Penicillin
G (IV), Penicillin V (oral)
Mech: Binds PBP’s, blocks transpeptidase X-linking
of cell wall, activates autolytic enzymes
Clinical
Use: Bactericidal for Gram+ cocci, rods, and
spirochetes. NOT penicillinase resistant.
Toxicity: Hypersensitivity reactions, hemolytic anemia
Methicillin,
Nafcillin, Dicloxacillin
Mech: Same as penicillin. Narrow spectrum;
Penicillinase RESISTANT because of bulkier R group.
Clinical Use: Staph. Aureus
Toxicity: Hypersensitivity reactions; Methicillin: Interstitial
nephritis
Ampicillin,
Amoxicillin
Mech: Same as penicillin. Wider
spectrum; penicillinase sensitive. Combine with clavulanic acid
(penicillinase inhibitor) to enhance spectrum. AmOxicillin has greater Oral
bioavailability than ampicillin.
Clinical Use: Extended-spectrum penicillin: certain gram+
bacteria and GNR’s (Haemophilus influenza, E. coli, Listeria monocytogenes,
Proteus mirabilis, Salmonella, enterococci – HELPS kill Enterococci)
Toxicity: Hypersensitivity; Ampicillin: rash, pseudomembranous
colitis
Carbenicillin,
Peperacillin, Ticarcillin
Mech: Same as penicillin. Extended
spectrum.
Clinical Use: Pseudomonas species and GNRs; susceptible to
penicillinase; use with clavulanic acid
Toxicity: Hypersensitivity
Cephalosporins
Mech: b-lactam drugs that inhibit
cell wall synthesis but are less susceptible to penicillinase. Bactericidal.
Clinical Use: 1st
Gen: Gram+ cocci, Proteus mirabilis, E. coli, Klebsiella pneumoniae (PEcK).
2nd Gen: Gram+ cocci, H. influenzae, Enterobacter aerogenes,
Neisseria species, Proteus, E. coli, Klebsiella, Serratia marcescens (HEN
PEcKS). 3rd Gen: Serious gram- infections resistant to other b-lactams; meningitis (most
penetrate the BBB). Eg. Ceftazidime
for Pseudomonas; ceftriaxone for gonorrhea. 4th Gen: increased
activity against Pseudomonas and gram+ orgs.
Toxicity: Hypersensitivity, increases
nephrotoxicity of aminoglycosides, disulfuram-like rxn w/ ethanol (in ceph. w/
methylthiotetrazole group)
Aztreonam
Mech:
Monobactam RESISTANT to b-lactamases. Inhibits cell wall synthesis (binds to PBP3)
Clinical
Use: GNRs: Klebsiella, Pseudomonas, and Serratia species. No activity against
gram+ or anaerobes. For penicillin-allergic patients and those with renal
insufficiency who cant take aminoglycosides
Toxicity:
Usually nontoxic; occasional GI upset
Imipenem/Cilastatin
Mech: Wide-spectrum, b-lactamase RESISTANT
carbapenem. Always given with cilastatin (inhib. of renal dihydropeptidase I)
to decrease inactivation in renal tubules. With imipenem “the kill is lastin
with cilastatin”
Clinical Use: Gram+ cocci,
GNRs, and anaerobes. Drug of choice for Enterobacter.
Toxicity: GI distress, skin rash,
and CNS toxicity (seizures) at high plasma levels.
Vancomycin
Mech: Inhibits cell wall
mucopeptide formation. Bactericidal. Resistance occurs
with amino acid change of D-ala D-ala to D-ala D-lac.
Clinical Use: Serious gram+
MDR bugs, incl. Staph aureus and C. difficile (pseudomembranous colitis).
Toxicity: Nephrotoxicity,
Ototoxicity, Thrombophlebitis, diffuse flushing – “red man syndrome” (mostly
prevented by pre-tx w/ antihistamine and slow infusion). Well tolerated in
general: does NOT have many problems.
Protein
Synthesis Inhibitors
30S
Subunit: A = Aminoglycosides
(streptomycin, gentomycin, tobramycin, amikacin); T = Tetracyclines
50S
Subunit: C = Chloramphenicol, E =
Erythromycin, L = Lincomycin, L = cLindamycin
Pneumonic:
“Buy AT 30, CELL at 50”
Aminoglycosides:
Gentamycin, neomycin, amikacin, tobramycin, streptomycin
Mech: Bactericidal; inhibit
formation of initiation complex and cause misreading of mRNA. Require O2
for uptake; therefore ineffective against anaerobes.
Clinical Use: Severe GNR
infection. Synergistic w/ b-lactam
abx. Neomycin for bowel surgery.
Toxicity: Nephrotoxicity
(esp. w/ cephalosporins), Ototoxicity (esp. w/ loop diuretics). Teratogenic.
AmiNOglycosides
Tetracyclines:
tetracycline, doxycycline, demeclocycline, minocycline
Mech: Bacteriostatic, binds to
30S and prevents attachment of aminoacyl-tRNA, limited CNS penetration.
Doxycycline is fecally eliminated so ok in renal failure. Do not take w/
mild/antacids because divalent cations inhibit its gut absorption.
Clinical Use: Vibrio
cholerae, Acne, Chlamydia, Ureaplasma, Urealyticum,
Mycoplasma pneumoniae, Borrelia burgdorferi (lyme dz), Rickettsia,
tularemia. VACUUM your BedRoom.
Toxicity: GI distress, discolors teeth
and inhibits bone growth in kids, Fanconi’s syndrome, photosensitivity.
Macrolides:
Erythromycin, azithromycin, clarithromycin
Mech: Inhibits protein synth by
blocking translocation; binds the 23S rRNA of the 50S subunit. Bacteriostatic.
Clinical Use: URI’s,
pneumonias, STD’s: gram+ cocci (strep in pts allergic to penicillin),
Mycoplasma, Legionella, Chlamydia, Neisseria.
Toxicity: GI discomfort (most common
cause of noncompliance), acute cholestatic hepatitis, eosinophilia, skin rash
Chloramphenicol
Mech: Inhibits 50S peptidyl
transferase. Bacteriostatic.
Clinical Use: Meningitis (H.
influenzae, Neisseria meningitides, Strep pneumoniae). Conservative use owning
to toxicities.
Toxicity: Anemia (dose dependent),
aplastic anemia (dose independent), gray baby syndrome (in preemies because
they lack liver UDP-glucuronyl transferase).
Clindamycin
Mech: Blocks peptide bond
formation at 50S subunit. Bacteriostatic.
Clinical Use: Anaerobic
infections (B. fagilis, C. perfringens). Treats anaerobes ABOVE
the diaphragm.
Toxicity: Pseudomembranous colitis
(C. difficile), fever, diarrhea.
Sulfonamides:
Sulfamethoxazole (SMX), sulfisoxazole, triple sulfas, sulfadiazine
Mech: PABA antimetabolites
inhibit dihydropteroate synthase (nucleotide synth). Bacteriostatic.
Clinical Use: Gram+, Gram-,
Nocardia, Chlamydia. Triple sulfas or SMX for simple UTI.
Toxicity: Hypersensitivity,
hemolysis if G6PD deficient, nephrotoxicity (tubulointerstitial nephritis),
kernicterus in infants, displace other drugs from albumin (eg. Warfarin), Stevens-Johnson Syndrome.
Trimethoprim
Mech: Inhibits bacterial
dihydrofolate recuctase (nucleotide synth). Bacteriostatic.
Clinical Use: Used in
combination with sulfonamides (TMP-SMX), causing sequential block of folate
synthesis. Combination used for recurrent UTI, Shigella, Salmonella, PCP.
Toxicity: Megaloblastic anemia,
leukopenia, granulocytopenia. (May alleviate with
supplemental folinic acid).
Trimethoprim
= TMP: Treats Marrow Poorly
Fluoroquinolones:
Ciprofloxacin, norfloxacin, ofloxacin, sparfloxacin, mortifloxacin,
gatifloxacin, enoxacin (fluoroquinolones), nalidixic acid (quinolone)
Mech: Inhibit DNA gyrase
(topoisomerase II). Bactericidal.
Clinical Use: GNRs of urinary
and GI origin (incl. Pseudomonas), Neisseria, some gram+ organisms. Anthrax.
Toxicity: GI upset, superinfections,
skin rash, HA, dizziness. Contraindicated in pregnant women and children
because may damage cartilage. Tendonitis and tendon rupture in adults.
Metronidazole
Mech: Forms toxic metabolites in
the bacterial cell. Bactericidal.
Clinical: Antiprotazoal. Giardia, Entamoeba, Trichomonas, Garnerella
vaginalis, anaerobes (Bacteroides, Clostridium). Used with bismuth and
amoxicillin or tetracycline for “triple tx” against H. pylori.
GET on the Metro!
Anaerobic infection BELOW the diaphragm.
Toxicity: Disulfuram-like reaction
with alcohol, HA.
Polymyxins: Polymyxin B, Polymyxin E
Mech: Bind to cell membrane of
bacteria and disrupt their osmotic properties. Polymyxins are cationic, basic
proteins that act like detergents.
Clinical: Resistant Gram- infections
Toxicity: Neurotoxicity, ATN
Isoniazid
(INH)
Mech: Decreases synthesis of
mycolic acids.
Clinical: TB. The only agent used as
solo prophylaxis against TB.
Toxicity: Hemolysis if G6PD
deficient, neurotoxicity, hepatotoxicity, SLE-like syndrome. Pyridoxine (vit. B6)
can prevent neurotoxicity.
INH Injures Neurons
and Hepatocytes.
Different
INH half-lives in fast vs. slow acetylators
Rifampin
Mech: Inhibits DNA-dependent RNA
polymerase.
Clinical: TB, delays resistance to
dapsone when used for leprosy. Always used in combination with drugs except in tx of meningococcal carrier state, and chemoprophylaxis in
contacts of children w/ H. influenzae type B.
Toxicity: Minor hepatotoxicity and
drug interactions (increased P450)
4 R’s: RNA
polym. Inhibitor, Revs up microsomal P450, Red/Orange
body fluids, Rapid resistance if used alone.
Anti-TB
Drugs
Rifampin,
Ethambutol, Streptomycin, Pyrazinamide, Isoniazid
Cycloserine
(second line)
All
are hepatotoxic. INH is used alone for
TB prophylaxis.
Amphotericin
B
Mech: Binds ergosterol (unique
to fungi), forms membrane pores that disrupt homeostasis. Amphotericin “tears”
holes in the membrane.
Clinical: Used for wide spectrum of
systemic mycoses. Cryptococcus, Blastomyces, Coccidioides,
Aspergillus, Histoplasma, Candida, Mucor (systemic mycoses).
Intrathecally for fungal meningitis; does not cross BBB.
Toxicity: Fever/chills, (shake and
bake), hypotension, nephrotoxicity, arrhythmias (amphoterrible)
Nystatin
Mech: Binds to ergosterol,
disrupting fungal membranes.
Clinical: “Swish and swallow” for
oral candidiasis (thrush).
Fluconazole,
Ketoconazole, Clotrimazole, Miconazole, Itraconazole
Mech: Inhibit fungal steroid
(ergosterol) synthesis.
Clinical: Systemic mycoses. Fluconazole for cryptocccal meningitis in AIDS patients and
candidal infections of all types. Ketoconazole for
Blastomyces, Coccidioides, Histoplasma, C. albicans; hypercortisolism.
Toxicity: Hormone synth inhibition
(gynecomastia), liver dysfxn (inhibits P450), fever, chills.
Griseofulvin
Mech: Interferes with
microtubule function; disrupts mitosis. Deposits in
keratin-containing tissues (eg. Nails).
Clinical: Oral tx
of superficial infections; inhibits growth of dermatophytes (tinea, ringworm).
Toxicity: Teratogenic, carcinogenic,
confusion, HA, increased coumadin metabolism.
Amantadine
Mech: Blocks viral
penetration/uncoating; may buffer pH of endosome. Also causes release of
dopamine from intact nerve terminals.
Clinical: Prophylaxis for influenza
A; Parkinson’s disease.
Toxicity: Ataxia, dizziness, slurred
speech.
Amantidine blocks influenza A
and rubellA and causes problems with the cerebellA
Rimantidine
is a derivative with fewer CNS side effects.
Zanamivir
Mech: Inhibits influenza
neuraminidase
Clinical: Influenza A and B
Ribavirin
Mech: Inhibits synthesis of
guanine nucleotides by competitively inhibiting IMP dehydrogenase.
Clinical: RSV
Toxicity: Hemolytic Anemia
Acyclovir
Mech: Preferentially inhibits
viral DNA polymerase when phosphorylated by viral thymidine kinase.
Clinical: HSV, VZV, EBV. Mucocutaneous and genital herpes lesions. Prophylaxis
in immunocompromised patients.
Toxicity: Delirium, tremor,
nephrotoxicity
Gancyclovir
- DHPG (dihydroxy-2-propoxymethyl guanine)
Mech: Phosphorylation by viral kinase,
preferentially inhibits CMV DNA polymerase.
Clinical: CMV, especially in
immunocompromised patients.
Toxicity: Pancytopenia, renal
toxicity. More toxic to host enzymes than acyclovir.
Foscarnet
Mech: Viral DNA polymerase
inhibitor that binds to the pyrophosphate binding site of the enzyme. Does not require activation by viral kinase.
Foscarnet = pyroFosphate
analog.
Clinical: CMV retinitis in
immunocompromised pt when gancyclovir fails.
Toxicity: Nephrotoxicity
HIV
Therapy
Protease Inhibitors:
Saquinavir, Ritinavir, Indinavir, Nelfinavir, Amprenavir
Mech: Inhibits assembly of new
viruses by blocking protease enzyme
Toxicity: GI intolerance (nausea,
diarrhea), hyperglycemia, lipid abnormalities, thrombocytopenia (indinavir)
Part
of triple therapy: 2 RT inhibitors + 1 protease inhibitor
Initiated
when CD4 counts drop below 500 or high viral load
HIV
Therapy
Reverse
Transcriptase Inhibitors: Nucleosides: Zidovudine
(AZT), didanosine (ddI), zalcitabine (ddC, stavudine (d4T), lamivudine (3TC),
abacavir; Non-Nucleosides:
Nevirapine, delavirdine, efanvirenz
Mech: Preferentially inhibit RT
of HIV; prevent incorporation of viral genome into host DNA.
Toxicity: Bone marrow suppression
(neutropenia, anemia), peripheral neuropathy, lactic acidosis (nucleosides),
rash (non-nucleosides), megaloblastic anemia (AZT)
Clinical: Triple therapy, AZT in
pregnancy to reduce vertical transmission.
Interferons
Mech: Glycoproteins from human
leukocytes that block various stages of viral RNA and DNA synthesis.
Clinical: Chronic hepatitis B and C,
Kaposi’s Sarcoma.
Toxicity: Neutropenia
Ivermectin
Onchocerciasis
(rIVER blindness treated with IVERmectin)
Mebendazole/thiabendazole
Nematode/roundworm (eg. pinworm, whipworm) infections.
Pyrantel
pamoate
Giant roundworm (ascaris), hookworm (Necator/Ancylostoma), pinworm
(Enterobius).
Praziquantel
Trematode/fluke (eg. schistosomes, Paragonimus, Clonorchis) and
cysticercosis.
Niclosamide
Cestode/tapeworm (eg. D. latum, Taenia species)
infections except cysticercosis.
Pentavalent
antimony
Leishmaniasis
Chloroquine,
quinine, mefloquine
Malaria
Primaquine
Latent
hypnozoite (liver) forms of malaria (P. vivax, P. ovale)
Metronidazole
Giardiasis,
amoebic dysentery (E. histolytica), bacterial vaginsitis (Garnerella),
Trichomonas
Pentamidine
Pneumocystis
carinii pneumonia prophylaxis
Nifurtimox
Chagas’
disease, American trypanosomiasis (Trypanosoma cruzi)
Suramin
African
trypanosomiasis (sleeping sickness)
Bethanechol
Mech: direct cholinergic agonist
Clinical: Postoperative and
neurogenic ileus and urinary retention. Activates bowel and
bladder smooth muscle.
Carbachol,
Pilocarpine
Mech: direct cholinergic agonist
Clinical: Glaucoma. Activates
ciliary muscle of eye (open angle), pupillary sphincter (narrow angle), opening
of trabecular meshwork and increased outflow of aqueous humor
Toxicity: Miosis, cyclospasm
Neostigmine
Mech: Anticholinesterases
(indirect cholinergic agonist). Increases endogenous ACh.
Clinical: Postoperative and
neurogenic ileus and urinary retention, myasthenia gravis, reversal of NMJ
blockade (postOP)
Pyridostigmine
Mech: Anticholinesterase
(indirect cholinergic agonist). Increases endogenous ACh; inreases strength.
Clinical: Myasthenia gravis
Edrophonium
(Tensilon)
Mech: Anticholinesterase
(indirect cholinergic agonist). Increases endogenous ACh.
Clinical: Diagnosis of myasthenia
gravis (extremely short acting)
Physostigmine
Mech: Anticholinesterase
(indirect cholinergic agonist). Increases endogenous ACh.
Clinical: Glaucoma – causes ciliary
muscle contraction, opening of trabecular meshwork and increased outflow of
aqueous humor (crosses BBB to CNS); and atropine overdose
Toxicity: Miosis, cyclospasm
Echothiophate
Mech: Anticholinesterase
(indirect cholinergic agonist). Increases endogenous ACh.
Clinical: Glaucoma - causes ciliary
muscle contraction, opening of trabecular meshwork and increased outflow of
aqueous humor
Toxicity: Miosis, cyclospasm
What
are the symptoms of cholinesterase poisoning?
DUMBBELSS
Diarrhea,
Urination, Miosis, Bronchospasm, Bradycardia, Excitation of skeletal muscle and
CNS, Lacrimation , Sweating, Salivation, and abdominal
cramping
Atropine
Mech: Muscarinic antagonist.
Clinical: Pupil dilation, reduce
acid secretion in acid-peptic disease, reduce urgency in mild cystitis,
decrease GI motility, reduce airway secretions, organophosphate poisoning,
dangerous arrhythmias.Blocks Salivation, Lacrimation, Urination, Defacation
Toxicity: Increased body temp, rapid
pulse, dry mouth, dry flushed skin, disorientation, mydriasis with cycloplegia,
and constipation.
Blind as a bat, Red as a
beet, Mad as a hatter, Hot as a hare, Dry as a bone
Hexamethonium
Mech: Ganglionic nicotinic ACh
receptor antagonist (blocks only at ganglion, so no NMJ blockade)
Pralidoxime
Mech: Cholinesterase regenerator
Clinical: regenerates active
cholinesterase, chemical antagonist, used to treat organophosphate exposure.
Scopolamine
Mech: Muscarinic cholinergic
antagonist
Clinical: Prevention of nausea and
vomiting a/w motion sickness
Toxicity: dry mouth, drowsiness,
blurred vision, disorientation
Benzotropine
Mech: Muscarinic antagonist
Clinical: Parkinson’s disease
Homatropine,
tropicamide
Mech: Muscarinic antagonist
Clinical: Produce mydriasis and
cycloplegia
Ipratropium
Mech: Muscarinic antagonist
Clinical: Asthma, COPD
Succinylcholine
Mech: NMJ ACh receptor
depolarizing blocker. Phase I (prolonged depolarization) – no antidote. Block
potentiated by cholinesterase inhibit. Phase II
(repolarized but blocked) – antidote: cholinesterase inhibitors (neostigmine).
Clinical: muscle paralysis in
surgery or mechanical ventilation
Tubocurarine,
atracurium, mivacurium, pancuronium, vercuronium, rapacuronium
Mech: NMJ ACh receptor
non-depolarizing blocker. To reverse blockade, give cholinesterase inhibitor.
Clinical: Muscle paralysis for
surgery or mechanical ventilation
Dantrolene
Mech: Prevents the release of
Ca++ from the sarcoplasmic reticulum of skeletal muscle.
Clinical: Treatment of malignant
hyperthermia, which is caused by the concomitant use of halothane and
succinylcholine. Also used to treat neuroleptic malignant
syndrome (a toxicity of antipsychotic drugs).
Epinephrine
Mech: Catecholamine
sympathomimetic. Direct
agonist at a1,a2, b1,
b2 adrenergic receptors.
Clinical: Anaphylaxis, glaucoma
(open angle – increased outflow of aqueous humor), asthma, hypotension.
Toxicity: Mydirasis, stinging; do
not use in closed-angle glaucoma
Norepinephrine
Mech: Catecholamine
sympathomimetic. Direct agonist at a1,a2, b1 adrenergic receptors.
Clinical: Hypotension (but decreases
renal perfusion)
Isoproterenol
Mech: Catecholamine
sympathomimetic. Direct agonist at b1=b2 adrenergic receptors
Clinical: AV block (rare)
Dopamine
Mech: Catecholamine sympathomimetic.
Direct agonist at D1=D2>b>a adrenergic receptors.
Clinical: Shock (increases renal
perfusion), heart failure.
Dobutamine
Mech: Catecholamine
sympathomimetic. Direct agonist at b1>b2 adrenergic receptors.
Clinical: Shock, Heart failure
Amphetamine
Mech: Indirect sympathomimetic. Stimulates release of stored catecholamines.
Clinical: Narcolepsy, obesity,
attention deficit disorder
Ephedrine
Mech: Indirect sympathomimetic. Stimulates release of stored catecholamines.
Clinical: Nasal decongestion,
urinary incontinence, hypotension
Phenylephrine
Mech: Sympathomimetic. a1>a2 adrenergic receptor
agonist.
Clinical: Pupil dilator,
vasoconstriction, nasal decongestion
Albuterol,
terbutaline
Mech: Sympathomimetic. b2>b1 adrenergic
receptor agonist.
Clinical: Asthma
Cocaine
Mech: Indirect general
sympathomimetic; catecholamine uptake inhibitor
Clinical: Vasoconstriction and
anesthesia
Clonidine
Mech: Centrally acting a2 agonist. Decreases central
adrenergic outflow.
Clinical: Hypertension, especially
with renal disease (no decrease in blood flow to the kidney)
Phenoxybenzamine
Mech: Nonselective, irreversible
alpha adrenergic blocker
Clinical: Pheochromocytoma
Toxicity: Orthostatic hypotension, reflex tachycardia
Phenolamine
Mech: Nonselective, reversible
alpha adrenergic blocker
Clinical: Pheochromocytoma
Prazosin,
terazosin, doxazosin
Mech: a1 selective blocker.
Clinical: Hypertension, urinary
retention in BPH
Toxicity: First-dose orthostatic
hypotension, dizziness, headache
Yohimbine
Mech: a2 selective blocker.
Clinical: Impotence (effectiveness
controversial)
b-Blockers: Propranolol, metoprolol, atenolol, nadolol, timolol,
pindolol, esmolol, labetalol
Mech: Nonselective (b1=b2
):
propranolol, timolol, pindolol, nadolol, labetolol (also blocks
alpha-1receptors)
b1 selective (b1>b2): metoprolol, atenolol,
esmolol (short acting)
Clinical: Hypertension (decrease CO
and renin secretion), Angina Pectoris (decrease HR, contractility, O2 consumption), MI (beta-blockers decrease mortality), SVT:
propranolol/esmolol (decrease AV conduction velocity), CHF (slow progression of
chronic failure), Glaucoma: timolol (decrease secretion of aqueous humor)
Toxicity: Impotence, exacerbation of
asthma, CV effects (bradycardia, AV block, CHF), CNS effects (sedation, sleep
prob), caution in DM
Brimonidine
Mech: Alpha antagonist
Clinical: Glaucoma – decreased
aqueous humor synthesis
Toxicity: No pupillary or vision
changes
Acetazolamide,
dorzolamide, brinzolamide
Mech: Carbonic anhydrase
inhibitor.
Clinical: Diuretic. Glaucoma –
decrease aqueous humor secretion due to decreased HCO3-
Toxicity: No pupillary or vision
changes.
Latanoprost
Mech: prostaglandin
Clinical: Increased flow of aqueous
humor
Toxicity: Darkens color of urine
(browning)
Barbiturates:
Phenobarbital, pentobarbital, thiopental, secobarbital
Mech: Facilitate GABAa action by
increasing duration of Cl- channel opening, thus decreasing neuron firing.
Clinical: Sedative for anxiety,
seizures, insomnia, induction of anesthesia (thiopental)
Toxicity: Dependence, additive CNS
depression with EtOH, resp or CV depression (can lead to death), drug
interactions owing to induction of liver microsomal enzymes (cyt. P450)
Benzodiazepines:
Diazepam, lorazepam, triazolam, temazepam, oxazepam, midazolam,
chlordiazepoxide
Mech: Facilitate GABAa action by
increasing frequency of Cl- channel opening. Most have long half lives and
active metabolites.
Clinical: Anxiety, spasticity,
status epilepticus (diazepam), detoxification (esp. after alcohol withdrawl DT’s)
Short
Acting = Triazolam, Oxazepam, Midazolam (TOM)
Toxicity: Dependence, additive CNS
depression w/ EtOH. Less resp depression and coma than barbi’s,
Treat
overdose with flumazenil (competitive antagonist at GABA receptor)
Classical
Antipsychotics (neuroleptics): Thioridazine, haloperidol, fluphenazine,
chlorpromazine
Mech: Most block dopamine D2
receptors (excess dopamine a/w schizophrenia)
Clinical: Schizophrenia, psychosis
Toxicity: Extrapyramidal system:
sedation, endocrine, muscarinic, alpha, and histamine receptor blocking
effects.
Neuroleptic
Malignant Syndrome: rigidity, autonomic instability, hyperpyrexia (tx
w/ dantrolene and dopamine agonists)
Tardive
Dyskinesia:
stereotypic oral-facial movements probably due to dopamine receptor
sensitization; results of long-term antipsychotic use
EPS: 4h acute dystonia-4d
akinesia-4wk akathisia-4mo TD
Atypical
Antipsychotics: Clozapine, olanzapine, risperidone
Mech: Block 5HT2 and dopamine
receptors
Clinical: Tx
of schizophrenia; +/- symptoms. Olanzapine is also used for OCD, anxiety
disorder, and depression.
Toxicity: Fewer EPS and
anticholinergic side effects than other antipsychotics. Clozapine may cause
agranulocytosis (wkly WBC cts)
Lithium
Mech: not established. May inhibit phosphoinositol cascade.
Clinical: Mood stabilizer for
bipolar affective disorder, blocks relapse and acute manic events.
Toxicity: Tremor, hypothyroidism,
polyuria (ADH antagonist causing nephrogenic DI), teratogenesis. Narrow therapeutic window requiring close monitoring of serum
levels.
Tricyclic
Antidepressants: Imipramine, amitriptyline, desipramine, nortriptyline,
clomipramine, doxepin
Mech: Block reuptake of NE and
serotonin
Clinical: Endogenous depression,
bedwetting (imipramine), OCD (clomipramine).
Side effects: Sedation, a-blocking, atropine-like
effects. Tertiary TCA’s (amitriptyline) have more anticholinergic effects than
secondary (nortriptyline). Desipramine is least sedating.
Toxicity: Tri-C’s: Convulsions,
Coma, Cardiotoxicity; resp depression, hyperpyrexia; confusion
and hallucinations in elderly
SSRI’s:
Fluoxetine, sertraline, paroxetine, citalopram
Mech: Serotonin-specific
reuptake inhibitors.
Clinical: Endogenous depression. It
may take 2-3 wks for SSRI’s to have an effect.
Toxicity: Fewer than TCA’s. CNS
stimulation: anxiety, insomnia, tremor, anorexia, nausea, and vomiting; Serotonin
Syndrome w/ MAOIs: hyperthermia, muscle rigidity, CV collapse.
Trazodone
Heterocyclics:
2nd and 3rd generation antidepressants with varied and
mixed mechanisms of action. Used in major depressive
disorders.
Mech: Primarily inhibits
serotonin reuptake.
Toxicity: Sedation, nausea,
priapism, postural hypotension
Buproprion
Heterocyclics:
2nd and 3rd generation antidepressants with varied and
mixed mechanisms of action. Used in major depressive
disorders.
Also
used for smoking cessation.
Mech: not known.
Toxicity: Stimulant effects
(tachycardia, agitation), dry mouth, aggravation of psychosis
Venlafaxine
Heterocyclics:
2nd and 3rd generation antidepressants with varied and
mixed mechanisms of action. Used in major depressive
disorders. Also used in GAD.
Mech: Inhibits serotonin and
dopamine reuptake.
Toxicity: Stimulant effects
(anxiety, agitation, headache, insomnia)
Mirtazapine
Heterocyclics:
2nd and 3rd generation antidepressants with varied and
mixed mechanisms of action. Used in major depressive
disorders.
Mech: a2-antagonist (increases
release of NE and serotonin) and potent 5HT2 receptor antagonist.
Toxicity: Sedation, increased serum
cholesterol, increased appetite.
MAO
Inhibitors: Phenelzine, tranylcypromine
Mech: Nonselective MAO
inhibition
Clinical: Atypical depressions (w/
psychotic or phobic features), anxiety, hypochondriasis.
Toxicity: Hypertensive crisis w/
tyramine ingestion (cheese or wine) and meperidine; CNS stimulation. Contraindication with SSRIs or beta-agonists.
Selegiline
(deprenyl)
Mech: Selectively inhibits
MAO-B, thereby increasing the availability of dopamine.
Clinical: adjunctive agent to L-dopa
in treatment of Parkinson’s dz.
Toxicity: May enhance adverse
effects of L-dopa.
L-Dopa
(levodopa)/carbidopa
Mech: Increases level of
dopamine in brain. Parkinsonism thought to be due to loss of dopaminergic
neurons and excess cholinergic fxn. Unlike dopamine, L-dopa can cross the BBB
and is converted by dopa decarboxylase in the CNS to dopamine.
Clinical: Parkinsonism
Toxicity: Nausea. Arrhythmias
from peripheral conversion to dopamine. Carbidopa, a peripheral
decarboxylase inhibitor, is given with L-dopa to increase bioavailability in
brain and limit peripheral side effects. Dyskinesias also occur.
Parkinson’s
disease drugs
Dopamine
agonists:
L-dopa/carbidopa, bromocriptine (ergot alk and partial dopamine agonist),
amantidine (enhances dopamine release)
MAO
inhibitors:
Selegiline (selective MAO-B inhibitor)
Antimuscarinic: Benztropine (improves
tremor and rigidity, but has little effect on bradykinesia)
Opioid
Analgesics: Morphine, fentanyl, codeine, heroin, methadone, meperidine,
dextromethorphan
Mech: Act as agonists at opioid
receptors (mu=morphine, kappa=dynorphin, delta=enkephalin) to modulate synaptic
transmission
Clinical: Pain, cough suppression
(dextromethorphan), diarrhea (loperamide and diphenoxylate), acute pulmonary
edema, maintenance programs for addicts (methadone)
Toxicity: Addiction, respiratory
depression, constipation, miosis (pinpoint pupils), additive CNS depression w/
other drugs. Tolerance does not develop to miosis and constipation. Tx toxicity w/ naloxone or naltrexone (opioid receptor
antagonists)
Sumatriptan
Mech: 5HT1D agonist. Half life
< 2hrs
Clinical: Acute migraine, cluster
headaches
Toxicity: Chest discomfort, mild
tingling (contraindicated in pts w/ CAD or Prinzmetal’s angina)
Ondansetron
Mech: 5HT3 antagonist. Powerful central-acting anti-emetic.
Clinical: Control vomiting post-OP
and in patients undergoing cancer chemotherapy
Toxicity: HA, diarrhea
Carbemazepine
Mech: Blocks voltage sensitive
Na+ channels. TCA with antiepileptic
effects
Clinical: Epilepsy (Simple, complex,
GTC, trigeminal neuralgia), Mania.
Contraindicated in absence seizures,
MAOI’s, glaucoma
Toxicity: Diplopia, ataxia,
induction of P450, blood dyscrasias (agranulocytosis, aplastic anemia), liver
toxicity (always check LFT’s)
Phenytoin
Mech: Use-dependent blockade of
Na+ channels. Also a class IB antiarrhythmic
Clinical: GTC, simple, complex
seizures, status epilepticus
Toxicity: Nystagmus, ataxia,
diplopia, lethargy, gingival hyperplasia (chronic use in children), peripheral
neuropathy, hirsutism, megaloblastic anemia (decreased
Vit. B12), malignant hyperthermia, teratogenic (fetal hydantoin syndrome)
Ethosuximide
Mech: Ca++ channel blocker
Clinical: Absence seizures
Toxicities: GI, lethargy, HA,
urticaria, Steven’s Johnson Syndrome
Phenobarbital
Mech: Facilitate GABAa action by
increasing duration of Cl- channel opening.
Clinical: Epilepsy (GTC), safer in
pregnant women and Crigler-Najjar II
Toxicity: Sedation, induction of
P450, tolerance, dependence
Valproic
Acid
Mech: Blocks Ca++ channels, weak
block of Na+ channels. May potentiate GABA
Clinical: Epilepsy (absence,
myoclonic, GTC), acute mania
Toxicity: GI, rare, but fatal
hepatotoxicity, neural tube defects in fetus (teratogen)
Lamotrignine
Mech: Blocks voltage sensitive
Na+ channels, inhibits excitatory neurotransmission
Clinical: Epilepsy (simple, partial,
GTC)
Toxicity: Life threatening rash,
Steven’s Johnson syndrome
Gabapentin
Mech: Unknown, GABA analog but
doesn’t affect GABA-R
Clinical: Adjunct in refractory
epilepsy (simple, partial, GTC), neurologic pain and neuropathy
Toxicity: renal excretion, sedation,
movement disorders
Topiramate
Mech: blocks voltage sensitive
Na+ channels, inhibits excitatory neurotransmission
Clinical: Adjunct in simple and
complex seizure management
Toxicity: Sedation, mental dulling,
kidney stones, weight loss
Lorazepam/Diazepam
Mech: Enhance GABAergic
inhibitory neurotransmission
Clinical: Epilepsy (GTC, status
epilepticus), anxiety, panic disorders, conscious sedation
Toxicity: sedation, tolerance,
dependence
Inhaled
anesthetics:
halothane(soluble-slow), enflurane (soluble-slow),
isoflurane(soluble-slow), sevoflurane(insoluble-fast), methoxyflurane, nitrous
oxide(insoluble-fast)
Mech: the lower the solubility
in blood, the quicker the anesthetic induction and the quicker the recovery
Effects: Myocardial depression,
resp depression, nausea/emesis, increased cerebral flow
Toxicity: Hepatotoxicity
(halothane), nephrotoxicity (methoxyflurane), proconvulsant (enflurane),
malignant hyperthermia
Thiopental
Mech: Barbiturate, high lipid
solubility, rapid entry into brain.
Clinical: IV anesthesia. Induction of anesthesia and
short surgical procedures. Effects terminated by redistribution from
brain.
Toxicity: Decreased cerebral blood
flow
Midazolam
Mech: Benzodiazepine.
Clinical: IV anesthetic. Most common
used drug for endoscopy; used adjunctively with gaseous anesthetics and
narcotics.
Toxicity: May cause severe
post-operative resp depression and amnesia
Ketamine
Mech: Arylcyclohexylamine. PCP analog.
Clinical: Dissociative IV
anesthetic, good for hypovolemic patients.
Toxicity: Cardiovascular stimulant,
dissorientation, hallucination, and bad dreams. Increases
cerebral blood flow.
Local
Anesthetics:
Esters: procaine, cocaine, tetracaine; amides: lidocaine, bupivicaine
Mech: Block Na+ channels by
binding to specific receptors on inner portion of channel. Tertiary amine local
anesthetics penetrate membrane in uncharged form, then
bind in charged form. 1. In infected (acidic) tissue, anesthetics are
charged and cannot penetrate membrane effectively. So more
anesthetic is needed. 2. Order of nerve blockade: small diameter
fibers>large diameter. Myelinated>unmyelinated.
Size predominates over myelination, so small unmyelinated>small myelinated
autonomic>large myelinated autonomic. Order of loss: pain>temp>touch>pressure.
3. Given w/ vasoconstrictors (epi) to enhance local action
Clinical: minor surgery, spinal
anesthesia
Toxicity: CNS excitation, severe CV
(bupivicaine), HTN/arrhythmias (coc)
Hydrochlorothiazide
Mech: Bind Cl site and block
Na-Cl cotransporter in the distal tubule
Clinical: Diuretic, hypertension,
edema
Toxicity: hypokalemia, slight
hyperlipidemia, hyperuricemia, lassitude, hypercalcemia, hyperglycemia
Furosemide
Mech: Sulfonamide loop diuretic.
Inhibits Na-K-2Cl cotransporter in the thick ascending limb
of the loop of henle. Abolishes the hypertonicity of
the medulla, preventing concentration of urine. Increases
Ca++ excretion.
Clinical: Edematous states (CHF,
cirrhosis, nephrotic syndrome, pulm. edema), HTN, hypercalcemia.
Toxicity: Ototoxicity, Hypokalemia,
Dehydration, Allergy (sulfa), interstitial Nephritis, Gout OH DANG
Hydralazine
Mech: Increased cGMP causes
smooth muscle relaxation. Vasodilates arterioles > veins; afterload
reduction
Clinical; Severe HTN, CHF
Toxicity: Compensatory tachycardia,
fluid retention, lupus-like syndrome, angina, salt retention, nausea, HA
Calcium
Channel Blockers: Nifedipine, verapamil, diltiazem
Mech: Block voltage-dependent
L-type Ca++ channels of cardiac and smooth muscle so reduce muscle contractility. AV nodal cells primarily. Decrease cond.
velocity, increase ERP, PR.
Vascular
smooth muscle: nifedipine>diltiazem>verapamil
Heart:
verapamil>diltiazem>nifedipine
Clinical: Class IV antiarrhythmic,
nodal arrhythmias (SVT), HTN, angina
Toxicity: Cardiac depression (CHF,
AV block, sinus node depression), peripheral edema, flushing, dizziness,
constipation, torsades de pointes.
Guanethidine
Mech: blocks catecholamine
release and causes depletion
Clinical: antihypertensive
Toxicity: Orthostatic and exercise
hypotension, sexual dysfunction, diarrhea
Reserpine
Mech: Blocks catecholamine
uptake into storage granules leading to depletion
Clinical: Hypertension,
Toxicity: sedation, depression,
nasal stuffiness, diarrhea
Methyldopa
Mech: a2-adrenergic agonist,
centrally acting decreasing adrenergic outflow from CNS
Clinical: Hypertension, esp renal insufficiency since it doesn’t block renal blood
flow
Toxicity: sedation, positive Coomb’s
test
Nitroprusside
Mech: causes vasodilation via
release of Nitrous oxide
Clinical: Malignant hypertension
Toxicity: Cyanide poisoning (can be
metabolized to cyanide)
ACE
Inhibitors: Captopril, enalapril, lisinopril
Mech: Inhibit ACE, reducing
levels of ATII and preventing inactivation of bradykinin, a potent vasodilator.
Renin release increased due to loss of feedback inhib.
Clinical: Hypertension, CHF,
diabetic renal disease
Toxicity: Cough, Angioedema,
Proteinuria, Taste changes, hypOtension, Pregnancy
problems (fetal renal damage), Rash, Increased renin,
Losartan
Mech: ATII receptor antagonist.
Clinical: Hypertension
Toxicity: Fetal renal toxicity,
hyperkalemia, does not cause cough
Acetazolamide,
dorzolamide, brinzolamide
Mech: Carbonic anhydrase
inhibitor. Causes self-limited NaHCO3 diuresis and reduction
in total body HCO3- stores. Acts at proximal
convoluted tubule.
Clinical: Diuretic. Glaucoma –
decrease aqueous humor secretion due to decreased HCO3-. Urinary
alkalinization, metabolic alkalosis, altitude sickness.
Toxicity: No pupillary or vision
changes. Hyperchloremic metabolic acidosis (normal anion
gap), neuropathy, ammonia toxicity, sulfa allergy.
Ethacrynic
Acid
Mech: Phenoxyacetic acid
derivative (not a sulfonamide). Same action as furosemide.
Clinical: Diuresis in patients
allergic to sulfa drugs
Toxicity: similar to furosemide,
except no hyperuricemia, no sulfa allergy
Hydrochlorothiazide
Mech: Thiazide diuretic. Inhibits NaCl cotransport in early distal tubule, reducing diluting
capacity of the nephron. Decreases Ca++ excretion.
Clinical: Hypertension, CHF, calcium
stones, nephrogenic DI
Toxicity: hypokalemic metabolic
alkalosis, hyponatremia, hyperGlycemia, slight hyperLipidemia, hyperUricemia,
lassitude, hyperCalcemia
hyperGLUC
Spirononlactone
Mech: K+ sparing diuretic: competitive aldosterone receptor antagonist
in cortical collecting tubule.
Clinical: Hyperaldosteronism, K+
depletion, CHF
Toxicity: hyperkalemia, endocrine
effects (gynecomastia, antiandrogen)
Triamterene,
Amiloride
Mech: K+ sparing diuretics:
Block sodium channels in the CCT.
Clinical: Hyperaldosteronism, K+
depletion, CHF
Toxicity: Hyperkalemia, no endocrine
effects
Mannitol
Mech: Osmotic diuretic,
increases tubular fluid osmolarity producing increased urine flow
Clinical: Acute renal failure, drug
overdose, decrease intracranial/intraocular pressure
Toxicity: pulmonary edema,
dehydration. Contraindicated in anuria, CHF
Electrolyte
changes with Diuretics:
Urine
NaCl:
increase (all diuretics)
Urine
K+:
increase (all diuretics except spironolactone, triamterene, amiloride)
Blood
pH: Acidosis (carbonic anhydrase inhib, K+
sparing) Alkalosis (loop diuretics, thiazides)
Urine
Ca++: increased (loop diuretics, spironolactone),
decreased (thiazides, amiloride)
:
What
is the effect of Nitrates on the heart?
Affect
Preload
Decrease
EDV, BP, Ejection time, MVO2
Increase
Contractility (reflex), HR (reflex)
What
is the effect of Beta Blockers on the heart?
Affect
afterload
Decrease
BP, Contractility, HR, MVO2
Increase
EDV, Ejection time
What
is the effect of Nitrates plus Beta Blockers on the heart?
No
effect or decrease EDV
Little/no
effect on Contractility and Ejection time
Decrease
BP, HR, MVO2
Nitroglycerin,
isosorbide dinitrate
Mech: Vasodilate by releasing
nitric oxide in smooth muscle, causing increase in cGMP and smooth muscle
relaxation. Dilate veins >> arteries
Clinical: Angina, pulmonary edema.
Also used as an aphrodisiac and erection enhancer.
Toxicity: Tachycardia (reflex),
hypotension, HA, “Monday disease” in industrial exposure, development of
tolerance for vasodilating action during work week and loss of tolerance over
weekend, resulting in tachy, dizziness and HA.
Digoxin
(Cardiac Glycoside)
Mech: Inhibit Na-K-ATPase of
cell membrane causing increase in intracellular Na. Na-Ca antiport does not
function as well causing increased Ca inside; leads to positive inotropy. May cause increased PR, decreased QT, scooping of ST segment, T
wave inversion on EKG.
Clinical: 75% bioavailability,
20-40% protein bound, T1/2 40 hrs, urinary excretion. CHF, atrial fibrillation.
Toxicity: Nausea, vomiting,
diarrhea, blurry yellow vision (Van Gogh), Arrhythmias. Toxicities increased in
renal failure, hypokalemia (potentiates drug effects), and quinidine (decreases
clearance, displaces digoxin from tissue binding sites). Antidote: Normalize K+
slowly, lidocaine, cardiac pacer, anti-dig Fab (digibind)
Quinidine,
Amiodarone, Procainamide, Disopyramide
Na
Channel blockers - Class Ia Antiarrhythmics
Mech: Increased AP duration,
increased ERP, increased QT. Decrease slope of phase 4
depolarization and increase threshold for firing in abnormal pacemaker
cells. Are state dependent (fast tachy).
Clinical: Affect both atrial and
ventricular arrhythmias.
Toxicity: Quinidine
(cinchonism: HA, tinnitus; thrombocytopenia; torsades de pointes due to
increased QT interval); Procainamide (reversible SLE-like syndrome)
Lidocaine,
mexiletine, tocainide
Na
Channel Blockers - Class Ib Antiarrhythmics
Mech: Decreased AP duration.
Affect ischemic or depolarized Purkinje and ventricular tissue. Decrease slope
of phase 4 depolarization and increase threshold for firing in abnormal
pacemaker cells. Are state dependent (fast tachy).
Clinical: Used in ventricular
arrhythmias (esp. post-MI) and in digitalis-induced arrhythmias.
Toxicity: Local anesthetic. CNS
stimulation/depression, CV depression
Flecainide,
encainide, propafenone
Na
Channel Blockers – Class Ic Antiarrhythmics
Mech: No effect on AP duration.
Decrease slope of phase 4 depolarization and increase threshold for firing in
abnormal pacemaker cells. Are state dependent (fast tachy).
Clinical: Useful in V-tachs that
progress to VF and in intractable SVT. Are used as a last
resort in refractory tachyarrhythmias because of toxicities.
Toxicity: proarrhythmic
Class
II Antiarrhythmics: Beta-blockers: Propranolol, esmolol, metoprolol, atenolol,
timolol
Mech: Decrease cAMP, Ca
currents. Suppress abnormal pacemakers by decreasing slope of phase 4. AV node
particularly sensitive: increased PR. Esmolol is very short acting.
Toxicity: Impotence, exacerbation of
asthma, CV effects (bradycardia, AV block, CHF), CNS effects (sedation, sleep
alterations). May mask signs of hypoglycemia.
Class
III Antiarrhythmics: K+ Channel blockers: Sotalol, ibutilide, bretylium,
amiodarone
Mech: Increase AP, ERP, QT.
Clinical: Used when other
antiarrhythmics fail.
Toxicity: Sotalol – torsades
de pointes, excessive beta-block; Ibutilide – torsades; Bretylium
– new arrhythmias, hypotension; Amiodarone – Pulmonary fibrosis, corneal
deposits, Hepatotoxicity, skin deposits resulting in photodermatitis,
neurologic effects, constipation, CV effects (bradycardia, heart block, CHF),
hyper/hypothyroidism.
Check
PFTs, LFTs, TFTs with amiodarone.
Class
IV Antiarrhythmics: Ca++ Channel blockers: Verapamil, diltiazem
Mech: Primarily effects AV nodal
cells. Decrease conduction velocity, increase ERP, PR.
Clinical: Used in preventing nodal
arrhythmias (SVT).
Toxicity: Constipation, flushing, edema, CV effects
(CHF, AV block, sinus node depression); torsades de pointes (bepridil)
Adenosine
Drug of choice for diagnosing/abolishing AV nodal arrhythmias.
Potassium
Depresses ectopic pacemakers, especially in digoxin toxicity.
Magnessium
Effective
in torsades de pointes and digoxin toxicity
Cholestyramine,
colestipol
Mech: Bile acid resins block
reabsorption of bile acids. Decrease LDL, no effect on HDL, slight increase in
triglycerides.
Clinical: Hypercholesterolemia
Toxicity: Patients hate it. Tastes
bad and causes GI discomfort.
Lovastatin,
pravastatin, simvastatin, atorvastatin
Mech: HMG-CoA Reductase
inhibitors. Significantly decrease LDL. Small increase in HDL, small decrease in triglycerides.
Clinical: Hypercholesterolemia
Toxicity: Myositis (muscle
pain/weakness), reversible increase in LFT’s, expensive
Niacin
Mech: block cholesterol
transport into VLDL particles. Moderate decrease in LDL,
Moderate increase in HDL, small decrease in TG.
Clinical: Hypercholesterolemia
Toxicity: Red, flushed face, which
is decreased by aspirin or long-term use.
Gemfibrozil,
clofibrate
Mech: Lipoprotein lipase
stimulators: stimulates conversion of VLDL to IDL. Small
decrease in LDL, small increase in HDL, Large decrease in TG’s.
Clinical: Hypercholesterolemia
Toxicity: Myositis, increased LFT’s
Methotrexate
Mech: S-phase specific
antimetabolite. Folic acid analog that inhibits dihydrofolate reductase,
resulting in decreased dTMP and thus decreased DNA and protein synthesis.
Clinical: Leukemias, lymphomas,
choriocarcinoma, sarcoma. Abortion, ectopic pregnancy,
rheumatoid arthritis, psoriasis.
Toxicity: Myelosuppression, which is
reversible with leucovorin (folinic acid) rescue. Macrovesicular
fatty change in liver.
5-Fluorouracil
(5-FU)
Mech: S-phase specific
antimetabolite. Pyrimidine analog bioactivated to 5F-dUMP,
which covalently complexes folic acid. This complex inhibits thymidylate
synthase, resulting in decreased dTMP and same effects as methotrexate.
Clinical:
Toxicity: Myelosuppression which is
not reversible with leucovorin; photosensitivity
6-Mercaptopurine
(6-MP)
Mech: Blocks purine synthesis
Clinical: Leukemias, lymphomas (not
CLL or Hodgkins)
Toxicity: Bone marrow, GI, liver.
Metabolized to xanthine oxidase, thus increases toxicity with allopurinol
Busulfan
Mech: Alkylates DNA
Clinical: CML
Toxicity: Pulmonary fibrosis, hyperpigmentation.
Cyclophosphamide
Mech: Alkylating agent;
covalently x-links (interstrand) DNA at guanine N-7. Requires
bioactivation by liver.
Clinical: NHL, breast and ovarian
ca. Also an immunosuppressant.
Toxicity: Myelosuppression,
hemorrhagic cystitis
Nitrosureas:
carmustine, lomustine, semustine, streptozocin
Mech: Alkylates DNA. Requires bioactivation. Crosses BBB to CNS.
Clinical: Brain tumors (including
glioblastoma multiforme)
Toxicity: CNS toxicity (dizziness,
ataxia)
Cisplatin
Mech: Acts like an alkylating
agent. X-links via hydrolysis of Cl- groups and reaction with
platinum.
Clinical: Testicular, bladder,
ovary, and lung ca.
Toxicity: Nephrotoxicity and
acoustic nerve damage
Doxorubicin
(adriamycin)
Mech: Noncovalently intercalates
in DNA, creating breaks to decrease replication and transcription and generate
free radicals. Anthracycline antibiotic.
Clinical: Part of AVBD combination
regimen for Hodgkins and for myelomas, sarcomas, and solid tumors (breast,
ovary, lung).
Toxicity: Cardiotoxicity; also
myelosuppression and marked alopecia. Toxic extravasation.
Bleomycin
Mech: Intercalates DNA strands
and induces free radical formation, causing strand breaks.
Clinical: Testicular ca, lymphomas.
Toxicity: Pulmonary fibrosis, skin
changes, minimal myelosuppression
Etoposide
Mech: G2-phase specific inhibits
topoisomerase II so that double strand breaks remain in DNA following
replication, with subsequent DNA degradation.
Clinical: Oat cell carcinoma of the
lung and prostate, testicular ca.
Toxicity: Myelosuppression, GI
irritation, alopecia
Prednisone
Mech: May trigger apoptosis. May even work on non-dividing cells. Phospholipase
A2 and COX-2 Inhibitor.
Clinical: Most commonly used
glucocorticoid in cancer chemotherapy. Used in CLL, Hodgkins
lymphomas (part of MOPP, CHOP). Also an immunosuppressant used in autoimmune
disease. Asthma.
Toxicity: Cushing-like symptoms;
immunosuppression, cataracts, acne, osteoporosis, hypertension, peptic ulcers,
hyperglycemia, psychosis.
Tamoxifen/raloxifene
Mech: Estrogen receptor mixed
agonist/antagonists that block the binding of estrogen to ER+ cells.
Clinical: Breast ca.
Toxicity: Tamoxifen may increase the
risk of endometrial ca. via partial agonist effects; hot flashes
Vincristine/Vinblastine
Mech: M-phase specific alkaloids
that bind to tubulin and block polymerization of microtubules so that mitotic
spindle can’t form.
Clinical: Part of MOPP/CHOP regimens
for Hodkins/NHL lymphomas, Wilms tumor, choriocarcinoma
Toxicity: Vincristine –
neurotoxicity (areflexia, peripheral neuritis), paralytic ileus. Vinblastine –
blasts bone marrow (myelosuppression)
Paclitaxel
Mech: M-phase specific agent
obtained from yew tree that binds to tubulin and hyperstabilizes polymerized
microtubules so that mitotic spindle can’t break down (anaphase cannot occur)
Clinical: Ovarian and breast ca.
Toxicity: Myelosuppression,
hypersensitivity
Lead
Poisoning
Lead lines on gingivae and on epiphyses of long bones on
x-ray.
Encephalopathy and Erythrocyte
basophilic stippling
Abdominal Colic and sideroblastic Anemia
Drops: wrist and foot drop. Dimercaprol
and EDTA are first line tx
LEAD – high risk in houses with
chipped paint
Drugs
that cause SLE-like syndrome:
Hydralazine
Procainamide
INH
Phenytoin
Drugs
that cause Stevens-Johnson Syndrome
Ethosuximide
Sulfonamides
Lamotrignine
Drugs
that induce P450:
Barbiturates,
phenytoin, carbamazepine, rifampin, griseofulvin, quinidine
Drugs
that Inhibit P450:
Cimetidine,
ketoconazole, grapefruit, erythromycin, INH, sulfonamides
Sildenafil
Mech: Inhibits cGMP
phosphodiesterase, causing increased cGMP, smooth muscle relaxation in the
corpus cavernosum, increased blood flow, and penile erection
Clinical: Tx
of erectile dysfunction
Toxicity: HA, flushing, dyspepsia,
blue-green color vision, risk of life-threatening hypotension in patients
taking nitrates.
Clomiphene
Mech: Partial agonist at
estrogen receptors in the pituitary gland. Prevents normal feedback inhibition
and increases release of LH and FSH from pituitary, which stimulates ovulation.
Clinical: Tx
of infertility
Toxicity: Hot flashes, ovarian
enlargement, multiple spontaneous pregnancies, visual disturbances.
Mifepristone
(RU486)
Mech: Competitive inhibitor of
progestins at progesterone receptors.
Clinical: Abortificant
Toxicity: Heavy bleeding, GI effects
(nausea, vomiting, anorexia), abdominal pain
H2-Blockers:
Cimetidine, ranitidine, famotidine, nizatidine
Mech: Reversible block of
histamine H2 receptors.
Clinical: Peptic ulcer, gastritis,
esophageal reflux, Zollinger-Ellison syndrome.
Toxicity: Cimetidine is a potent
inhibitor of P450; it also has an antiandrogenic effect and decreases renal
excretion of creatinine. Other H2 blockers are relatively free of these
effects.
Omeprazole,
lansoprazole
Mech: Irreversible inhibits
H+/K+ ATPase in stomach parietal cells.
Clinical: Peptic ulcer, gastritis,
esophageal reflux, Zollinger-Ellison syndrome.
Sucralfate
Mech: Aluminum sucrose sulfate
polymerizes in the acid environment of the stomach and selectively binds
necrotic peptic ulcer tissue. Acts as a barrier to acid,
pepsin, and bile. Sucralfate cannot work in the presence of antacids or
H2 blocers (requires acidic pH to polymerize)
Clinical: Peptic ulcer disease.
Misoprostol
Mech: A PGE1 analog. Increases production and secretion of gastric mucous barrier.
Clinical: Prevention of
NSAID-induced peptic ulcers, maintains a patent PDA.
Toxicity: Diarrhea. Contraindicated in
women of childbearing age (abortificant)
Signs/Symptoms
of Antacid overuse:
Can affect absorption, bioavailability, or urinary excretion of other
drugs by altering gastric and urinary pH or by delaying gastric emptying. Overuse can cause:
1. Aluminum
hydroxide: constipation and hypophosphatemia
2. Magnesium
hydroxide: diarrhea
3. Calcium
carbonate: hypercalcemia, rebound acid increase
All
can cause hypokalemia
Heparin
Mech: Catalyzes the activation
of antithromin III. Short half-life. Check aPTT.
Clinical: Immediate anticoagulation
for PE, stroke, angina, MI, DVT. Used during pregnancy (does not cross
placenta). Follow PTT.
Toxicity: Bleeding,
thrombocytopenia, drug-drug interactions. Use protamine sulfate for
rapid reversal of heparinization (positively charged molecule that acts by
binding negatively charged heparin)
Note: Newer low molec. wt heparins (enoxaparin) have better bioavailability and 2-4
times longer half life. Admin. SQ
and w/o PTT.
Warfarin
(Coumadin)
Mech: Interferes with normal synthesis
and gamma carboxylation of vit-K dependent clotting factors II, VII, IX, X,
Protein S and C via vit. K antagonism. Long half-life, slow onset.
Clinical: Chronic anticoagulation.
Not used in pregnant women (does cross placenta). Follow PT.
WEPT:
Warfarin affects Extrinsic
pathway and prolongs PT
Toxicity: Bleeding, teratogenic,
drug-drug interactions
Thrombolytics:
Streptokinase, urokinase, tPA (alteplase), APSAC
(antistreplase)
Mech: Directly or indirectly aid
conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. It is claimed that tPA
specifically converts fibrin-bound plasminogen to plasmin
Clinical: Early MI
Toxicity: Bleeding, hypersensitivity
Aminocaproic acid inhibits
Plasminogen activation to Plasmin
Clopidogrel,
Ticlopidine
Mech: Inhibits platelet
aggregation by irreversibly inhibiting the ADP pathway involved in the binding
of fibrinogen.
Clinical: Actue coronary syndrome;
coronary stenting. Decreases the incidence of recurrence of
thrombotic stroke. Secondary stroke prevention.
Toxicity: Neutropenia (ticlopidine);
reserved for those who cannot tolerate aspirin.
Zileuton
Mech: Selective and specific
inhibitor of 5-lipoxygenase preventing formation of both LTB4 and the cysteinyl
leukotrienes.
Clinical: Asthma
Toxicity: Liver, Churg-Strauss
syndrome (eosinophilic vasculitis), inhibit P450.
Zafirlukast
Mech: Selective, reversible
inhibitors of the cysteinyl leukotriene-1 receptor
Clinical: Asthma
Toxicity: Liver, Churg-Strauss
syndrome (eosinophilic vasculitis), inhibit P450.
Aspirin
Mech: Acetylates and
irreversibly inhibits cyclooxygenase (1 & 2) to prevent coversion of
arachidonic acid to prostaglandins
Clinical: Antipyretic, analgesic,
anti-inflammatory, anti-platelet
Toxicity: Gastric ulceration,
bleeding, hyperventilation, Reye’s syndrome, tinnitus (CN VIII), renal toxicity
NSAIDS:
Ibuprofen, naproxen, indomethacin
Mech: Reversibly inhibit
cyclooxygenase (1 & 2). Block
prostaglandin synthesis.
Clinical: Antipyretic, analgesic,
anti-inflammatory. Indomethacin used to close a PDA.
Toxicity: Renal damage, aplastic
anemia, GI distress
COX-2
Inhibitors: Celecoxib, rofecoxib
Mech: Selectively inhibit
cyclooxygenase isoform 2, which is found in inflammatory cells and mediates
inflammation and pain; spares COX-1, which helps maintain the gastric mucosa.
Thus, should not have the corrosive effects of other NSAIDS on the GI lining.
Clinical: Rheumatoid and
osteoarthritis
Toxicity: Similar to other NSAIDS;
may have less toxicity to the GI mucosa (lower incidence of ulcers and
bleeding)
Acetaminophen
Mech: Reversibly inhibits COX-1
and 2, mostly in CNS. Inactivated peripherally.
Clinical: Antipyretic, analgesic,
but lacking anti-inflammatory properties.
Toxicity: Overdose produces hepatic
necrosis; acetominophen metabolite depletes glutathione and forms toxic tissue
adducts in liver. Give Mucomyst (N-acetylcysteine) for overdose – replenishes
glutathione.
Glucocorticoids:
Hydrocortisone, prednisone, triamcinolone, dexamethasone, beclomethasone
Mech: Decrease the production of
leukotrienes and prostaglandins by inhibiting phospholipase A2 and expression
of COX-2.
Clinical: Addison’s disease,
inflammation, immune suppression, cancer therapy, asthma (drug of choice in
status asthmaticus along with albuterol)
Toxicity: Iatrogenic Cushing’s
syndrome: buffalo hump, moon facies, truncal obesity, muscle wasting, thin
skin, easy bruising, osteoporosis, adrenocortical atrophy, peptic ulcers
Albuterol
Mech: b2 agonist. Relaxes bronchial smooth muscle.
Clinical: Asthma – use during acute
exacerbation
Salmeterol
Mech: b2 agonist. Long-acting agent for prophylaxis.
Clinical: Asthma. Controller
Toxicity: tremor and arrhythmia
Theophylline
Mech: Methylxanthine.
Bronchodilation mechanism unclear – may cause bronchodilation by inhibiting
phosphodiesterase, enzyme involved in degrading cAMP (controversial)
Clinical: Asthma
Toxicities: Seizures, arrhythmias,
drug-drug interactions
Cromolyn
Mech: Prevents release of
mediators from mast cells.
Clinical: Prophylaxis of asthma
only. Not effective in an acute attack.
Toxicity: rare
Colchicine
Mech: Depolymerizes
microtubules, impairing leukocyte chemotaxis and degranulation.
Clinical: Acute gout
Toxicity: GI, esp. orally. Indomethacin
is less toxic and more commonly used.
Probenecid
Mech: Inhibits reabsorption of
uric acid (also inhibits secretion of penicillin)
Clinical: Chronic gout.
Allopurinol
Mech: Xanthine oxidase
inhibitor, decreases conversion of xanthine to uric acid
Clinical: Chronic gout
Toxicity: increased with
6-mercaptopurine
Insulin
Mech: Binds insulin receptor,
which has tyrosine kinase activity. In liver, increases storage of glucose as
glycogen. In muscle, stimulates glycogen and protein synthesis, and K+ uptake.
In adipose tissue, facilitates triglyceride storage.
Clinical: Diabetes mellitus. Life-threatening
hyperkalemia, stress-induced hyperglycemia.
Toxicity: hypoglycemia,
hypersensitivity (rare)
Sulfonylureas:
Tolbutamide, chlorpropamide, glyburide, glipizide
Mech: Oral hypoglycemics used to
stimulate release of endogenous insulin in NIDDM. Close K+ channels in b-cell membrane – cell
depolarizes – insulin release triggered owing to an increase in Ca++ influx
Clinical: NIDDM. Inactive in IDDM
because requires islet fxn
Toxicity: hypoglycemia (more common
with 2nd generation: glyburide, glipizide) and disulfuram-like
effects (not seen with 2nd gen)
Metformin
Mech: Unknown. Possibly inhibits
gluconeogenesis and increases glycolysis; decreases serum glucose levels.
Clinical: Used as oral hypoglycemic.
Can be used in both IDDM/NIDDM
Toxicity: most grave effect is
lactic acidosis
Glitazones:
Pioglitazone, rosiglitazone
Mech: Increase target cell
response to insulin.
Clinical: Used as monotherapy for
NIDDM or in combination with above agents.
Toxicity: Weight gain, hepatotoxic (troglitazone)
a-glucosidase inhibitors: Acarbose, miglitol
Mech: Inhibits intestinal brush
border enzymes; delayed hydrolysis of sugars and absorption of glucose leads to
decreased post-prandial hyperglycemia.
Clinical: Used as monotherapy in
NIDDM or in combination with above agents
Toxicity: GI disturbances
Leuprolide
Mech: GnRH analog with agonist
properties when used in pulsatile fashion and antagonist properties when used
continuously (but causes transient initial burst of LH/FSH)
Clinical: Infertility (pulsatile),
prostate cancer (continuous, use with flutamide), uterine fibroids
Toxicity: Antiandrogen, nausea,
vomiting
Propylthiouracil
Mech: Inhibits organification
and coupling of thyroid hormone synthesis. Also decreases peripheral conversion
of T4 to T3.
Clinical: Hyperthyroidism
Toxicity: Skin rash,
agranulocytosis, aplastic anemia
Finasteride
Mech: 5a-reductase inhibitor
(decreases conversion of testosterone to dihydrotestosterone)
Clinical: BPH
Flutamide
Mech: Non-steroidal competitive
inhibitor of androgens at the testosterone receptor.
Clinical: Prostate cancer
Ketoconazole,
spironolactone
Mech: Inhibit steroid synthesis
Clinical: Used in treatment of
polycystic ovarian syndrome to prevent hirsutism
Cyclosporine
Mech: Binds to cyclophilins
(peptide proline cis-trans isomerase), blocking differentiation and activation
of T cells mainly by inhibiting the production of IL-2 and its receptor.
Clinical: Suppresses organ rejection
after transplantation; selected autoimmune disorders.
Toxicity: Predisposes patients to
viral infections and lymphoma; nephrotoxic (preventable with mannitol diuresis)
Azathioprine
Mech: Antimetabolite derivative
of 6-mercaptopurine that interferes with the metabolism and synthesis of
nucleic acid.
Clinical: Kidney transplantation,
autoimmune disorders (including glomerulonephritis and hemolytic anemia)
Toxicity: Toxic to proliferating
lymphocytes after antigenic stimulus.
Tacrolimus
(FK506)
Mech: Similar to cyclosporine;
binds to FK binding protein, inhibiting secretion of IL-2 and other cytokines
Clinical: Potent immunosuppressive
used in organ transplant
Toxicity: Significant:
nephrotoxicity, peripheral neuropathy, hypertension, pleural effusion,
hyperglycemia