1. Complic of empiric antibiotic use:

Resistance: primary through conjugation via F plasmid (also transduction (thru bacteriophage) and transformation (the great vacuum cleaner); transposon = mobile genetic element which insert into phages, plasmids, chromosomes w/o DNA homology è carry genes for resistance/virulence

Fungal Infection: vaginitis (yeast infect; Candida) when taking abx (also oral contraceptives, during menses/pregnancy) è inflamed vaginal mucosa and patches of cottage cheese-appearing white clumps affixed to vaginal wall; treat w/ imidazole

Pseudomembranous colitis from C.difficle: kill all normal colonic flora w/ abx (clindamycin and penicillin family drugs) and C. difficle can proliferate è secrete exotoxin è epithelial death and colonic ulcerations covered w/ exudative memb; present w/ severe diarrhea; treat w/ oral vancomycin or metronidazole (neither absorbed by GI tract; therefore, highly concentrated in the colon).

Question 2 - secondary effects of common drugs

I used coursepack notes, phi chi’s, my notes, micro made ridiculously simple, appleton and lange pharm. i also decided not to do the autonomic drugs, since i think that they are easier to learn as examples of the autonomic pharmacology, as opposed to isolated in a table. but if anyone wants me to do them , or if there are any questions/suggestions, please let me know.

drug	secondary effects
antiorganisms
penicillin	anaphalaxis
cephalosporin	bleeding (interferes with vit k clotting factors); disulfiram-like effect
vancomycin	ototoxicity; nephrotoxicity; red man syndrome (after rapid infusion)
aminoglycosides	vestibulotoxicity; ototoxicity; nephrotoxicity;curare-like effect
tetracycline/doxycycline	effects on bone (don’t give to kids under 8 or if pregnant);gi irritation; phototoxic dermatitis; renal, hepatic toxicity
chloramphenicol	gray baby syndrome; aplastic anemia
macrolides (erythro-, clarithro-, azithromycin)	inhibitor of p450; gi irritation; cholestatic hepatitis
sulfonamides	p450 interactions; displaces drugs from plasma proteins
quinolones (-floxacin)	don’t give to kids (tendon rupture, damage to growing cartilege)
clindamycin	pseudomembranous colitis (treat with metronidazole or vancomycin orally)
metronidazole	metallic taste
amphotericin b	nephrotoxic; anemia
flucytosine	bone marrow toxicity; elevated hepatic enzymes
-azole antifungals	hepatotoxic; gi toxic; p450
isoniazid	peripheral neuritis; hepatotoxic
rifampin	red color to body fluids; p450
ethambutol	vision loss
ganciclovir	bone marrow toxicity (neutropenia, thrombocytopenia)
ribavirin	very toxic (anemia, bone marrow toxicity); teratogenic, mutagenic—do not use in pregnant women
foscarnet	bone marrow toxicity,; nephrotoxic
interferons	flu-like syndrome; bone marrow toxicity; suicidal tendencies (CNS toxicity); p450
azt	bone marrow toxicity (granulocytopenia, anemia)
acyclovir	nephrotoxic (prevented by giving adequate water)
cancer drugs
cyclophosphamide	hemorrhagic cystitis; bone marrow ablation
nitrosoureas	bone marrow toxicity
cisplatinum	cisplatinum-renal toxicity; ototoxicity (don’t give with loop diuretics)
methotrexate	renal toxicity; myelosuppression; liver fibrosis; do not use if pregnant
fluorouracil (5-fu)	bone marrow toxicity; hand foot syndrome
cytosine arabinoside (ara-c) + gemcitabine	bone marrow toxicity
6-mercaptopurine (6-mp)	bone marrow toxicity; tumor lysis syndrome leads to hyperuricemia, give allopurinol to prevent
vinca alkaloids	vincristine-peripheral neuropathy vinblastine-myelosuppression
paclitaxel	hypersensitivity reactions; bone marrow toxicity
doxorubicin (adriomycin)	cardiomyopathy; red urine
bleomycin	pulmonary fibrosis; anaphylaxis
heart drugs
quinidine	cinchonism (gi upset, tinnitus, visual disturbances, dizziness)
procainamide	lupus-like syndrome
flecaininde, propafenone	av block, ventricular fibrillation
amiodarone	pulmonary fibrosis; neuropathy; abn. epithelial pigmentation; hypothyroid; haloes around lights; blurred vision; corneal epithelial whorls; optic neuropathy
lidocaine	seizures
disopyramide	atropine-like side effects
aspirin	gi toxicity; ototoxicity
adp receptor antagonists (ticlopidine, clopidogrel)	neutropenia
gp 2b/3a receptor antagonists
nitroglycerin	headache; flushing; dizziness; palpitations
nifedipine	reflex tachycardia
statins	myopathy (esp. if used with niacin or gemfibrozil)
fibrates	gemfibrozil-cholelithiasis; displaces other drugs from plasma proteins clofibrate-in men, gi and malignant disease
niacin	flushing, pruritis; don’t use if ulcers, gout, diabetes mellitus
heparin	osteoporosis
warfarin	bleeding; don’t use if pregnant (bone defects in fetus)
ace inhibitors	cough; angioedema; don’t use if pregnant
prazosin	orthostatic hypotension (first dose)
clonidine	use during pregnancy
hydralazine	peripheral neuritis
nitroprusside	cyanide poisoning
digoxin	signs of digoxin toxicity-colored vision; anorexia; nausea, vomiting; lethargy
respiratory drugs
leukotriene synthesis inhibitor (zileuton)	p450; hepatotoxic
theophylline	seizures
renal drugs
thiazides	gout; hyperlipidemia; hyperglycemia; hypercalcemia; sulfonamide cross-sensitivity
loop diuretics	hypochloremic alkalosis; ototoxicity
spironolactone	endocrine imbalances (gynecomastia, altered libido, impotence, hirsutism)
cyclosporin a + tacrolimus	nephrotoxic
mycophenolate	gi, hematopoietic toxicities
sirolimus	hyperlipidemia; hematopoietic toxicity
okt3	pulmonary edema; high fevers
derm drugs
accutane (and other retinoids)	dermatitis; hyperlipidemia; teratogen (do not take when pregnant); depression
gi drugs
h2-receptor antagonists (cimetidine…)	p450; thrombocytopenia; endocrine (impotence, decreased sperm, gynecomastia)
proton pump inhibitors (omeprazole…)	p450
antacids	aluminum-constipation; hypophosphotemia calcium-constipation magnesium-diarrhea
sucralfate (aluminum salt)	constipation; hypophosphotemia; neurotoxicity; bezoar formation
misoprosol (prostaglandin analog)	do not use if pregnant
bismuth	dark stools; use with caution if renal failure
cisapride	cardiac arrhythmias
seratonin receptor antagonists (alosetron )	ischemic colitis; constipation
neuro drugs
narcotics side notes: dextromethorphan-cough suppressant etorphine-short acting, very potent apomorphine-induces vomiting (dopamine)	respiratory depression; nausea, vomiting; miosis; release of anti-diuretic hormone; convulsions (esp. with meperidine, propoxyphene); constipation (diphenoxylate, loperimide used as anti-diarrheals); increased smooth muscle tone; hypotension
esters (procaine)	more allergenic than amides (lidocaine)
phenytoin	binds plasma proteins; p450; gingival hyperplasia; folate/vit k deficiency in newborns if given iv for status epilepticus-ph 12, irritating to veins, so fos-phenytoin used instead
carbamazepine	agranulocytosis; aplastic anemia; vit k deficiency in newborns
phenobarbital	p450; vit k deficiency in newborns
valproic acid	weight gain; alopecia; do not use if pregnant; thrombocytopenia; hepatotoxic
felbamate	aplastic anemia
halothane	arrhythmogenic; bronchodilator; malignant hyperthermia if used with succinylcholine; uterine relaxation; hepatotoxicity
nitrous oxide	long term exposure-vit b12 deficiency
sedative-hypnotic drugs benzodiazepines, zolpidem barbiturates buspirone	cognitive impairment; decreased psychomotor skills; daytime sedation; cns depression (but rare for buspirone); respiratory, cardio depression; barbiturates-induce liver enzymes, displaces other drugs from plasma proteins
antipsychotics (p. 529 neuro coursepack) clozapine-almost no motor side effects, used to treat parkinson’s, high affinity for serotonin receptors	side effects dependent on potency 1. increased potency means increased binding to dopamine d2 receptors, giving increased motor side effects 2. decreased potency means drug binds to lots of things, giving increased autonomic side effects
tricyclic antidepressants (p.615 neuro coursepack)	sedation, atropine like effects (tertiary>secondary amines); cardiovasc effects
serotonin-selective reuptake inhibitors (fluoxetine)	stimulant; nausea, diarrhea; weight loss
moa inhibitors	hypotension; don’t eat with tyramine foods; hepatotoxic
mirtazapine	agranulocytosis
lithium	nephropathy
eye topical anesthetics	don’t use chronically
corticosteroids	cataracts; glaucoma; makes infections worse if systemic, also get pseudotumor cerebri
amiodarone (used for heart)	haloes around lights; blurred vision; corneal epithelial whorls; optic neuropathy; pulmonary fibrosis; neuropathy; abn. epithelial pigmentation; hypothyroid
anticholinergics	loss of accomodation; blurred vision; pupillary dilation; angle-closure galucoma
digoxin (used for heart)	color vision defects
hydroxychloroquine (used for lupus)	retinal atrophy
tamoxifen	corneal whorls; crystalline retinopathy
endocrine drugs
sulfonylureas (glyburide)	hypoglycemia; sulfa allergic reactions
metformin	appetite suppression; gi distress; lactic acidosis
thiazolidinediones (-glitazones)	liver failure; gi distress
acarbose	gi distress
repro drugs
oral contraception (p.79 repro coursepack)	increased coagulability; breast cancer
estrogen	breast cancer
progesterone	increases cholesterol; mood changes
triphenyethylenes	stimulates endometrium, ovaries (but not breast)
benzothiaphenes	increased hot flashes
musculoskeletal drugs
nsaids	gi, renal, liver; cns toxicity
hydroxychloroquine	retinal atrophy
methotrexate	renal toxicity; myelosuppression; liver fibrosis; do not use if pregnant
cyclophosphamide	hemorrhagic cystitis; bone marrow ablation
allopurinol	gi upset; peripheral neuritis; vasculitis
corticosteroids	adrenal suppression; metabolic effects (growth inhibition, diabetes, muscle wasting, osteoporosis); salt retention; psychosis

3. Fundamental Pharmacodynamics

Agonist	drug that activates its R upon bindg
Effector	component of bio sys that accomplishes the bio effect after being activated by a R; channel/enz
Pharmacologic Antagonist	drug that binds to its R w/o activating it
Compet Antag	can be overcome by increasing the dose of agonist
Irrev Antag	cannot be overcome by increasing dose of agonist
Physio Antag	drug that counters the effects of another by binding to a different R and causing opposing effects
Chem Antag	counters effects of another drug by binding it and blocking its actions
Partial Agonist	binds its R but produces a smaller effect at full dosage than a full agonist
Graded dose-response curve	increasing responses to increasing doses of drug
Quantal dose-response curve	a graph of the fraction of a pop that shows a specified response to increasing doses of a drug
EC50	· in a graded dose-response curve, the conc/dose that prod 50% of the max possible response · in a quantal dose response curve, the dose that causes the specified response in 50% of the pop
Kd	conc of drug that results in binding to 50% of R
Therapeutic Index	LD50/ED50; ratio of lethal/effective dose
Efficacy	Max effect a drug can bring about, regardless of dose; asymptote of curve
Potency	dose/conc req to bring about 50% of drug’s MAX effect; =EC50
Spare R	receptors that do not have to bind drug in order for max effect to be produced; Kd>ED50

4. Drug efficacy and potency on dose-response curves:

Efficacy: asymptotic max of curve; Emax

Potency: dose at ½ max; EC50

Please see page 11 of Lange’s Pharmacology for a picture.

5. Pharmacogenetics:

Women have a lower first-pass metabolism than men for EtOH. Gender differences rare.

Genetic differences:

1. Hydrolysis of esters: succinylcholine is metabolized by cholinesterase; mostly è very rapid (5min); 1/2500 è slow à neuromuscular paralysis for hours after a single dose.

2. Acetylation of amines: isoniazid and procainamide è inact by N-acetylation; slow acetylators (auto recess); 50% of caucasians and African-Americans in USA.

3. Oxidation by p450: affects metabolism of debrisoquin, sparteine, phenformin, dextromethorphan, metoprolol, some tricyclic antidep

6. Anesthesia:

MAC: conc of anesthetic (% of inhaled gas) è abolish specified painful stim in 50% of pts.

1/MAC = Potency

Blood: gas partition coefficient: the more rapidly a drug equilibrates w/ the blood, the more quickly the drug passes into the brain to prod anesthetic effects. Drugs w/ low blood:gas coeff (i.e. NO; MAC = 105%; fast onset, fast recovery; low solubility in blood) equilibrate more rapidly than do drugs w/ a higher coeff (i.e. halothane; MAC = 1%; high solubility in lipid; high potency).

Rate of induction depends on:

1. Blood:gas partition coeff: low coeff è fast onset

2. Inspired gas PP: high PP à faster induction

3. Ventilation rate: inc vent rate à faster induction

4. Pulmonary blood flow: low flow à faster onset (b/c PP rises as a faster rate)

5. Arteriovenous conc gradient: uptake of soluble anesthetics into highly perfused tissues may decrease gas tension in mixed venous blood. This can influence the rate of onset, since achievement of equilibrium is dependent on the differences in anesthetic tension between arterial and venous blood.

Different IV agents: see p. 283 of First Aid

Toxicities: see p. 283

Malignant hyperthermia: from any volatile liq anesthetic (but esp w/ the interaction of halothane w/ succinylcholine in a genetically predisposed individual); à decreased SR Ca++ uptake è seizures, ventilation impairment, hyperkalemia, arrhythmias; tx w/ dantrolene, oxygen, lower temp, other drugs

8. Prevention/tx of cerebrovascular ds:

ASA: for primary prevention à never proven efficacious; used for secondary prevention

Heparin/Warfarin: used for secondary prevention

Tissue plasminogen activator (tPA): used to treat acute stroke; must present w/in 3 hours of symptoms;

no evidence of hemorrhage on CT; no age exclusion; symptoms consistent w/ stroke

Surgery (Carotid endarterectomy): clean out blockage

10. Vaccines: indications, potential SE

· Don’t give live attenuated vaccines to immunocompromised/preg pts

· SE of Live attenuated: prod symptomatic infect; transfer strain to others

· SE of killed: toxic rxns and adverse responses

· Pneumococcus vaccine for: >65 yo, chronic cardiac/pul ds, asplenic, alcoholics, AIDS, diabetes, mellitus, CSF leaks, renal failure, organ transplant, chemotherapy; don’t necessarily need to vaccinate all medical professionals.

· Lyme vaccine only for people who live in/travel to endemic areas

· Haemophilus vaccine for 2 mo old, asplenics, others at risk.

· Meningococcus vaccine for outbreaks.

· Rabies vaccine after you’ve been bit by a rabid animals (w/ rabies Ig) or as prophylaxis if you work w/ animals

· Chickenpox vaccine for: kids, HC workers, women of child bearing age; not for old people.

· Influenza vaccine for: nursing home pts, pts w/ emphysema/heart ds/chronic cond/long-term aspirin use, pts >50 yo; if nursing home outbreak, vaccinate residents, personal

· MMR at 15 mo and school age. Avoid during pregnancy!!!

· DPT as immunoprophylaxis for kids only; booster every 10 years of dT.

· Polio (IPV; killed) for kids and non-immune adults; don’t give OPV (live) b/c you’re more likely to get polio from a rxn to OPV than from a natural source of polio; boosters for people traveling to places w/ lots of polio, people taking care of pts excreting lots of polio, people who to lab work w/ polio.

· Hepatitis B vaccine for kids, IV drug users, hemodialysis pts, institutionalized pts, immigrants, prisoners, babies whose moms = +, hemophiliacs, gays, people w/ multiple sexual partners/STDs, healthcare workers.

· Hep A give 2-4 wks before travel to endemic areas.

· Typhoid: exposure from travel, epidemic, or household contact; last 3 years.