Usmel Step 1: Pharmacology

Front 1

Which microbial drugs blocks cell wall synthesis by
inhibition of peptidoglycan cross-linking?

Back 1

Penicillin, ampicillin, ticarcillin, piperacillin, imipenem, aztreonam, cephalosporins

Front 2

Which microbial drugs block peptidoglycan synthesis?

Back 2

Bacitracin, vancomycin

Front 3

Which microbial drugs block nucleotide synthesis?

Back 3

Sulfonamides, trimethoprim

Front 4

PCN?

Back 4

Penicillin G (IV form), penicillin V (oral). Prototype p-lactam antibiotics. 1. Bind penicillin-binding proteins 2. Block transpeptidase cross-linking of cell wall 3. Activate autolytic enzymes
Mostly used for gram-positive organisms (S. pneumoniae, S.pyogenes, Actinomyces) and syphilis. Bactericidal for gram-positive cocci, gram-positive rods, gram-negative cocci, and spirochetes. Not penicillinase resistant.
1
Hypersensitivity reactions, hemolytic anemia.

Front 5

Methicillin, nafcillin, dicloxacillin(penicillinase-resistantpenicillins)?

Back 5

Same as penicillin. Narrow spectrum; penicillinase resistant because of bulkier R group.
S. aureus (except MRSA; resistant because of altered penicillin-binding protein target site).
Hypersensitivity reactions; methicillin-interstitial nephritis.

Front 6

Ampicillin, amoxicillin (aminopenicillins)?

Back 6

Same as penicillin. Wider spectrum; penicillinase sensitive. Also combine with clavulanic acid to enhance spectrum. AmOxicillin has greater Oral bioavailability than ampicillin.
Extended-spectrum penicillin-certain gram-positive bacteria and gram-negative rods (Haemophilus influenzae, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, enterococci).
Hypersensitivity reactions; ampicillin rash; pseudomembranous colitis. (Coverage: ampicillin1 amoxicillin HELPS kill enterococci.) (AMPed up penicillin)

Front 7

Ticarcillin, carbenicillin, piperacillin (antipseudomonals)?

Back 7

Same as penicillin. Extended spectrum. Pseudomonas spp. and gram-negative rods;
susceptible to penicillinase; use with clawlanic
acid. Hypersensitivity reactions. (TCP: Takes Care of Pseudomonas)

Front 8

B-lactamase inhibitors

Back 8

Include clavulanic acid, sulbactam, tazobactam. Often added to penicillin antibiotics to protect the antibiotic from destruction by klactamase (penicillinase). (CAST)

Front 9

Cephalosporins?

Back 9

B-lactam drugs that inhibit cell wall synthesis but are less susceptible to penicillinases. Bactericidal.
1st generation (cefazolin, cephalexin) -gram-positive cocci, Proteus mirabilis, E. coli, Klebsiella pneumoniae.
2nd generation (cefoxitin, cefaclor, cefuroxime)- gram-positive cocci, Haemophilus influenzae, Enterobacter aerogenes, Neisseria spp., Proteus mirabilis, E. coli, Klebsiella pneumoniae, Serratia marcescens.
3rd generation (ceftriaxone, cefotaxime, ceftazidime) -serious gram-negative infections resistant to
other p-lactams. 4th generation (cefepime)-'I' activity against
Pseudomonas and gram-positive organisms. Hypersensitivity reactions, vitamin K deficiency.
Imipenem/cilastatin, meropenem
Mechanism
Clinical use
Toxicity
Imipenem is a broad-spectrum, klactamase-resistant carbapenem. Always administered with cilastatin (inhibitor of renal dihydropeptidase I) to & inactivation of drug in renal tubules.
Gram-positive cocci, gram-negative rods, and anaerobes. Wide spectrum, but the significant side effects limit use to life-threatening infections, or after other drugs have failed. Meropenem, however, has a reduced risk of seizures and is stable to dihydropeptidase I.
GI distress, skin rash, and CNS toxicity (seizures) at high plasma levels.
With imipenem, "the kill is LASTIN' with ciLASTATIN."
Cross-hypersensitivitywith penicillins occurs in 5-10% of patients. 'I' nephrotoxicity of aminoglycosides; disulfiram-like reaction with ethanol (in cephalosporins with a methylthiotetrazole group, e.g., cefamandole).

Front 10

Aztreonam?

Back 10

A monobactam resistant to p-lactamases. Inhibits cell wall synthesis (binds to PBP3) Synergistic with aminoglycosides. No cross-allergenicity with penicillins.
Gram-negative rods only-No activity against gram-positives or anaerobes. For penicillin-allergic patients and those with renal insufficiency who cannot tolerate aminoglycosides.
Usually nontoxic; occasional GI upset. No cross-sensitivity with penicillins or cephalosporins.

Front 11

Imipenem/cilastatin, meropenem?

Back 11

Imipenem is a broad-spectrum, klactamase-resistant carbapenem. Always administered with cilastatin (inhibitor of renal dihydropeptidase I) to & inactivation of drug in renal tubules.
Gram-positive cocci, gram-negative rods, and anaerobes. Wide spectrum, but the significant side effects limit use to life-threatening infections, or after other drugs have failed. Meropenem, however, has a reduced risk of seizures and is stable to dihydropeptidase I.
TOXICITITY: GI distress, skin rash, and CNS toxicity (seizures) at high plasma levels. (With imipenem, "the kill is LASTIN' with ciLASTATIN.")

Front 12

Vancomycin?

Back 12

Inhibits cell wall mucopeptide formation by binding D-ala D-ala portion of cell wall precursors. Bactericidal.
Clinical use Gram positive ONLY!-serious, multidrug-resistant organisms, including S. aureus, enterococci and Clostridiumdificile (pseudomembranouscolitis).
Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse flushing-"red man syndromen (can largely prevent by pretreatment with antihistamines and slow infusion rate). Well tolerated in general-does NOT have many problems. Resistance occurs with amino acid change of D-ala D-ala to D-ala D-lac.

Front 13

Protein synthesis inhibitors?

Back 13

30s inhibitors: A = Aminoglycosides [bactericidal] T = Tetracyclines [bacteriostatic]. 50s inhibitors: C = Chloramphenicol, Cli-ndamycin [bacteriostatic]
E = Erythromycin [bacteriostatic] L = Lincomycin [bacteriostatic]
L= Lincomycin
L = Linezolid [variable]. ("Buy AT 30, CCELL(sell) at 50!!)

Front 14

Aminoglycosides?

Back 14

Gentamicin, Neomycin, Amikacin, Tobramycin,Streptomycin.
Bactericidal; inhibit formation of initiation complex and cause misreading of mRNA. Require O2for uptake; therefore ineffective against anaerobes.
Severe gram-negative rod infections. Synergistic with p-lactam antibiotics. Neomycin for bowel surgery.
Nephrotoxicity (especiallywhen used with cephalosporins), Ototoxicity (especiallywhen used with loop diuretics). Teratogen.
RESISTANCE: Transferase enzymes that inactivate the drug by acetylation, phosphorylation, or adenylation. ("Mean" GNA TS canNOT kill anaerobes)

Front 15

Tetracyclines?

Back 15

Tetracycline, doxycycline,demeclocycline, 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. Must NOT take with milk, antacids, or iron-containing preparations because divalent cations inhibit its absorption in the gut.
Borrelia burgdoferi, H. pylori, M. pneumoniae. Drug's ability to accumulate intracellularly makes it very effective against Rickettsia and Chlamydia.
GI distress, discoloration of teeth and inhibition of bone growth in children, photosensitivity.
Contraindicated in pregnancy. -RESISTANCE: uptake into cells or 'I'efflux out of cell by
plasmid-encoded transport pumps. (Demeclocycline- ADH antagonist; acts as a Diuretic in SIADH.)

Front 16

Clopidogrel?

Back 16

Antiplatelet – ADP-receptor antagonist; all members are prodrugs; thiol- containing active metabolite causes irreversible inhibition of P2Y12 receptor (RECEPTOR ON PLATELETS WHERE ADP BINDS), blocking stimulated adenylyl cyclase activity. Rapid Oral Absorption Hepatic Metabolism to a short-lived, active metabolite (isozyme) (genetic polymorphisms – makes clinical efficacy variable) INDICATIONS for ACS, recent MI, recent stroke, PAD Possible interaction with PPIs and statins. SIDE EFFECTS: Severe rash; Diarrhea Bleeding Complications Thrombocytopenia; TTP Black Box Warning for the CYP2C19 poor metabolizers No significant rate of neutropenia (like in ticlopidine)

Front 17

Macrolides? Binds where?

Back 17

Erythromycin, azithromycin, clarithromycin. MECHANISM: Inhibit protein synthesis by blocking translocation; bind to the 23s rRNA of the 50s ribosomal subunit. Bacteriostatic. CLINICAL USE: Atypical pneumonias (Mycoplasma,Chlamydia, Legionella), URIs, STDs,
gram-positive cocci (streptococcal infections in patients allergic to penicillin), and
Neisseria. TOXICITY:Prolonged Q T interval (especially erythromycin), GI discomfort (most common cause
of noncompliance), acute cholestatic hepatitis, eosinophilia, skin rashes. Increases
serum concentration of theophyllines, oral anticoagulants. RESISTANCE: Methylation of 23s rRNA binding site.

Front 18

Chloramphenicol? MOA?

Back 18

MOA: Inhibits 50s peptidyltransferaseactivity. Bacteriostatic. CLINICAL USE: Meningitis (Haemophilus influenzae, Neisseria meningitidis, Streptococcuspneumoniae).
Conservative use owing to toxicities but often still used in developing countries due to low cost. TOXICITIY: Anemia (dose dependent), aplastic anemia (dose independent), gray baby syndrome (in
premature infants because they lack liver UDP-glucuronyl transferase). RESISTANCE: Plasmid-encoded acetyltransferasethat inactivates drug.

Front 19

Clindamycin? Indications for use?

Back 19

MECHANISM: Blocks peptide bond formation at 50s ribosomal Treats ANAEROBES above the subunit. Bacteriostatic. diaphragm vs. metronidazole. DOES NOT CROSS BBB (Metronidazole does) so cant use for anarerobic
CLINCAL USE: Anaerobic infections (e.g., Bacteroides fiagilis, (anaerobic infections below Clostridium perf;ingens) in aspiration pneumonia diaphragm). or lung abscesses.
SIDE EFFECTS: Pseudomembranous colitis (C. difficile overgrowth), fever, diarrhea.

Front 20

Sulfonamides?

Back 20

Sulfamethoxazole (SMX),sulfisoxazole,sulfadiazine. MECHANISM: PABA antimetabolites inhibit dihydropteroatesynthetase.Bacteriostatic. CLNICAL USE: Gram-positive, gram-negative,Nocardia, Chlamydia. Triple sulfas or SMX for simple UTI. SIDE EFFECTS: Hypersensitivity reactions, hemolysis if G6PD deficient, nephrotoxicity (tubulointerstitial
nephritis), photosensitivity, kemicterus in infants, displace other drugs from albumin (e.g., warfarin). RESISTANCE: Altered enzyme (bacterialdihydropteroatesynthetase),&uptake, or ?PABA synthesis.

Front 21

Trimethoprim?

Back 21

MECHANISM: Inhibits bacterial dihydrofolate reductase. Bacteriostatic. CLINICAL USE: Used in combination with sulfonamides (trimethoprim-sulfamethoxazole [TMP-SMX]), causing sequential block of folate synthesis. Combination used for recurrent UTIs, Shigella, Salmonella,Pneumocystisjiroveci pneumonia.
SIDE EFFECTS: Megaloblastic anemia, leukopenia, granulocytopenia. (May alleviate with supplemental folinic acid [leucovorin rescue].) MNEMONIC: Trimethoprim = TMP: "Treats Marrow Poorly."

Front 22

Patients who do not tolerate sulfa drugs should not be given?

Back 22

sulfonamidesor other sulfa drugs, such as sulfasalazine, sulfonylureas, thiazide diuretics, acetazolamide, furosemide, celecoxib, or probenecid.

Front 23

Fluoroquinolones?

Back 23

Ciprofloxacin, norfloxacin, ofloxacin, sparfloxacin, moxifloxacin, gatifloxacin, enoxacin (fluoroquinolones), nalidixic acid (a quinolone).
MECHANISM: Inhibit DNA gyrase (topoisomerase 11).Bactericidal. Must not be taken with antacids.
CLNICAL USE: Gram-negative rods of urinary and GI tracts (including Pseudomonas),Neisseria, some gram- positive organisms.
SIDE EFFECTS: GI upset, superinfections, skin rashes, headache, dizziness. Contraindicated in pregnant women and in children because animal studies show damage to cartilage.!!! Tendonitis and tendon rupture in adults; leg cramps and myalgias in kids.
RESISTANCE: Chromosome-encoded mutation in DNA gyrase. MNEMONIC: FluoroquinoLONES hurt attachments to your BONES.

Front 24

Metronidazole?

Back 24

MECHANISM: Forms free radical toxic metabolites in the bacterial cell that damage DNA. Bactericidal, antiprotozoal.
CLINICAL USE: Treats Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, Anaerobes (Bacteroides, Clostridium). Used with bismuth and amoxicillin (or tetracycline) for "triple therapy" against H. Pylori. TREATS ANAERBOIC INFECTIONS BELOW DIAPHRAM VS CLNIDAMYCIN WHICH TREATS ANAEROBIC INFECTIONS ABOVE DIAPHRAM!!
SIDE EFFECTS: Disulfiram-like reaction with alcohol; headache, metallic taste.

Front 25

Polymyxins? MOA?

Back 25

PolymyxinB,colistimethate (polymyxinE). MENMONIC: 'MYXinsMIXupmembranes. MECHANISM: Bind to cell membranes of bacteria and disrupt their osmotic properties. Polymyxins are
cationic, basic proteins that act like detergents.CLINICAL USE: Resistant gram-negative infections. SIDE EFFECTS: Neurotoxicity, acute renal tubular necrosis.

Front 26

What are the 1st line and 2nd line drugs for treating TB?

Back 26

First Line: "RIPE" 1. RIFAMPIN, 2. ISONIAZID, 3. PYRAZINAMIDE, 4. ETHAMBUTOL

Second Line: Streptomycin, Kamamycin/Amikacin (Aminoglycosides), Capreomycin, Cycloserine, Ethionamide, Flouroquinoline, Aminosalicylic acids

Front 27

Isoniazid? Side effects? Used to treat?

Back 27

This is a first line agent used in the treatment of TB. Other first Line: "RIPE" 1. RIFAMPIN, 2. ISONIAZID, 3. PYRAZINAMIDE, 4. ETHAMBUTOL
MECHANISM OF ACTION:
It works by inhibiting catalase peroxidase enzymes which are enzymes involved in the synthesis of mycolic acid, a component of the cell wall. This drug is bacteriocidal in actively growing infections and bacteriostatic in non replicating infections.

RESISTANCE:
Resistance to isoniazid is manifested by a mutation in the target enzyme – Catalase peroxidase. Therefore a mutation will block the bacteriocidal effect of the drug.
FAFACTS:
1. This drug can be administered orally or parentrally

2. Will penetrate the intracellular space

3. Has a broad distribution, penetrates the CNS

4. Crosses the placenta but is not teratogenic.

METABOLISM:

Isoniazid is metabolized by hepatic acetylation. There is genetic variability in this acetyl transferase within the poppulation. In the United States half of the population is categorized as rapid metabolizers and the other half is slow metabolizers. This difference is usually not clinically significance so there is not a need to test for it. The metabolites of this drug are then excreted renally. This drug may need to be dose adjusted in hepatic insufficiency and in a slow acetylator who is has renal impairment.

SIDE EFFECTS:

Adverse side effects of isoniazid include:
1. Hepatotoxicity that is typically more common in patients over age 35 and is potentiated by alcohol. Therefore, patients on this therapy should be urged not consume alcohol. Hepatotoxicity from isoniazid usually presents early after the onset of treatment. (WHEREAS RIFAMPIN HEPATIC DYSFUNCTION OCCURS LATER IN THERAPY---KNOW THIS!!!)

2. Pyridoxine responsive peripheral neuropathy

3. Hypersensitivity

4. MAO inhibition.

DRUG INTERATIONS
1. This drug is also a potent inducer and inhibitor of CYP 450 enzymes meaning that there is a lot of potential drug interactions.

2. Isoniazid can potentiate acetaminophen toxicity when they are taken together.

3. Lastly, this drug inhibits parahydroxylation of phenytion which is an antiepileptic that can accumulate and cause toxicities at higher levels.
MNEMONIC: I-N-H I-njures N-eurons and H-epatocytes.

PLEASE DON’T FORGET THIS -- Isoniazid should always be used in combination with another first line drug when being used to treat active TB infections.
The ONLY time Isoniazid can be used as monotherapy in chemoprophylaxis of a latent TB infection – the same goes for rifampin. Once again, never use monotherapy to treat active TB!!!

Front 28

Rifampin? Side effects?

Back 28

Rifampin is another first line drug used in the treatment of mycobacterial infections. Other First Line: "RIPE" 1. RIFAMPIN, 2. ISONIAZID, 3. PYRAZINAMIDE, 4. ETHAMBUTOL


MECHANISM:

It works by inhibiting the DNA dependent RNA polymerase. This drug will work for many other types of bacterial infections. Inhibiting the DNA dependent RNA polymerase allows it to suppress the chain formation in RNA synthesis thereby inhibiting protein synthesis.

INDICATIONS:

The drug is bacteriocidal and is highly effective in the treatment of TB when used in combination with Isoniazid. This combination has shown the highest and fastest rates of tissue and sputum sterilization in infected individuals. Therefore, this drug combination will allow for a shorter duration of infectivity which allows for less risk to public health.

RESISTANCE:
Unfortunately, resistance to this drug can occur and is due to a change in the beta subunit of the bacterial RNA polymerase. This is a change intrinsic to the microbe and affects the target of the drug. Again, this should not be used as monotherapy when treating an active TB infection!!

METABOLISM:

Metabolism of rifampin is via deacetylation (Isoniazid is acetylated) in the liver and elimination of metabolites in the bile, feces, and urine. Therefore the half life can be increased with hepatic dysfunction so dose adjustment may be needed. No dose adjustment is necessary with renal insufficiency.
FACTS:
1. Rifampin can be adminsistered orally or by IV

2. Will distribute widely in the tissues including the CNS

3. Will penetrate the intracellular compartment (needed if you want to treat an intracellular infection).

4. This drug will cross the placenta and is excreted in breast milk but is not teratogenic.

SIDE EFFECTS:

As with Isoniazid, Rifampin can cause liver toxicity. Whats that you say? How the heck do you determine which drug is responsibe when they are both part of the multidrug therapy? So glad you ask! Rifampin will cause liver toxicity much later in treatment whereas Isoniazid will cause toxicity early in treatment (first few months). So… if you are giving multidrug therapy containing the drugs rifampin and isoniazid and the patient develops liver toxicity in the first month of treatment, isoniazid should be identified as the causative agent.

Other toxicities from rifampin will present when intermittent administration is given, therefore this treatment regime should be avoided.
Rifampin may also:

1. Depress T-cell and other immune functions

2. Turn your urine, saliva, sweat and contact lens orange. This is troublesome to the patient but is not really a huge clinical issue.

DRUG INTERACTIONS:

Lastly, rifampin has a many CYP 450 isoenzyme interactions and can act as inducer or inhibitor. Therefore, a review of the patient’s current drug regimen should be analyzed before starting treatment. Also, rifampin induces the CYP450 enzyme that metabolizes itself so the levels of rifampin in the body will decrease overtime despite a consistent dose.

INDICATIONS:
The antimicrobial spectrum of rifampin includes:
1. M. tuberculosis
2. Atypical mycobacteria
3. M. Leprae
4. Many gram negative and gram positive organisms.
5. It is synergistic with ciprofloxacin against staph and is used together with vancomycin to treat PRSP.
**Since this is such a valuable drug in the treatment of TB we try to limit the use for non TB infections in an effort to avoid resistance**

Another drug very similar to Rifampin is RIFAPENTINE. This drug is longer acting but is very similar to rifampin. It is a good alternative when you need to treat patient who is unable to take rafimpin regularly…. Remember rifampin is not tolerated intermittently. However, a down side to rifapentine is that it may interact with HIV drugs, an infection often associated with superimposing mycobacterial infections.
MNEMONIC: Rifampin's 4 R's: 1. RNA polymerase inhibitor 2. Revs up microsomal P-450 3. Red/orange body fluids 4. Rapid resistance if used alone

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NAME THE PROPHYLAXIX DRUG OF CHOICE?

1. MENIGOCOCCAL

2. GONORRHEA

3. SYPHILLIS

4. HISTORY OF RECURRENT UTI'S

5. PNEUMOCYSTIS JIROVECI PNEMONIA (PCP)

6. ENDOCARDITIS WITH SURGICAL OR DENTAL PROCEDURES

7. MYCOBACTERIUM AVIUM INTRACELLULARIE (MAI)

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1. RIFAMPIN

2. CEFTRIAXONE

3. PENCILLIN G

4. TMP-SMX

5. TMP-SMX

6. PCN

7. AZITHROMYCIN

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Amphotericin B? Used to treat? Side effects?

Back 30

Amphotericin B is a polyene antifungal that is widely used for systemic fungal infections (around 50% of cases). It is active against most pathogenic fungi, and can be fungistatic or fungicidal depending on the fungus.

MECHANISM OF ACTION:

Binds to ergosterol in the fungal cell membrane, which results in increased membrane permeability and leakage of intracellular contents.


RESISTANCE:

There has been an emergence of amphotericin B-resistant fungi, although it is not considered a large problem. Resistance is due to an alteration in the ergosterol molecule in certain fungi cell membranes.

FACTS:

1. Amphotericin B is poorly absorbed from the GI tract and MUST be be given by IV!!

2. It is generally given once a day because of its long half-life.

3. Additionally, amphotericin B does NOT cross the blood-brain-barrier well.

4. It is still used sometimes to treat fungal infections of the CNS (like Cryptococcal meningitis, or more correctly, Cryptococcal meningo-encephatlitis). This is especially the case when treating more resistant fungi like Coccidioidomycosis. In such cases, it is administered directly into the CSF, often at the lateral ventricles to avoid the complications of repetitive lumbar punctures.

5. The metabolic pathway of amphotericin B still
remains unknown

6. There is no significant accumulation of amphoatericin B in cases of renal or hepatic insufficiency. Thus, no dose adjustment is necsessary.

7. However, nephrotoxicity is a large side effect of amphotericin B, so doses may need to be reduced in renal insufficiency to mitigate progressive nephrotoxicity.



VARIOUS FORMS OF AMPHOTERCIN B:

Amphotericin B exists in a variety of forms. Conventional amphotericin B is a deoxycholate colloidal suspension in 5% dextrose in water (D5W). In this form, amphotericin B is very effective but has a high incidence of adverse effects. Every infusion of conventional amphotericin B results in fever, chills, headache, nausea, vomiting, phlebitis, anemia, decreased [K+], and decreased [Mg2+]. In 80% of people, administration of amphotericin B results in impaired renal function. There is a potential additive or synergistic effect on renal injury with other nephrotoxic agents (other antibiotics, etc.). It is hypothesized that these effects are a result of amphotericin B attaching to the plasma membranes of red blood cells (anemia) and renal tubule cells (hypokalemia and reduced magnesium) by the same mechanism as how it attaches to fungal cell walls. Note that amphotericin B would be attaching to some molecule other than ergosterol because animal cells do not contain that compound.
The other forms of amphotericin B are referred to as amphotericin B lipid formulations, including: amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AMB), and amphotericin B colloidal dispersion (ABCD). All of these preparations have the same clinical efficacy as the colloidal suspension, but have less adverse effects from toxicity. Of note, they are associated with fewer cases of anemia, less nephrotoxicity, and less hypokalemia. With all other things being equal, lipid formulations of amphotericin B are the best form. However, cost is an important factor as the colloidal suspension of amphotericin B costs $35 per day, while the lipid formulations can cost from $480 to $1300 per day. Since amphotericin B is often prescribed from weeks to months, this price discrepancy can be a large hindrance in developing countries as well as the US.


Amphotericin B can have additive or deleterious effects when co-administered with other antifungal agents. Administration of amphotericin B with flucytosine is synergistic against Cryptococcal infections. [Cryptococcus is an opportunistic fungal infection that can cause pulmonary disease and/or meningo-encephalitis.] It may also be synergistic when administered with echinocandins when treating Cryptococcal infections. Finally, co-administration of amphotericin B with azole antifungal agents may be antagonistic. This is because azole antifungal agents inhibit the synthesis of ergosterol, the target of amphotericin B.


Amphotericin B is prescribed as the primary or second line of treatment for many fungal infections. These infections include:
1. Aspergillosis
2. Systemic Candidemia
3. Blastomycosis
4. Coccidioidomycosis
5. Crytococcosis
6. Fusariosis
7. Histoplasmosis
8. Paracoccidioidomycosis
9. Systemic Sporotrichosis
10. Zygomycosis.

Due to their synergistic effects, amphotericin B and flucytosine is the treatment of choice for Cryptococcal meningitis. Also, amphotericin B is the preferred treatment for deep fungal infections during pregnancy. This is because it has been around long enough for studies to determine that it is NOT teratogenic and does not specifically harm the fetus.

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Nystatin?

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MECHANISM: Same as amphotericin B. Topical form because too toxic for systemic use. CLINICAL USE:M "Swish and swallow" for oral candidiasis (thrush); topical for diaper rash or vaginal
candidiasis.

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AZOLES?

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MECHANISM:

Azole antifungal agents are inhibitors of fungal CYP-450 enzymes involved in the synthesis of ergosterol.

Inhibition of these CYP-450 enzymes inhibits the synthesis of ergosterol, which alters fungal cell membrane permeability, and results in fungal cell death.

Several azole antifungals are available for either oral or topical administration.

The systemic azole antifungal agents include:

1. Fluconazole
2. Itraconazole
3. Voriconazole
4. Posaconazole
5. Ketoconazole.

Ketoconazole was the first azole prescribed as an antifungal. Again, azole administration with amphotericin B may result in antagonism since depletion of membrane ergosterol may reduce binding sites for amphotericin B. There is experimental but NOT clinical evidence for this.

The azole antifungal agents can also inhibit mammalian CYP-450 enzymes, so you should always ask patients what medications they are taking since there are many drug interactions that must be considered.

ITRACONASOLE:

Is the most widely used azole antifungal agent because of its broad spectrum of activity. It is available for oral and topical administration, but the parenteral administration is now discontinued.

It is active against:

1. Aspergillus
2. Sporothrix (Sporotrichium)
3. Cryptococcus
4. Candida
5. Coccidioides
6. Blastomyces
7. Histoplasma.

Itraconazole is more effective than fluconazole against Aspergillus, Blastomyces, Histoplasma, and Sporothrix.


MAIN USES OF ITRACONAZOLE:

1. Histoplasmosis
2. Blastomycosis
3. Paracoccidioidomycosis
4. Sporothrix WITHOUT CNS INVOLVEMENT
5. Non-meningeal Coccidiomycosis
6. Dermatophyte infection.

METABOLISM:

Itraconazole is metabolized in the liver by CYP-450 enzymes (also inhibits them) and excreted in the feces. Therefore, no dose adjustment is necessary in cases of renal insufficiency, but is required in severe liver insufficiency.

Itraconazole does NOT cross the blood-brain-barrier to enter the CNS!!!

SIDE EFFECTS:

Itraconazole has several known adverse effects. Since it inhibits CYP-450 enzymes, it will have many drug-drug interactions.


1. Although rare, hepatotoxicity is the most important adverse effect to consider.

2. There is a dose-related GI toxicity, but no suppression of adrenal or testicular function (side effect that only occurs with ketoconazole).

3. Lastly, drugs that decrease gastric acidity decrease the absorption of itraconazole.


FLUCONAZOLE:

is active against:
1. Candida
2. Cryptococcus
3. Coccidioides
4. but NOT against Aspergillus!!!

It is available for oral and intravenous administration, and crosses the blood-brain-barrier well.
CROSSES BBB!!!

METABOLSIM:

Fluconazole is excreted in the urine, so you may need to adjust the dose in cases of renal insufficiency. Unlike itraconazole, GI absorption of fluconazole is NOT affected by gastric acidity. It is a weaker inhibitor of CYP-450 enzymes than itraconazole, but does still interact.

SIDE EFFECTS:

Importantly, fluconazole causes less liver and GI toxicity than other azoles, and is therefore very well tolerated. The drawback is that the spectrum of action is much smaller than itraconazole, but is useful for CNS fungal infections and coccidiodes.

INDICATIONS:

Fluconazole is indicated in the treatment of:
1. Various Candida infections, which typically cause vulvo-vaginal, oropharyngeal, esophageal, and systemic infections

2. Candidemia in immune- compromised people. It is also prescribed for the treatment of Cryptococcal meningitis, although the gold standard is amphotericin B with flucytosine.

3. Coccidioides meningitis infections.

4. Disseminated non-meningeal Coccidiodes.

VORICONAZOLE and POSACONAZOLE are 2 newer azole antifungal agents.

VORICONAZOLE:

similar to fluconazole, it crosses the blood-brain-barrier, but has enhanced activity against Aspergillus and yeasts.

POSACONAZOLE :

is similar to itraconazole, but has enhanced activity against Zygomycetes, Aspergillus, and Candida.

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Flucytosine? Indication for use? Side effects?

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Flucytosine is a fluorinated pyrimidine that is converted in fungal cells by Cytosine Deaminase into 5-fluorouracil (5-FU). [Cytosine Deaminase is not present in mammalian cells, so this conversion does not occur in human cells.]

MECHANISM: In fungal cells, the 5-FU inhibits DNA synthesis by inhibiting Thymidylate Synthase.
(INHIBITS FUNGAL DNA SYNTHESIS)

NO MONOTHERAPY!!
Flucytosine is not prescribed as a monotherapy because, when it is administered alone, resistance arises rapidly.

FACTS:
1. Flucytosine is well absorbed from the GI tract, and is therefore only available for oral administration.

2. It crosses the blood-brain-barrier well, and results in appreciable levels within the CSF. It is excreted by the kidney, and is found in high levels within the urine as well.


3. Concentration of flucytosine in the urine makes it useful for treatment of Candida infections, as they often involve the kidneys. However, this fact also makes dose modification necessary in renal insufficiency.

4. The main use of flucytosine is as a companion drug to amphotericin B in the treatment of Cryptococcal meningitis!!!

SIDE EFFECTS:

Flucytosine does cause some adverse effects, and some of these can be serious. Since flucytosine has the ability to inhibit DNA synthesis, it can suppress bone marrow, a potentially lethal situation. Additionally, flucytosine can cause GI tract irritation and colitis as well as liver toxicity. Since flucytosine is excreted by the kidneys, however, dose adjustment is not necessary in patients with impaired liver function as long as their renal function is normal.

Front 34

Casofungin? SIDE EFFECTS?

Back 34

The echinocandins are fungicidal agents, and include: mneumonic: “CAME”
1. Caspofungin
2. Micafungin
3. Aanidulafungin.

MECHANISM OF ACTION:

Echinocandins inhibit the fungal enzyme Glucan Synthase, which inhibits the formation of !-1,3-D-glucan (fungal cell wall component). [Both glucan synthase and glucan itself are not present in mammalian cells.]

USED TO TREAT:
Echinocandins are active against a number of fungi, including:

1. Candida
2. Aspergillus
3. Cryptococcus.
4. They are possibly synergistic with amphotericin B against Cryptococcus.

FACTS:

Caspofungin is administered intravenously generally once a day due to its 9-11 hour half-life.

METABOLISM:

It is metabolized in the liver and excreted by the kidneys.

Caspofungin does NOT interact with CYP-450 enzymes. Therefore, dose adjustment is not necessary in cases of mild liver insufficiency, but is required if liver insufficiency becomes severe. This is because caspofungin is associated with liver toxicity. Even though caspofungin is excreted by the kidneys, it is not necessary to adjust the dose in cases of renal insufficiency because its metabolites are not nephrotoxic.

SIDE EFFECTS:

Caspofungin has several adverse effects:

1. Liver toxicity
2. Histamine mediated fever
3. Nausea
4. Flushing
5. Headache
6. Facial swelling
7. Pruritis
8. Hypokalemia
9. Hypoalbuminemia
10. GI reactions
11. Anemia
12. Phlebitis.

Additionally, caspofungin crosses the placenta and is embryo-toxic!!!!


INDICATIONS:

The major indications for the administration of caspofungin are:

1. Invasive Aspergillosis that is refractory to other treatments

2. Oropharyngeal/esophageal Candidiasis.

Front 35

Terbinafine?

Back 35

Terbinafine is a fungicidal synthetic allylamine.

MECHANISM:
It functions by inhibiting sterol synthesis
through the inhibition of the enzyme Squalene Monooxygenase, resulting in altered fungal cell membranes.

FACTS:
1. Terbinafine is readily absorbed through the GI tract

2. Has a wide distribution

3. Has a long half- life

4. Has a good penetration into nails with oral intake.

INDICATIONS:

Terbinafine is active against:
1. Trichophyton: is a species that causes onchomycosis (infections of the nail bed). This is because it penetrates the nail bed well, and remains in the nails at high concentrations for 2 months after discontinuation of treatment.

2. However, terbinafine is less effective than itraconazole against Candida, which can also cause onchomycosis. It may be synergistic when used in combination with both amphotericin B and azole antifungals.

METABOLISM:

Terbinafine is metabolized by and inhibits liver CYP-450 enzymes. So, you must ask all patients receiving terbinafine what medications they are taking, as it will cause many drug-drug interactions.

DRUG INTERACTIONS:

Some notable drug-drug interactions to consider with terbinafine include:

1. Beta-blockers
2. SSRIs
3. MAO inhibitors
4. Tricyclic antidepressants
5. Warfarin
6. Dextromethorphan
7. Anti-arrhythmics
8. Codeine
9. Phenothiazines, and many others.


Terbinafine’s metabolites are excreted by the kidneys. Therefore, dose adjustment is necessary for both hepatic and renal insufficiency.

SIDE EFFECTS:
Terbinafine is also associated with several adverse effects. These include:
1. Headache
2. GI symptoms
3. Taste disturbance
4. Rash (including Stevens-Johnson Syndrome)
5. Hepatotoxicity
6. Pancytopenia
7. Anaphylaxis.

Front 36

Griseofulvin?

Back 36

MECHANISM: Interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing tissues (e.g.,nails).
CLINICAL USE: Oral treatment of superficial infections; inhibits growth of dermatophytes (tinea, ringworm).
SIDE EFFECTS: Teratogenic, carcinogenic, confusion, headaches, INCREASE 'P-450 and warfarin metabolism.

Front 37

Pyrimethamine?

Back 37

Selectively inhibits plasmodia1 dihydrofolate reductase (best for P. falciparum). Drug of choice for toxoplasmosiswhen combined with sulfadiazine.

Front 38

Suramin?

Back 38

Antiprotozoan that Inhibits enzymes involved in energy metabolism. NO CNS involvement!!

Front 39

Melarsoprol?

Back 39

Antiprotozoan that Inhibits sulfhydryl groups in parasite enzymes. CNS involvement.

Front 40

Nifurtimox?

Back 40

Antiprotozoan that Forms intracellular oxygen radicals, which are toxic to the organism.

Front 41

Sodium stibogluconate?

Back 41

Antiprotozoan that Inhibits glycolysis at PFK reaction.

Front 42

Chloroquine?

Back 42

Antiprotozoan that Blocks plasmodium heme polymerase, leading to accumulation of toxic hemoglobin breakdown products that destroy the organism.

Front 43

Quinine?

Back 43

Antiprotozoan that For chloroquine-resistant species when used in combination with pyrimethamine/sulfonamide.

Front 44

Mebendazole?

Back 44

anti-helminthic that Inhibits glucose uptake and microtubule synthesis.

Front 45

Pyrantel pamoate?

Back 45

anti-helminthic that Stimulates nicotinic receptors at neuromuscular junctions. Contraction occurs, followed by depolarization-induced paralysis. No effect on tapeworms or flukes.

Front 46

Ivermectin?

Back 46

anti-helminthic that Intensifies GABA-mediated neurotransmission and causes immobilization. Does not cross the blood-brain barrier; therefore, no effect on humans.

Front 47

Praziquantel?

Back 47

anti-helminthic that Increases membrane permeability to calcium, causing contraction and paralysis of tapeworms and flukes.

Front 48

Amantadine?

Back 48

Active against influenza A only, Parkinson's disease.
2 concentration dependant mechanisms
Low conc inhibits ion channel formation of M2 protein preventing viral uncoating
High concentrations in lysosomes increases pH thus inhibiting virus induced membrane fusion
>90% excreted unchanged in the urine
Dose adjustment needed with renal impairment] SIDE EFFECTS: Ataxia, dizziness, slurred speech. RESISTANCE: Mutated M2 protein. 90%of all influenza A strains are resistant to amantadine, so not used.

Front 49

Zanamivir, oseltamivir?

Back 49

MECHANISM: Inhibit influenza neuraminidase, decreasing the release of progeny virus. CLINICAL USE: Both influenza A and B.

Front 50

Ribavirin?

Back 50

MECHANISM: Inhibits synthesis of guanine nucleotides by competitively inhibiting IMP dehydrogenase. CLINICAL USE: RSV, chronic hepatitis C. TOXICITY: Hemolytic anemia. Severe teratogen.

Front 51

Acyclovir?

Back 51

-Analogue of guanine. Taken up by viruses DNA polymerase and terminates the chain -Prodrug, phosphorylated three times to become activated:
• By a thymidine kinase made by the virus
• Twice more by host thymidine kinases -Taken up selectively by virally infected cell, very low toxicity because the viral thymidine kinase has a much greater affinity -Poor oral bioavailability (15-20% makes it into bloodstream). Relatively short half-life: two and a half to three hours. -When given intravenously, it does cross the blood brain barrier and into the CSF. This makes it useful for treating meningitis. Also still used in some transplants because it is fairly safe. -Kidney eliminates it both by filtration through glomerulus and secretion. Once into the tubules it can crystallize, so it’s important to watch urine creatinine levels for renal insufficiency and give with plenty of fluids.
-Side effects generally mild: • Orally: headache, nausea, vomiting • IV: nephropathy in 5%, must hydrate well; encephalopathy in high concentrations • Topically: pain, inflammation locally
-Viruses can develop resistance, which wipes out is efficacy. Mutations to viral thymidine kinase make it harder for drugs to target them. This prevents the FDA from making acyclovir over-the- counter. RESISTANCE: Lack of viral thymidine kinase. CLINICAL USE: HSV, VZV, EBV. Used for HSV-induced mucocutaneous and genital lesions as well as for encephalitis. Prophylaxis in immunocompromised patients. For herpes zoster, use a related agent, famciclovir. No effect on latent forms of HSV and VZV.

Front 52

Ganciclovir?

Back 52

Used in treatment for CMV. Structurally similar to acyclovir:
CH2OH added as hydroxymethyl group on the acyclic side chain
100x more active against CMV in cell culture than acyclovir
Phosphorylated to mono-PO4 by viral and cellular kinases, then to bi- and tri-PO4 by cellular kinases
Triphosphate form competitively inhibits incorporation of deoxyguanosine triphosphate into DNA; selectively inhibits viral DNA polymerase
Inhibits DNA chain elongation

Oral bioavailability only 5-10%
Must administer drug daily through central IV catheter
Most eliminated unchanged in the urine
Plasma half-life 3-4 hours; increases with renal insufficiency
Intracellular half life is 16-24 hours
Toxicities (32% of discontinuation)
BM suppression: 15% neutropenia, 21% thrombocytopenia
Renal toxicity
Teratogenic and mutagenic in animals. RESISTANCE: Mutated CMV DNA polymerase or lack of viral kinase.

Front 53

FOSCARNET?

Back 53

Inorganic pyrophosphate analogue used in treatment of CMV retinitis in immunocompromised pts when ganciclovir fails.
Active in its parent form
No significant intracellular metabolism
Directly inhibits DNA polymerase by blocking the pyrophosphate binding site
In vitro activity against many viruses
CMV, HSV, Influenza, hepatitis B, HIV
Role in treatment of acyclovir and gancyclovir resistant virus
GCV’s resistance occurs by point mutations
Only available IV; poor oral absorption
70-90% excreted unchanged in urine
Plasma half-life 4-5 hours

Narrow therapeutic index
Renal toxicity
common at 30%
renally excreted - needs dose adjustment in renal insuff.
Chelates divalent metal ions
30% of drug deposited in bone
Can cause electrolyte imbalances
Hypocalcemia 15-35%, hypokalemia 10-16%, hypomagnesemia 15-44%
Seizures, perioral numbness,other CNS changes
?? Due to electrolyte shifts/imbalances
Administered daily through central IV catheter. RESISTANCE: Mutated DNA polymerase

Front 54

What drugs are included in the nucleoside inhibitors for HIV pts? What is the mechanism for these drugs?

Back 54

Zidovudine
Didanosine
Lamivudine
Stavudine
(Zalcitabine)
Abacavir
Emtricitabine
Intracellular phosphorylation to active compound by cellular enzymes to the triphosphate derivative
Greater affinity for reverse transcriptase than for human DNA polymerases
Causes chain termination during DNA synthesis
Short half-life but high intracellular concentration
Point mutations occur conferring resistance, these TAM’s can occur in stepwise fashion causing cross resistance in the class
All NRTI’s can cause a potentially fatal syndrome of lactic acidosis with hepatic steatosis (mitochondrial toxicity)
Associated with peripheral lipoatrophy, central fat accumulation and hyperlipidemia
Mostly seen with stavudine and zidovudine, rarely with others in the class

Front 55

Name some protease inhibitors for HIV pts? How do they work? What are potential side effects?

Back 55

Indinavir
Nelfinavir
Saquinavir
Amprenavir
Fosamprenavir
Lopinavir/Ritonavir
Atazanavir
Tipranavir
Darunavir
Mechanism of Action: Inhibit HIV Protease
Acts to prevent cleavage of viral polyproteins which are essential for maturation of infectious virus. Diffuse across cell membranes so subtherapeutic levels can occur with missed doses
Metabolized by and inhibit cytochrome P450 enzymes, especially 3A (in liver and in small intestine). (THESE DRUGS INHIBIT CYP3A ENZYMES--WATCH DRUG INTERACTIONS WHEN GIVING PROTEASE INHIBITORS)
Ritonavir especially potent, pharmacoenhancer
Important clinical interactions with other therapeutics used in the management of HIV infected patients which are metabolized by and/or inhibit these enzymes
Dose modifications of some drugs are necessary
Some concomitant therapies contraindicated

Use of Ritonavir as a pharmacoenhancer
Called “boosting”
Exploits this interaction to use Ritonavir at non-therapeutic doses to “boost” the effect and half life of other protease inhibitors (Kaletra = Lopinavir and Ritonavir)
Strategy employed in “treatment experienced” patients
Allows for less pills, less frequent dosing

Gastrointestinal distress, bleeding in hemophiliacs, hyperglycemia, insulin resistance, hyperlipidemia
Possibly coronary artery disease
Lipodystrophy – (abdominal lipohypertrophy)
Hepatotoxicity
Metabolized by and inhibit CYP3A4
Drug Interactions are very challenging!!
Medication compliance critical, especially if dose modifications needed

Front 56

Name the non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s) and how do they differ from nucleoside reverse trancriptase inhibitors?

Back 56

Nevirapine (Viramune™)
Efavirenz (Sustiva™)
Etravirine (Intelence™)
Rilpivirine (Edurant™) = NEER

Do not require phosphorylation
Non-competitive inhibitors of RT
Bind at sites distinct from nucleosides and tides
Long half-life, may take two weeks to clear
A single mutation can cause resistance to the entire class (with the exception of Etravirine)
Rilpivirine failure can induce resistance to Etravirine

Front 57

Enfuvirtide?

Back 57

HIV fusion inhibitor that binds viral gp41 subunit; inhibit conformational change required for fusion with CD4 cells, blocking entry and replication. Used in patients with persistent viral replication despite antiretroviral therapy.SIDE EFFECTS: Hypersensitivity reactions, reactions at subcutaneous injection site, INCREASED 'risk of bacterial pneumonia.

Front 58

Interferons?

Back 58

Glycoproteins synthesized by virus-infected cells block replication of both RNA and DNA viruses.

IFN-A: chronic hepatitis B, C and Kaposi's sarcoma.

IFN-B-Multiple sclerosis

IFN-gamma: NADPH oxidase deficiency.

SIDE EFFECTS:

Neutropenia.

Front 59

What antibotics should NOT be used in pregnancy?

Back 59

1. Sulfonamides- kernicterus.

2. Aminoglycosides-ototoxicity.

3. Fluoroquinolones-cartilage damage.

4. Erythromycin-acutecholestatic heptatitis in mom
(and clarithromycin-embryotoxic).

5. Metronidazole - mutagenesis.

6. Tetracyclines-discolored teeth, inhibition of bone
growth.

7. Bavirin (antiviral)- teratogenic.

8.Griseofulvin (antifungal)- teratogenic.

9. Chloramphenicol-"gray baby."


MNEMONIC: SAFE Moms Take Really Good Care.

Front 60

Cyclosporine?

Back 60

Immunosuppresant that binds to cyclophilins. Complex blocks the differentiation and activation of T cells by inhibiting calcineurin, thus preventing the production of IL2 and its receptor.
CLINICAL USE: Suppresses organ rejection after transplantation; selected autoimmune disorders.SIDE EFFECTS: Predisposes patients to viral infections and lymphoma; nephrotoxic (preventable with mannitol diuresis).

Front 61

Tacrolimus (FK506)?

Back 61

Immunosuppresant that is similar to cyclosporine; binds to FK-binding protein, inhibiting secretion of IL-2 and other cytokines.
CLINICAL USE: Potent immunosuppressive used in organ transplant recipients. SIDE EFFECTS: Significant-nephrotoxicity, peripheral neuropathy, hypertension, pleural effusion, hyperglycemia.

Front 62

Sirolimus (rapamycin)?

Back 62

Immunosuppresant that binds to mTOR. Inhibits T-cell proliferation in response to IL2. CLINICAL USE: Immunosuppression after kidney transplantation in combination with cyclosporine
and corticosteroids. SIDE EFFECTS: Hyperlipidemia, thrombocytopenia, leukopenia.

Front 63

Daclizumab?

Back 63

Immunosuppresant and monoclonal antibody with high affinity for the IL-2 receptor on activated T cells.

Front 64

Azathioprine?

Back 64

Immunosuppressant and antimetabolite precursor of 6-mercaptopurine that interferes with the metabolism and synthesis of nucleic acids. Toxic to proliferating lymphocytes.
CLINICAL USE: Kidney transplantation, autoimmune disorders (including glomemlonephritis and hemolytic anemia).
SIDE EFFECTS: Bone marrow suppression. Active metabolite mercaptopurine is metabolized by xanthine oxidase; thus, toxic effects may be T' by allopurinol.

Front 65

Muromonab-CD3 (OKT3)?

Back 65

Immunosuppressant and monoclonal antibody that binds to CD3 (epsilon chain) on the surface of T cells. Blocks cellular interaction with CD3 protein responsible for T-cell signal transduction.
CLINICAL USE: Immunosuppression after kidney transplantation. SIDE EFFECTS: Cytokine release syndrome, hypersensitivity reaction.

Front 66

Aldesleukin (interleukin-2)?

Back 66

Recombinant cytokine used for Renal cell carcinoma, metastatic melanoma

Front 67

Therapeutic antibody used for B-cell non-Hodgkin's lymphoma?

Back 67

Rituximab (targets CD20)

Front 68

Therapeutic antibody for HER-2 overexpressing breast cancer?

Back 68

Trastuzumab (Herceptin)-targets erb-B2

Front 69

Antidote for digoxin intoxication?

Back 69

Digoxin Immune Fab

Front 70

Prevent acute rejection of renal transplant by binding to IL-2 receptor?

Back 70

Daclizumab

Front 71

Prevent acute transplant rejection by binding to CD3?

Back 71

Muromonab-CD3 (OKT3)

Front 72

Volume of distribution(Vd)?

Back 72

Relates the amount of drug in the body to the plasma concentration. Vd of plasma protein-bound drugs can be altered by liver and kidney disease.
vd= amount of drug in the body/ plasma drug concentration
Drugs with: Low Vd (4-8 L) distribute in blood. Medium Vd distribute in extracellular space or body water. High Vd (>body weight) distribute into all tissues.

Front 73

direct cholinomimetic agent that is used postoperatively and for neurogenic ileus or urinary retention?

Back 73

Bethanechol. MECHANISM-Activates Bowel and Bladder smooth muscle; resistant to AChE. Beth Anne, call (bethanechol) me if you want to activate your Bowels and Bladder.

Front 74

Carbachol?

Back 74

direct cholinomimetic agent that is used for glaucoma, pupillary contraction, and relief of intraocular pressure

Front 75

Pilocarpine?

Back 75

direct cholinomimetic agent that is a potent stimulator of sweat, tears, saliva. MECHANISM: Contracts ciliary muscle of eye (open angle), pupillary sphincter (narrow angle); resistant to AChE. PILE on the sweat and tears.

Front 76

Stimulates muscarinic receptors in airway when inhaled AND Challenge test for diagnosis of asthma?

Back 76

Methacholine

Front 77

Indirect cholinomimetic agonist (anticholinesterases) that is used postoperatively and for neurogenic ileus, urinary retention, myasthenia gravis, reversal of neuromuscular junction blockade (postoperative)?

Back 77

Neostigmine. ACTION: INCREASE endogenous ACh; no CNS penetration. NEO CNS = NO CNS penetration.

Front 78

Indirect cholinomimetic agonist (anticholinesterases) that is used in the diagnosis of myasthenia gravis (hint: extremely short acting)?

Back 78

Edrophonium-Increases Ach levels

Front 79

Physostigmine?

Back 79

Indirect cholinomimetic agonist (anticholinesterases) that is used for glaucoma (crosses blood-brain barrier + CNS) and atropine overdose

Front 80

Cholinesterase inhibitor poisoning?

Back 80

Often due to organophosphates, such as parathion, that irreversibly inhibit AchE.

Organophosphates are components of insecticides; poisoning usually seen in farmers.

Causes: DUMB BELLS
1. Diarrhea

2. Urination

3. Miosis

4. Bronchospasm

5. Bradycardia

6. Excitation of skeletal muscle and CNS

7. Lacrimation

8. Sweating and Salivation.



ANTIDOTE: atropine and pralidoxime (regeneratesactive AchE).

Front 81

Muscarinic antagonist that reduces urgency in mild cystitis and reduce bladder spasms?

Back 81

oxybutynin and glycopyrolate

Front 82

Hexamethonium?

Back 82

Nicotinic antagonist. CLINICAL USE: Ganglionic blocker. Used in experimental models to prevent vagal reflex responses to changes in blood pressure-e.g., prevents reflex bradycardia caused by NE.
SIDE EFFECTS: Severe orthostatic hypotension, blurred vision, constipation, sexual dysfunction.

Front 83

Clinical uses for phenylephrine (alpha 1 agonist)?

Back 83

Pupillary dilation, vasoconstriction, nasal decongestion

Front 84

Name the 4 Beta-2 agonists?

Back 84

MAST:

Metaproterenol and Albuterol for acute asthma;

Salmeterol for long-term treatment;

Terbutaline to reduce premature uterine contractions

Front 85

Ritodrine?

Back 85

B-2 agonist that reduces premature uterine contractions

Front 86

Dobutamine?

Back 86

b1 > b2 inotropic but not chronotropic used in heart failure and cardiac stress testing

Front 87

Indirect general agonist that releases stored catecholamines and used in narcolepsy, obesity, attention deficit disorder?

Back 87

Amphetamine (an Indirect syrnpatho-mimetics)

Front 88

Indirect general agonist that releases stored catecholamines and used for nasal decongestion, urinary incontinence, hypotension?

Back 88

Ephedrine (an Indirect syrnpatho-mimetics)

Front 89

Clonidine and a-methyldopa?

Back 89

Centrally acting a2-agonists,&central adrenergic. Used in HTN (especially pregnant women) and especially renal disease (no decrease in blood flow to kidney)

Front 90

Mirtazapine?

Back 90

alpha 2 blocker used in depression. SIDE EFFECTS: Sedation, INCREASED serum cholesterol, INCREASED appetite

Front 91

Phenoxybenzamine?

Back 91

Alpha 1 blocker used for pheochromocytoma (use phenoxybenzamine before removing tumor, since high levels of released catecholamineswill not be able to overcome blockage). SIDE EFFECTS: Orthostatic hypotension, reflex tachycardia

Front 92

Antidote for acetaminophen toxicity?

Back 92

N-acetylcysteine

Front 93

Antidote for Digitalis?

Back 93

Stop dig, normalize K+,
lidocaine, anti-dig Fab
fragments, Mg2

Front 94

Antidote for Methemoglobin?

Back 94

Methylene blue, vitamin C

Front 95

Antidote for Salicylates?

Back 95

NaHC03 (alkalinizeurine), dialysis

Front 96

Antidote for Acetylcholinesteraseinhibitors,
organophosphates?

Back 96

Atropine,pralidoxime

Front 97

Antidote for beta-blockers?

Back 97

Glucagon

Front 98

Antidote for Iron?

Back 98

Deferoxamine

Front 99

Antidote for Lead?

Back 99

CaEDTA, dimercaprol, succimer, penicillamine

Front 100

Antidote for Cyanide?

Back 100

Nitrite, hydroxocobalamin,
thiosulfate

Front 101

Antidote for Carbon monoxide?

Back 101

100% O2 ,hyperbaric 02

Front 102

Antidote for Benzodiazepines?

Back 102

Flumazenil

Front 103

Antidote for Heparin?

Back 103

Protamine

Front 104

Antidote for tPA, streptokinase?

Back 104

Aminocaproic acid

Front 105

Antidote for Theophylline?

Back 105

P-blocker

Front 106

Antidote for TCAs?

Back 106

NaHC03 (plasma alkalinization)

Front 107

Antidote for Methanol, ethylene glycol (antifreeze)?

Back 107

Ethanol, dialysis, fomepizole

Front 108

Drugs that cause dilated cardiomyopathy?

Back 108

Doxorubicin (Adriamycin),daunorubicin

Front 109

Drugs that cause cutaneous flushing?

Back 109

VANC: Vancomycin, Adenosine, Niacin, Ca2+channel blockers

Front 110

Drugs that cause Hemolysis in G6PD-
deficient patients?

Back 110

Hemolysis IS PAIN!


Isoniazid (INH)

Sulfonamides

Primaquine

Aspirin

Ibuprofen

Nitrofurantoin

Front 111

Drug that causes Acute cholestatic
hepatitis?

Back 111

Macrolides

Front 112

Drug that causes Pseudomembranous
colitis?

Back 112

Clindamycin, ampicillin

Front 113

Drugs that cause Hemorrhagic cystitis?

Back 113

Cyclophosphamide and ifosfamide (prevent by coadministering with mesna)

Front 114

Drugs that cause Tendonitis, tendon
rupture, and cartilage damage (kids)?

Back 114

Fluoroquinolones

Front 115

Drugs that cause SLE-like syndrome?

Back 115

Hydralazine, INH, Procainamide, Phenytoin (She has LUPUS but has some nice HIPPs on her

Front 116

Corticosteroids and heparin are common in that they both can cause?

Back 116

Osteoporosis

Front 117

Furosemide and thiazides are are common in that they both can cause?

Back 117

Gout

Front 118

Drug that causes gingival hyperplasia?

Back 118

Phenytoin

Front 119

Drugs that cause photosensitivity?

Back 119

Sulfonamides,Amiodarone,Tetracycline (SAT for a photo)

Front 120

Methicillin, NSAIDs and furosemide all cause?

Back 120

Interstitial nephritis

Front 121

What 2 drugs cause Diabetes insipidus?

Back 121

Lithium and demeclocycline

Front 122

What drugs cause Parkinson-like
syndrome?

Back 122

Haloperidol, chlorpromazine, reserpine, metoclopramide

Front 123

What 3 drugs cause seizures?

Back 123

Bupropion, imipenemlcilastatin, isoniazid

Front 124

What drugs cause disulfiram like reactions?

Back 124

Metronidazole, certain cephalosporins, procarbazine, 1st-generationsulfonylureas

Front 125

Patients with sulfa allergies may develop

Back 125

-fever
-pruritic rash
- Stevens-Johnson syndrome
-hemolytic anemia
-thrombocytopenia
-agranulocytosis
-urticaria (hives).

Symptoms range from mild to life-threatening!!


SULFA DRUGS:

1. Celecoxib
2. furosemide
3. probenecid
4. thiazides
5. TMP-SMX
6. sulfasalazine
7. sulfonylureas
8. acetazolamide
9. sulfonamide antibiotics.

Front 126

Hydralazine?

Back 126

Increases cGMP+smooth muscle relaxation. Vasodilates arterioles>veins;afterload reduction. CLINICAL USE: Severe hypertension, CHF. First-line therapy for hypertension in pregnancy, with methyldopa. Frequently coadministered with a kblocker to prevent reflex tachycardia. SIDE EFFECTS: Compensatory tachycardia (contraindicated in anginaICAD), fluid retention, nausea, headache, angina. Lupus-like syndrome.

Front 127

isosorbide dinitrate?

Back 127

Nitrogylercin used for angina. This preparation is a little more stable against liver breakdown so it can be given orally (and is the nitrate in the Bidil combination with hydralazine). The active parent compound is metabolized into two equally as active metabolites—Isosorbide-2 Mononitrate and Isosorbide-5-Mononitrate.

--Isosorbide-5 Mononitrate a.Most prescribe of the nitrates, including being used for prophylaxis. Isosrorbide-5 Mononitrate has a high bioavailability, is easily absorbed, and can be given twice a day to cover someone prophylactic-ly. b. It has a longer duration of action because it is not metabolized (already a metabolite) and we depend on renal excretion to get rid of it.

CLINICAL USE:

Angina, pulmonary edema. Also used as an aphrodisiac and erection enhancer.

SIDE EFFECTS:
Reflex tachycardia, hypotension, flushing, headache, "Monday disease" in industrial
exposure; development of tolerance for the vasodilating action during the work week and loss of tolerance over the weekend, resulting in tachycardia, dizziness, and headache on reexposure.

Front 128

Name 3 drugs used for malignant HTN?

Back 128

1. NITROPRUSSIDE:
Short acting; 1'cGMP via direct release of NO.

SIDE EFFECT:
Can cause cyanide toxicity (releases CN).

2. Fenoldopam-Dopamine Dl receptor agonist- relaxes renal vascular smooth muscle.

3. Diazoxide-K+channel opener-hyperpolarizes and relaxes vascular smooth muscle.

SIDE EFFECT:
Can cause hyperglycemia (reduces insulin release).

Front 129

Niacin?

Back 129

Also known as Nicotinic Acid or Vitamin B3, is a substance that can increase HDL and lower LDL when given in high doses. HDL is a transport of cholesterol from the tissues to the liver, where it is metabolized and excreted. Increased HDL levels are associated with a lower CAD risk, and HDL levels below 40mg/dL in men and 50mg/dL in women are associated with an increased risk for CAD. Having an HDL above 60mg/dL can theoretically cancel out a negative risk factor and for every 1 point increase in HDL, there is a 2-3% decrease in risk of MI. Therefore a high HDL is important, and the first life of therapy to increase HDL levels is the TLC that was previously discussed for all other medications. However, moderate alcohol use can increase HDL. If TLC doesn’t work, then Niacin can be used. Niacin is CONTRAINDICATED in patients with liver disease, severe gout, or peptic ulcer disease.
The exact mechanism is unclear, but Niacin does cause a decrease in the synthesis of LDL particles in the liver as well as a decrease in TG and fatty acids from fat stores. Niacin can increase serum HDL by decreasing hepatic uptake of HDL. The result is a 20-30% reduction in TG, 5-25% reduction in LDL, and a 15-35% increase in HDL. Niacin is generally considered to be the best choice for raising HDL, because there are more effective drugs used to lower LDL and TG.
Dosing
There are different formulations of Niacin taken once a day. The immediate release formula is 2-4 grams per day and the extended release form (Niaspan) is 1-2 grams per day. There is an over the counter Naicin formula, which is about 2 grams per day. The most effective treatment for raising HDL and lowering LDL is the immediate release formula, and according to the graph on slide 69 the effect plateaus at around 2 grams/day.
Adverse effects
1. Flushing Flushing is the main adverse effect of Naicin, and it occurs with itching and headache. These effects occur more with the immediate release than with the extended release. Flushing occurs first in the face and then spreads to the arms, and can last up to one hour. Dr. Gortler has tried this out for himself and says that it can be quite uncomfortable. The good news is that tolerance to these side effects develops with time. The bad news is that missing one dose can reinstate sensitivity. Patients are advised to avoid hot drinks/showers, spicy foods, and alcohol 1-2 hours after taking a dose. Taking NSAIDs 30 minutes prior to taking Niacin can help alleviate flushing problems.
2. Hepatotoxicity Naicin related hepatitis is more common with sustained release
3. GI upset Niacin can activate peptic ulcers and cause dyspepsia. Taking the immediate release formula with food can help to decrease GI problems.
4. Gout 5. Hyperglycemia and reduced insulin sensitivity 6. Increased myopathy risk – especially if taken with statin or gemfibrozil

Front 130

Side effect of HMGCoA reductase inhibitors (lovastatin. pravastatin, simvastatin, atorvastatin,rosuvastatin)?

Back 130

Hepatotoxicity (Increase LFTs) and rhabdomyolysis

Front 131

Digoxin?

Back 131

Of the three cardiac glycosides described (digoxin, digitoxin, and ouabain), only digoxin is prescribed in the US and most pertinent to our study.

These agents are steroid derivatives from the plant genus digitalis (which coincidentally you can find in the flower beds on the podium), with sugars at the 3 position and a lactone ring at the 17 position.

Table 13-2 outlines the properties of the cardiac glycosides. The middle column contains data for digoxin and is the information we are responsible for. On this table (on pg 22 of the handout), we see that digoxin has:

1. medium lipid solubility

2. 75% oral bioavailability

3. 40 hour half life

4. non-significant protein binding

5. little liver metabolism.


Digoxin has a very narrow therapeutic window, with 2 times the therapeutic dose having toxic effects.

Patients are started on a maintenance dose because of the narrow therapeutic window and long half-life; peak blood level, and thus maximum toxicity, is achieved at 4 x t1/2, and thus patients are observed for 7 days for side effects.

ELIMINATION:
The drug is eliminated by kidney excretion and therefore the creatinine clearance determines the dose. This also means that a depression in renal function can lead to toxicity. Digoxin is mainly distributed in lean body mass; as one ages and lean body mass is lost, the dose must be decreased to avoid toxicity.

DIGOXIN EFFECTS IN PTS WITH HF VS NON-HF PATIENTS:

The cardiac glycosides have different effects in patients with and without heart failure. In the absence of heart failure:

1. digoxin acts as a arterial vasoconstrictor, increasing total peripheral resistance (increasing afterload)

2. increasing venous tone (increasing preload)

3. increasing blood pressure, and decreasing blood pressure, but exhibiting NO change in cardiac output.


When given to patients with heart failure, digoxin causes:

1. doubling of cardiac output in 1 hr (positive inotropic)
2. decrease in TPR (not to normal because of digoxin’s vasoconstriciton effects)

3. increase in blood flow

4. decrease in venous tone

5. INCREASE in cardiac output.

WHY DO YOU SEE THIS DIFFERENCE:

The differences in effects in patients with and without heart failure are due to differences in the baseline state of the sympathetic nervous system; as we know, patients with heart failure have increased activation of the sympathetic nervous system and circulating catecholamines. In patients with heart failure, digoxin works by a positive inotropic effect on the heart as well as by senstilizing the baroreceptors, such that at any given pressure, the baroreceptors fire more. Thus, as any given pressure, there is an increase in PSNS activation and a decrease in SNS activation.
In heart failure, digitalis causes:

1. a positive inotropic effect

2. vasodilation, diuresis

3. slowing of rapid ventricular rate

4. reducing plasma neurohormones

5. increasing baroreceptor sensitivity

6. increasing vagal tone.


MECHANISM:

Digoxin blocks the phosphorylated alpha subunit of the Na/K ATPase in a dose- dependent fashion, causing a buildup of Na in the cells. The buildup and increased concentration of Na in the cell decreases the concentration gradient of Na across the cell membrane, thus decreasing (or reversing) the activity of the Na-Ca exchanger in the cell membrane (3Na in, 1Ca out), which depends
on low Na inside the cell to drive Na into the cell from the extracellular space and drive Ca out of the cell. Calcium then builds up inside of the cell. The increase in intracellular NA also drives more free Ca into the sarcoplasmic reticulum by activation of the Ca pump in the membrane of the sarcoplasmic reticulum (SR). The positive inotropic effect results from the increased Ca in the SR, causing a more robust release of Ca from the SR upon activation by the extracellular trigger Ca that enters the cell in an action potential. The Ca released from the SR inhibits tropomyosin C, allowing for actin-myosin cross- linking, causing contraction. The increase in Ca release with each action potential causes increased contraction, therefore accounting for digoxin’s inotropic effect. Potassium can inhibit digoxin binding by dephosphorylating the alpha subunit, which prevents digoxin binding. If there is too much Na in the cell, it will depolarize the cell, and arrythmias can result.
The electrophysiologic actions of digoxin contribute to the anti-arrhythmic effects as well as digitoxicity. Digoxin also stimulates the parasympathetic nervous system systemically by exciting the vagal center in the brain and sensitizes the baroreceptors (which in turn increases parasympathetic activity and decreases sympathetic activity. Digoxin also causes the Ach in the AV node to have a much stronger effect at its receptors. The increase of parasympathetic activity increases Ach release at the AV node, decreases the rate of rise of phase 0 Ca current, slowing conduction through the AV node and indirectly prolonging the refractory period, slowing ventricular rate. In patients with atrial flutter and atrial fibrillation, administration of digoxin will decrease the ventricular rate.

INDICATIONS FOR USE:
The therapeutic uses of digoxin are in

1.) patients with heart failure and atrial flutter or atrial fibrillation and
2.) symptomatic heart failure patients whose symptoms are not relieved with other therapeutic agents (diuretic, ACEI, beta-blocker, ARB).

Digoxin DOES NOT prolong mortality, but does decrease symptoms and hospitalizations due to heart failure.

Front 132

Class IA anti-arrythmics? Name the 3 drugs and their side effects

Back 132

Class I: NaChB (intermediate potency. Class IC flecainide and propafanone are most potent!!)
These drugs depress phase 0 depolarization. Class IA, IB, and IC differ in their intensity of sodium flow depression and the resulting change in repolarization.

Class IA: • Older class of drugs that prolong the QT interval • Many side effects, including the potential for Torsades

Procainamide: most likely the only drug you will ever use in class IA.

INDICATIONS:

It is given IV for any sort of complex supraventricular or ventricular arrhythmia.

PREGNACY USE:

Many arrhythmias in pregnancy are treated with procainamide since has been proven completely safe.

SIDE EFFECTS:

Major side effects include a lupus-like syndrome, and nearly all patients will seroconvert to a positive ANA titer. 15-20% of patients will experience lupus-like symptoms, including arthritis, arthralgias, or pleuritis. Conveniently, these side effects only occur after long term use. One metabolite of procainamide, called N-acetyl-procainamide (NAPA), can be used in lieu of the original and carries none of the side effects. NAPA, however, is only a KChB, and loses its NaChB activity.
**WHEN IN DOUBT, USE PROCAINAMIDE!!**


RECAP: USED FOR SUPRAVENTRICULAR AND VENTRICULAR ARRYTHMIAS!! SAFE IN PREGNACY!! A CLASS IA DRUG SO BLOCKS SODIUM CHANNELS. CAUSES LUPUS LIKE SYMPTOMS!


2. Quinidine: never used in practice anymore, mainly because of the terrible, terrible diarrhea it causes. Back in the old days, quinidine helped maintain sinus rhythm and prevent A-fib or A-flutter. Another drawback, though, is the MOA is not only through NaChB; IV use also produces an alpha receptor adrenergic block, as well as vagal inhibition. Think that through – alpha blockers tend to cause hypotension, and vagal inhibition means an increase in heart rate. Seems pretty counterproductive, since the loss of vagal stimulation will allow more of the beats from A-fib through the AV node down to the ventricles.


3. Disopyramide: used only in hypertrophic cardiomyopathy.


MECHANISM:

Disopyramide (Norpace) depresses myocardial contractility (precipitating heart failure) and exhibits anticholinergic effects.

CONTRAINDICATIONS:

1. Never give this drug to patients with glaucoma or BPH, as the effects are similar to atropine – urinary retention, constipation, dry mouth, etc – and can make those diseases worse.

2. Dont give to patients in heart failure-causes myocardial contractility depression

METABOLISM

1. ELIMINATED BY BOTH HEPATIC AND RENAL
-ADJUST DOSE IN RENALLLY IMPAIRED

INDICATIONS
On the positive side, the drug does live up to its class and prolongs diastole, which is the biggest problem for patients born with hypertrophic cardiomyopathy. Their biggest issues are A-fib and profound diastolic dysfunction because the ventricle cannot relax and fill. Disopyramide gives the non-compliant heart muscle more of a chance to relax, thereby increasing cardiac function.

Front 133

Class IC anti-arrythmics? Name the 2 drugs in this class. How do they differ and name their side effects?

Back 133

Class IC:
• Extremely potent NaChB given orally

• Very slow dissociation from sodium channels only in diastole • Use-dependence
o When tachycardic, the heart is not in diastole for long periods of time. Coronaries cannot fill, and class IC drugs are not able to dissociate. This is the MOA – drug build up causing it to exert effects (i.e. decreasing heart rate)
o This is also the mechanism of toxicity – if the tachycardia doesn’t slow, drug will build up and exert proarrhythmic effects (Torsades) **few other side effects!


All class IC drugs are contraindicated in hearts with any structural abnormality, including previous MI (scar)!!!


CAST TRIAL:

CAST trial indicates that these drugs are most useful in atrial arrhythmias on hearts with NO structural abnormalites!!

PVCs should not be treated at all! The risk of proarrhythmic effects and toxicity do not outweigh the potential risks from PVC

Flecainide:

ONLY available orally

Needs twice/day dosing

ELIMINATION:

Eliminated by both renal and hepatic

SIDE EFFECTS:

1. Few extra cardiac side effects (blurry vission-but rare)
2. Negative inotropic effects-DONT use in HF pt's


***NEED TO GIVE BETA BLOCKER BEFORE THIS DRUG***

MECHANISM:

prolongs PR, QRS, and QT intervals at normal rates. This drug is tricky, and you’ll see why in a minute. Let’s start with AV nodal physiology during A-flutter. A typical heart rate in A-flutter is about 350 bpm. A healthy young person’s AV node will allow up to 200 of those beats to pass to the ventricles; an older person’s ventricles will see up to 150 or less. Now add in flecainide. The NaChB effects will slow the atrial contractions of A-flutter down to somewhere around 150 bpm. Now all of the beats are passing through the AV node to the ventricles, putting the patient at risk for V-fib, which we all know is bad news. So why give this drug at all? It works very well at slowing the rate of A-fib and A-flutter. You will give flecainide in combination with a beta blocker in order to block the AV node a bit to provide a ventricular block.

CONTRAINDICATIONS:

1. DONT use in pts with HF: causes negative ionotropic effects
2. DONT use in pts with renal failure: renally excreted
3. DONT use in pts with structurally damaged hearts (from ischemia, previous MI):


Most serious adverse events:
Provocation or exacerbation of potentially lethal arrhythmias
•Acceleration of ventricular rate in patients with atrial flutter
•Increased frequency of re-entrant ventricular tachycardia
•Increased mortality in patients after an MI


ADDITONAL:

1. A dose dependent drug (other one is propafenone-ALL Class IC drugs are dose dependent)- meaning they work better/have better effiacy at high HR's VS reverse dose dependent drugs like Class III anti-arrythmics (amiodarone and satalol) which do the opposite and work best at slow HR's.

2. Also has some K+ channel blocking activity and can increase action potential duration in ventricular myocytes


Propafenone: a drug very similar to flecainide, with added beta blocking activity

INDICATIONS:

Useful for Supraventricular tachycardia (SVT)

SIDE EFFECTS:

Has significant beta blocking activity--> can cause bradycardia and bronchospasm.

CONTRAINDICATIONS:

Asthmatics

People with slow HR

ELIMINATION

Hepatic (mostly) and renal routes!

Front 134

Class II anti-arrythmics?

Back 134

Mechanism of Action (MOA)

Beta-blockers act by inhibiting sympathetic activity and reduce:

1. REDUCE HR
2. REDUCE INTRACELLULAR CALCIUM OVERLOAD
3. INHIBIT AFTERDEPOLARIZATION MEDIATED AUTOMACTICITY

Beta-blockers are also cardioprotective and reduce mortality in patients post MI.

Beta-blockers are very useful in patients with coronary artery disease (CAD) as beta-blockers decrease the intracellular calcium overload that occurs in ischemic myocytes. In acutely ischemic tissue, beta-blockers increase the energy required to fibrillate the heart. Remember ischemic myocytes build up intracellular calcium therefore it is very easy for the cells to depolarize. Easy depolarization leads to tachycardia and arrhythmias. Note: It is considered MEDICAL MALPRACTICE if a patient with CAD is NOT put on a beta-blocker. Beta-blockers protect CAD patients from sudden death, ventricular fibrillation, etc.

Therapeutic Uses:

1. Beta-blockers are very useful in re-entrant arrhythmias involving the AV node, for example AV nodal re-entrant tachycardia (a single macro-circuit that uses the AV node). If we give a beta-blocker it will block current going through the re-entrant pathway.

2. They are also used in arrhythmias caused by anomalous pathways like Wolf Parkinson White Syndrome. Patients with WPW syndrome commonly present with atrial flutter. Beta-blockers slow conduction in both the antigrade and retrograde route through the anomalous pathway

We can also use procainamide for WPW atrial flutter because procainamide has K channel blocking effects that increase the refractory period of the anomalous pathway. Remember the refractory period is the time when no action potentials can be initiated so procainamide inhibits extra APs from conducting through. We cannot use a Ca channel blocker or digoxin because they decrease the refractory period of the anomalous pathway thus allowing more impulses to be conducted.

Adverse Effects:

Beta-blockers can cause
1. fatigue
2. depression
3. impotence
4. bronchospasm so be careful when using beta-blockers in COPD patients.
5. severe hypertension in patients with arrhythmias due to excess sympathetic stimulation.

Patients with pheochromocytoma (tumor of the adrenal gland that causes too much release of epinephrine and norepinephrine) or patients experiencing clonidine withdrawal (alpha2 agonist that inhibits sympathetic vasomotor center, decreasing sympathetic outflow. Rebound hypertension occurs following abrupt withdrawal) have excessive stimulation of both alpha and beta adrenergic receptors. If we block just the beta-receptors, alpha-receptor stimulation will cause hypertension. So for these patients we need to give both an alpha-receptor blocker along with the beta- blocker.
Sometimes patients cannot tolerate these side effects (especially tired old ladies and impotent old men... not a good combination).

It is very important to know that you CANNOT abruptly stop beta- blocker therapy!! Beta-blockers need to be tapered off to avoid rebound symptoms like rebound hypertension, angina, arrhythmias, or even stroke!


1. SOTALOL (BETAPACE)

-Non selective beta blocker with some K+blocking activity

INDICATIONS:

-Approved for ventricular tachyarrhythmias (Betapace) as well as for atrial fibrillation or flutter (Betapace AF)

-Unchanged drug is excreted renally

SIDE EFFECTS:

1. causes early after deopolarization (EAD= so torsades de pointes
(1.5 to 2% incidence)

CONTRAINDICATIONS:

1. DONT give to astmatics or COPD pts (b/c is a beta blocker)


2. ESMOLOL:

B-1 selective agent

-Very short T1/2 (9mins) so useful in ICU

Front 135

Class III anti-arrythmics? Name the 5 drugs and the side effects of each? How do they work?

Back 135

Class III: K Channel Blockers
1. Amiodarone
2. Dronedarone
3. Ibutilide
4. Dofetilide
5. Sotalol-also is a class II beta blocker**

General Characteristics:

Class III drugs block the K channels of phase 3 so they prolong the action potential duration and refractory period. This is manifested on the ECG as a QT prolongation -- the basis for torsades de pointes. The exception is amiodarone which has very low proarrythmic effects.

1. Ibutilide:

Therapeutic Uses

Ibutilide is ONLY available as IV and the ONLY drug approved for treating a-fib and a-flutter!!

Ibutilide is used for conversion of atrial fibrillation and flutter to normal sinus rhythm.
After conversion, oral dofetilide is used to maintain sinus rhythm (dofetilide is only available as oral drug). Oral dofetilide, because of its QT prolonging activity, can only be prescribed by a cardiologist.


Adverse Effects:

IV Ibutilide has a high incidence of torsades de pointes (4-8% of patients). After giving ibutilide we must monitor patients for at least 4 hours before we let them go home – this is an FDA Black Box Label.
Oral dofetilide has a lower incidence of torsades (1-3% of patients) but we should still know the risk is there.


2. DOFETILIDE:

-Pure QT prolonging drug

MECHANISM:

The mechanism of action is blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. (virtually no extra-cardiac adverse effects)

Restricted use:

available only through specially trained physicians, hospitals!! Must admit to ICU to do this!

INDICATIONS:

Oral dofetilide- used for the conversion of atrial fibrillation and flutter to sinus rhythm, or maintenance of sinus rhythm after cardioversion

CAUSES:

Torsade de pointes
In 1-3% of those receiving dofetilide
Once patient has converted to sinus rhythm—need to observe in hospital for 12 hours

METABOLSIM:
Dofetilide is renally excreted unchanged


-If patients do not convert to normal sinus rhythm within 24 hours of initiation of Dofetilide therapy, electrical cardioversion should be considered.

-Patients continuing on Dofetilide after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of Dofetilide therapy, whichever is greater.

CONTRAINDICATIONS:

l. in patients with congenital or acquired long QT syndromes (should not be used if baseline QTc >440 msec (500 msec in patients with ventricular conduction abnormalities).

2. Severe renal impairment (calculated Cr cl <20 mL/min).

3. When using drugs which increase serum levels by interference with renal excretion and hepatic metabolism:
A. Verapamil or the cation transport system inhibitors B. cimetidine
C. trimethoprim (alone or in combination with sulfamethoxazole)
D. ketoconazole
E. hydrochlorothiazide (alone or in combinations such as with triamterene)



3. Sotalol

MECHANISM:
Sotalol blocks K channels but is also a nonselective beta-blocker.

Therapeutic Uses:
Sotalol is effective in both ventricular and supraventricular arrhythmias. Therefore, sotalol can be prescribed for atrial flutter, fibrillation, or ventricular tachyarrthythmias. (similar to procainamide)

Pharmacokinetics:
Sotalol is excreted unchanged by the kidney and is only available in an oral formulation.

Adverse Effects:
Sotalol’s side effects are related to its beta-blocking effects (see the side effects from Class II drugs) and it’s QT prolongation. Usually when we start a patient on sotalol we monitor them in the hospital for a few days or, in the case of an outpatient patient, we have them come in daily for the first few days for an ECG to monitor the QT interval.

CONTRAINDICATED IN:

1. Pt with HF (b/c has a moderate iontropic depressing effect)
2. DONT use in pts with renal failure


3. Amiodarone:

MECHANISM:

Amiodarone not only has K channel blocking effects but also Na channel, Ca channel, and Beta-blocking effects. Therefore amiodarone has all four class actions.

Therapeutic Uses:

Amiodarone was originally developed as an antianginal in the 1960’s but was found to have antiarrhythmic effects. It is now used for both atrial and ventricular arrhythmias. Amiodarone is used for patients with recurrent ventricular tachycardia or fibrillation that are resistant to other drugs.

Amiodarone is somewhat a “last resort” drug because of its multitude of toxic effects. Dr. Lazarous mentions that amiodarone is the most common drug used for atrial fibrillation -- this is an off label use. “On label use” is for recurrent ventricular fibrillation or tachycardia. However the only life saving measure for recurrent ventricular arrhythmias are implantable cardioverter defibrillators (ICDs)

Adverse Effects:
Unfortunately amiodarone has many toxic effects. Amiodarone has such a multitude of side effects because it is a structural analog of thyroid hormone, highly lipophilic, and has an extremely long half life (13 days to 3 months-LONGEST OF ANY DRUG ON MARKET!!). Because it is so lipophilic (lipid tissue to plasma ratio of 300:1) amiodarone initiation (IV) requires a loading dose of 800-1600 mg/day for several weeks! If using an oral dose of amiodarone, it takes several months of a loading dose before adequate levels in the heart are reached. Also, since it has such a long half-life, toxic effects can be seen up to 3 months after stopping the drug.

Amiodarone has many drug-to-drug interactions i.e.
1. digoxin
2. warfarin
3. theophylline.

This is because amiodarone is both an inhibitor of hepatic metabolism and inhibitor of renal elimination of many compounds. In the liver, amiodarone inhibits CYP3A4, CYP2C, and P-glycoprotein. If a patient is on digoxin, a Ca channel blockers or a beta-blockers, the plasma concentration of these drugs will go up in the presence of amiodarone. The increase in digoxin, Ca channel blockers, or beta-blockers will cause bradycardia and QT prolongation. So when we load with amiodarone we have to decrease the doses of these drugs by !. Amiodarone also affects warfarin elimination so we need to decrease the dose of warfarin!! Keep in mind many patients with atrial fibrillation are on warfarin to prevent blood clots.

When remembering Amiodarone toxicity think through all systems of the body.
1. First, thinking about the skin, amiodarone causes photosensitivity and a blue discoloration.
2. Neurologically it can cause tremors and a “glove and stocking” neuropathy. This refers to little old ladies who tremor so much they have difficultly putting on their stockings and gloves.

3. In the eyes, there will be corneal deposits but these do not hurt the eye at all.

4. Since amiodarone is a structural analog of thyroid hormone so it can cause hypothyroidism or hyperthyroidism.

5. There can be acute toxicity in the lung which can be “very very bad”. Patients can get an ARDS (acute respiratory distress syndrome) like syndrome which has a high fatality rate. This decreases the diffusion capacity of the lungs (DLCO). So before we start amiodarone we have to do a pulmonary function test to make sure the DLCO is initially normal.

6. Liver toxicity can occur resulting in serum AST or ALT more than two times normal. Hepatitis and cirrhosis are rare but can occur. When a patient is on amiodarone we have to do liver function tests and thyroid function tests every 6 months to monitor for these toxicities.






4. Dronedarone

Therapeutic Uses:

Dronedarone is referred to as the “poorer sister of amiodarone” – poorer due to decreased effectiveness as dronedarone is only approved for atrial fibrillation (amiodarone is also approved for ventricular fibrillation).

SIDE EFFECTS:
However dronedarone has fewer side effects due to two reasons. (1) The iodine was removed thus dronedarone is not toxic to the thyroid. (2) A sulfonamide group was added to reduce lipid solubility – this decreases the half-life and prevents neurotoxicity (dronedarone cannot cross the blood brain barrier as well).

ATENA TRIAL:
The Athena Trial (don’t need to remember name) showed that dronedarone reduces cardiovascular hospitalization and cardiovascular mortality by 24% versus placebo. This was the first trial showing that an anti-arrhythmic drug improved cardiovascular morbidity and mortality. BUT dronedarone increased mortality in symptomatic heart failure patients. Eeeek! Big problem as heart failure patients are prone to developing atrial fibrillation. Heart failure patients are in fact the main patient population we give amiodarone to.

CONTRAINDICATIONS:

Dronedarone is contraindicated in symptomatic heart failure patients.
The data suggests that dronedarone is probably less effective than amiodarone but worth trying. Dronedarone is a very expensive drug ($9 a day) but as of this year insurance companies are covering it

Front 136

Adenosine?

Back 136

Increase K+ out of cells= hyperpolarizing the cell and decreasing Calcium. The Drug of choice in diagnosing/ abolishing supraventricular tachycardia.Very short acting(- 15sec). SIDE EFFECTS: includes flushing, hypotension, chest pain. Effects blocked by theophylline.

Front 137

Effective in torsades de pointes and digoxin toxicity?

Back 137

Magnesium

Front 138

Propylthiouracil, methimazole?

Back 138

MECHANISM: Inhibit organification of iodide and coupling of thyroid hormone synthesis. Propylthiouracil decreases peripheral conversion of T4 to T3.
CLINICAL USE: Hyperthyroidism. SIDE EFFECTS: Skin rash, agranulocytosis (rare), aplastic anemia. Methimazole is a possible teratogen.

Front 139

Levothyroxine, triiodothyronine?

Back 139

MECHANISM: Thyroxine replacement.

CLINICAL USE: Hypothyroidism, myxedema.

TOXICITY: Tachycardia, heat intolerance, tremors, arrhythmias.

Front 140

Demeclocycline?

Back 140

MECHANISM: ADH antagonist (member of the tetracycline family).

CLINICAL INDICATION: SIADH.

SIDE EFFECTS: Nephrogenic DI, photosensitivity, abnormalities of bone and teeth.

Front 141

Glucocorticoids?

Back 141

Hydrocortisone, prednisone, triamcinolone, dexamethasone, beclomethasone

MECHANISM: Decrease the production of leukotrienes and prostaglandins by inhibiting phospholipase A2 and expression of COX-2.

CLINICAL USE: Addison's disease, inflammation, immune suppression, asthma.

SIDE EFFECTS: Iatrogenic Gushing's syndrome-buffalo hump, moon facies, truncal obesity, muscle
wasting, thin skin, easy bruisability, osteoporosis, adrenocortical atrophy, peptic ulcers, diabetes (if chronic).

Adrenal insufficiency when drug stopped after chronic use.

Front 142

Name the rapid, intermediate and long acting insulins?

Back 142

Lispro (rapid-acting)

Aspart (rapid-acting)

Regular (rapid-acting)

NPH (intermediate)

Glargine (long-acting)

Detemir (long-acting)

MECHANISM:

Bind insulin receptor (tyrosine kinase activity).

1. Liver: increase glucose stored as
glycogen.

2. Muscle: increase glycogen and
protein synthesis, K+ uptake.

3. Fat: aids T G storage.

CLINICAL USE:

1. Type 1 DM
2. Type 2 DM
3. gestational diabetes
4. life-threatening hyperkalemia
5. stress-induced hyperglycemia.


SIDE EFFECTS:
Hypoglycemia, hypersensitivity reaction (very rare)

Front 143

Metformin?

Back 143

Exact mechanism is unknown.

1. decrease gluconeogenesis
2. Increase glycolysis
3. Increase periphera glucose uptake (insulin sensitivity).

CLINICAL USE:

Oral. Can be used in patients without islet function.

SIDE EFFECTS:

Most grave adverse effect is lactic acidosis (contraindicated in renal failure).

Front 144

Sulfonylureas? Name the (2) 1st generation and (3) 2nd generation drugs? Side effects?

Back 144

Sulfonylureas:
First generation:
1. Tolbutamide
2. Chlorpropamide

Second generation:
1. Glyburide
2. Glimepiride
3. Glipizide


MECHANISM:

Close K+ channel in B-cell membrane, so cell depolarizes = triggering of insulin release via increase Ca2+influx

CLINICAL USE:

Stimulate release of endogenous insulin in type 2 DM. Require some islet function,
useless in type 1 DM.

SIDE EFFECTS:

First generation: disulfiram-like effects.

Second generation: hypoglycemia

Front 145

Pramlintide (mimetics)?

Back 145

diabetes drug that decreases glucagon and is used for DM type 2. Side effects include: Hypoglycemia, nausea, diarrhea.

Front 146

Pioglitazone and Rosiglitazone?

Back 146

Glitazones/thiazolidinediones

DIABETES DRUGS


MECHANISM:

Increase insulin sensitivity in peripheral tissue. Binds to PPAR gamma nuclear transcription regulator

CLINICAL USE:

Used as monotherapy in DM type 2 or combined with other agents

SIDE EFFECTS:

-Weight gain
-Edema.
-Hepatotoxicity
-CVtoxicity.

Front 147

a-glucosidase inhibitors? Name 2 drugs in this class of diabetes drugs?

Back 147

1. Acarbose
2. Miglitol


MECHANISM:

Inhibit intestinal brush border a-glucosidases.

Delayed sugar hydrolysis and glucose absorption
lead to decreased postprandial hyperglycemia.

CLINICAL USE:

Used as monotherapy in type 2 DM or in combination with abov agents.

SIDE EFFECTS:

GI disturbances.

Front 148

Omeprazole, lansoprazole?

Back 148

Proton pump inhibitors. MECHANISM: Irreversibly inhibit H+/K+-ATPase in stomach parietal cells.

CLINCAL USE:
1. Peptic ulcer
2. gastritis
3. esophageal reflux
4. Zollinger-Ellison syndrome.

Front 149

Name 4 H2 blockers and MOA?

Back 149

Cimetidine, ranitidine, famotidine, nizatidine.

MECHANISM: Reversible block of histamine H2 receptors and decrease H+ secretion by parietal cells.

CLINICAL USE:

Peptic ulcer, gastritis, mild esophageal reflux.

SIDE EFFECTS:

Cimetidine is a potent inhibitor of P-450; it also
has antiandrogenic effects (prolactin release, gynecomastia, impotence, DECREASE libido in males); can cross blood-brain barrier (confusion, dizziness, headaches) and placenta. Both cimetidine and ranitidine DECREASE renal excretion of creatinine. Other H2 blockers are relatively free of these effects.

MNEUMONIC:

Take H2 blockers before you DINE.

Think "table for 2" to remember H2.

Front 150

Bismuth, sucralfate?

Back 150

MECHANISM:

Bind to ulcer base, providing physical protection, and allow HCO3 secretion to reestablish pH gradient in the mucous layer.

CLINICAL USE:

Increase ulcer healing, traveler's diarrhea.


Triple therapy of H. pylori ulcers- Metronidazole, Amoxicillin (or Tetracycline), Bismuth.

Can also use PPI-Please MAke Tummy Better.

Front 151

Misoprostol?

Back 151

MECHANISM:

A PGEl analog. Increase production and secretion of gastric mucous barrier and decrease acid production.

CLINICAL USE:

Prevention of NSAID-induced peptic ulcers; maintenance of a patent ductus arteriosus.
Also used to induce labor.


SIDE EFFECTS:

Diarrhea. Contraindicated in women of childbearing potential (abortifacient).

Front 152

Octreotide?

Back 152

MECHANISM:

Somatostatin analog.

CLINICAL USE:

Acute variceal bleeds, acromegaly, VIPoma, and carcinoid tumors.

SIDE EFFECTS:

Nausea, cramps, steatorrhea.

Front 153

Pirenzepine, propantheline?

Back 153

MECHANISM:

Muscarinic anatognist.

Block M1 receptors on ECL cells (decrease histamine secretion) and M3 receptors on
parietal cells (decrease H+ secretion).


CLINICAL USE:

Peptic ulcer (rarely used).

SIDE EFFECT:

Tachycardia, dry mouth, difficulty focusing eyes.

Front 154

A monoclonal antibody to TNF, proinflammatory cytokine that is used for Crohn's disease and rheumatoid arthritis?

Back 154

lnfliximab. SIDE EFFECTS: Respiratory infection (including reactivation of latent TB), fever, hypotension.

Front 155

Antacid use can affect absorption, bioavailability, or urinary excretion of other drugs by altering gastric and urinary pH or by delaying gastric emptying. Overuse can cause what problems?

Back 155

Overuse can also cause the following problems:

1. Aluminum hydroxide-constipation and
hypophosphatemia; proximal muscle
weakness, osteodystrophy, seizures

2. Magnesium hydroxide-diarrhea, hyporeflexia,
hypotension, cardiac arrest

3. Calcium carbonate- hypercalcemia,
rebound acid increase

**All can cause hypokalemia**

Front 156

Sulfasalazine?

Back 156

MECHANISM:

A combination of sulfapyridine (antibacterial) and 5-aminosalicylic acid (anti-inflammatory).

Activated by colonic bacteria.

CLINICAL USE:

Ulcerative colitis, Crohn's disease.

SIDE EFFECTS:

Malaise, nausea, sulfonamide toxicity, reversible oligospermia.

Front 157

Ondansetron?

Back 157

MECHANISM:

5-HT3 antagonist. Powerful central-acting antiemetic.

CLINICAL USE:

Control vomiting postoperatively and in patients
undergoing cancer chemotherapy.

SIDE EFFECT:
Headache, constipation.

MNEUMONIC:

You will not vomit with ONDANSetron, so you can go ON DANCing.

Front 158

Metoclopramide?

Back 158

MECHANISM:

D2 receptor antagonist. Increase resting tone, contractility, LES tone, motility. Does not influence colon transport time.

CLINICAL USE:

Diabetic and post-surgery gastroparesis.

SIDE EFFECTS:
Increase parkinsonian effects.

Restlessness

drowsiness

fatigue

depression

nausea and diarrhea.

Drug interaction with digoxin and diabetic agents!!

Contraindicated in patients with small bowel obstruction!!

Front 159

Aspirin? Side effects?

Back 159

MECHANISM:
Acetylates and irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) to prevent conversion of arachidonic acid to thromboxane A2 (TxA2).

Increases bleeding time. No effect on PT, PTT!!

CLINICAL USE:
Antipyretic, analgesic, anti-inflammatory, antiplatelet drug.

SIDE EFFECTS:
Gastric ulceration, bleeding, hyperventilation, Reye's syndrome, tinnitus (CN VIII).

Front 160

Warfarin?

Back 160

Vitamin K Antagonists – inhibit Vit K-dependent activation of factors II, VII, IX, X – require carboxylation for stimulation of their pro-coagulant activity; also hits Protein C & S (can be pro-coagulant in this sense). Half-Life: 24-36 hrs Start with low dose, INR monitoring every 2-3 days; bridging tx common Hepatic Clearance – P450-mediated Reversal with Vit K administration Never warfarin-load! [Metabolism is influenced by many extrinsic factors – Rx, change in diet/nutrition, disease states Need to monitor closely with INR Antibiotics are huge risk – decrease Vit K synthesis from GI flora]. PRINCIPLES TO KNOW ABOUT THIS DRUG AKA Essential principles of warfarin initiation
Start with reasonably low dose (especially for older patients)
Assess concurrent medication use
Educate your patient about the risks and intended benefits of therapy (true for all meds)
Monitor INR every 2-3 days
Most cases require bridging therapy for immediate anticoagulation – once INR therapeutic, overlap 4 days to assure true therapeutic levels achieved. Do not warfarin-load! Distinguish between the “anticoagulant effect” and “antithrombotic effect” of warfarin therapy
Anticoagulant effect – disruption of initiation of the coagulation cascade
Reduction of factor VIIa  short half life (hours) / rapid depletion  diminished ability to form NEW thrombi

Antithrombotic effect – disruption of the final stages of coagulation
Reduction of factor Xa and factor IIa (long half life)  inhibition of propagation of EXISTING thrombi

SIDE EFFECTS: Bleed Risk High Thrombotic Complications (limb gangrene, skin necrosis) Associated w. Protein C deficiency *Teratogenic effects in early pregnancy. DONT GIVE IF PREGANT; fetal bleeding in late pregnancy

Front 161

Used as an alternative to heparin for anticoagulating patients with HIT?

Back 161

Direct thrombin inhibitors: Lepirudin, bivalirudin

Front 162

Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. increase PT and PTT, no change in platelet count?

Back 162

Fibrinolytic system dissolves intravascular clots
Plasminogen --> plasmin (active form)
Plasmin is a nonspecific protease, digests fibrin clots and other proteins

Fibrinolytic drugs are also non-specific – promote digestion of pathologic thrombi and fibrin deposits at sites of injury
Potential for hemorrhage is high
Examples: STREPTOKINASE (1st gen), ALTEPLASE (2nd gen), RETEPLASE (3rd gen)

SIDE EFFECTS:

Bleeding. Contraindicated in patients with active bleeding, history of intracranial
bleeding, recent surgery, known bleeding diatheses, or severe hypertension. Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis.

Front 163

Clopidogrel?

Back 163

Antiplatelet – ADP-receptor antagonist; all members are prodrugs; thiol- containing active metabolite causes irreversible inhibition of P2Y12 receptor (RECEPTOR ON PLATELETS WHERE ADP BINDS), blocking stimulated adenylyl cyclase activity. Rapid Oral Absorption Hepatic Metabolism to a short-lived, active metabolite (isozyme) (genetic polymorphisms – makes clinical efficacy variable) INDICATIONS for ACS, recent MI, recent stroke, PAD Possible interaction with PPIs and statins. COMBINATION EFFECTS: CLOPIDOGREL + ASA COMBINTION IS BETTER THAN ONE OR OHER ALONE!! (BUT ASSOCIATED WITH INCREAESED BLEEDING RISKS)
SIDE EFFECTS: Severe rash; Diarrhea Bleeding Complications Thrombocytopenia; TTP Black Box Warning for the CYP2C19 poor metabolizers No significant rate of neutropenia (like in ticlopidine)

Front 164

GP-IIb/IIIa Receptor Antagonists?

Back 164

Developed to block the final common pathway of platelet activation:
Inhibits functionally active integrin GP-IIb/IIIa receptor

GP-IIb/IIIa inhibitors include
1. Monoclonal antibodies directed against the receptor
2. Peptide/nonpepetide mimetics that compete with fibrinogen binding.
Includes: ABCLIXIMAB (KNOW!-IN FIRST AID) Antiplatelet – monoclonal antibody; blocks the final common pathway of platelet activation (integrin GP- IIa/IIIb); Given as bolus and then continuous infusion (needs high receptor occupancy) Half-Life: 30 min; renal clearance Recover normal platelet function in 12 hours after discontinuation Indicated for ACS patients undergoing PCI or for medical management. SIDE EFFECTS: Major bleeding AV nodal block Thrombocytopenia (rapid onset, must monitor platelets closely) Anti-abciximab antibodies (anaphylactic risk). and EPTIFIBATIDE: Antiplatelet – synthetic cyclic heptapeptide; platelet aggregation blocker (reversible receptor inhibition). INDICATION: PTS COMES IN WITH HEART ATTACK. LIMITED TO ACUTE SETTING AND NOT USED FOR LONG TERM.
Rapid onset: peak plasma in 5 min. Half-Life: 1.5 hrs, renal clearance Recover normal platelet function in 1 hour after discontinuation Indicated acutely for ACS patients undergoing PCI (medical management role questioned). SIDE EFFECTS: Bleeding Thrombocytopenia

Front 165

Methotrexate (MTX)?

Back 165

MECHANISM:

Folic acid analog that inhibits dihydrofolate reductase +decreases dTMP, DNA and therefore protein synthesis.

CLINICAL USE:

1. Cancers: Leukemias, lymphomas, choriocarcinoma, sarcomas.

2. Non-neoplastic: Abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis.


SIDE EFFECTS:

1. Myelosuppression, which is reversible with leucovorin (folinic acid) "rescue."

2. Macrovesicular fatty change in liver.

3. Mucositis.

4. Teratogenic.

Front 166

5-fluorouracil (5-FU)?

Back 166

MECHANISM:

Pyrimidine analog bioactivated to 5F-dUMP,which covalently complexes folic acid.
This complex inhibits thymidylate synthase= decrease dtMP, DNA and protein synthesis.

CLINICAL USE:

1. Colon cancer and other solid tumors
2. basal cell carcinoma (topical)

Synergy with MTX!!

SIDE EFFECTS:

1. Myelosuppression, which is not reversible with leucovorin. Overdose: "rescue" with thymidine.

2. Photosensitivity.

Front 167

6-mercaptopurine (6-MP)?

Back 167

MECHANISM:

Purine (thiol) analog= decreases de novo purine synthesis.
-Activated by HGPRTase.


CLINICAL USE:

Leukemias, lymphomas (NOT CLL or Hodgkin's).

SIDE EFFECTS:

Bone marrow, GI, liver. Metabolized by xanthine oxidase; thus increase toxicity with allopurinol.

Front 168

Dactinomycin (ACTinomycin D)?

Back 168

MECHANISM:

Anti-tumor antibotic that Intercalates into DNA.


CLINICAL USE:

Wilms' tumor, Ewing's sarcoma, rhabd~m~osarcoma. Used for childhood tumors (children ACT out).

SIDE EFFECTS:

Myelosuppression

Front 169

Doxorubicin (Adriamycin), daunorubicin?

Back 169

MECHANISM:

Anti-tumor antibotic that generates free radicals. Noncovalently intercalate
in DNA= breaks in DNA= decreased replication.

CLINICAL USE:

Hodgkin's lymphomas; also for myelomas, sarcomas, and solid tumors (breast, ovary, lung).

SIDE EFFECTS:

Cardiotoxicity, myelosuppression,and alopecia. Toxic to tissues with extravasation.

Front 170

Bleomycin?

Back 170

MECHANISM:

Anti-tumor antibotic that Induces free radical formation, which causes breaks in DNA strands.


CLINICAL USE:

Testicular cancer, Hodgkin's lymphoma.

SIDE EFFECTS:

Pulmonary fibrosis, skin changes. Minimal myelosuppression.

Front 171

Etoposide (VP-16), teniposide?

Back 171

MECHANISM:

Anti-tumor antibotic that Inhibits topoisomerase II= INCREASE DNA degradation.

CLINICAL USE:

Small cell carcinoma of the lung and prostate, testicular carcinoma.

SIDE EFFECTS:

Myelosuppression, GI irritation, alopecia.

Front 172

Cyclophosphamide, ifosfamide?

Back 172

MECHANISM:

Alkylating agent that covalently X-links (interstrand) DNA at guanine N-7.

Requires bioactivation by liver!

CLINICAL USE:

Non-Hodgkin's lymphoma, breast and ovarian carcinomas. Also immuno- suppressants.


SIDE EFFECTS:

Myelosuppression; hemorrhagic cystitis, partially prevented with mesna (thiol group of mesna binds toxic metabolite).

Front 173

Busulfan?

Back 173

MECHANISM:

Alkylates DNA

CLINICAL USE:

CML. Also used to ablate patient's bone marrow before bone marrow transplantation


SIDE EFFECTS:

Pulmonary fibrosis, hyperpigmentation.

Front 174

Nitrosoureas (carmustine, lomustine, semustine, streptozocin)?

Back 174

MECHANISM:

Alkylates DNA

Requires bioactivation.

Cross blood-brain barrier!!!


CLINICAL USE:

Brain tumors (including glioblastoma multiforme).

SIDE EFFECTS:

CNS toxicity (dizziness, ataxia).

Front 175

Alkaloids that bind to tubulin in M-phase and block polymerization of microtubules so that mitotic spindle cannot form? (Microtubules are the vines of your cells)

Back 175

Vincristine, vinblastine


CLINICAL USE:

Hodgkin's lymphoma, Wilms' tumor, choriocarcinoma.


SIDE EFFECTS:

Vincristine:
1. neurotoxicity (areflexia, peripheral neuritis)
2. paralytic ileus.

VinBLASTine: BLASTS Bone marrow (suppression).

Front 176

Paclitaxel? and other taxols

Back 176

MECHANISM:

Hyperstabilizepolymerized microtubules in M-phase so that mitotic spindle cannot break down (anaphase cannot occur).

MNEUMONIC:

It is TAXing to stay polymerized.

CLINICAL USE:
Ovarian and breast carcinomas.

SIDE EFFECTS:
Myelosuppressionand hypersensitivitv.

Front 177

Cross-link DNA. Clinical use: Testicular, bladder, ovary, and lung carcinomas. Side effects: Nephrotoxicity and acoustic nerve damage?

Back 177

Cisplatin and carboplatin

Front 178

Inhibits Ribonucleotide Reductase= decrease DNA Synthesis (S-phase specific)?

Back 178

HYDROXYUREA. CLINICAL USE: Melanoma, CML, sickle cell disease (INCREASES HbF). SIDE EFFECTS: Bone marrow suppression, GI upset.

Front 179

Prednisone?

Back 179

MECHANISM:

May trigger apoptosis. May even work on nondividing cells.

CLINICAL USE:

Most commonly used glucocorticoid in cancer chemotherapy. Used in CLL, Hodgkin's lymphomas (part of the MOPP regimen).

Also an immunosuppressant used in
autoimmune diseases.


SIDE EFFECTS: Cushing-like symptoms; immunosuppression, cataracts, acne, osteoporosis, hypertension, peptic ulcers, hyperglycemia, psychosis.

Front 180

Tamoxifen, raloxifene?

Back 180

MECHANISM:

SERMs-receptor antagonists in breast and agonists in bone. Block the binding of estrogen to estrogen receptor-positive cells.
CLINICAL USE:

Breast cancer. Also useful to prevent osteoporosis.

SIDE EFFECTS:

Tamoxifen:
-may INCREASE the risk of endometrial carcinoma via partial agonist effects
-"hot flashes."

Raloxifene:
-NO increase in endometrial carcinoma because it is an endometrial antagonist.

Front 181

Monoclonal antibody against CD20, which is found on most B-cell neoplasms and is used for Non-Hodgkin's lymphoma and rheumatoid arthritis (with methotrexate)?

Back 181

Rituximab

Front 182

Philadelphia chromosome bcr-abl tyrosine kinase inhibitor?

Back 182

lmatinib (Gleevec)- Used for CML and GI stromal tumors. SIDE EFFECTS: Fluid retention.

Front 183

Monoclonal antibody against HER-2 (erb-B2).Helps kill breast cancer cells that overexpress HER-2, possibly through antibody-dependent cytotoxicity?

Back 183

Trastuzumab (Herceptin). SIDE EFFECT: Cardiotoxicity.

Front 184

COX-2 inhibitors (celecoxib)?

Back 184

MECHANISM:

Reversibly inhibits specifically the cyclooxygenase (COX) isoform2, which is found in inflammatory cells and vascular endothelium 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 USE: Rheumatoid and osteoarthritis; patients with gastritis or ulcers.

SIDE EFFECTS:
Increase risk of thrombosis. Sulfa allergy!! Less toxicity to GI mucosa (lower incidence of ulcers, bleeding than NSAIDs).

Front 185

Inhibit osteoclastic activity; reduce both formation and resorption of hydroxyapatite?

Back 185

Bisphosphonates

1. Etidronate
2. pamidronate
3. alendronate
4. risedronate
5. zoledronate (IV).


CLINCAL USE:

Malignancy-associated hypercalcemia, Paget's disease of bone, postmenopausal
osteoporosis.

SIDE EFFECTS:

Corrosive esophagitis (EXCEPT ZOLEDRONATE)

Nausea

diarrhea

osteonecrosis of jaw

Front 186

Colchicine?

Back 186

Gout drug (used with NSAIDS). Binds and stabilizes tubulin to inhibit polymerization, imparining leukocyte chemotaxis and degranulation. GI side effects, especially if given orally. (Note:indomethacin is less toxic,also used in acute gout.)

Front 187

Used in chronic gout. Inhibits reabsorption of uric acid in PCT (also inhibits secretion of PCN)?

Back 187

Probenecid

Front 188

Allopurinol?

Back 188

Chronic gout. Inhibits xanthine oxidase, Lconversion of xanthine to uric acid. Also used in lymphoma and leukemia to prevent tumor lysis-associated urate nephropathy. 1'concentrations of azathioprine and 6-MP (both normally metabolized by xanthine oxidas

Front 189

Recombinant form of human TNF receptor that binds TNF?

Back 189

Etanercept. CLINICAL USE: Rheumatoid arthritis, psoriasis, ankylosing spondylitis

Front 190

Latanoprost?

Back 190

prostaglandin glaucoma drug that Increases outflow of aqueous humor. Side effect: Darkens color of iris (browning)

Front 191

Opioid analgesics? Mechanism of action?

Back 191

1. Morphine
2. fentanyl
3. codeine
4. heroin
5. methadone
6. meperidine
7. dextromethorphan.

MECHANISM:
-Act as agonists at opioid receptors (mu = morphine, delta = enkephalin, kappa = dynorphin) to modulate synaptic transmission-open K+ channels, close Ca2+channels + decrease synaptic transmission.

-Inhibit release of ACh, NE, 5-HT, glutamate, substance P.

CLINICAL USE:

Pain, cough suppression (dextromethorphan), diarrhea (loperamide and diphenoylate), acute pulmonary edema, maintenance programs for addicts (methadone).

SIDE EFFECTS:
Addiction, respiratory depression, constipation, miosis (pinpoint pupils), additive CNS depression with other drugs. Tolerance does not develop to miosis and constipation.

Toxicity treated with naloxone or naltrexone (opioid receptor antagonist)!!

Front 192

Butorphanol?

Back 192

MECHANISM:

Partial agonist at opioid mu receptors, agonist at kappa receptors.


CLINICAL USE:

Pain; causes less respiratory depression than full agonists.

SIDE EFFECTS:

Causes withdrawal if on full opioid agonist.

Front 193

Tramadol?

Back 193

MECHANISM:

Very weak opioid agonist; also inhibits serotonin and NE reuptake (works on multiple neurotransmitters- "tram it all" in).

CLINICAL USE:

Chronic pain.

SIDE EFFECTS:

Similar to opioids. Decreases seizure threshold.
(CAUSES SEIZURES)

Front 194

Carbamazepine (anti-seizure drug) side effect?

Back 194

Diplopia, ataxia, blood dyscrasias (agranulocytosis,
aplastic anemia), liver toxicity, teratogenesis, induction of cytochrome P-450, SIADH, Stevens-Johnsonsyndrome.

Front 195

Phenobarbital side effect?

Back 195

Sedation, tolerance, dependence, induction of cytochrome P-450.

Front 196

Phenytoin side effect?

Back 196

Nystagmus, diplopia, ataxia, sedation, gingival hyperplasia, hirsutism, megaloblastic anemia, teratogenesis (fetal hydantoin syndrome), SLE-like syndrome, induction of cytochrome P-450.

Front 197

Phenytoin?

Back 197

MECHANISM:

Anti-epileptic drug. Use-dependent blockade of Na+ channels; Increase refractory period; inhibition of glutamate release from excitatory presynaptic neuron.

CLINICAL USE:

Tonic-clonic seizures. Also a class IB antiarrhythmic.

SIDE EFFECTS:

Nystagmus, ataxia, diplopia, sedation, SLE-like syndrome, induction of cytochrome
P-450. Chronic use produces gingival hyperplasia in children, peripheral neuropathy, hirsutism, megaloblastic anemia (decrease folate absorption). Teratogenic (fetal hydantoin syndrome).

Front 198

Barbiturates? Name 4 examples

Back 198

1. Phenobarbital
2. pentobarbital
3. thiopental
4. secobarbital.

MECHANISM:

Faciliate GABAa action by increasing duration of chloride channel openining, thus decreasing neuron firing.

CLINICAL USE:

Sedative for anxiety, seizures, insomnia, induction of anesthesia (thiopental).

SIDE EFFECTS:
Dependence, additive CNS depression effects with alcohol, respiratory or cardiovascular depression (can lead to death), drug interactions owing to induction of liver microsomal enzymes (cytochrome P-450).


Treat overdose with symptom management (assist respiration, increase BP).
CONTRAINDICATED IN PORYPHIA!!

Front 199

Benzodiazepines?

Back 199

1. Diazepam
2. lorazepam
3. triazolam
4. temazepam
5. oxazepam
6. midazolam
7. chlordiazepoxide
8. alprazolam

MECHANISM:

Facilitate GABA action by increasing frequency of C1- channel opening. Decrease REM sleep. Most have long half-lives and active metabolites.

CLINICAL USE:
Anxiety, spasticity, status epilepticus (lorazepam and diazepam), detoxification (especially alcohol withdrawal-DTs), night terrors, sleepwalking, general anesthetic (amnesia, muscle relaxation), hypnotic (insomnia).


SIDE EFFECTS:
Dependence, additive CNS depression effects with alcohol. Less risk of respiratory depression and coma than with barbiturates.

Treat overdose with flumazenil (competitive antagonist at GABA benzodiazepine receptor)!!


MNEUMONICS:
Short acting = TOM Thumb = Triazolam, Oxazepam, Midazolam. Highest addictive potential.

Benzos, barbs, and EtOH all bind GABA(A)-R,which is a ligand-gated chloride channel.

Front 200

Inhaled anesthetics?

Back 200

1. Halothane
2. enflurane
3. isoflurane
4. sevoflurane
5. methoxyflurane
6. nitrous oxide.

MECHANISM: unknown

SIDE EFFECTS:

Myocardial depression, respiratory depression, nausealemesis, Increase cerebral blood flow
(decrease cerebral metabolic demand). Hepatotoxicity (halothane), nephrotoxicity (methoxyflurane), proconvulsant
(enflurane), malignant hyperthermia (rare), expansion of trapped gas (nitrous oxide).

Front 201

most common drug used for endoscopy; used adiunctively with gaseous anesthetics and narcotics. May cause severe postoperative respiratory depression, decrease BP (treat overdose with flumazenil), and amnesia?

Back 201

Midazolam (a Benzodiazepine)

Front 202

PCP analogs that act as dissociative anesthetics. Block NMDA receptors. Cardiovascular stimulants. Cause disorientation, hallucination, and bad dreams. Increase cerebral blood flow?

Back 202

Arylcyclohexylamines (Ketamine)

Front 203

Used for rapid anesthesia induction and short procedures. Less postoperative nausea than thiopental. Potentiates GABAa?

Back 203

Propofol

Front 204

Dantrolene?

Back 204

-Used in the treatment of malignant hyperthermia, which is caused by inhalation anesthetics (exceptN20)and succinylcholine.

-Also used to treat neuroleptic malignant syndrome (a toxicity of antipsychotic drugs).

MECHANISM:

prevents the release of Ca2+from the sarcoplasmic reticulum of skeletal muscle.

Front 205

Neuromuscular blocking drugs?

Back 205

CLINICAL USE:

Used for muscle paralysis in surgery or mechanical ventilation. Selective for motor (vs. autonomic) nicotinic receptor.

DEPOLARIZING:
Succinylcholine (complications include hypercalcemia and hyperkalemia).

Reversal of blockade:
Phase I (prolonged depolarization) -no antidote. Block potentiated by cholinesterase inhibitors.

Phase II (repolarized but blocked)-antidote consists of cholinesterase inhibitors (e.g., neostigmine).

NON-DEPOLARIZING:
Tubocurarine, atracurium, mivacurium, pancuronium, vecuronium, rocuronium. Competitive-compete with ACh for receptors.

Reversal of blockade-neostigmine, edrophonium, and other cholinesterase inhibitors!!

Front 206

L-dopa (levodopa)/carbidopa?

Back 206

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.

CLINCAL USE:
Parkinsonism. Arrhythmias from peripheral conversion to dopamine. Long-term use can lead to dyskinesia following administration, akinesia between doses. Carbidopa, a peripheral decarboxylase inhibitor, is given with L-dopain order to increase the bioavailability of L-dopa in the brain and to limit peripheral side effects.

Front 207

Selegiline?

Back 207

MECHANISM:

Selectively inhibits MAO-B, which preferentially metabolizes dopamine over NE and 5-HT, thereby increasing the availability of dopamine.

CLINICAL USE:

Adjunctive agent to L-dopa in treatment of Parkinson's disease.

SIDE EFFECTS:

May enhance adverse effects of L-dopa.

Front 208

drugs used for Huntington's?

Back 208

Disease: Increase dopamine, decrease GABA +ACh.

Reserpine +tetrabenazine=amine depleting.

Haloperidol= dopamine receptor antagonist.

Front 209

Sumatriptan?

Back 209

5-HT (1B/ID) agonist. Causes vasoconstriction, inhibition of trigeminal activation and vasoactive peptide release. Half-life < 2 hours.

CLINICAL USE:
Acute migraine, cluster headache attacks.

SIDE EFFECTS:

Coronary vasospasm (contraindicated in patients
with CAD or Prinzmetal's angina), mild tingling.

Front 210

Lithium?

Back 210

MECHANISM:

Not established; possibly related to inhibition of phosphoinositol cascade.

CLINICAL USE:
Mood stabilizer for bipolar disorder; blocks relapse and acute manic events. Also SIADH.

SIDE EFFECTS:
Tremor, sedation, edema, heart block, hypothyroidism,polpria (ADHantagonist causing nephrogenic diabetes insipidus), teratogenesis. Fetal cardiac defects include Ebstein anomaly and malformation of the great vessels. Narrow therapeutic window requires close monitoring of serum levels. Almost exclusively excreted by the kidneys; most is reabsorbed at the proximal convoluted tubules following Na+ reabsorption.

MNEUMONIC:

"LMNOP"

Lithium side effects
Movement (tremor)
Nephrogenic diabetes insipidus
HypOthyroidism
Pregnancy problems

Front 211

Buspirone?

Back 211

MECHANISM:

Stimulates 5-HT (1A) receptors

CLINICAL USE: Generalized anxiety disorder.

Does not cause sedation, addiction, or tolerance!

Does not interact with alcohol (vs. barbiturates, benzodiazepines)!

MNEUMONIC:

I'm always anxious if the BUS will be ON time, so I take BUSpirONe.

Front 212

SSRls?

Back 212

1. Fluoxetine
2. Paroxetine
3. Sertraline
4. Citalopram

MECHANISM:

Serotonin-specific reuptake inhibitors

CLINICAL USE

Depression, OCD, bulima, social phobias


SIDE EFFECTS:

Fewer than TCAs. GI distress, sexual dysfunction (anorgasmia)."Serotonin syndromenwith any drug that increases serotonin (e.g., MA0 inhibitors) -hyperthermia, muscle rigidity, cardiovascular collapse, flushing, diarrhea, seizures.


Treatment: cyproheptadine (5-HTz receptor antagonist).

It normally takes 2-4 weeks for antidepressants for work.

Front 213

SNRls?

Back 213

1. Venlafaxine-used for generalized anxiety-disorder also
2. duloxetine-used for diabetic peripheral neuropathy also

MECHANISM:

Inhibit serotonin and NE reuptake.

CLINICAL USE: atypical Depression, anxiety indicated for diabetic peripheral neuropathy. Duloxetine has greater effect on NE.

SIDE EFFECTS: Increase BP most common; also stimulant effects, sedation, nausea.

Front 214

Monoamine oxidase (MAO) inhibitors?

Back 214

1. Phenelzine
2. tranylcypromine
3. isocarboxazid
4. selegiline (selective MAO-B inhibitor).


MECHANISM: Nonselective MA0 inhibition increasing levels of amine neurotransmitters (NE, serotonin, dopamine).

CLINICAL USE: Atypical depression, anxiety, hypochondriasis. Hypertensive crisis with tyramine ingestion (in many foods, such as wine and cheese) and kagonists; CNS stimulation.

Contraindicated with SSRIs or meperidine (to prevent serotonin syndrome)!!

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Mannitol?

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MECHANISM:

Osmotic diuretic, Increase tubular fluid osmolarity, producing Increase urine flow.

CLINICAL USE: Shock, drug overdose, Increase intracranial/intraocular pressure.

SIDE EFFECTS: Pulmonary edema, dehydration.

Contraindicated in anuria, CHF

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Acetazolamide?

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MECHANISM:

Carbonic anhydrase inhibitor. Causes self-limited NaHC03 diuresis and reduction in total-body HC03- stores.

CLINICAL USE:
Glaucoma, urinary alkalinization, metabolic alkalosis, altitude sickness.

SIDE EFFECTS:
Hyperchloremic metabolic acidosis, neuropathy, NH3 toxicity, sulfa allergy.

ACIDazolamide causes ACIDosis.

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Furosemide?

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powerful diuretic; used to treat CHF, not HTN
- Inhibits Na-K-2Cl cotransporter. Result: Low Na/Cl in cellstimulates JG receptor=↑ renin release
=↑ plasma renin (bad effect). HALF LIFE: only 1.5hrs VS TORSEMIDE (another drug similar to lasix) but used more now b/c longer half life of 3.5hrs. INDICATIONS: HYPERKALEMIA, ACUTE PULOMANRY EDEMA, ACUTE RENAL FAILURE, ANION OVERDOSE (USEFUL IN TREATING TOXIC INGESTIONS OF BROMIDE, FLUORIDE, IODIDE WHICH ARE REASORBED IN THE THICK ASCENDING LIMB). SIDE EFFECTS OF LOOP DIURETICS: HYPOKALEMIC METABOLIC ALKALOSIS-INCREASE THE AMT OF NACI IN COLLECTING TUBULE AND THIS CAN RESULT IN THE EXCRETION OF K+ AND H+, OTOTOXICITY: MOST LIKELY TO OCCUR IN PTS RECIEVING OTHER OTOTOXIC AGENTS SUCH AS AMINOGLYCOSIDE ANTIBOTICS, HYPERURICEMIA: CAUSED BY HYPOVOLUME CONTRACTION WITH INCREASES THE ABSORPTION OF URIC ACID IN PCT AND HYPOMAGNESIUM. CONTRAINDICATIONS: HEPATIC COMA

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Ethacrynic acid?

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MECHANISM:

Phenoxyacetic acid derivative (NOT a sulfonamide). Essentially same action as furosemide.

CLINICAL USE:

Diuresis in patients allergic to sulfa drugs.

SIDE EFFECTS:

Similar to furosemide; can be used in hyperuricemia, acute gout (never used to treat gout).

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Hydrochlorothiazide (HCTZ)?

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MECHANISM:

Thiazide diuretic. Inhibits NaCl reabsorption in early distal tubule, reducing diluting capacity of the nephron. Decreases Ca2+excretion.

CLINICAL USE:

Hypertension, CHF, idiopathic hypercalciuria, nephrogenic diabetes insipidus.

SIDE EFFECTS:

Hypokalemic metabolic alkalosis, hyponatremia, hyperGlycemia, hyperlipidemia, hyperuricemia, and hypercalcemia. Sulfa allergy!!

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K+ sparring diuretics? Name 4 examples

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MECHANISM:

1. Spironolactone
2. Triamterene
3. Amiloride
4. eplerenone.

1. Spironolactone is a competitive aldosterone receptor antagonist in the cortical collecting tubule.

2. Triamterene and amiloride act at the same part of the tubule by blocking Na+ channels in the CCT.

CLINICAL USE:
Hyperaldosteronism, K+ depletion, CHF .

SIDE EFFECTS:

Hyperkalemia (can lead to arrhythmias), endocrine effects with aldosterone antagonists (e.g., spironolactone causes gynecomastia, antiandrogen effects).

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Ace inhibitors?

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1. Captopril
2. enalapril
3. lisinopril.

MECHANISM:

Inhibit angiotensin-converting enzyme, reducing
levels of angiotensin I1 and preventing inactivation of bradykinin, a potent vasodilator. Renin release is increase due to loss of feedback inhibition.

CLINICAL USE:
Hypertension, CHF, diabetic renal disease.

SIDE EFFECTS: Cough, Angioedema, Proteinuria, Taste changes, hypotension, Pregnancy problems (fetalrenal damage), Rash, Increased renin, Lower angiotensin II.Also hyperkalemia.

Avoid with bilateral renal artery stenosis because ACE inhibitors significantly and decrease GFR by preventing constriction of efferent arterioles.

Losartan is an angiotensin I1 receptor antagonist. It is not an ACE inhibitor and does not cause cough!!

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Leuprolide?

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MECHANISM:

GnRH analog with agonist properties when used in pulsatile fashion; antagonist properties when used in continuous fashion.

CLINICAL USE:

Infertility (pulsatile), prostate cancer (continuous- use with flutamide), uterine fibroids.

SIDE EFFECTS":
Antiandrogen, nausea, vomiting.

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Testosterone (methyltestosterone)?

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MECHANISM:
Agonist at androgen receptors.

CLINICAL USE:

Treat hypogonadism and promote development of 2" sex characteristics; stimulation of
anabolism to promote recovery after burn or injury; treat ER-positive breast cancer
(exemestane).

SIDE EFFECTS:

Causes masculinization in females; reduces intratesticular testosterone in males by
inhibiting release of LH (via negative feedback), leading to gonadal atrophy. Premature closure of epiphyseal plates. Increase LDL, HDL.

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Finasteride (Propecia)?

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A 5a-reductase inhibitor (decrease conversion of testosterone to dihydrotestosterone). Useful in BPH. Also promotes hair growth-used to treat male-pattern baldness.

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Estrogens (ethinyl estradiol, DES, mestranol)?

Back 225

MECHANISM:
Bind estrogen receptors.

CLINICAL USE:
Hypogonadism or ovarian failure, menstrual abnormalities, HRT in postmenopausal
women; use in men with androgen-dependent prostate cancer.

SIDE EFFECTS:
Increase risk of endometrial cancer, bleeding in postmenopausal women, clear cell
adenocarcinoma of vagina in females exposed to DES in utero, Increase risk of thrombi.

Contraindications-ER-positive breast cancer, history of DVTs.

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Clomiphene?

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- An Estrogen partial agonists (selective estrogen receptor modulators-SERMs)

MECHANISM:

Partial agonist at estrogen receptors in hypothalamus. Prevents normal feedback inhibition and increase release of LH and FSH from pituitary, which stimulates ovulation. Used to treat infertilityand PCOS. May cause hot flashes, ovarian enlargement, multiple simultaneous pregnancies, and visual disturbances.

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Tamoxifen?

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Estrogen partial agonists (selective estrogen receptor modulators-SERMs)

MECHANISM:

Antagonist on breast tissue; used to treat and prevent recurrence of ER-positive breast cancer.

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Raloxifene?

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Estrogen partial agonists (selective estrogen receptor modulators-SERMs)

Agonist on bone; reduces resorption of bone; used to treat osteoporosis.

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Hormone replacement therapy (HRT)?

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Used for relief or prevention of menopausal symptoms (e.g., hot flashes, vaginal atrophy) and osteoporosis (INCREASE estrogen, & DECREASE osteoclast activity).

Unopposed estrogen replacement therapy (ERT) INCREASE the risk of endometrial cancer, so progesterone is added. Possible INCREASE CV risk.

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Anastrozole/ exemestane?

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Aromatase inhibitors used in postmenopausal women with breast cancer.

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Mifepristone (RU-486)?

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MECHANISM:

Competitive inhibitor of progestins at progesterone receptors.

CLINICAL USE:

Termination of pregnancy. Administered with misoprostol (PGE1).

SIDE EFFECTS:

Heavy bleeding, GI effects (nausea, vomiting, anorexia), abdominal pain.

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Oral contraception (synthetic progestins, estrogen)?

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MECHANISM:

Oral contraceptives prevent estrogen surge, LH surge does not occur and ovulation does not occur.

ADVANTAGES:
1. Reliable (<1% failure)
2. Decrease risk of endometrial and ovarian cancer
3. Decrease incidence of ectopic pregnancy
4. Decrease risk of pelvic infection
5. Regulation of menses

DISADVANTAGES:

1. Taken daily
2. No protection against STDs
3. INCREASE triglycerides
4. Depression, weight gain, nausea, HTN
5. Hypercoagulable state

CONTRAINDICATIONS:

1. Smokers > 35yrs old
2. Pts with history of thromboembolism and stroke or history of estrogen dependent tumor.

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Dinoprostone?

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PGE2 analog causing cervical dilation and uterine contraction, inducing labor.

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Ritodrine/terbutaline?

Back 234

B-2-agonists that relax the uterus; reduce premature uterine contractions.

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Tamsulosin?

Back 235

a1-antagonist used to treat BPH by inhibiting smooth muscle contraction. Selective for receptors found on prostate (alpha 1aD) and vascular (alB) receptors.

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Sildenafil, vardenafil?

Back 236

MECHANISM:

Inhibit cGMP phosphodiesterase, causing INCREASE cGMP, smooth muscle relaxation in the corpus cavernosum, INCREASE blood flow, and penile erection.

CLINICAL USE:
Treatment of erectile dysfunction.


SIDE EFFECTS:
Headache, flushing, dyspepsia, impaired blue-green
color vision. Risk of life-threatening hypotension in patients taking nitrates.


MNEUMONIC:

SildenaFIL and vardenaFIL FILLthe penis.

"Hot and sweaty," but then Headache, Heartburn, Hypotension.

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H1 blockers?

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Reversible inhibitors of Hl histamine receptors.

1ST GENERATION:

1. Diphenhydramine (Benadryl)
2. Dimenhydrinate
3. Chlorpheniramine.

CLINICAL USES: Allergy, motion sickness, sleep aid.
SIDE EFFECTS:

Sedation, antimuscarinic, anti-a-adrenergic.

2ND GENERATION:
1. Loratadine (Claratin)-sedation at high doses
2. Fexofenadine (allergra)-NON SEDATION!
3. Desloratadine
4. Cetirizine (Zyrterc)

CLINCAL USE:

Allergy

SIDE EFFECTS:

Far less sedating than 1st generation because of decrease entry into CNS.

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Theophylline?

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An methylxanthine asthma med.

MECHANISM:
Likely causes bronchodilation by
inhibiting phosphodiesterase, thereby decrease CAMP hydrolysis. Usage is limited because of narrow therapeutic index (cardiotoxicity, neurotoxicity); metabolized by P-450.

Blocks actions of adenosine!

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Ipratropium?

Back 239

short acting competitive blocker of muscarinic receptors, preventing bronchoconstriction.

Also used for COPD.

Titotroprim-long acting

I (short) comes before T (long)

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Bosentan?

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Used to treat pulmonary hypertension. Competitively antagonizes endothelin-l receptors, decreasing pulmonary vascular resistance.

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PHENYTOIN (Dilantin)? What is its pharmacologic complication? Mechanism of action? Side effects?

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This drug was originally developed as a non-sedating analog of phenobarbital. Its primary mechanism is to reduce the spread of seizure discharge from a focus by modulating sodium channels. As said above, it is metabolized by CYP2C9 and 2C19. Remember that this system is saturable and displays non-linear kinetics. This can lead to dramatically increased blood levels at higer doses. This can be different for every individual as there is be a spectrum of isozymes, making phenytoin difficult to dose clinically. It is heavily protein-bound and can be displaced by other protein-binding drugs. Drug levels can also be affected in patients with liver or kidney disease as they may have abnormal protein levels or altered metabolism of the drug. It induces CYP450 enzymes and therefore can alter other drug levels. It has limited solubility and variable bioavailability with relatively slow absorption.

Pharmacologic complications:

Enzyme saturation-at higher doses, the drug saturates the enzyme responsible for its metabolism. This causes a dramatic increase in drug levels in the blood!!


Uses:
1. partial and generalized tonic-clonic seizures
2. status epilepticus

SIDE EFFECTS:

• Nystagmus, diplopia, ataxia, stupor and coma (these are all dose related and can help monitor drug levels)

• Cerebellar syndrome (can result in permanent ataxia in children)

• Skin rash, connective tissue changes


Drug interactions:

• INCREASED by chloramphenicol, dicumarol, cimetidine, disulfarim, isoniazid

• DECREASED by carbamazepine and phenobarbital

• Can INCREASE the metabolism of other AEDs and oral contraceptives

*this is important as phenytoin is also a teratogen

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CARBAMAZEPINE? Mechanism of action? Side effects?

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The main effect of this drug is on sodium channels. It also affects synaptic transmission and other receptors so it is not a perfectly clean drug. It also has limited solubility and slow absorption (4-8 hours). It is not as heavily protein bound as phenytoin, about 75%. It is metabolized to an epoxide by hepatic microsomal enzymes including the CYP450 system. This epoxide has both toxic and efficacious properties. It is an autoinducer and an inducer of other drugs as well. Remember that carbamazepine’s autoinduction gives rise to a sub-linear curve.

PHARMALOGIC COMPLICATION:

Dose and time-dependent metabolism-the drug induces its own metabolism so that the more drug given, the faster it is metabolized. However this takes time, initial levels are normal and drop below what is expected only later!!

Uses:
1. partial and generalized tonic-clonic seizures

SIDE EFFECTS:

• Nausea, headache, dizziness, coma, movement disorders (tics, dystonia)

• Allerigic rashes (more common in asians with certain HLA types-can screen for this)


DRUG INTERACTIONS:

• INCREASED by erythromycin, isoniazid, cimetidine, diltiazem

• DECREASED by phenobarbital and phenytoin

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ETHOSUXIMIDE? Used for what type of seizures? Mechanism of action?

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This drug is the primary treatment for absence seizures. It is well absorbed with little protein binding. It is metabolized primarily in the liver. Ethosuximide’s half life is around 40-50 hours in adults and slightly shorter in children. This drug blocks low threshold T type calcium channels to prevent burst firing in the thalamus. Remember that the thalamus is a kind of gateway in the brain. It has two modes of firing, tonic and bursting. During awake states the thalamus operates in a tonic mode, allowing an input from the periphery to continue as an output to the cortex. During sleep-like states, the thalamus goes into an oscillatory, or bursting mode. This allows neurons that project to the cortex to become hyperpolarized. In order for this to happen, low threshold calcium channels must be activated. In the normal person, this allows a sleep spell. In patients with seizures, this may give rise to an absence seizure.

Use: Absence seizures

Toxicity:

• Dizziness, lethargy and headache

• GI irritation, skin rash and bone marrow suppression

*all these side effects tend to be rare and mild



Quick aside before we begin on the benzodiazepines: Most of the thalamus is covered by a thin shell called the reticular nucleus. This nucleus mainly sends inhibitory GABA outputs to the thalamus. Activating the reticular nucleus can hyperpolarize thalamic neurons going to the cortex thus stimulating the bursting mode discussed above. Using GABA enhancers like benzodiazpines could affect this system in two ways. The reticular nucleus itself could be shut down via its inhibitory interneurons but its inhibition of the thalamus could be increased (confusing, I know-hang in there!). Theoretically, enhancing GABAergic effects could actually throw the thalamus into burst mode. Fortunately this does not happen in reality. There are number of different GABA receptor subtypes and these subtypes can be distributed differently throughout the brain. The alpha 3 channel in particular is found in the reticular nucleus. The benzos, specifically clonazepam, tend to act only on the alpha 3 channels and inhibit the reticular nucleus without having an effect on the thalamus. In conclusion, benzodiazepines also may be effective in some patients with absence.

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BENZODIAZEPINES? Mechanism of action? Side effects? Used for what type of seizures?

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BENZODIAZEPINES (clonazepam and lorazepam)


This class of drugs interacts directly with GABAa receptors to enhance GABA-gated transmission. This is subunit dependent, which allows for very specific effects. Their direct mechanism of action is to increase the number of channel openings. They are metabolized hepatically by the CYP450 system.

Uses:

• Second-line for generalized absence and myoclonic seizures (clonazepam)

• First-line treatment for status epilepticus (lorazepam)


Toxicity:

• Respiratory depression and sedation or drowsiness

• Ataxia, cognitive and behavioral changes

• Can cause a paradoxical increase in seizure frequency

• Withdrawal effects

Drug interactions

• DECREASED by carbamezepine and phenobarbital

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PHENOBARBITAL? Which drug has a similar mechanism of action? Side effects?

Back 245

This drug also enhances GABAergic effects but through a different mechanism that the benzos. It does this by acting as a positive allosteric modulator of GABAa receptors and therefore increasing the length of time the channel stays open (rather than the frequency at which they open). Phenobarbital does have some sodium channel effects as well. This drug is not heavily protein bound and is metabolized by the liver however some of it may be renally excreted. It is an enzyme inducer, has a very long half life with a slow absorption rate.

Uses:

1. partial seizures
2. generalized tonic-clonic seizures
3. status epilepticus
4. withdrawal states


SIDE EFFECTS:

• Drowsiness, ataxi and vertigo in high doses

Drug interactions:

• INCREASED BY valproic acid and phenytoin



RECAP DIFFERENCE BTWN BENZO'S AND PHENOBARBITAL

BENZO'S: Increases the number of times (frequency) the GABA channel opens

PHENOBARBITAL: Increase the amount of time the GABA stays open

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Tiagabine? Mechanism of action? Used for what?

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Tiagabine also enhances GABA effects but in a much less specific way than the previous drugs. It increases GABA levels in the neuropil (the space between neuronal cell bodies that consists of a dense tangle of axon terminals, dendrites and glial cell processes-thank you, Wikipedia) by inhibiting GABA GAT-1 transporter and blocking GABA uptake. This increases the amount of GABA in the synapse.


Uses:

1. partial seizures with or without generalization


SIDE EFFECTS:

• Confusion, sedation and dizziness

Drug interactions:

DECREASED by carbamazepine, phenytoin and phenobarbital


VS

VIGABATRIN: This is the only AED that is a selective, irreversible inhibitor of GABA transaminase, the enzyme responsible for GABA breakdown. This increases the pools of GABA available to be released from the nerve terminals leading to higher GABA levels to activate extrasynaptic GABAa receptors. This does not discriminate between cells that are actively releasing GABA or not whereas Tiagabine does (this may lead to differences in how the two drugs act but Dr. Balish did not elaborate).

Uses:
1. infantile spasms and partial seizures (only in the most refractory of patients due to side effects)

Side effects:

Sedation and fatigue are most common Psychosis and depression Approved in 2010 but with concerns regarding visual function!

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The only AED that is a selective, irreversible inhibitor of GABA transaminase, the enzyme responsible for GABA breakdown?

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VIGABATRIN: This is the only AED that is a selective, irreversible inhibitor of GABA transaminase, the enzyme responsible for GABA breakdown. This increases the pools of GABA available to be released from the nerve terminals leading to higher GABA levels to activate extrasynaptic GABAa receptors. This does not discriminate between cells that are actively releasing GABA or not whereas Tiagabine does (this may lead to differences in how the two drugs act but Dr. Balish did not elaborate).

Uses:
1. infantile spasms and partial seizures (only in the most refractory of patients due to side effects)

Side effects:

Sedation and fatigue are most common Psychosis and depression Approved in 2010 but with concerns regarding visual function!

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This drug acts by binding the synaptic vesicle protein 2 (SV2) in the presynaptic terminal, which mediates neurotransmitter uptake into vesicles. This allows for certain neurotransmitters to be released or to be more present in the synaptic region?

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LEVITERACETAM (Keppra)

This drug acts by binding the synaptic vesicle protein 2 (SV2) in the presynaptic terminal, which mediates neurotransmitter uptake into vesicles. This allows for certain neurotransmitters to be released or to be more present in the synaptic region. This drug has linear kinetics and metabolism takes place in the kidneys, which avoids many of the side effects associated with liver metabolism.

Uses: myoclonic, partial or tonic clonic seizures in children or adults


Toxicity:

• Psychosis, hyperactivity or aggression
(This could be due to the drug increasing testosterone release)

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VALPROIC ACID? Side effects?

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This durg has multiple mechanisms including blocking high frequency firing of sodium channels, augmenting the GABA synthesizing enzyme GAD, and restricting GABA transaminase. It also acts to block T type calcium channels, but not as strongly as ethosuximide. It is heavily protein bound and exhibits sublinear kinetics due to its saturable binding.Valproic acid is rapidly and completely absorbed and then metabolized through mutiple pathways resulting in several metabolites. It inhibits CYP2C.


Uses: partial, generalized tonic clonic, absence and myclonic seizures

Toxicity:

• Sedation, ataxia, tremor

• Alopecia, weight gain

• Cognitive slowing, dyskinesias

• Teratogenic (causes neural tube defects)

• Developmental delay in offspring

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Oligomyin?

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ATPase inhibitor
-Directly inhibits mitochondrial ATPase causing increase in protein gradient. No ATP is produced b/c electron transport stops