T4 to T3.
Levothyroxine (T4), triiodothyronine (T3) mechanism
Hormone replacement
Levothyroxine (T4), triiodothyronine (T3) clinical use
Hypothyroidism, myxedema. Off label use as weight loss supplements
Levothyroxine (T4), triiodothyronine (T3) toxicity
Tachycardia, heat intolerance, tremors, arrhythmias
ADH antagonists
Conivaptan, tolvaptan
ADH antagonist clinical use
SIADH, block action of ADH at V2-receptor.
Desmopressin acetate clinical use
Central (not nephrogenic) DI.
GH clinical use
GH deficiency, Turner syndrome
Oxytocin clinical use
Stimulates labor, uterine contractions, milk let-down; controls uterine hemorrhage
Somatostatin (octeotride) clinical use
Acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, esophageal varices
Demeclocycline (mechanism, use, and toxicity)
-Mechanism: ADH antagonist (member of tetracycline family).
-Use: SIADH.
-Toxicity: Nephrogenic DI, photosensitivity, abnormalities of bone and teeth.
Glucocorticoids (the ridiculist)
Beclomethasone, dexamethasone, fludrocortisone (mineralocorticoid and glucocorticoid activity), hydrocortisone, methylprednisolone, prednisone, triamcinolone.
Basically anything ending in -sone/lone
Glucocorticoids mechanism
Metabolic, catabolic, anti-inflammatory, and immunosuppressive effects mediated by interactions with glucocorticoid response elements, inhibition of phospholipase A2, and inhibition of transcription factors such as NF-?B.
Glucocorticoids clinical use
Addison disease, inflammation, immunosuppression, asthma
Glucocorticoids toxicity
-Iatrogenic Cushing syndrome (hypertension, weight gain, moon facies, truncal obesity, buffalo hump, thinning of skin, striae, osteoporosis, hyperglycemia, amenorrhea, immunosuppression), adrenocortical atrophy, peptic ulcers, steroid diabetes, steroid ps
Cinacalcet (mechanism, use, and toxicity)
-Mechanism: Sensitizes Ca2+-sensing receptor (CaSR) in parathyroid gland to circulating Ca2+ and thus decreases PTH.
-Use: Hypercalcemia due to 1� or 2� hyperparathyroidism.
-Toxicity: Hypocalcemia.
Acid suppression therapy general overview image
List the H2 blockers
-Cimetidine, ranitidine, famotidine, nizatidine.
-Take H2 blockers before you "dine". Think "table for 2" to remember H2.
H2 blocker mechanism
Reversible block of histamine H2 receptors decreasing H+ secretion by parietal cells
H2 blocker clinical use
Peptic ulcer, gastritis, mild esophageal reflux
H2 blocker toxicity
-Cimetidine is a potent inhibitor of cytochrome P-450 (multiple drug interactions); it also has antiandrogenic effects (prolactin release, gynecomastia, impotence, decreased libido in males); can cross blood-brain barrier (confusion, dizziness, headaches)
Name those proton pump inhibitors
Omeprazole, lansoprazole, esomeprazole, pantoprazole, dexlansoprazole.
Proton pump inhibitor mechanism
Irreversibly inhibits H+/K+ ATPase in stomach parietal cells
PPI use
Peptic ulcer, gastritis, esophageal reflux, Zollinger-Ellison syndrome
PPI toxicity
-Increased risk of C. difficile infection, pneumonia.
-Decreased serum Mg2+ with long term use
Bismuth, sucralfate mechanism
Bind to ulcer base, providing physical protection and allowing HCO3- secretion to reestablish pH gradient in the mucus layer
Bismuth, sucralfate use
Increased ulcer healing, travelers' diarrhea
Misoprostol (mechanism, use, and toxicity)
-Mechanism: A PGE1 analog. Increased production and secretion of gastric mucous barrier, decreased acid production.
-Use: Prevention of NSAID-induced peptic ulcers (NSAIDs block PGE1 production); maintenance of a
PDA. Also used off-label for induction of
Octreotide (mechanism, use, and toxicity)
-Mechanism: Long-acting somatostatin analog; inhibits actions of many splanchnic vasoconstriction hormones.
-Use: Acute variceal bleeds, acromegaly, VIPoma, carcinoid tumors.
-Toxicity: Nausea, cramps, steatorrhea.
Overuse of aluminum hydroxide
Causes constipation and hypophosphatemia; proximal muscle weakness, osteodystrophy, seizures
Overuse of calcium carbonate
-Hypercalcemia, rebound acid increase
-Can chelate and decrease effectiveness of other drugs
Overuse of magnesium hydroxide
Diarrhea, hyporeflexia, HoTN, cardiac arrest
Osmotic laxatives (drugs, mechanism, clinical use and toxicity)
Magnesium hydroxide, magnesium citrate, polyethylene glycol, lactulose.
-Mechanism: provide osmotic load to draw water into the GI lumen.
-Use: Constipation. Lactulose also treats hepatic encephalopathy since gut flora degrade it into metabolites (lactic
Sulfasalazine (mechanism, clinical use and toxicity)
-Mechanism: A combination of sulfapyridine (antibacterial) and 5-aminosalicylic acid (anti-inflammatory). Activated by colonic bacteria.
-Use: Ulcerative colitis, Crohn disease (colitis component).
-Toxicity: Malaise, nausea, sulfonamide toxicity, reversi
Ondansetron (mechanism, clinical use and toxicity)
-Mechanism: 5-HT3 antagonist; decrease vagal stimulation. Powerful central-acting antiemetic.
-Use: Control vomiting postoperatively and in patients undergoing cancer chemotherapy.
-Toxicity: Headache, constipation, QT interval prolongation.
Metoclopramide (mechanism, clinical use and toxicity)
-Mechanism: D2 receptor antagonist. Increase resting tone, contractility, LES tone, motility. Does not influence colon transport time.
-Use: Diabetic and postsurgery gastroparesis, antiemetic.
-Toxicity: Increased parkinsonian effects, tardive dyskinesia.
Orlistat (mechanism, clinical use and toxicity)
-Mechanism: Inhibits gastric and pancreatic lipase breakdown and absorption of dietary fats.
-Use: Weight loss.
-Toxicity: Steatorrhea, decreased absorption of fat-soluble vitamins.
Heparin mechanism
Activator of antithrombin; decrease thrombin and decrease factor Xa. Short half-life.
Heparin use
Immediate anticoagulation for pulmonary embolism (PE), acute coronary syndrome, MI, deep venous thrombosis (DVT). Used during pregnancy (does not cross placenta). Follow PTT.
Heparin toxicity
Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions. For rapid reversal (antidote), use protamine sulfate (positively charged molecule that binds negatively charged heparin).
What is the heparin toxicity antidote, and how does it work?
Protamine sulfate, positively charged molecule that binds negatively charged heparin
Low molecular weight heparins (e.g., enoxaparin, dalteparin) and fondaparinux
Act more on factor Xa, have better bioavailability, and 2-4 times longer half-life; can be administered subcutaneously and without laboratory monitoring. Not easily reversible
Heparin-induced thrombocytopenia (HIT)
Development of IgG antibodies against heparin- bound platelet factor 4 (PF4). Antibody-heparin-PF4 complex activates platelets leading to thrombosis and thrombocytopenia.
Bivalirudin
Related to hirudin, the anticoagulant used by leeches; inhibit thrombin directly. Alternatives to heparin for anticoagulating patients with HIT
See also argatroban, dabigatran
Warfarin mechanism
-Interferes with ?-carboxylation of vitamin K- dependent clotting factors II, VII, IX, and X, and proteins C and S. -Metabolism affected by polymorphisms in the gene for vitamin K epoxide reductase complex (VKORC1). In laboratory assay, has effect on EXtr
Warfarin use
Chronic anticoagulation (e.g., venous thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation). Not used in pregnant women (because warfarin, unlike heparin, crosses placenta). Follow PT/INR.
Warfarin toxicity
Bleeding, teratogenic, skin/tissue necrosis
A , drug-drug interactions. Proteins C and S
have shorter half-lives than clotting factors
II, VI, IX, and X, resulting in early transient hypercoagulability with warfarin use. Skin/tissue necrosis believed to b
Reversal of warfarin toxicity
Vitamin K; for rapid reversal give fresh frozen plasma
What coagulation pathway is affected by heparin?
PTT (intrinsic pathway)
What coagulation pathway is affected by warfarin?
PT (extrinsic pathway)
Direct factor Xa inhibitors (drugs, mechanism, use, toxicity)
Apixaban, rivaroxaban
-Mechanism: bind to and directly inhibit factor Xa.
-Use: treatment and prophylaxis for DVT and PE (rivaroxaban); stroke prophylaxis in patients with atrial fibrillation. Oral agents do not usually require coagulation monitoring.
-To
Thrombolytics (drugs, mechanism, use, toxicity)
Alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA)
-Mechanism: Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. Increase PT, increase PTT, no change in platelet count.
-Use: Ear
Aspirin mechanism
Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) enzyme by covalent acetylation. Platelets cannot synthesize new enzyme, so effect lasts until new platelets are produced: increase bleeding time, decrease TXA2 and prostaglandins. No effect on PT
Aspirin use
Antipyretic, analgesic, anti-inflammatory, antiplatelet (decreased aggregation).
Aspirin toxicity
-Gastric ulceration, tinnitus (CN VIII). Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding. Reye syndrome in children with viral infection.
-Overdose initially causes hyperventilation and respiratory alkalosis, but
ADP receptor inhibitors (drugs, mechanism, use, toxicity)
Clopidogrel, prasugrel, ticagrelor (reversible), ticlopidine.
-Mechanism: inhibit platelet aggregation by irreversibly blocking ADP receptors. Prevent expression of glycoproteins IIb/IIIa on platelet surface.
-Use: acute coronary syndrome; coronary stenti
Cilostazol, dipyridamole (mechanism, use, toxicity)
-Mechanism: phosphodiesterase III inhibitor; increase cAMP in platelets, resulting in inhibition of platelet aggregation; vasodilators.
-Use: intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with aspirin), angina pr
GP IIb/IIIa inhibitors (drugs, mechanism, use, toxicity)
Abciximab, eptifibatide, tirofiban
-Mechanism: bind to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. Abciximab is made from monoclonal antibody Fab fragments.
-Use: unstable angina, percutaneous transluminal coronary a
Cancer drugs - cell cycle
-G1: alkylating agents (carmustine, cisplatin, lomustine)
-S: antimetabolites (azanthroprine, cladribine, cytarabine, 5-fluouracil, hydroxyurea, methotrexate, 6-MP, 6-thioguanine), also etoposide, teniposide
-G2: bleomycin, etoposide, teniposide
-M: micro
6-mercaptopurine (6-MP), Azathioprine, 6-thioguanine (6-TG) mechanism
-Purine (thiol) analogs leading to decreasedde novo purine synthesis.
-Activated by HGPRT. Azathioprine is metabolized into 6-MP.
6-mercaptopurine (6-MP), Azathioprine, 6-thioguanine (6-TG) clinical use
Preventing organ rejection, rheumatoid arthritis, IBD, SLE; used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease.
6-mercaptopurine (6-MP), Azathioprine, 6-thioguanine (6-TG) toxicity
-Myelosuppression, GI, liver.
-Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have increase toxicity with allopurinol or febuxostat.
Cladribine (2-CDA) (mechanism, use, toxicity)
-Mechanism: purine analog - multiple mechanisms (e.g., inhibition of DNA polymerase, DNA strand breaks).
-Use: hairy cell leukemia.
-Toxicity: myelosuppression, nephrotoxicity, and neurotoxicity.
Cytarabine (mechanism, use, toxicity)
-Mechanism: pyrimidine analog inhibition of DNA polymerase.
-Use: leukemias (AML), lymphomas.
-Toxicity: leukopenia, thrombocytopenia, megaloblastic anemia. Cytarabine causes pancytopenia
5-fluorouracil (5-FU) mechanism
-Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid.
-This complex inhibits thymidylate synthase decreasing dTMP and decreasing DNA synthesis.
5-fluorouracil (5-FU) use
Colon cancer, pancreatic cancer, basal cell carcinoma (topical)
5-fluorouracil (5-FU) toxicity
Myelosuppression, which is not reversible with leucovorin (folinic acid)
Methotrexate (MTX) mechanism
Folic acid analog that competitively inhibits dihydrofolate reductase decreasing dTMP and decreasing DNA synthesis.
Methotrexate (MTX) use
-Cancers: leukemias (ALL), lymphomas, choriocarcinoma, sarcomas.
-Non-neoplastic: ectopic pregnancy, medical abortion (with misoprostol), rheumatoid arthritis, psoriasis, IBD, vasculitis.
Methotrexate (MTX) toxicity
-Myelosuppression, which is reversible with leucovorin "rescue."
-Hepatotoxicity.
-Mucositis (e.g., mouth ulcers).
-Pulmonary fibrosis.
Bleomycin (mechanism, use, toxicity)
-Mechanism: induces free radical formation causing breaks in DNA strands.
-Use: testicular cancer, Hodgkin lymphoma.
-Toxicity: Pulmonary fibrosis, skin hyperpigmentation, mucositis, minimal myelosuppression.
Dactinomycin/actinomycin D (mechanism, use, toxicity)
-Mechanism: intercalates in DNA.
-Use: Wilms tumor, Ewing sarcoma, rhabdomyosarcoma. **Used for childhood tumors ("children act out").
-Toxicity: myelosuppression.
Doxorubicin, daunorubicin (mechanism, use, toxicity)
-Mechanism: generate free radicals. Intercalate in DNA causing breaks in DNA decreasing replication.
-Use: solid tumors, leukemias, lymphomas.
-Toxicity: cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. Toxic to tissues following extra
What is used to prevent cardiotoxicity with doxorubicin?
Dexrazoxane (iron chelating agent)
Busulfan (mechanism, use, toxicity)
-Mechanism: cross-links DNA.
-Use: CML. Also used to ablate patient's bone marrow before bone marrow transplantation.
-Toxicicty: severe myelosuppression (in almost all cases), pulmonary fibrosis, hyperpigmentation
Cyclophosphamide, ifosfamide (mechanism, use, toxicity)
-Mechanism: cross-link DNA at guanine N-7. Require bioactivation by liver.
-Use: solid tumors, leukemia, lymphomas.
-Toxicity: myelosuppression; hemorrhagic cystitis, partially prevented with mesna (thiol group of mesna binds toxic metabolites).
Nitrosoureas (drugs, mechanism, use, toxicity)
Carmustine, lomustine, semustine, streptozocin
-Mechanism: require bioactivation. Cross blood-brain barrier into CNS. Cross-link DNA.
-Use: brain tumors (including glioblastoma multiforme).
-Toxicity: CNS toxicity (convulsions, dizziness, ataxia)
Paclitaxel, other taxols (mechanism, use, toxicity)
-Mechanism: hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur). "It is taxing to stay polymerized."
-Use: ovarian and breast carcinomas.
Toxicity: myelosuppression, alopecia, hypersensitivi
Vincristine, vinblastine (mechanism, use, toxicity)
-Mechanism: vinca alkaloids that bind ?-tubulin and inhibit its polymerization into microtubules preventing mitotic spindle formation (M-phase arrest).
-Use: Solid tumors, leukemias, Hodgkin (vinblastine) and non-Hodgkin (vincristine) lymphomas.
-Toxicity
Cisplatin, carboplatin (mechanism, use, toxicity)
-Mechanism: cross-link DNA.
-Use: testicular, bladder, ovary, and lung carcinomas.
-Toxicity: nephrotoxicity, ototoxicity. Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride (saline) diuresis.
How do you prevent nephrotoxicity when taking cisplatin?
With amifostine, a free radical scavenger, and chloride (saline) diuresis.
Etoposide, teniposide (mechanism, use, toxicity)
-Mechanism: etoposide inhibits topoisomerase II causing increased DNA degradation.
-Use: solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas.
-toxicity: myelosuppression, GI upset, alopecia.
Irinotecan, topotecan (mechanism, use, toxicity)
-Mechanism: inhibit topoisomerase I and prevent DNA unwinding and replication.
-Use: colon cancer (irinotecan); ovarian and small cell lung cancers (topotecan).
-Toxicity: severe myelosuppression, diarrhea.
Hydroxyurea (mechanism, use, toxicity)
-Mechanism: inhibits ribonucleotide reductase decreasing DNA Synthesis (S-phase specific).
-Use: melanoma, CML, sickle cell disease ( HbF).
-Toxicity: severe myelosuppression, GI upset.
Prednisone, prednisolone (mechanism, use, toxicity)
-Mechanism: various; bind intracytoplasmic receptor; alter gene transcription.
-Use: most commonly used glucocorticoids in cancer chemotherapy. Used in CLL, non-Hodgkin lymphoma (part of combination chemotherapy regimen). Also used as immunosuppressants (
Bevacizumab (mechanism, use, toxicity)
-Mechanism: monoclonal antibody against VEGF. Inhibits angiogenesis.
-Use: solid tumors (colorectal cancer, renal cell carcinoma).
-Toxicity: hemorrhage, blood clots, and impaired wound healing.
Erlotinib (mechanism, use, toxicity)
-Mechanism: EGFR tyrosine kinase inhibitor.
-Use: non-small cell lung carcinoma.
-Toxicity: rash.
Imatinib (mechanism, use, toxicity)
-Mechanism: tyrosine kinase inhibitor of BCR-ABL (Philadelphia chromosome fusion gene in CML) and c-kit (common in GI stromal tumors).
Use: CML, GI stromal tumors.
-Toxicity: fluid retention.
Rituximab (mechanism, use, toxicity)
-Mechanism: monoclonal antibody against CD20, which is found on most B-cell neoplasms.
-Use: non-Hodgkin lymphoma, CLL, IBD, rheumatoid arthritis.
Toxicity: increased risk of progressive multifocal leukoencephalopathy.
Tamoxifen, raloxifene (mechanism, use, toxicity)
-Mechanism: selective estrogen receptor modulators (SERMs)�receptor antagonists in breast and agonists in bone. Block the binding of estrogen to ER ? cells.
-Use: breast cancer treatment (tamoxifen only) and prevention. Raloxifene also useful to prevent o
Difference between tamofixen and raloxifene?
Tamoxifen has increased risk of endometrial carcinoma whereas raloxifene does not because it is an estrogen receptor antagonist in endometrial tissue
Trastuzumab (Herceptin) (mechanism, use, toxicity)
-Mechanism: monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor. Helps kill cancer cells that overexpress HER-2, through inhibition of HER2-initiated cellular signaling and antibody- dependent cytotoxicity.
-Use: HER-2 ? breast cancer
Vemurafenib (mechanism, use)
-Mechanism: small molecule inhibitor of BRAF oncogene ? melanoma
-Use: metastatic melanoma.
Common chemotoxicities (chemo-tox man)
-Cisplatin/Carboplatin acoustic nerve damage (and nephrotoxicity)
-Vincristine peripheral neuropathy
-Bleomycin, Busulfan: pulmonary fibrosis
-Doxorubicin: cardiotoxicity
-Trastuzumab cardiotoxicity
-Cisplatin/Carboplatin: nephrotoxic (and
acoustic nerve
Inflammatory mediators image
Acetaminophen (mechanism, use, toxicity)
-Mechanism: reversibly inhibits cyclooxygenase, mostly in CNS. Inactivated peripherally.
-Use: antipyretic, analgesic, but not anti-inflammatory. Used instead of aspirin to avoid Reye syndrome in children with viral infection.
-Toxicity: overdose produces
What is the antidote to acetaminophen toxicity?
N-acetylcysteine - regenerates glutathione
Aspirin (mechanism, use, toxicity)
-Mechanism: irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) via acetylation, which synthesis of TXA2 and prostaglandins. bleeding time. No effect on PT, PTT. A type of NSAID.
-Use: low dose (< 300 mg/day): platelet aggregation. Intermediate do
Celecoxib (mechanism, use, toxicity)
-Mechanism: reversibly inhibits specifically the cyclooxygenase (COX) isoform 2, which is found in inflammatory cells and vascular endothelium and mediates inflammation and pain; spares COX-1, which helps maintain gastric mucosa. Thus, does not have the c
NSAIDs (drugs, mechanism, use, toxicity)
Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac.
-Mechanism: reversibly inhibit cyclooxygenase (both COX-1 and COX-2). Block prostaglandin synthesis.
-Use: antipyretic, analgesic, anti-inflammatory. Indomethacin is used to close a PDA.
-Toxicity:
Bisphosphonates (drugs, mechanism, use, toxicity)
Alendronate, other -dronates.
-Mechanism: pyrophosphate analogs; bind hydroxyapatite in bone, inhibiting osteoclast activity.
-Use: osteoporosis, hypercalcemia, Paget disease of bone.
-Toxicity: corrosive esophagitis (patients are advised to take with wat
Teriparatide (mechanism, use, toxicity)
-Mechanism: recombinant PTH analog given subcutaneously daily. Increases osteoblastic activity.
-Use: osteoporosis. Causes increase bone growth compared to antiresorptive therapies (e.g., bisphosphonates). -Toxicity: transient hypercalcemia. May increase
Chronic gout drugs
Allopurinol, febuxostat, pegloticase, probenecid
Allopurinol
-Gout
-Inhibits xanthine oxidase after being converted to alloxanthine, decrease conversion of xanthine to uric acid. Also used in lymphoma and leukemia to prevent tumor lysis-associated urate nephropathy. Increase concentrations of azathioprine and 6-MP
Febuxostat
-Gout
-Inhibits xanthine oxidase
Pegloticase
-Gout
-Recombinant uricase that catalyze metabolism of uric acid into allantoin (a more water soluble product)
Probenecid
Inhibits reabsorption of uric acid in proximal convoluted tubule (also inhibits secretion of penicillin). Can precipitate uric acid calculi.
Gout drugs general diagram
Acute gout drugs
NSAIDs (naproxen, indomethacin), glucocorticoids, colchicine
Colchicine
-Acute gout
-Binds and stabilizes tubulin to inhibit microtubule polymerization, impairing neutrophil chemotaxis and degranulation.
-Acute and prophylactic value. GI side effects.
TNF-? inhibitors
All TNF-? inhibitors predispose to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.
Etanercept
-Mechanism: fusion protein (receptor for TNF-? + IgG1 Fc), produced by recombinant DNA. Etanercept is a TNF decoy receptor.
-Use: rheumatoid arthritis, psoriasis, ankylosing spondylitis
Infliximab, adalimumab
-Mechanism: anti-TNF-? monoclonal antibody.
-Use: inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriasis
Goal of glaucoma drugs
Decrease IOP via reducing amount of aqueous humor (inhibit synthesis/secretion or increase drainage)
Epinephrine (?1 agonist) as a glaucoma drug
-Mechanism: decrease aqueous humor synthesis via vasoconstriction
-Side effects: mydriasis (?1); do not use in closed-angle glaucoma. Blurry vision, ocular hyperemia, foreign body sensation, ocular allergic reactions, ocular pruritus
Brimonidine (?2 agonist)
Decrease aqueous humor synthesis
?-blockers as glaucoma drugs (drugs, mechanism, side-effects)
Timolol, betaxolol, carteolol
-Mechanism: decreased aqueous humor synthesis
-Side effects: No pupillary or vision changes
Acetazolamide as a glaucoma drug
-Mechanism: diuretic; decrease aqueous humor synthesis via inhibition of carbonic anhydrase
-No pupillary or vision changes
Direct cholinomimetics as glaucoma drugs
Pilocarpine, carbachol
-Mechansism: increase outflow of aqueous humor via contraction of ciliary muscle and opening of trabecular meshwork
-Use pilocarpine in emergencies�very effective at opening meshwork into canal of Schlemm
-Side effects: miosis and c
Indirect cholinomimetics as glaucoma drugs
Physostigmine, echothiophate
-Mechanism: increase outflow of aqueous humor via contraction of ciliary muscle and opening of trabecular meshwork
-Side effects: miosis and cyclospasm (contraction of ciliary muscle)
Latanoprost (PGF2?) as a glaucoma drug
-Decrease outflow of aqueous humor
-Side effect: darkens color of iris (browning)
Morphine mechanism
Act as agonists at opioid receptors (? = full, ? = full, decreased potency) to modulate synaptic transmission�open K+ channels, close Ca2+ channels decreasing synaptic transmission.
Morphine clinical use
Relief of Moderate-Severe Acute & Chronic Pain associated with: Cancer, MI (vasodilating properties), Relief of Dyspnea (caused by acute LV failure & pulmonary edema), Preanesthetic Medication
Adverse effects of morphine
-CSA Schedule 2 drug
-Behavioral restlessness, tremulousness, hyperactivity, respiratory depression, N/V, ?intracranial pressure, postural HoTN accentuated by hypovolemia, constipation, urinary retention, itching around nose, urticaria
-CI: concomitant us
Methadone mechanism
Full agonist at ? receptor; NMDA receptor antagonist and MAOI
Methadone use
-Opioid abuse
-Increasingly Recognized as a useful analgesic (can be used in opioid rotation)
Methadone side effects
-CSA Schedule 2 drug
-Same as morphine, plus prolonged QT interval, and cardiac arrhythmia.
-CI: ?metabolism (by drug-drug interaction or impaired hepatic function) ?risk of respiratory depression & cardiac adverse effects. Potential for drug-drug interac
Meperidine mechanism
Full agonist at ? receptor with antimuscarinic effects
Meperidine use
No longer first line analgesic due to high adverse effect profile
Meperidine adverse effects
-CSA Schedule 2
-Drug-drug interactions w/ MAOIs & SSRIs (due to weak inhibition of serotonin reuptake and/or inhibition of hepatic CYP enzymes)? Serotonin Syndrome, Coma, Death
-Use w/ MAOIs (or 2 weeks after) is CI
Fentanyl mechanism
Full agonist at ? receptor
Fentanyl use
-One of the Most Used Synthetic Opioids
-Relief of Moderate-Severe Pain
-Anesthetic Adjuvant (Preoperative Analgesia)
-Postoperative or Labor Analgesia (Epidural)
-Chronic Pain (Patch)
-Breakthrough in Cancer pain (Oral Lozenge)
Fentanyl adverse effects
-CSA Schedule 2
-As for morphine (except histamine release)
-Chest muscle rigidity if infused IV too fast
-CI: As for morphine
-Use w/ MAOIs (or 2 weeks afterwards)
Partial agonist at ? receptor
codeine and hydrocodone
Codeine (mechanism, use, adverse effects)
-Mechanism: partial agonist at ? receptor; biotransformed into a number of active metabolites: morphine (<10%)
-Use: relief of moderate pain; antitussive in selected patients (at doses much less than needed for analgesia)
-Adverse effects: same as morphin
Hydrocodone (mechanism, use, adverse effects)
-Mechanism: partial agonist at ? receptor; partially biotransformed to hydromorphone
-Use: in combination w/ acetaminophen for relief of mild-moderate pain (MC prescribed generic drug); antitussive in selected patients (doses are ?than needed for analgesi
Pentazocine (mechanism, use, adverse effects)
-Mechanism: partial agonist at ? receptor and full agonist at ? receptor
-Use: relief of moderate to severe pain; preoperative sedative and supplement to anesthesia
-Adverse effects: as for morphine (except CVS effects), HTN, tachycardia (opposite to morp
Buprenorphine (mechanism, use, adverse effects)
-Mechanism: partial agonist at ? receptor and full antagonist at ? and ? receptor. Prolonged actions: slow dissociation from ? receptors which also reduces naloxone antagonism; highly lipophilic
-Use: relief of moderate-severe pain (acute=IM, chronic=tran
Naloxone (mechanism, use, adverse effects)
-Mechanism: antagonist at all opioid receptor sites
-Use: treatment of acute opioid overdose; low dose treatment for adverse effects of opioid agonist delivered IV or epidural
-Adverse effects: can precipitate withdrawal syndrome in individuals already re
Naltrexone (mechanism, use, adverse effects)
-Mechanism: antagonist at all opioid receptors
-Use: alcohol dependence treatment; maintenance treatment to prevent relapse in opioid dependent patients.
-Adverse effects: multiple effects including CNS, hepatic & injection site effects; can precipitate w
Tramadol (mechanism, use, adverse effects)
-Mechanism: inhibition of serotonin & NE reuptake (main mechanism); ? receptors (partial agonist)? analgesic effect only partially inhibited by naloxone
-Use: mild to moderate pain; chronic neuropathic pain (can be insensitive to opioids)
-Adverse effects
Butorphanol (mechanism, use, toxicity)
-Mechanism: ?-opioid receptor agonist and ?-opioid receptor partial agonist; produces analgesia.
-Use: severe pain (e.g., migraine, labor). Causes less respiratory depression than full opioid agonists.
-Toxicity: can cause opioid withdrawal symptoms if pa
Ethosuximide (mechanism, use, side effects)
-Mechanism: blocks thalamic T-type Ca2+ channels
-Use: Absence seizures (Sux to have Silent (absence) Seizures)
-Side effects:
Stevens-Johnson syndrome
, GI, fatigue, headache, urticaria,
Benzodiazepines as anti-epileptic (diazepam, lorazepam)(mechanism, use, side effects)
-Mechanism: increase GABA-A action
-Use: first line for acute status epilepticus. Also for eclampsia seizures (1st line is MgSO4)
-Adverse effects: sedation, tolerance, dependence, respiratory depression
Phenytoin (mechanism, use, side effects)
-Mechanism: Increase Na+ channel inactivation, zero order kinetics
-Use: all seizure types except for absence; first line tonic-clonic; first line prophylaxis for status epilepticus
-Adverse effects: gingival hyperplasia, hirsutism, peripheral neuropathy,
Carbamazepine (mechanism, use, side effects)
-Mechanism: increase Na+ channel inactivation
-Use: first line for simple, complex, and tonic-clonic seizures. 1st line for trigeminal neuralgia
-Side effects: blood dyscrasias (agranulocytosis, aplastic anemia), liver toxicity, teratogenesis, induction o
Valproic acid/valproate (mechanism, use, side effects)
-Mechanism: increase Na+ channel inactivation, increase GABA concentration by inhibiting GABA transaminase; action at the T-type Ca2+ channels
-Use: all seizure types except for status epilepticus; first line for tonic-clonic; also used for myoclonic seiz
Gabapentin (mechanism, use, side effects)
-Mechanism: primarily inhibits high- voltage-activated Ca2+ channels; designed as GABA analog
-Use: partial (focal) seizures - simple and complex. Also used for peripheral neuropathy, postherpetic neuralgia
-Adverse effects: sedation and ataxia
Phenobarbital (mechanism, use, side effects)
-Mechanism: increased GABA-A receptor action (keeps receptor open longer)
-Use: simple, complex, and tonic-clonic seizures; 1st line in neonates
-Adverse effects: sedation, tolerance, dependence, induction of cytochrome P-450, cardiorespiratory depression
Topiramate (mechanism, use, side effects)
-Mechanism: blocks Na+ channels, increases GABA action
-Use: simple, complex, and tonic-clonic seizures; also used for migraine prevention
-Adverse effects: sedation, mental dulling, kidney stones, weight loss
Lamotrigine (mechanism, use, side effects)
-Mechanism: blocks voltage gated Na+ channels
-Use: all seizure types except for status epilepticus
-Adverse effects:
Stevens-Johnson syndrome
(titrate slowly)
Levetiracetam (mechanism, use, side effects)
-Mechanism: largely unknown; but drug binds to a synaptic vesicle glycoprotein, SV2A, and inhibits presynaptic calcium channels reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses
Tiagabine (mechanism, use, side effects)
-Mechanism: increase GABA by inhibiting reuptake
-Use: partial (focal) seizures - simple and complex
-No notable side effects
Vigabatrin (mechanism, use, side effects)
-Mechanism: increase GABA by irreversibly inhibiting GABA transaminase
-Use: partial (focal) seizures - simple and complex
-No notable side effects
What is Stevens-Johnson syndrome and which epilepsy drugs can cause it?
-SJ syndrome is a prodrome of malaise and fever followed by a rapid onset of erythematous/purpuric macules (oral, ocular, genital). Skin lesions progress to epidermal necrosis and sloughing
-Drugs that can cause this horrific motha ****a: lamotragine, car
Drugs for simple seizure
-Carbamazepine is 1st choice
-All other epilepsy drugs can be used except for ethosuxamide and the benzodiazepines
Drugs for complex seizure
-Carbamazepine is 1st choice
-All other epilepsy drugs can be used except for ethosuxamide and the benzodiazepines
Drugs for tonic-clonic seizure
-Carbamazepine, valproate, and phenytoin are 1st choice
-Phenobarbital, lamotragine, topiramate, and levetiracetam can all be used 2nd line
Drugs for absence seizures
-Ethosuxamide is 1st line
-Lamotragine and valproate may also be used
Drugs for status epilepticus
-Benzodiazepines (diazepam, lorazepam) are first line for acute
-Phenytoin is first line prophylaxis
Barbiturates (drugs, mechanism, use, toxicity)
Phenobarbital, pentobarbital, thiopental, secobarbital
-Mechanism: facilitate GABA-A action by increasing duration of Cl? channel opening, thus decreasing neuron firing (barbidurates increase duration). Contraindicated in porphyria.
-Use:sedative for anxi
Benzodiazepines (drugs, mechanism, use, toxicity)
Diazepam, lorazepam, triazolam, temazepam, oxazepam, midazolam, chlordiazepoxide, alprazolam
-Mechanism: Facilitate GABA-A action by increasinf the frequency of Cl? channel opening. Decrease REM sleep. Most have long half-lives and active metabolites (exc
Nonbenzodiazepine hypnotics (drugs, mechanism, use, toxicity)
Zolpidem, Zaleplon, esZopiclone. "All ZZZs put you to sleep."
-Mechanism: act at BZI subtype of the GABA receptor;
-Use: insomnia
-Toxicity: ataxia, headaches, confusion. Short duration because of rapid metabolism by liver enzymes. Unlike older sedative-h
What is the ultra-short acting barbiturate used in IV anesthesia?
Thiopental
Remember "Thio Hucksable had an ultra short acting career
What are the 4 intermediate acting benzos?
Alprozolam, lorazepam, oxzepam, temazepam
Which benzos are used in the elderly?
Lorazepam, oxazepam, temazepam
"The elderly like Benzos a LOT
Flumazenil (mechanism, use, toxicity)
-Mechanism: : competitive BZ receptor antagonist that can block the effects of BZ and any drug that binds to the BZ site, including the Z drugs. Does not block effects of other sedative hypnotics: alcohol, barbiturates or buspirone
-Use: antidote to exces
Buspirone (mechanism, use, toxicity)
-Mechanism: partial agonist at 5-HT 1A, acts as agonist when 5-HT is low and an antagonist when 5-HT is high; may also have effects on D2 receptors; uses P450 enzyme system for elimination; onset of action takes 1-2 weeks; does not work through GABA syste
Zaleplon (mechanism, use, toxicity)
-Mechanism: agonist at GABA-A ?1-subunit (omega 1 receptor); ?melatonin; shortens sleep latency
-Use: Can be used in middle of the night Tx (4 hours prior to wakening); used for people w/ difficulty falling asleep but normally stay asleep; effective up to
Zolpidem (mechanism, use, toxicity)
-Mechanism: selective agonist at GABA-A ?1-site; shortens sleep latency, prolongs sleep time; onset w/in 30 minutes; extended release available? 7 hours of sleep; T �: 2-4 hours; greater in hepatic insufficiency & the elderly
-Use: approved for bedtime us
Eszopiclone (mechanism, use, toxicity)
-Mechanism: agonist at GABA-A ?1-subunit (S-isomer of zopiclone); shortens sleep latency & ?sleep time;
improves daytime alertness
ss*, gives full night sleep 7-8 hours, effective for 6-12 months
-Use: only Z drug approved for long-term use
-Can use inter
Ramelteon (mechanism, use, toxicity)
-Mechanism: melatonin agonist (MT1 & 2); shortens sleep latency
-Use: may be used in the elderly, ICU & those who travel
-No bad side effects, tolerance or dependency
Drugs with solubility in blood =
Rapid induction and recovery times.
Drugs with solubility in lipids =
increased potency = 1 / MAC
MAC
-Minimal Alveolar Concentration (of inhaled anesthetic) required to prevent 50% of subjects from moving in response to noxious stimulus (e.g., skin incision).
-Examples: nitrous oxide (N2O) has blood and lipid solubility, and thus fast induction and low p
Inhaled anesthetics (drugs, mechanism, use, toxicity)
Halothane, enflurane, isoflurane, sevoflurane, methoxyflurane, N2O
-Mechanism: unknown.
-Use: myocardial depression, respiratory depression, nausea/emesis, cerebral blood flow ( cerebral metabolic demand).
-Toxicity: hepatotoxicity (halothane), nephrotoxi
Most common drug used for endoscopy?
Midazolam; used adjunctively with gaseous anesthetics and narcotics. May cause severe postoperative respiratory depression, BP (treat overdose with flumazenil), anterograde amnesia.
Arylcyclohexylamines (Ketamine)
PCP analogs that act as dissociative anesthetics. Block NMDA receptors. Cardiovascular stimulants. Cause disorientation, hallucination, bad dreams. cerebral blood flow.
Propofol
Used for sedation in ICU, rapid anesthesia induction, short procedures. Less postoperative nausea than thiopental. Potentiates GABA-A
Esters (local anesthetics)
Procaine, cocaine, tetracaine
Amides (local anesthetics)
Lidocaine, mepIvacaIne, bupIvacaIne
(amIdes have 2 I's in name)
Local anesthetics mechanism
Block Na+ channels by binding to specific receptors on inner portion of channel. Preferentially bind to activated Na+ channels, so most effective in rapidly firing neurons. 3� amine local anesthetics penetrate membrane in uncharged form, then bind to ion
Why give a local anesthetic with vasoconstrictors?
Enhance local action - decrease bleeding, increase anesthesia by decreasing systemic concentration
Local anesthetic and infected tissue?
Infected tissue is acidic, thus alkaline anesthetics are charged and cannot penetrate the membrane effectively - need more anesthetic
Order of nerve bockade
small-diameter fibers > large diameter. Myelinated fibers > unmyelinated fibers. Overall, size factor predominates over myelination such that small myelinated fibers
> small unmyelinated fibers > large myelinated fibers > large unmyelinated fibers
Order of loss with local anesthetic
1. pain 2. temp 3. touch 4. pressure
Clinical use of local anesthetics
Minor surgical procedures, spinal anesthesia. If allergic to esters, give amides
Local anesthetic toxicity
CNS excitation, severe cardiovascular toxicity (bupivacaine), hypertension, hypotension, arrhythmias (cocaine), methemoglobinemia (benzocaine).
Neuromuscular blocking drugs
Muscle paralysis in surgery or mechanical ventilation. Selective for motor (vs. autonomic) nicotinic receptor.
Depolarizing neuromuscular blocking drugs
Succinylcholine�strong ACh receptor agonist; produces sustained depolarization and prevents muscle contraction
Reversal of blockade of depolarizing neuromuscular blocking drugs
-Phase I (prolonged depolarization)�no antidote. Block potentiated by cholinesterase inhibitors.
-Phase II (repolarized but blocked; ACh receptors are available, but desensitized)�antidote is cholinesterase inhibitors.
Complications of depolarizing neuromuscular blocking drugs
Complications include hypercalcemia, hyperkalemia, malignant hyperthermia.
Nondepolarizing neuromuscular blocking drugs
Tubocurarine, atracurium, mivacurium, pancuronium, vecuronium, rocuronium�competitive antagonists�compete with ACh for receptors.
Nondepolarizing neuromuscular blocking drugs blockade reversal
Neostigmine (must be given with atropine to prevent muscarinic effects such as bradycardia), edrophonium, and other cholinesterase inhibitors.
Dantrolene
-Mechanism: prevents release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle.
-Use: malignant hyperthermia and neuroleptic malignant syndrome (a toxicity of antipsychotic drugs).
Baclofen
-Mechanism: inhibits GABA-B receptors at spinal cord level, inducing skeletal muscle relaxation.
-Use: muscle spasms (e.g., acute low back pain).
Cyclobenzaprine
-Mechanism: centrally acting skeletal muscle relaxant. Structurally related to TCAs, similar anticholinergic side effects.
-Use: muscle spasms
Dopamine agonists
Ergot�Bromocriptine
Non-ergot (preferred)�pramipexole, ropinirole
Amantadine
-Mechanism: increase dopamine release and decrease dopamine reuptake)
-Use: Parkinson disease; also used as an antiviral against influenza A and rubella
-Toxicity: ataxia, livedo reticularis
Levodopa (L-dopa)/carbidopa
-Mechanism: carbidopa blocks peripheral conversion of L-DOPA to dopamine by inhibiting DOPA decarboxylase. Also reduces side effects of peripheral L-dopa conversion into dopamine (e.g., nausea, vomiting).
-Use: Parkinson disease therapy
Entacapone, tolcapone
-Mechanism: prevent peripheral L-dopa degradation to 3-O-methyldopa (3-OMD) by inhibiting COMT
-Use: Parkinson disease therapy
Selegiline
-Mechanism: blocks conversion of dopamine
into 3-MT by selectively inhibiting MAO-B.
-Use: Parkinson disease therapy
Tolcapone
-Mechanism: blocks conversion of dopamine to DOPAC by inhibiting central COMT
-Use: Parkinson disease therapy
Benztropine
-Mechanism: antimuscarinic; improves tremor and rigidity but has little effect on bradykinesia
-Use: Parkinson disease therapy
Parkinson disease drugs schematic
l-dopa (levodopa)/carbidopa
-Mechanism: increase level of dopamine in brain. Unlike dopamine, l-dopa can cross blood-brain barrier and is converted by dopa decarboxylase in the CNS to dopamine. Carbidopa, a peripheral DOPA decarboxylase inhibitor, is given with l-dopa to the bioavai
Memantine
-Mechanism: NMDA receptor antagonist; helps prevent excitotoxicity (mediated by Ca2+).
-Use: Alzheimer disease
-Toxicity: dizziness, confusion, hallucinations
Donepezil, galantamine, rivastigmine, tacrine
-Mechanism: AChE inhibitors
-Use: Alzheimer disease
-Toxicity: nausea, dizziness, insomnia
Treatment of Huntington disease
-Neurotransmitter changes in Huntington disease: decrease GABA, decrease ACh, increase dopamine.
-Treatments: 1. tetrabenazine and reserpine�inhibit vesicular monoamine transporter (VMAT); limit dopamine vesicle packaging and release; 2. haloperidol�D2 re
Sumatriptan
-Mechanism: 5-HT1B/1D agonists. Inhibit trigeminal nerve activation; prevent vasoactive peptide release; induce vasoconstriction.
-Use: acute migraine, cluster headache attack
-Toxicity: Coronary vasospasm (contraindicated in patients with CAD or Prinzmet
Nonspecific depressant intoxication
Mood elevation, anxiety, sedation, behavioral disinhibition, respiratory depression.
Nonspecific depressant withdrawal
Anxiety, tremor, seizures, insomnia
Alcohol intoxication
Emotional lability, slurred speech, ataxia, coma, blackouts. Serum ?-glutamyltransferase (GGT)�sensitive indicator of alcohol use. AST value is twice ALT value.
Alcohol withdrawal
Mild alcohol withdrawal: symptoms similar to other depressants. Severe alcohol withdrawal can cause autonomic hyperactivity and DTs (5-15% mortality rate). Treatment for DTs: benzodiazepines.
Opioids (e.g., morphine, heroin, methadone) intoxication
Euphoria, respiratory and CNS depression,
gag reflex, pupillary constriction (pinpoint pupils), seizures (overdose).
Treatment: naloxone, naltrexone.
Opioids (e.g., morphine, heroin, methadone) withdrawal
Sweating, dilated pupils, piloerection ("cold turkey"), fever, rhinorrhea, yawning, nausea, stomach cramps, diarrhea ("flu-like" symptoms). Treatment: long-term support, methadone, buprenorphine.
Barbiturates intoxication
Low safety margin, marked respiratory depression. Treatment: symptom management (e.g., assist respiration, BP).
Barbiturates withdrawal
Delirium, life-threatening cardiovascular collapse.
Benzodiazepines intoxication
-Greater safety margin that barbiturates; ataxia, minor respiratory depression.
-Treatment: flumazenil (benzodiazepine receptor antagonist, but rarely used as it can precipitate seizures).
Benzodiazepines withdrawal
Sleep disturbance, depression, rebound anxiety, seizure
Nonspecific stimulant intoxication
Mood elevation, psychomotor agitation, insomnia, cardiac arrhythmias, tachycardia, anxiety.
Nonspecific stimulant withdrawal
post-use "crash," including depression, lethargy, weight gain, headache
Amphetamines intoxication
Euphoria, grandiosity, pupillary dilation, prolonged wakefulness and attention, hypertension, tachycardia, anorexia, paranoia, fever. Severe: cardiac arrest, seizure
Amphetamines withdrawal
Anhedonia, appetite, hypersomnolence, existential crisis.
Cocaine intoxication
Impaired judgment, pupillary dilation, hallucinations (including tactile), paranoid ideations, angina, sudden cardiac death. Treatment: ?-blockers, benzodiazepines. ?-blockers not recommended.
Cocaine withdrawal
Hypersomnolence, malaise, severe psychological craving, depression/suicidality.
Caffeine intoxication
Restlessness, increase diuresis, muscle twitching
Caffeine withdrawal
Lack of concentration, headache
Nicotine intoxication
Restlessness
Nicotine withdrawal
Irritability, anxiety, craving. Treatment: nicotine patch, gum, or lozenges; bupropion/ varenicline
PCP intoxication
Belligerence, impulsivity, fever, psychomotor agitation, analgesia, vertical and horizontal nystagmus, tachycardia, homicidality, psychosis, delirium, seizures. Treatment: benzodiazepines, rapid-acting antipsychotic
PCP withdrawal
Depression, anxiety, irritability, restlessness, anergia, disturbances of thought and sleep.
LSD intoxication
Perceptual distortion (visual, auditory), depersonalization, anxiety, paranoia, psychosis, possible flashbacks.
Marijuana intoxication
Euphoria, anxiety, paranoid delusions, perception of slowed time, impaired judgment, social withdrawal, appetite, dry mouth, conjunctival injection, hallucinations. Pharmaceutical form is dronabinol (tetrahydrocannabinol isomer): used as antiemetic (chemo
Marijuana withdrawal
Irritability, depression, insomnia, nausea, anorexia. Most symptoms peak in 48 hours and last for 5-7 days. Generally detectable in urine for up to 1 month.
DOC for ADHD
Stimulants (e.g. methylphenidate)
DOC for alcohol withdrawal
Long-acting benzodiazepine (e.g. chlordiazepoxide, lorazepam, diazepam)
DOC for bipolar disorder
Lithium, valproic acid, atypical antipsychotics
DOC for bulimia
SSRIs
DOC for depression
SSRIs
DOC for generalized anxiety disorder
SSRIs, SNRIs
DOC for OCD
SSRIs, clomipramine
DOC for panic disorder
SSRIs, venlafaxine, benzodiazepines
DOC for PTSD
SSRIs, venlafaxine
DOC for schizophrenia
Atypical antipsychotics
DOC for social phobias
SSRIs, ?-blockers
DOC for Tourette syndrome
Antipsychotics(e.g. fluphenazine, pimozide), tetrabenazine, clonidine
Methylphenidate
-Mechanism: ?dopamine & NE tone by blocking their reuptake & facilitating their release;
-Use: ADHD; narcolepsy
Amphetamine
-Mechanism: ?dopamine & NE tone by blocking their reuptake & facilitating their release
-Use: ADHD; improves attention, concentration, execution, wakefulness, hyperactivity
Lisdexamfetamine Demisylate
-Mechanism: prodrug (1xDay) for dextroamphetamine; Schedule II drug; must be absorbed & metabolized in the blood? once converted to dextroamphetamine, it ?dopamine & NE tone by blocking their reuptake & facilitating their release
-Use: ADHD
Atomoxetine
-Mechanism: selective NE reuptake inhibitor? boost NT NE & may ?dopamine (from ?NE levels) in prefrontal cortex; not a controlled stimulant; metabolized by liver (CYP450 2D6) so inhibitors ?plasma levels
-Use: ADHD; improves attention, concentration, exec
Bupropion SR
-Mechanism: boosts NE & DA, blocks reuptake sites; XL best for ADHD; inhibits CYP450 2D6
-Use: major depression, SAD, smoking cessation, ADHD
-Toxicity: peripheral NE effects: dry mouth, constipation, weight loss, anorexia, nausea; DA: insomnia, headache,
Guanfacine
-Mechanism: works like clonidine? CNS postsynaptic ?-2A receptor agonist; ?noradrenergic effects directly; phenobarbitol & phenytoin may ?plasma levels
-Use: improves attention, concentration, execution, wakefulness, hyperactivity; often used when too act
List the typical (neuroleptics) antipsychotics
Haloperidol, trifluoperazine, fluphenazine, thioridazine, chlorpromazine (haloperidol + "-azines")
Typical antipsychotic mechanism
All typical antipsychotics block dopamine D2 receptors ( [cAMP])
Typical antipsychotic use
Schizophrenia (primarily positive symptoms), psychosis, acute mania, Tourette syndrome
Typical antipsychotic toxicity
-Highly lipid soluble and stored in body fat; thus, very slow to be removed from body.
-Extrapyramidal system side effects (e.g., dyskinesias). Treatment: benztropine or diphenhydramine.
-Endocrine side effects (e.g., dopamine receptor antagonism hyperpro
High potency typical antipsychotics
Trifluoperazine, fluphenazine, haloperidol
"Try to Fly through the Halo
Side effects of high potency typical antipsychotics
-Neurologic side effects (e.g. Huntington disease, delirium, EPS symptoms)
Low potency typical antipsychotics
Chlorpromazine, thioridazine
Side effects of low potency typical antipsychotics
Non-neurologic side effects (anticholinergic, antihistamine, and ?1-blockade effects).
Side effect of chlorpromazine
Corneal deposits
Side effect of thioridazine
ReTinal deposits
Side effect of haloperidol
NMS, tardive dyskinesia
Evolution of EPS side effects
-4 hr acute dystonia (muscle spasm, stiffness,
oculogyric crisis)
-4 day akathisia (restlessness)
-4 wk bradykinesia (parkinsonism)
-4 mo tardive dyskinesia
Neuroleptic malignant syndrome (NMS)
Rigidity, myoglobinuria, autonomic instability, hyperpyrexia.
Treatment: dantrolene, D2 agonists (e.g., bromocriptine).
For NMS, think FEVER
Fever
Encephalopathy
Vitals unstable
Enzymes up
Rigidity of muscles
Tardive dyskinesia
stereotypic oral- facial movements as a result of long-term antipsychotic use.
List the atypical antipsychotics
Olanzapine, clozapine, quetiapine, risperidone, aripiprazole, ziprasidone
Atypical antipsychotics mechanism
Not completely understood. Varied effects on 5-HT2, dopamine, and ?- and H1-receptors
Atypical antipsychotics use
Schizophrenia�both positive and negative symptoms. Also used for bipolar disorder, OCD, anxiety disorder, depression, mania, Tourette syndrome.
Atypical antipsychotic toxicity
-Fewer extrapyramidal and anticholinergic side effects than traditional antipsychotics.
-Olanzapine/clozapine may cause significant weight gain. --Clozapine may cause agranulocytosis (requires weekly WBC monitoring) and seizure.
-Risperidone may increase
Lithium mechanism
-Mechanism: not established; possibly related to inhibition of phosphoinositol cascade.
Lithium use
Mood stabilizer for bipolar disorder; blocks relapse and acute manic events. Also SIADH.
Lithium toxicity
-Tremor, hypothyroidism, polyuria (causes nephrogenic diabetes insipidus), teratogenesis.
-Causes Ebstein anomaly in newborn if taken by pregnant mother.
-Narrow therapeutic window requires close monitoring of serum levels.
-Almost exclusively excreted by
Buspirone
-Mechanism: stimulates 5-HT1A receptors.
-Use: generalized anxiety disorder. Does not cause sedation, addiction, or tolerance. Takes 1-2 weeks to take effect. Does not interact with alcohol (vs. barbiturates, benzodiazepines).
Antidepressants schematic
SSRIs
Fluoxetine, paroxetine, sertraline, citalopram.
SSRIs mechanism
5-HT-specific reuptake inhibitors.
SSRIs use
-Depression, generalized anxiety disorder, panic disorder, OCD, bulimia, social phobias, PTSD.
SSRIs toxicity
Fewer than TCAs. GI distress, SIADH, sexual dysfunction (anorgasmia, decreased libido).
Serotonin syndrome
With any drug that increases 5-HT (e.g., MAO inhibitors, SNRIs, TCAs) hyperthermia, confusion, myoclonus, cardiovascular instability, flushing, diarrhea, seizures.
-Treatment: cyproheptadine (5-HT2 receptor antagonist).
How long does it take for antidepressants to have an effect?
It normally takes 4-8 weeks for antidepressants
to have an effect
SNRIs
Venlafaxine, duloxetine
SNRIs mechanism
Inhibit 5-HT and norepinephrine reuptake.
SNRIs use
Depression. Venlafaxine is also used in generalized anxiety disorder, panic disorder, PTSD. Duloxetine is also indicated for diabetic peripheral neuropathy
SNRIs toxicity
Increase BP most common; also stimulant effects, sedation, nausea.
Tricyclic antidepressants
Amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin, amoxapine.
Tricyclic antidepressants mechanism, use, and toxicity
-Mechanism: block reuptake of norepinephrine and 5-HT.
-Use: major depression, OCD (clomipramine), peripheral neuropathy, chronic pain, migraine prophylaxis.
-Toxicity: sedation, ?1-blocking effects including postural hypotension, and atropine-like (antic
Monoamine oxidase (MAO) inhibitors (drugs, mechanism, use, toxicity)
Tranylcypromine, Phenelzine, Isocarboxazid, Selegiline (selective MAO-B inhibitor)
-Mechanism: nonselective MAO inhibition increases levels of amine neurotransmitters (norepinephrine, 5-HT, dopamine).
-Use: atypical depression, anxiety.
-Toxicity: hyperte
Bupropion (use, mechanism, toxicity)
-Use: Depression; also used for smoking cessation and ADHD.
-Mechanism: increase norepinephrine and dopamine via unknown mechanism.
-Toxicity: stimulant effects (tachycardia, insomnia), headache, seizures in anorexic/bulimic patients. No sexual side effec
Mirtazapine (use, mechanism, toxicity)
-Use: depression
-Mechanism: ?2-antagonist (increase release of norepinephrine and 5-HT) and potent 5-HT2 and 5-HT3 receptor antagonist.
-Toxicity: sedation (which may be desirable in depressed patients with insomnia), increase appetite, weight gain (whic
Trazodone
-Mechanism: primarily blocks 5-HT2 and ?1-adrenergic receptors.
-Used primarily for insomnia, as high doses are needed for antidepressant effects.
-Toxicity: sedation, nausea, priapism, postural hypotension. Called trazobone due to male-specific side effe
Diuretics: sites of action schematic
Mannitol (mechanism, use, toxicity)
-Mechanism: osmotic diuretic; increase tubular fluid osmolarity - increase urine flow, decreasing intracranial/intraocular pressure.
-Use: drug overdose, elevated intracranial/intraocular pressure.
-Toxicity: pulmonary edema, dehydration. Contraindicated
Acetazolamide (mechanism, use, toxicity)
-Mechanism: carbonic anhydrase inhibitor. Causes self- limited NaHCO3 diuresis and decreased total body HCO3? stores.
-Use: glaucoma, urinary alkalinization, metabolic alkalosis, altitude sickness, pseudotumor cerebri.
-Toxicity: hyperchloremic metabolic
Loop diuretics (drugs, mechanism, use, toxicity)
Furosemide, bumetanide, torsemide
-Mechanism: sulfonamide loop diuretics. Inhibit cotransport system (Na+/K+/2Cl?) of thick ascending limb of loop of Henle. Abolish hypertonicity of medulla, preventing concentration of urine. Stimulate PGE release (vasodi
Ethacrynic acid (mechanism, use, toxicity)
-Mechanism: phenoxyacetic acid derivative (not a sulfonamide). Essentially same action as furosemide.
-Use: diuresis in patients allergic to sulfa drugs.
-Toxicity: similar to furosemide; can cause hyperuricemia; never use to treat gout
Thiazide diuretics (drugs, mechanism, use, toxicity)
Chlorthalidone, hydrochlorothiazide.
-Mechanism: inhibit NaCl reabsorption in early DCT decreasing diluting capacity of nephron. Decreased Ca2+ excretion.
-Use: hypertension, HF, idiopathic hypercalciuria, nephrogenic diabetes insipidus, osteoporosis.
-To
K+-sparing diuretics (drugs, mechanism, use, toxicity)
Spironolactone and eplerenone; Triamterene, and Amiloride.
-Mechanism: spironolactone and eplerenone are competitive aldosterone receptor antagonists in cortical collecting tubule. Triamterene and amiloride act at the same part of the tubule by blocking N
Urine NaCl changes with diuretic therapy
Increase with all diuretics except acetazolamide. Serum NaCl may decrease as a result
Urine K+ changes with diuretic therapy
Increase with loop and thiazide diuretics. Serum K+ may decrease as a result.
Diuretics that decrease blood pH (acidemia)
Carbonic anhydrase inhibitors: decrease HCO3? reabsorption. K+ sparing: aldosterone blockade prevents K+ secretion and H+ secretion. Additionally, hyperkalemia leads to K+ entering all cells (via H+/K+ exchanger) in exchange for H+ exiting cells.
Diuretics that increase blood pH (alkalemia)
Loop diuretics and thiazides cause alkalemia through several mechanisms:
-Volume contraction increase AT II increasing Na+/H+ exchange in PCT increasing HCO3? reabsorption ("contraction alkalosis")
-K+ loss leads to K+ exiting all cells (via H+/K+ exchang
Urine Ca2+ changes with diuretic therapy
-Increase with loop diuretics: decrease paracellular Ca2+ reabsorption causing hypocalcemia
-Decreases with thiazides: enhanced Ca2+ reabsorption in DCT
ACE inhibitors (drugs, mechanism, use, toxicity)
Captopril, enalapril, lisinopril, ramipril
-Mechanism: inhibit ACE -> decrease AT II -> decrease GFR by preventing constriction of efferent arterioles. Levels of renin increase as a result of loss of feedback inhibition. Inhibition of ACE also prevents in
Angiotensin II receptor blockers (ARBs) (drugs, mechanism, use, toxicity)
Losartan, candesartan, valsartan
-Mechanism: selectively block binding of angiotensin II to AT1 receptor. Effects similar to ACE inhibitors, but ARBs do not increase bradykinin.
-Use: hypertension, HF, proteinuria, or diabetic nephropathy with intolerance
Aliskiren (mechanism, use, toxicity)
-Mechanism: direct renin inhibitor, blocks conversion of angiotensinogen to angiotensin I.
-Use: hypertension
-Toxicity: hyperkalemia, decreased renal function, hypotension.
-Contraindicated in diabetics taking ACE inhibitors or ARBs.
Control of reproductive hormones schematic
Leuprolide (mechanism, use, toxicity)
-Mechanism: GnRH analog with agonist properties
when used in pulsatile fashion; antagonist properties when used in continuous fashion (downregulates GnRH receptor in pituitary causing decreased FSH/LH).
-Use: infertility (pulsatile), prostate cancer (cont
Estrogens (ethinyl estradiol, DES, mestranol) (mechanism, use, toxicity)
-Mechanism: bind estrogen receptors.
-Use: hypogonadism or ovarian failure, menstrual abnormalities, hormone replacement therapy in postmenopausal women; use in men with androgen-dependent prostate cancer.
-Toxicity: increased risk of endometrial cancer,
Clomiphene (mechanism, use, toxicity)
-Mechanism: antagonist at estrogen receptors in hypothalamus. Prevents normal feedback inhibition and
release of LH and FSH from pituitary, which stimulates ovulation.
-Use: to treat infertility due to anovulation (e.g., PCOS). ----Toxicity: may cause hot
Tamoxifen (mechanism, use, toxicity)
-Mechanism: antagonist at breast; agonist at bone, uterus;
-Used to treat and prevent recurrence of ER/PR ? breast cancer;
-Increased risk of thromboembolic events and endometrial cancer (as opposed to raloxifine)
Raloxifene (mechanism, use, toxicity)
-Mechanism: antagonist at breast, uterus; agonist at bone; -Use: primarily to treat osteoporosis
-Increased risk of thromboembolic events but no increased risk of endometrial cancer (vs. tamoxifen);
Hormone replacement therapy
-Used for relief or prevention of menopausal symptoms (e.g., hot flashes, vaginal atrophy), osteoporosis (increased estrogen, decreased osteoclast activity).
-Unopposed estrogen replacement therapy increases risk of endometrial cancer, so progesterone is
Anastrozole/ exemestane
Aromatase inhibitors used in postmenopausal women with ER ? breast cancer.
Progestins (mechanism, use)
-Mechanism: bind progesterone receptors, decrease growth and increase vascularization of the endometrium
-Used in oral contraceptives and to treat endometrial cancer, abnormal uterine bleeding.
Mifepristone (RU-486) (mechanism, use, toxicity)
-Mechanism: competitive inhibitor of progestins at progesterone receptors.
-Use: termination of pregnancy. Administered with misoprostol (PGE1).
Toxicity: heavy bleeding, GI effects (nausea, vomiting, anorexia), abdominal pain.
Oral contraception (synthetic progestins, estrogen)
-Estrogen and progestins inhibit LH/FSH and thus prevent estrogen surge. No estrogen surge, then no LH surge then no ovulation.
-Progestins cause thickening of cervical mucus, thereby limiting access of sperm to uterus. Progestins also inhibit endometrial
Terbutaline, ritodrine
?2-agonists that relax the uterus; used to contraction frequency in women during labor.
Danazol (mechanism, use, toxicity)
-Mechanism: synthetic androgen that acts as partial agonist at androgen receptors.
-Use: endometriosis, hereditary angioedema.
-Toxicity: weight gain, edema, acne, hirsutism, masculinization, decreased HDL levels, hepatotoxicity.
Testosterone, methyltestosterone (mechanism, use, toxicity)
-Mechanism: agonists at androgen receptors.
-Use: treats hypogonadism and promotes development of 2� sex characteristics; stimulation of anabolism to promote recovery after burn or injury.
-Toxicity: causes masculinization in females; decreased intratesti
Finasteride
-A 5?-reductase inhibitor ( conversion of testosterone to DHT).
-Useful in BPH and male-pattern baldness
Flutamide
-A nonsteroidal competitive inhibitor at androgen receptors.
-Used for prostate carcinoma.
Ketoconazole
Inhibits steroid synthesis (inhibits 17,20-desmolase)
Spironolactone
Inhibits steroid binding, 17?-hydroxylase, and 17,20-desmolase.
Use and side effects of ketoconazole and spironolactone
Ketoconazole and spironolactone are used to treat polycystic ovarian syndrome to reduce androgenic symptoms. Both have side effects of gynecomastia and amenorrhea
Tamsulosin
?1-antagonist used to treat BPH by inhibiting smooth muscle contraction. Selective for ?1A,D receptors (found on prostate) vs. vascular ?1B receptors
Sildenafil, vardenafil, tadalafil (mechanism, use, toxicity)
-Mechanism: inhibit PDE-5 increasing cGMP, smooth muscle relaxation in corpus cavernosum, increase blood flow, penile erection. "Sildenafil, vardenafil, and tadalafil fill the penis"
-Use: erectile dysfunction.
-Toxicity: headache, flushing, dyspepsia, cy
Minoxidil
-Mechanism: direct arteriolar vasodilator
-Use: androgenetic alopecia; severe refractory hypertension
1st generation H1 blockers
Diphenhydramine, dimenhydrinate, chlorpheniramine
1st generation H1 blockers mechanism, use, and toxicity
-Mechanism: reversible inhibitors of H1 histamine receptors.
-Use: allergy, motion sickness, sleep aid.
-Toxicity: sedation, antimuscarinic, anti-?-adrenergic.
2nd generation H1 blockers
Loratadine, fexofenadine, desloratadine, cetirizine
2nd generation H1 blockers mechanism, use, and toxicity
-Mechanism: reversible inhibitors of H1 histamine receptors.
-Use: Allergy.
-Toxicity: far less sedating than 1st generation because of decreased entry into CNS.
Guaifenesin
Expectorant�thins respiratory secretions; does not suppress cough reflex.
N-acetylcysteine
Mucolytic�can loosen mucous plugs in CF patients by disrupting disulfide bonds. Also used as an antidote for acetaminophen overdose.
Dextromethorphan
-Antitussive (antagonizes NMDA glutamate receptors).
-Synthetic codeine analog. Has mild opioid effect when used in excess.
-Naloxone can be given for overdose. Mild abuse potential. -May cause serotonin syndrome if combined with other serotonergic agents
Pseudoephedrine, phenylephrine (mechanism, use, toxicity)
-Mechanism: ?-adrenergic agonists, used as nasal decongestants.
-Use: reduce hyperemia, edema, nasal congestion; open obstructed eustachian tubes. Pseudoephedrine
also illicitly used to make methamphetamine.
-Toxicity: hypertension. Can also cause CNS sti
Endothelin receptor antagonists
-Pulmonary hypertension therapy
-Include bosentan.
-Competitively antagonize endothelin-1 receptors decreasing pulmonary vascular resistance.
-Hepatotoxic (monitor LFTs)
PDE-5 inhibitors
-Pulmonary hypertension therapy
-Include sildenafil. Inhibit cGMP PDE5 and prolong vasodilatory effect of nitric oxide. Also used to treat erectile dysfunction
Prostacyclin analogs
-Include epoprostenol, iloprost.
-Prostacyclins (PGI2) with direct vasodilatory effects on pulmonary and systemic arterial vascular beds.
-Inhibit platelet aggregation.
-Side effects: flushing, jaw pain
Bronchoconstriction is mediated by
(1) inflammatory processes and (2) parasympathetic tone; therapy is directed at these 2 pathways
Albuterol
-?2-agonists
-Relaxes bronchial smooth muscle (?2).
-Used during acute exacerbation
Salmeterol, formoterol
-?2-agonists
-Long-acting agents for prophylaxis.
-Adverse effects are tremor and arrhythmia.
Fluticasone, budesonide
-Corticosteroids
-Inhibit the synthesis of virtually all cytokines. Inactivate NF-?B, the transcription factor that induces production of TNF-? and other inflammatory agents. 1st-line therapy for chronic asthma.
Ipratropium
-Muscarinic antagonist
-Competitively blocks muscarinic receptors, preventing bronchoconstriction. Also used for COPD. Tiotropium is long acting.
Montelukast, zafirlukast
-Antileukotrienes
-Block leukotriene receptors (CysLT1).
-Especially good for aspirin-induced asthma.
Zileuton
-Antileukotrienes
-5-lipoxygenase pathway inhibitor. Blocks conversion of arachidonic acid to leukotrienes.
-Used for asthma
-Hepatotoxic
Omalizumab
-Monoclonal anti-IgE antibody. Binds mostly unbound serum IgE and blocks binding to Fc?RI.
-Used in allergic asthma resistant to inhaled steroids and long-acting ?2-agonists.
Theophylline
-Methylxanthine
-Likely causes bronchodilation by inhibiting phosphodiesterase increasing cAMP levels due to decreased cAMP hydrolysis.
-Usage is limited because of narrow therapeutic index (cardiotoxicity, neurotoxicity); metabolized by cytochrome P-450.
Methacholine
-Muscarinic receptor (M3) agonist.
-Used in bronchial challenge test to help diagnose asthma.