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Pharmacotherapeutics I > Drugs for Final > Flashcards

Flashcards in Drugs for Final Deck (278):
1

Methyldopa

Can initiate an autoimmune reaction
Blood pressure medication that is an alpha receptor drug and is used to tx HTN.
Causes hemolytic anemia-destruction of the RBC.
Monitor H&H and CBC

2

Hydralazine

Can initiate an autoimmune reaction
Lupus like syndrome
Notify and follow up

3

Isoniazid

Can initiate an autoimmune reaction
Lupus like syndrome
Notify and follow up

4

Procainamide

Can initiate an autoimmune reaction
Lupus like syndrome
Notify and follow up

5

Barbituates

Can cause a skin rash stevens-johnson in toxicity

6

Sulfonamides

Can cause a skin rash stevens-johnson in toxicity

7

Phenytoin

Can cause a skin rash stevens-johnson in toxicity

8

Carbamazepine

Can cause a skin rash stevens-johnson in toxicity

9

Allopurinal

Can cause a skin rash stevens-johnson in toxicity

10

NSAIDs

Can cause a skin rash stevens-johnson in toxicity

11

Penicillins

Can cause a skin rash stevens-johnson in toxicity

12

Gentamicin

Progressive renal failure- renal tubular injury reversible upon cessation

13

Amphotericin B

Progressive renal failure- high frequency of injury because mechanism for efficacy is shared by the mechanism responsible for toxicity

14

Contrast-Media

Progressive renal failure- dose related nephrotoxicity

15

Doxorubicin

Cardiovascular toxicity
Leads to production of reactive oxygen species

16

Bleomycin

Can result in pulmonary toxicity by pulmonary fibrosis

17

Amiodarone

Can result in pulmonary toxicity by pulmonary fibrosis

18

Vancomycin

Causes red-man syndrome
Flushing, pruritis, chest pain, muscle spasm, and hypotension during vancomycin infusion.
Pretreatment w/ IV antihistamines attenuates the sx of red-man syndrome.

19

Cromolyn

Blocks the release of histamine from mast cells.
Inhaled as a powder.
Stabalized mast cells preventing noncytolytic degranulation.
Decreases sx of allergic rhinitis
Prophylactic use to block asthmatic rxns but not useful in managing acute asthmatic attacks.
Poorly absorbed- with few adverse effects (irritation/taste)
Effective only if used BEFORE a challenge

20

Nedocromil

Blocks the release of histamine from mast cells.
Inhaled as a powder.
Stabalized mast cells preventing noncytolytic degranulation.
Decreases sx of allergic rhinitis
Prophylactic use to block asthmatic rxns but not useful in managing acute asthmatic attacks.
Poorly absorbed- with few adverse effects (irritation/taste)
Effective only if used BEFORE a challenge

21

Trirolidine, DIPHENHYDRAMINE (benydryl), PROMETHAZINE, HYDROXYZINE, chlorpheniramine

Histamine H1 receptor blockers
1st generation drugs that are widely used, effective and inexpensive.

22

Loratadine (claritin OTC), desloratadine (clarinex), azelastine (astelin), cetirizine (Zyrtec OTC), fexofenadine (allegra, OTC)

Less CNS toxicity or side effects compared to first generations since they do not cross the blood brain barrier or are excluded by p-glycoprotein (cause less drowsiness.

23

H1 blockers- active metabolites of the 2nd generation compounds are used therapeutically

Loratadine (Claritin) to desloratadine (clarinex)
terfenadine (seldane) to fexofenadine (Allegra)

24

Terfenadine (Seldane)- process

Terfenadine undergoes first-pass metabolism to fexofenadine.
Terfenadine blocks potassium channels in myocardium, which causes a prolonged QT interval and increases the risk of ventricular tachyarrhythmias. (torsades de pointes)

25

Terfenadine (Seldane)

Active metabolites of the 2nd generation compound that is used therapeutically is fexofenadine (allergra)

26

Loratadine (Claritin)

Active metabolites of the 2nd generation compound that is used therapeutically is desloratadine (clarinex)

27

Promethazine

The most effective antihistamine used to treat motion sickness.
Administered 1 hr before the anticipated motion.
Prevention of nausea and vomiting by blockage of dopamine D2 receptors

28

Phenothiazine class

Promethazine and timeprazine
Blockade of dopamine D2 receptors to prevent nausea and vomiting

29

Diphenhydramine

OTC tx of hyposomnia
Antimuscarinic actions

30

Magic Mouthwash

Formulated from prescription
Used to treat oral ulcers, infections, inflammation, pain
Contains diphenhydramine

31

Syrup of Ipecac

Onset 15-20 minutes
95% vomit in 20 mins, 30% reduction in bioavailability at 1 hour
Side effects- acute- diarrhea, drowsiness, chronic- cardiac arrhythmia's, neuropathy, muscle weakness.

32

cathartics

activated charchol
Promote movement of AC bound drug through GI tract, may cause hypovolemia and electrolyte imbalance

33

Activated Charcol

Absorbant 1gm/kg
Will NOT bind- low molecular weight, charge compounds; cyanide, bromide, potassium, ethanol, methanol, iron, lithium, alkaline corrosives, mineral acids, highly concentrated solutions such as gasoline, kerosene, and ETOH
Efficacy 40% reduced bioavailability at 1 hour
ADR- Vomiting, constipation, aspiration, GI obstruction, charcoal empyema, GI perforation.

34

Golytely

Used in whole bowel irrigation
Used prior to colonoscopy.

35

Dimercaprol (BAL)

Chelator used for metal poisonings because they bind to metal
uses for As, Hg, Pb, Cd and toxicities include HTN and tachycardia

36

Penicillamine

Chelator used for metal poisonings because they bind to metal
uses for Cu, Pb, Hg, As, toxicities include allergic rxns

37

DSMA (succimer)

Chelator used for metal poisonings because they bind to metal
used for Pb, As, Hg, toxicities include Gas and ABD pain

38

Edetate calcium disodium (EDTA)

Chelator used for metal poisonings because they bind to metal
used for Pb and toxicities include nephrotoxicity

39

Deferoxamine

Chelator used for metal poisonings because they bind to metal
used for Fe, toxicities include hypotension, anaphyactoid rxn and ARDS

40

Crotalidae Antivenin

Antivenins/biologics
rattle snake envenomation

41

Lactrodectus Antivenin

Antivenins/biologics
black widow spider envenomation

42

Elapidae Antivenin

Antivenins/biologics
eastern and texas coral snake envenomation

43

Trivalent botulinum

Antivenins/biologics
botulisms type A, B, and E

44

Digoxin immune fab

Antivenins/biologics
digoxin and digitoxin

45

N-acetylcysteine

Pharmacologic Antagonists
poisoning is acetaminophen and mechanism is prevents NAPQI binding at hepatocyte.

46

Naloxone

Pharmacologic Antagonists
poisoning is opioids and mechanisms is opioid receptor antagonist

47

Flumazenil

Pharmacologic Antagonists
poisoning is benzodiazepines and mechanism is benzodiazepine receptor antagonist

48

Atropine

Pharmacologic Antagonists
poisoning is organophosphates and pesticides and mechanism is muscarinic receptor antagonist

49

Fomepizole

Pharmacologic Antagonists
poisoning is methanol and ethylene glycol and mechanism is blocks metabolite formation.

50

Defuroxamine

Metal antidote for iron

51

Deferasirox

Metal antidote for iron
Oral option

52

Penicillamine

Metal Antidote for copper

53

Trientine

Metal antidote for copper

54

Parathion

Pesticide
Organophosphate
Acetylcholinesterase inhibitors producing muscarinic and nicotinic toxicity

55

Malathion

Pesticide
Organophosphate
Acetylcholinesterase inhibitors producing muscarinic and nicotinic toxicity

56

Diazinon

Pesticide
Organophosphate
Acetylcholinesterase inhibitors producing muscarinic and nicotinic toxicity

57

Atropine

Pesticide treatment
Muscarinic antagonist

58

Pralidoxime

Pesticide treatment
Regenerated ACHE

59

Classifications of ABX- Agents that inhibit cell wall synthesis

Penicillins
Cephalosporins
Cycloserine
Vancomycin
Bacitracin

60

Classifications of ABX- Agents that act directly on the cell membrane of the microorganism affecting permeability and leading to leakage of intracellular compounds

Detergents
- polymyxin

61

Classifications of ABX- Agents that interfere with protein synthesis by interaction with bacterial ribosomes

Chloramphenicol
Tertracyclines
Macrolides
Clindamycin
Streptogramins
Ketolides

62

Classifications of ABX- Agents that interfere with protein synthesis by blocking initiation

Oxazolidinoses (linezolid)

63

Classifications of ABX- Agents that interfere with protein synthesis by inhibition of tRNA synthesis

Mupirocin

64

Classifications of ABX- Agents that interfere with protein synthesis by multiple mechanisms leading to disruption of RNA processing

Aminoglycosides

65

Classifications of ABX- Agents that inhibit DNA processing by

Inhibition of DNA topoisonerases
Quinolones
Inhibition of DNA-dependent RNA polymerase (Directly-rifampin and indirectly- nitrofurantoin)

66

Classifications of ABX- The antimetabolites- blocking bacterial folic acid pathway

Trimethoprim
Sulfonamides

67

Methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacteria tuberculosis

Multiple drug-resistance bacteria

68

Beta Lactam Compounds

Penicillins
Cephalosporins
Cabapenems
Monobactams
Beta lactamase inhibitors

69

Beta Lactam Compounds- Penicillins

Natural penicillin
Aminopenicillins
Penicillinase Resistanct Penicillins
Extended spectrum penicillins (Anti-psuedomonal)

70

Beta Lactam Compounds- Cephalosporin

First generation- fifth generation

71

Penicillins Mechanism of Action

Interfere with the last step in bacterial cell wall growth
Works best on rapidly proliferating organisms
No effect on organisms without a cell wall (protozoa, mycoplasma, mycobacteria, fungi, and viruses)

72

Penicillin resistance

Inactivated by beta-lactamase
Modification of PBP target (mechanisms of MRSA and penicillin resistant to pneumococci)
Impaired penetration of drug to target PBP

73

Penicillin classification- Natural Penicillins

Penicilling G or V
Narrow spectrum, PCN G acid labile, penicillinase sensitive.
Highly active against sensitive stains of gram positive cocci (Not staphylococcus)
Anaerobes
Some gram negative

74

Penicillin G or V

Tx infections of upper and lower respiratory tract, throat, skin, and GU tract.
Prophylaxis in rheumatic fever, dental procedure for those at risk of endocarditis, gonorrhea or syphilis expose.

75

Penicillin G or V- gram positive cocci

Streptococcus, enterococcus faecalis, listeria morlocytogenes

76

Penicillin G or V- Anaerobes

Bacteroides species and fusebacterium species

77

Penicillin G or V- gram negative

E. coli, H. influenzae, N. gonorrhoeae, Treponema be, and suspectible psuedomonas species.

78

Amniopenicillins

Ampicillin and amoxicillin

79

Ampicillin and Amoxicillin

Activity of PCN G plus improved coverage of gram negative cocci adn Enterobacteriaceae
Not active against treponema or actinomyces

80

Ampicillin and Amoxicillin- therapeutic uses

URI (Otitis, sinusitis), uncomplicated UTI, meningitis, salmonella infections

81

Ampicillin and amoxicillin- resistance leading to combinatins with beta-lactamase inhibitors

Augmentin = Amoxicillin + Clavulanic acid
Ampicillin + sulbactam (unasyn)
Better coverage against H. Influenzae and Klebsiella sp.

82

Penicillinase-Resistance Penicillins (antistaphylococcal penicillins)

Nafcillin, oxacillin, dicloxacillin
Methicillin and cloxacillin no longer available in US
Penicillinase resistance, narrow spectrum
Staph resistant to this class is called MRSA

83

Penicillinase-Resistance Penicillins (antistaphylococcal penicillins)- tx

Used in treatment of staphylococcal infection with high beta-lactamase production (cellulitis and endocarditis)
Not active against gram-negative or anaerobic organisms

84

Antipseudomonal penicillins

Piperacillin, ticarcillin, carbenicillin (PO)
Maintains activity of PCN G but gain great gram negative coverage including psuedomonas
Coverage against H. influenzae and kelbsiella sp
No coverage against treponema palladium or actinomyces
Gram negative infections in combo with aminoglycosides (bacteremias, pneumonias, resistant UTIs, infections in burn patients)

85

Antipseudomonal penicillins- resistance issues and are paired with beta-lactamase inhibitors

Piperacillin + tazobactam = zosyn
Ticarcillin + clavulanic acid= timentin

86

Beta-lactamase inhibitors

Clavulanic acid, sulbactam, tazobactam
Structurally similar but lack antibacterial activity
Act as suicide inhibitors -> potent, irreversible inhibitors of many lactamases.
Extends the spectrum of the ABX its paired with

87

Addition of Beta-lacamase inhibitors- Aminopenicillins

Amoxicillin + clavulanic acid (augementen)
Ampicillin + sulbactam (unasyn)

88

Addition of Beta-lacamase inhibitors- Antipseudomonal penicillins

Piperacillin + tazobactam (Zosyn)

89

Addition of Beta-lacamase inhibitors

Increased coverage against H. flu, staph, moraxella catarrhailis
Variable coverage against gram (-) bacteria- pseudomonas, enterobacter, E. coli, klebsiella, serratia due to resistance to these beta-lactamase inhibitors.

90

Penicillin pharmacokinetics-absorption

Many cannot be administered orally (due to destruction in acid)
Food may decrease the absorption of available oral penicillins
IV route bypasses absorption considerations and is preferred for serious infections.

91

Penicillin pharmacokinetics- Distribution

Widely distributed with tissue level=to serum
Poorly penetrate the eyes, CNS, and prostate
ONLY PENETRATE THE CNS WHEN MENINGES ARE INFLAMED.

92

Penicillin pharmacokinetics- metabolism

Most penicillins are not metabolized by dependent on the kidney for elimination

93

Penicillin pharmacokinetics- elimination

Kidney excretion is the main route of elimination (except antipseudomonal PCN and nafcillin via billiary excretion)
Penicillins are filtered (10%) and actively secreted (90%) into the urine
Active secretion can be blocked by probenecid
Doses need to be adjusted in renal insufficiency

94

Penicillins Adverse Effects

Hypersensitivity
Allergic responses develop in respinse to beta-lactam ring and derivatives (Cross rxn)
Anaphylactic shock is rare
Serum sickness- urticaria, rash, fever, angioedema
Interstitial nephritis and hemolytic anemia
Desensitization protocols are available.

95

Penicillins adverse effects

GI upset with oral agents
Diarrhea
Secondary infections- vaginal candidiasis
Hepatitis w/ oxacillin
Neutropenia w/ nafcillin
Abnormal platelet aggregation with ticarcillin and carbenicillin

96

Cephalosporins Intro

Discovered 1948 by Guisepee Brotzu
Similar to penicillins chemically, MOA, and toxicity
Bactericidal
Inhibit bacterial-cell wall synthesis similar to PCNS
Structurally contain a dihydrothiazine ring connected to the B-lactam ring making them more resistant to hydrolysis by B-lactamase (Broader spectrum of activity)
Classified by 5 generations
Category B in pregnancy

97

Cephalosporin Resistance

Mutations or carried on plasmids
Mutations in PBP
Production of Beta-lactamases
Alteration in cell-membrane porins in gram negative bacteria

98

1st Generation Cephalosporins Spectrum

Good aerobic gram-positive, above the diaphragm anaerobes and community acquired gram negative coverage.
Stable against staph produced penicillinase
IV= Cefazolin (Ancef)
PO= Cephalexin (keflex)

99

1st Generation Cephalosporins - Use

Used for septic arthritis in adults, skin infections, acute otitis media, prophylaxis for clean surgeries, and gram (+) infections in pts that cannot take penicillin

100

2nd Generation Cephalosporins- Spectrum

Two classes w/in second generation
Added gram (-) coverage (ie moraxella, neisseria, salmonella, shigella, haemophilus influenzae)
IV and PO= cefuroxime (zinacef, ceftin)
Added anaerobic coverage (especially B. Fragilis)
IV= cefotetan (cefotan)

101

2nd Generation Cephalosporins- Use

Added gram (-)
IV and PO= cefuroxime (zinacef, ceftin)
Useful for sinusitis, otitis, CAP
Added anaerobic coverage
IV- cefotetan (cefotan)
Useful for tx of abd and gynecological infections

102

Summary of 2nd generation cephalosporins

Gram (+): 2nd generation < 1st generation (somewhat)
Gram (-): 2nd generation > 1st generation (Significantly)

103

3rd Generation Cephalosporins- Spectrum

Expanded gram-negative coverage and penetration of BBB
Cefpodoximine (Vantin), cefdinir (omnicef), cefixime (suprax)=oral
Cefotaxime (claforan)
Ceftriaxone (rocephin) = IV and IM
Ceftazidime (fortaz) distinguishes itself w/ increased anti-pseudomonal

104

3rd Generation Cephalosporins- clinical use

Used to tx a wide variety of serious infections caused by organism that may be resistant to other antimicrobial agents
Drugs of first choice in tx of meningitis, pneumonia in children and adults, sepsis, peritonitis
Tx of UTI, skin infections, and oesteomyelitis, Neisseria gonorrhea infections

105

Summary of 3rd generations cephalosporins

Gram (+): 1st generations > 2nd generation or 3rd generation
Gram (-): 3rd generation= 2nd generation > 1st generation

106

4th Generation Cephalosporins- Spectrum

Cefepime (maxipime) IM/IV
Good activity against both gram(+) and gram (-) bacteria; ALSO ANAEROBIC COVERAGE

107

4th Generation Cephalosporins- coverage

P. aeruginosa, H. influenzae, N. meningitidis, N. gonorrhoeae
Enterobacteriasceae that are resistant to other cephalosporins

108

4th Generation Cephalosporins- clinical use

Intra-abdominal infections, respiratory tract infections, skin infections

109

Summary of 4th generation cephalosporins

Improved gram (+) compared to 2nd and 3rd generations (Closer to 1st generation)
Retain gram (-) = or > 2nd and 3rd generations

110

5th Generation Cephalosporin

Ceftobiprole medocaril
Approved March 2008
Tx of complicated skin and skin structure infections (MRSA)
Inhibits PBPs involved in cell wall synthesis
Well tolerated-nausea and taste disturbances
IV form only

111

Cephalosporins Pharmacokinetics

Orally administered absorbed rapidly
Presence of food may increase, decrease, or not affect absorption
Extensive distribution (most don't cross CSF except cefuroxime, cefotaxime, ceftriaxone, cefepime)
Most eliminated via kidneys

112

Cephalosporins toxicities/ side effects

Hypersensitivity same spectrum as PCN
Structure is structurally different allowing use in PCN allergy pts
5-10% cross sensitivity
Pts w/ anaphylaxis or angioedema with PCN should not recive
Suprainfection- resistant organism and fungi may proliferate.

113

Cephalosporins toxicities/ side effects (2)

GI upset- N/V/D
1-3% allergic rxn - rash, fever, eosinophilia, urticaria
Cholelithiasis
Blood dyscrasias- eosinophilia, thrombocytopenia, leukopenia
Methylthiotetrazole side chains

114

Cephalosporin drug interactions

Increased serum levels if co-administered with probencecid
Increased effects of warfarin- cefotetan, cefazollin, cefoxitin, ceftriaxone

115

Carbapenems (the most broad spectrum)

Resistant to many beta-lactamases, most broad spectrum of beta-lactam class of ABX (gram + and gram - coverage)
Ertapenem (Ivanz), and imipenem-cilastin (primaxin)
Meropenem (merrem)

116

Carbapenems- Ertapenem (Ivanz), and imipenem-cilastin (primaxin)

Coverage included resistant gram (-) bacilli (P. aeruginosa), gram (+) bacteria (MRSA, enterococcus), and anaerobes (bacteroides)
Tx of UTI, pneumonia, intra-abdominal infections, skin and soft tissue infections

117

Carbapenems- meropenem (Merrem)

Greater activity against gram-negative
Intra-abdominal infections
Meningitis > 3 mo. of age

118

Carbapenems- Pharmacokinetics

Given parenterally-> unstable in stomach acid
Cilastin inhibits dehydropeptidase I which inhibits imipenem by breaking beta-lactam ring
Well distributed in the body
Renal excretion

119

Carbapenems- toxicities

Well tolerated- N/V, phlebitis at infusion site, leukopenia, elevated LFTs
Seizures in pts w/ renal failure
High degree of cross-sensitivity with PCN

120

Carbapenems- Drug interactions

Ertapenem cant be infused w/ dextrose or other medications
Meropenem reduces valproic acid levels
Meropenem and ertapenem category B- safe
Imipenem/cilatin category C- not removed from option when considering risk vs. benefit

121

Monobactams

Aztreonam (Azactam) the only monbactam available in the US
Spectrum of activity is purely gram-negative rods (inihibits mucopeptide synthesis in cell wall by binding to PBP, resistant to most beta lactamases)
No cross reactivity with PCN or cephalosporin allergic pts

122

Monobactams- pharmacokinetics

Tx of gram (-) infections- pneumonia, soft-tissue infections, UTI, intra-abdominal and pelvis infections
Acid Labile
Widely distributed including inflames meningeal tissue
Excreted in urine unchanged

123

Monobactams- Toxicity

No major toxicity- rash, N/V, elevated LFT, transient eosinophilia
No reported drug interations
Special populations- category B in pregnancy and safe in kids over 9 mo.

124

Cycloserine

Inhibition that ultimately disrupts assembly of cell wall synthesis.
HIghly susceptible to resistance

125

Cycloserine- indications

restricted for use as a secondary anti-tubercular drug

126

Cycloserine- ADRs- very toxic

CNS toxicity-reversible w/pyridoxine
Renal impairment will accelerate toxicity

127

Vancomycin Mechanism and Spectrum

Acts on diff binding site than beta-lactamase but has the same effect on cell wall synthesis.
Bactericidal

128

Vancomycin Mechanism and Spectrum- mechanism of resistance

Acquired (plasmid born)- VanA phenotypes. A component of the peptidoglycan has modified so that vancomycin can not bind.
Innate resistance- most gram negatives-outer membrane resistance penetration

129

Vancomycin

Active against gram positive organisms only.
Including beta-lactamase producing varieties
Reserved for pts allergic to B-lactams with serious gram (+) infections, infections resulting from MRSA, and used in antibiotic associated enterocolitis.

130

Vancomycin Pharmacokinetics

Not absorbed when given orally and used orally in tx of C. Diff.
Given IV to maintain levels in a range that enhances outcome and avoids toxicity.
Widely distributed including CNS when meninges are inflamed.
Not metabolized by 90% renally excreted

131

Vancomycin clinical use

Main indication for parenteral vancomycin is for methicillin resistant staph aureus or staph epu
Used for penicillin resistant pnemococcus pneumonia

132

Vancomycin-adverse effects

Local and infusion related reactions- red man syndrome (very flushed, hot, and itchy); phlebitis
Ototoxicity- irreversible hearing damage
Nephrotoxicity- reversible damage to the kidneys

133

Bacitracin-MOA

Polypeptide compound
Interferes w/ recycling steps of the phospholipid carrier of petidoglycan synthesis
Not a very specific target (membrane lipid)

134

Bacitracin- clinical use

Very nephrotoxic, so limited to topical use
Most gram (+) cocci and bacilli are sensitive
Often combined with neomycin or polymyxin or both

135

Aminoglycosides- spectrum of activity

Active against aerobic gram-negative bacilli (klebsiella species, enterobacter, psudeomonas aeruginosa)
Little activity against anaerobes due to lack of stability
Tx- UTI, respiratory tract, skin and soft-tissue infections

136

Aminoglycosides- combination w/ other agents

To broaden coverage in serious illness (bacteremia or sepsis and psuedomonal infections)
For synergism w/ vancomycin or penicillins in the tx of endocarditis

137

Aminoglycosides- spectrum of activity

Exhibit concentration-dependent killing and have a pronounced post-antibiotic effect

138

Aminoglycosides- streptomycin

Useful in treating enterococcal infections

139

Aminoglycosides- gentamicin, tobramycin, amikacin

Most widely used Aminoglycosides.
Cross-resistance b/w these drugs

140

Aminoglycosides- Neomycin, kanamycin

Limited to oral or topical due to neprhotoxicity

141

Aminoglycosides-Spectinomycin

Structurally related to Aminoglycosides but lack amino sugars and glycosidic bonds. Used to tx for gonorrhea in PCN allergy patients.

142

Aminoglycosides- Adverse Effects

otoxicity- may be irreversible (sterptomycin is the most ototocix; not reported w/ genatamicin)
Nephrotoxicity- usually reversible

143

Aminoglycosides- Adverse Effects Neuromuscular blockage

Aggravate muscle weakness; respiratory paralysis in myasthenia gravis or Parkinson's disease due to curare-like effect

144

Aminoglycosides- hypersensitivity

Hypersensitivity rxn not common (rash, fever, urticaria, angioneurotic, edema, eosinophilia)

145

Aminoglycosides- Rare reactions

Optic nerve dysfunction, peripheral neuritis, encephalopathy, pancytopeniam exfoliative, dermatitis, amblyopia

146

Aminoglycosides- Adverse Effects tobramycin

Bronchospam and hoarseness with inhalation solution

147

Aminoglycosides- streptomycin

Contains metabisulfits avoid in sulfite allergies.

148

Aminoglycosides Phamacokinetics

No oral absportion (parenteral administration)
Widley distributed in ECF
Insoluble in lipid
Poor distribution in bile, aqueous humor, bronchial secretions, sputum, CSF
Clearance is proportional to creatinine clearance.

149

Gentamicin Dosing Strategies

Once daily dosing- Recommended for most clinical situations. Exclusion of Gram (+) infections, CrCl<30 ml/min, CF, spinal cord infections and burn patients
Multiple daily dosing- smaller amounts more times a day

150

Aminoglycoside drug interactions

Increased nephrotoxicity w/ loop diuretics
Respiratory depression when given w/ non-depolarizing muscle relaxants
Neomycin effects digoxin levels

151

Tetracyclines- Semisynthetic

Tetracycline
Doxycycline
Minocycline

152

Tetracycline- broad spectrum

Gram (+), gram (-), aerobic and anaerobes.
Mycoplasma pneumoniae. chlamydia, rickettsia, borrelia burgdorferi, inflammatory acne, sinusitis, inhalation anthrax,
Concern for opportunistic infections

153

Tetracyclines- 3 groups based on PK traits

Short acting- Oxytertracycline, tertracycline (frequent dosing needed)
Intermediate acting- demeclocycline (Tx of SIADH)
Long acting- doxycycline and minocycline (BID dosing)

154

MOA of tetracycline

Inhibit protein synthesis by reversibly binding to the 30 S subunit of RNA

155

Tetracycline resistance

Bacterial efflux pump is the most important mechanism
Mutations that prevent entrance of TCN into the cell cause resistance.

156

Tetracyclones ROA and ADRs

Oral, parenteral, and ophthalmic
GI- N/V/D most common, Modified GI flora can develop candidiasis C diff
Bony-structures and teeth- binds to newly formed/forming bones and teeth
Photosensitization
Vestibular rxns- dizziness, vertigo
Pseudotumor cerbri
Lupus like rxn

157

Tertracyclines- pharmacokinetics

Absorption- Incomplete absorption from GI, impaired further by concurrent ingestion (Dairy, aluminum, Ca2+, Mg2+, iron, zinc, bimuth subsalicylates)
Distribution- throughout the body including meninges, accumulation in the liver, spleen, bone marrow, bone, and enamel of unerupted teeth
Elimination- mostly kidneys (except doxycycline through hepatic)

158

3rd Generation TCN- Tigecycline (tygacil)

Broad spectrum antimicrobial activity including MRSA
Indicated for tx of complicated intra-abdominal infections and complicated skin and skin structure infections in adults
Develped to overcome bacterial resistance mechanisms to TCNs

159

Chloramphenicol

50S inhibitor
Broad spectrum- gram (+), gram (-)
Due to blood dyscrasias it is reserved for life threatening infections such as typhoid fever, RMSF, and meningitis in pts allergic to PCN

160

Chloramphenicol- MOA

Both bactericidal and bacteriostatic depending on bacterial species
Reversibly binds 50S inhibiting formation of peptide bonds
Inhibits mitochondrial protein synthesis in mammalian cells
Broad tissue distribution, CNS and CSF.

161

Chloramphenicol- contraindications

very limited use- never in neonates or pregnant women

162

Chloramphenicol-ADRs

Myelosuppression
Reversible anemia
Neutropenia and thrombocytopenia
Gray baby syndrome in neonates (pallor, abd distention, vomiting, and collapse)

163

Macrolides

50S inhibitors
Erythromycin
Semisynthetic derivatives:
Clarithromycin and Azithromycin

164

Macrolides- MOA

Inihibit protein synthesis by binding to 50 S ribosomal unit, blocking translocation and preventing peptide elongation
Bacteriostatic; at high concentrations or with rapid bacterial growth -> bactericidal

165

Macrolides- spectrum of activity

Erythromycin is effective against most gram (+) bacteria and spirochetes (Legionella pneumophila, N gonorrhoeae, N meningitidis) poor anaerobic coverage
Clarithromycin- active against gram (+) and anaerobic bacteria (H. influenzae, H. pylori, mycobacterium avium)
Azithromycin- as above with anaerobic coverage.

166

Macrolides-resistance

H. Influenzae resistant to erythromycin alone, susceptible in combo with sulfonamide
Resistance is usually plasmid mediated.

167

Erythromycin Pharmacokinetics

Erythromycin base is destroyed by stomach acid and must be administered as enteric coated tablet or capsule.
Widely distributed including prostate and macrophages
Available PO, IV, and ophthalmic
Erythro, azithro excreted unchanged in bile
Clarithromycin excreted unchanged in bile and urine

168

Erythromycin Adverse Effects

GI- N/V/D and cramps, binds to motilin reveptor and increased peristalsis
Cholestatic jaundice (most common with estolate salt form)
CV- concern w/ macrolide ABX IV
Ventricular arryhtmias (Erythro), palpitations, CP, Dizziness, HA, IV- QT prolongation

169

Semisynthetic Macrolides- Clarithromycin (Biaxin)

Spectrum of activity = to erythromycin + enhanced coverage of atypical mycobacteria.
Less GI upset and BID dosing
ADRs- N/D, abnormal taste, dyspepsia, HA, tooth discoloration, transient anxiety and behavioral changes

170

Semisynthetic Macrolides- Azithromycin (Zithromax)

Spectrum of activity- atypical mycobacterial and heamophilus influenza coverage
Great tissue penetration and pronlonged intracellular 1/2 life
Angioedema

171

Macrolide Drug Interactions

Extensive
Erythro and clarithromycin= CYP3A4 substrates and inhibitors (erythro and clarithromycin are contraindicated w/ current use of cisapride. many interactions that increase/decrease effect- statins, ergots, dixogin, cabamezepine, warfarin)
Azithromycin NOT metabolized by CYP3A4

172

Ketolides

New gen of macrolide ABX
Semi-synthetic derivative of erythromycin
Higher binding affinity to 50S subunit
DIsplays greater potency against gram (+) organisms
Displays activity against macrolide-resistant strains

173

Telithromycin (Ketek)

Tx of respiratory tract infects in 2004
Tx of CAP, sinusitis, bronchitis
Feb 2007 dropped chronic bronchitis and sinusitis
2006 black box linked to liver failure and death

174

Telithromycin (Ketek)

Hepatic metabolism w/ elimination in bile and urine
ADRs- N/D, HA, Dizziness, V, reversible LFT elevation, hepatitis, reversible blurred vision, diplopia, exacerbation of myasthenia gravis, and QT prolongation

175

Lincosamides: Clindamycin (cleocin)

Inhibits protein synthesis
Spectrum of activity- gram (+)- strep, staph, pneumococci, anaerobes = gram (+) and (-) except C diff

176

Clindamycin (cleocin)- clinical uses

Tx of anaerobic or mixed (polymicrobial infections)
Perforated viscus, infections of the female GU tract, decubitis, venous stasis, or arterial insufficiencyulcers
Aspiration pneumonia
Mild inflammatory acne- topical

177

Clindamycin (cleocin)- Adverse effects

Gi-N/V/D
Hepatotoxicity
Neutropenia
Most common ABx to cause Clostridium difficile toxin mediated to diarrhea

178

Streptogramins: Quinupristin Dalfopristin (Synercid)

Inhibit protein synthesis
Bacteriostatic
Indications- life threatening infections associated with VRE bactermia
Tx of complicated skin/structure infections by Methicillin-suspeptible S aureus or S. pyrogenes

179

Quinupristin Dalfopristin (Synercid)

P450 3A4 inhibitor (nifedipine, cyclosporin drug interactions)
IV only, limited tissue distribution, metabolized in the liver to active metabolites

180

Quinupristin Dalfopristin (Synercid) ADRS

Phelbitis, arthralgias, myalgias, hyperbilirubinemia

181

Ozazolidinones: Linezolid (Zyvox)- indications

Vanco-resistant enterococcus faecium (VRE), nosocomial pneumonia due to S aureus including MRSA or S. pneumoniae; complicated/uncomplicated skin/structure infections; gram (+) CAP

182

Ozazolidinones: Linezolid (Zyvox)- MOA

Prevents function of initiation complex
Mechanism distinct from other 50S ribosomal inhibitors -> active bacteria that is resistant to other protein synthesis inhibitors.

183

Linezolid

Bacteriostatic against enterococci and staph; bactericidal against strept
Oral and IV preps available
Metabolized by non-P450 enzymes, excreted in urine

184

Linezolid- ADRs

GI, HA, thrombocytopenia, linezolid=MAOI-> HTN if used with adrenergic and serotonergic drugs

185

Sulfandomides

Susceptible microorganisms require extracellular PBA to form dihydrofolic acid required for pruine synthesis.
Structural analogs of PABA and competitively inhibit the`enzyme dihydropteroate synthase.
Bacteriostatic against gram (+) and gram (-) bacertia

186

Three major groups of Sulfanomides

Oral absorbable, oral nonabsorbable, and topical agents.

187

Sulfanomides- oral absorbables

Sulfanomides- oral absorbables

188

Sulfonamides- oral non-absorbable agents

Sulfasalazine- used for UC, enteritis, delayed release of tablets is used to treat RA.
Anti-inflammatory properties

189

Sulfonamides- topical agents

Sodium sulfacetamide (sulamyd)- use in opthalmic solution or ointment for tx of bacterial conjunctivitis. Also used to tx chlamydia trachoma infections
SIlver sulfadiazine (Silvadene)- burn infection prophylaxis

190

Sulfonamide Pharmacokinetics

Well absorbed
Distributed throughout the body including CNS and fetus
Elimination is primarily renal

191

Sulfonamides Adverse Effects

NVD, HA, PHOTOSENSITIVITY
Up to 10% will have adverse rxn mixture of allergy and toxicity: rash, fever, blood dyscrasias (hemolytic anemia), many itis's (nephritis, hepatitis, vasculitis), and crystalluria.

192

Trimethopim

Competitive inhibitor of dihydrofolic acid reductase (Second step of folic acid synthesis)
Similar spectrum of sulfonamides but more potent
Similar pharmacokinetics with improved penetration into the prostate
Adverse effects- GI, megaloblastic anemai, leukopenia, granulocytopenia
Used for community aquired UTI or prophylaxis of UTI.

193

Sulfamethoxazole/Trimethoprim (Bactrim or Septra)

Produces sequential blocking in the metabolic sequence leading to marked synergism. Combination is bactericidal
Same spectrum as the individual agents
Only available IV sulfonamide antibiotic.

194

Sulfamethoxazole/Trimethoprim- Clinical uses

Alternative agent for CAP, UTI and prostatitis, acute otitis media
Tx o pneumocystitis carinii, bacterial diarrhea
Prophylaxis of UTI, PCP and taxoplasma gondii in AIDS pts, and peritonitis prevention in patients with cirrhosis.

195

Drugs that alter nucleic acid processing

Inhibit DNA processing
Quinolones, rafampin, and nirtrofurantoin

196

Qoinolones- MOA

Block bacterial DNA synthesis by inhibiting DNA topoisomerase IV and topoisomerase II.

197

Quinolones- Spectrum of Activity

Primary target differs according to organism-
Topo II primary, Topo IV secondary- E.coli
Topo IV primary, Topo II secondary- staphylococci and streptococci
Active against Gram (+) and gram (-) bacteria, Activity against topo IV accounts for gram (+) spectrum

198

Quinolone "classes"

Excellent gram negative coverage with only moderate gram (+) activity (Ciprofloxacin)
Excellent gram (-) coverage with improved gram (+) coverage
Continues gram (-) and (+) coverage with enhanced anaerobic coverage (Trovafloxacin)

199

Quinolone Spectrum of Activity 2

Atypical pneumonia organisms (Chlamydia pneumoniae and mycoplasma pneumoniae)
Intracellular pathogens (Legionella, mycobacteria tuberculosis, and mycobacteria avium complex)

200

Quinolone Clinical Uses

UTI, sinusitis, mycobacterial infections, bacterial diarrhea, soft tissue, bone, and joint infections, gonoccocal and chlamydial infections, pneumonia, post exposure prophylaxis for anthrax, tx inhalation antrhax infection
Trovafloxacin FDA restricted to life-or limb threatening infections due to severe hepatic toxicity.

201

Fluoroquinolone resistance

Due to one or more point mutations in bacterial chromonsomes, high levels usually confers resistance to all quinolones.
SHould not be used for routine URI or LRI or skin/soft tissue infections

202

Quinolones pharmacokinetics

Well absorbed (oral is decreased by divalent and trivalent cations)
Widley distributed including prostate
Excretion is renal, non renal, bile, and urine depending on the drug

203

Quinolone Adverse Effects

Mostly- N/V/D
Secondary- HA, dizziness, insomnia
Rarely- seizures, blood dyscrasias, and peripheral neuropathy that is irriversible.
May damage growing cartilage, tendinitis and rupture in elderly, renal failure with glucocorticoid use

204

Quinolone Drug interactions

Interactions if taken at the same time as antacids, sucralfate, iron, and multivitamins
CYP interactions most common with ciprofloxacin

205

Quinolone- Moxifloxacin (avelox)

Oral or IV
Broad spectrum single dose daily
Targets DNA gyrase instead of topo IV in gram (+)

206

Quinolone- Gemifloxacin (factive)

Approved to treat mild-moderate CAP due to multi-drug resistant Streptococcus pneumoniae.

207

Metronidazole (Flagyl) MOA

Bacteriacidal
Metabolized to an intermediate that inhibits bacterial DNA synthesis and decreases existing DNA
Selectivity due to its toxic metabolite that is not produced in mammalian cells
ROA- oral, IV, topical

208

Metronidazole (Flagyl)- spectrum of activity and pharmacokinetics

Anaerobic and protozoan infections- amebiasis, trichomoniasis, skin infections, CNS infections, inra-abdominal infections, systematic anaerobic infections, tx C. diff, bacterial vaginosis, H. pylori and acne rosacea
Pharmacokinetics- absorption- 80% food delays and excreted in urine

209

Metronidazole (flagyl)- contracindications/cautions and drug interactiosn

Hx of blood dyscrasias, alcoholism, hepatic dz, CNS disorders, visual changes, 1st trimester of pregnancy
Drug interactions- warfarin, cimetidine, lithium toxicity, ETOH

210

Metronidazole (flagyl)- ADRs

Vertigo, HA, confusion, seizures (w/ previous condition)
Edema
N/V/D, abd cramping, constipation
Darkened urine, polyuria, dysuria
Transient leukopenia, neutropenia
Extreme reaction when combines with ETOH

211

Nitrofurantoin (Macrodantin, Macrobid)- MOA, spectrum of activity, and ROA

MOA- poorly defined reactive form damages DNA nd interferes with RNA synthesis and DNA replication
Spectrum- Gram (+) and (-)
ROA- oral and reaches highest [] in the urine
TX UTI

212

Nitrofurantoin (marcodantin, macrobid)- ADRs

Gi- N/V
Interstitial pulmnary fibrosis with chronic use
Hemolysis in pt with G6PD deficiency
Aggranulocytosis, thrombocytopenia
Peripheral neuropathies, HA, Dizziness,
Significant skin reactions w/ allergies.

213

Polymyxin B- MOA

Bactericidal
Interact w/ phospholipis on the outer plasma cell membrane of gram (-) bacteria disrupting their structure
Disruption destroys bacteria's osmotic battier leading to lysis
Resistance is low

214

Polymyxin B- spectrum and ROA

Gram (-) bacteria (pseudomonas aeruginosa)
ROA- high nephro- and neuro- toxicity limits to topical application
IV, IM, intrathecal admin in hospitalized pts w/ serious infections
Topical= gut sterilization, bladder, irrigation, and ophthalmic.

215

Daptomycin (Cubicin)

Used for multi-drug resistant gram (+) bacteria
Bactericidal disruption of plasma membrane
Once daily dosing
ADRs- reversible myopathy, GI

216

Isoniazid (INH)- MOA

Inhibition of cell wall synthesis by inhibiting acid synthesis
Bacteriostatic for stationary phase and bactericidal for rapid dividing phase
Penetrates host cell and drug retained within hose cell longer
Metabolized by N-acetylation and hydrolysis

217

Isoniazid (INH)- Resistance and Adverse effects

No cross resistance to other TB drugs
AE- peripheral neuritis- pyroxidine deficiency
Inhibits phenytoin metabolism and may produce convulsions in seizure prone patients
Hepatitis/hepatotoxicity- most severe and increased with rifampin and daily ETOH

218

Isoniazid (INH)- Black box Warning

Sever and sometimes fatal hepatitis associated with isoniazid therapy may occur & may develop even after many months of tx

219

Rifamycins- Mechanism

Blocks transcription by interacting w. the beta subunit of bacterial DNA-dependent RNA polymerase.
Antimicrobial spectrum- Broader spectrum vs INH

220

Rifamycins- Spectrum of activity

Bactericidal against gram (+) and (-) organisms: used prophylactically in individuals exposed to meningitis.
Rifabutin, analog of rigampin, active against mycobacterium gyium complex, but less active for TB

221

Rifamycin- pharmacokinetics

Oral admin, distribution all body fluids and organs
Induces hepatic mixed-function oxidases increasing its own metabolism and other drugs
Eliminated via feces and urine which may have an orange-red color.
Adverse effects- nausea and vomiting.

222

Pyrazinamide- MOA

Bactericidal
Enters M. tuberculosis by passive diffusion, concerted to pyrazinoic acid by PZase
Inhibits fatty acid synthase I
Accumulates within acidic environment of macrophages monocytes and kills tubercle bacill.

223

Pyrazinamide- Adverse Effects

Liver injury (15%) with jaundice (2-3%), rarely fatal
Get liver function test, do not use if problems

224

Ethambutol

Bacteriostatic
Inhibits cell wall synthesis by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall.
Helps prevent emergence of RIF resistant organisms

225

Ethambutol- Adverse reactions

Optic neuritis
Results in diminished visual acuity and loss of red/green discrimination
Decreases urate excretion= gout if predisposed.

226

Isoniazid (INH)- MOA

Inhibition of cell wall synthesis by inhibiting acid synthesis
Bacteriostatic for stationary phase and bactericidal for rapid dividing phase
Penetrates host cell and drug retained within hose cell longer
Metabolized by N-acetylation and hydrolysis

227

Isoniazid (INH)- Resistance and Adverse effects

No cross resistance to other TB drugs
AE- peripheral neuritis- pyroxidine deficiency
Inhibits phenytoin metabolism and may produce convulsions in seizure prone patients
Hepatitis/hepatotoxicity- most severe and increased with rifampin and daily ETOH

228

Isoniazid (INH)- Black box Warning

Sever and sometimes fatal hepatitis associated with isoniazid therapy may occur & may develop even after many months of tx

229

Rifamycins- Mechanism

Blocks transcription by interacting w. the beta subunit of bacterial DNA-dependent RNA polymerase.
Antimicrobial spectrum- Broader spectrum vs INH

230

Rifamycins- Spectrum of activity

Bactericidal against gram (+) and (-) organisms: used prophylactically in individuals exposed to meningitis.
Rifabutin, analog of rigampin, active against mycobacterium gyium complex, but less active for TB

231

Rifamycin- pharmacokinetics

Oral admin, distribution all body fluids and organs
Induces hepatic mixed-function oxidases increasing its own metabolism and other drugs
Eliminated via feces and urine which may have an orange-red color.
Adverse effects- nausea and vomiting.

232

Pyrazinamide- MOA

Bactericidal
Enters M. tuberculosis by passive diffusion, concerted to pyrazinoic acid by PZase
Inhibits fatty acid synthase I
Accumulates within acidic environment of macrophages monocytes and kills tubercle bacill.

233

Pyrazinamide- Adverse Effects

Liver injury (15%) with jaundice (2-3%), rarely fatal
Get liver function test, do not use if problems

234

Ethambutol

Bacteriostatic
Inhibits cell wall synthesis by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall.
Helps prevent emergence of RIF resistant organisms

235

Ethambutol- Adverse reactions

Optic neuritis
Results in diminished visual acuity and loss of red/green discrimination
Decreases urate excretion= gout if predisposed.

236

Inhibitors of viral attachment, uncoating or release

Pleconaril
Docosanol
Amantadine
Rimantadine
Osteltamivir
Zanamivir

237

Amantadine and Rimatadine- Inhibitors of Viral Attachment

Bind viral protein M2 and inhibit viral uncoating
Used to tx and prophylaxis of influenza type A, no effect on type B-lack M2
Large volume distribution
Amatadine-90% excreted unchanged in urine (used in parkinson's disease)
Rimantadine- metabilized by the liver

238

Neuraminidase Inhibitors- Oseltamivir and Zanamivir

Selective inhibitors of viral neuraminidases which are essential for release of virus from the infected cell.
Tx of influenza A and B, duration 5 days
Prophylaxis before or after exposure to influenza A or B
Oseitamivir- oral
Zanamivir- intranasal or inhalation of dry powder

239

Inhibit attachment- Pleconaril

Prevents attachment of the virus and viral uncoating within the human cell
Effective against picornavirus- not FDA approved

240

Non-specific inhibition of RNA and protein synthesis- Interferons

Immunomodulatory and antiviral
Dose limiting toxicities include- neutropenia and anemia, flu like sx, fever, fatigue, and myalgia
Interferons mainly act to prevent translation of viral proteins.

241

Drugs that block DNA synthesis from Viral DNA

Active against herpes family of viruses
Guanosine analogs- acyclovir, valacyclovir, penciclovir, famiciclovir, ganciclovir
Adenosine analog- vidarabine
Cytosine analog- cidfovir

242

Acyclovir and Valacyclovir (oral prodrug of acyclovir)

Tx and prophylaxix prevention of herpes simplex (type I and II), and zoster
Varicella zoster- treatment

243

Drugs that block DNA synthesis from viral DNA- penciclovir and Famciclovir (oral prodrug of penciclovir)

Used to tx herpes zoster, herpes simplex Type II, topical tx of oral/labial herpes simplex virus

244

Drugs that block DNA synthesis from viral DNA- acyclovir and penciclovir

Pregnancy category B

245

Drugs that block DNA synthesis from viral DNA- Ganciclovir and Valganciclovir (oral prodrug)

Active against all herpes virus
Tx of CMV in immunocompromised patients
Neutropenia, thrombocytopenia, teratogenic- catergory C
Vitasert- an intraocular sustained release implant for CMV retinitis.

246

Drugs that block DNA synthesis from viral DNA- vidarabine

Broad spectrum antiviral activity- herpes, pox viruses, rhabdoviruses, hepadenaviruses, some RNA tumor viruses
Primary use- keratitis, keratoconjunctivitis, life threatening herpes simplex virus, varicella zoster infections

247

Drugs that block DNA synthesis from viral DNA- cidofovir

Broad spectrum antiviral activity- herpes and pox viruses, adenoviruses, papilloma viruses, and hepadenavirus
Primary use for tx of cytomegalovirus in AIDS pts who are intolerant, relapsed, or nonresponsive to ganciclovir or foscarnet
Neutropenia and nephrotoxicty

248

Drugs that block DNA synthesis from viral DNA- Foscarnet

Does not require phosphorylation- broad spectrum
Active against all herpes viruses, influenza, and HIV
Primary uses- CMV (cytomegalvirus) infections, acyclovir, resistant herpes simplex or varicella zoster
Nephrotoxicty

249

Drugs that block DNA synthesis from viral DNA- Ribarvirin

Purine nucledoside analog
Ribavirin aerosol treatment of RSV
Ribavirin plus pegiterferon- Hep C

250

Non-specific inhibition of RNA and protein synthesis- Interferons

Immunomodulatory and antiviral
Dose limiting toxicities include- neutropenia and anemia, flu like sx, fever, fatigue, and myalgia
Interferons mainly act to prevent translation of viral proteins.

251

Antifungal Drugs

Polyene antibiotics
Imidazole antifungals
Triazole antifungals
Other antifungal agents
Tx can last weeks to months and is more effective on the skin than the nails.

252

Amphortericin B

Polyene ABX
Naturally occuring polyene macrolide antibiotic produced by streptomyces nodosus
MOA- Bind to ergosterol in the fungal cell membrane and form pore-> leak "-cidal"
Selective toxicity
Resistance- infrequent due to decreased ergosterols in membrane

253

Nystatin

Polyene ABX
MOA- Bind to ergosterol in the fungal cell membrane and form pore-> leak "-cidal"
Selective toxicity
Active transport mechanism

254

Amphortericin- pharmacokinetics

ROA- IV
Liposomal preps less renal and infusion toxicity

255

Amphortericin indications and ADRS

Broad specturm anti-fungal used in potentially fatal systemic infections
-Candida albicans, histoplamsa capsulatum, cyrptococcus neoformans, coccidoices immites, blastomyces dermatitides, aspergillis
ADRs- HYPOTENSiON, anemia, nephrotoxocity, thrombophlebitis, fever/chills, allergic reactions

256

Nystatin-pharmacokinetics

Topically as a cream
Vaginal troches
Suspension deliver drugs to oral mucosa

257

Nystatin- indications and ADRS

Used to supress candidiasis on the sin and mucous membranes (oral&vaginal)
ADRs- N/V/D

258

Flucytosine (Ancobon)

Polyene ABX
MOA- inhibits synthesis of fungal pyrimidines
ROA- PO
Indications- in combination w/ amphoB to treat systemic candiasis and cryptococcuss meningitis
ADRs- N/V/D, rare hepatotoxicity and seen more often is thrombocytopenia, neutropenia, bone marrow suppression

259

Griseofulvin (Fulvicin)

Polyene ABX
MOA- binds to fungal microtubules disrupting mitotic spindles "-static"
Indications- DOC in kinds for wide spread dermatophyte or intractable dermatophyte infection where topical agents have failed. No longer for dermatophyte infection of nails
ADRs- fever, HA, mental confusion, rashes, GI disturbances.

260

Griseofulvin (Fulvicin)- drug interactions

P450 inducer- barbiturates, OCP, warfarin
High fat meals increase absorption
Potentiates intoxicating effects of ETOH

261

Ketoconazole (nizoral)- MOA

Azoles Imidazoles
MOA- broad spectrum: histoplasma, blastomyces, candida, coccidioides, NO ASPERGILLUS
Predominately fungistatic but can be -cidal depending on dose
Inhbits C-14-alpha-demethylase (P450 enzyme) disruptong the membrane
Also inhibits human steroid synthesis leading to decreased testosterone and cortisol production.

262

Ketoconazole (nizarol)- Pharmacokinetics and ADR

PO-requires gastric acid for dissolution
Penetration into tissues limites, effective in tx of histoplasmosis in lung, bone, skin, soft tissue
Doesn't enter CNS
ADRs- N/V, anorexia, endocrine effects such as gynecomastia, impotence, irreg menses, teratogenic due to endocrine effects

263

Ketoconazole (nizarol)- Drug interactions and resistance

P450 INHIBITOR
Resistance- mutation of p450 enzyme leasts to decreased azole binding
Ability to pump azole out of the cell.

264

Azoles Imidazoles

Clotrimazole (Lortimin, mycelex)
Miconazole (Monostat, desenex)
Terconazole (terazol)
Butoconazole (Femstat3)
Topical only; severe toxicity when used IV
MOA and spectrum same as ketoconazole
Topical use w/ contact dermititis, vulvar irritation, edema
TOPICAL MICONAZOLE IS A POTENT INHIBITOR OF WARFARIN METABOLISM

265

Fluconazole (diflucan)- MOA

Azoles Triazoles
Inhibits synthesis of fungal membrane ergosterol
Lacks endocrine side effects
Penetrates CSF of normal and inflammed meninges

266

Fluconozole (diflucan)- uses, ROA and ADRs

DOC- cryptococcuss neoformans, candidemia and coccidioidomycosis, effective against all forms of mucocutaneous candidiasis; used prophylactically in immunocompromised pts
ROA- Oral or IV
ADRs- N/V and rash

267

Fluconazole (diflucan)- drug interactions

Moderate inhibitor of CYP3A4 (cyclosporin, lovastatin) and strong inhibitor of CYP2C9
Tetratogenic

268

Itraconazole (Sporanox)

Azoles triazoles
MOA- inhibits synthesis of fungal membrane ergosterol lacks endocrine side effects; -static
DOC- blastomycosis, aspergillis, sporotrichosis, paracoccidiodomycosis, histoplasmosis

269

Itraconazole (sporanoz)- pharmacokinetics and ADRs

PO- requires acid for dissolution
Extensively protein bound and distributes throughout most tissues including bone and adipose, but not CSF
Biologically an active metabolite
P450 INHIBITOR
Avoid in pregnancy
ADRs- N/V, rash, hypokalemia, HTN, edema, HA

270

Itraconazole (sporanox)- contraindications

Strong inhibitor and substrate of CYP34A, contraindicated w/ lovastatin, simvastatin, midazolam, triazolam. May decrease OCP effectiveness, and increased digoxin levels

271

Voriconazole (vfend)

Azole triazoles
PO or IV
Invasive aspergillosis and serious infections caused by scedosproium apiospermum and fusarium species
Penetrates tissues and CSF
ADRs- similar to other azoles; transient visual disturbance occurring shortly after dose

272

Voriconazole (vfend)- Contraindictations

Inhibitor of CYP2C18, 2C9, 3A4. Contraindicated in patients taking rifampin, phenobarital, carbamasepine. Dose adjustments may be required w/ statins, benzodiazepines, and warfarin

273

Posaconazole

Azole triazoles (new antigungal)
Only available as oral suspension and must be taken with high fat meal for adequate absorption
Spectrum similar to itraconazole, w/ additional effect on Zygomycetes such as mucor
More effective than other azoles in treating fungal infections in immunosuppressed patients (myelogenous leukemia, stem cell transplantation, refractory esophageal candidiasis)
Inhibits CYP3A4

274

Terbinafine (Lamisil)

Allylamines
MOA- prevents ergosterol synthesis by inhibiting the enzyme squalene oxidase; -cidal
PK- lipophillic- penetrates superficial tissues including the nails
Administered orally- fingernail and toenail regimens differ, 40% bioavailability due to 1st pass metabolism, therapy is 3 months.

275

Terbinafine (lamisil)- indications and ADRS

Active against dermatophytes and candida albicans
ADR- mild- HA, N/Dm rash, taste and visual disturbance
Rare but serious effects- cholestatic jaundice, blood dyscrasias, steven-johnson syndrome
Baseline LFTs and CBC (repeat q 4-6wks)

276

Onychomycosis (nail infection) treatments

Terbinafine- 1st line agent (not candida)
Itraconazole- alternative 1st line therapy (preferred for candida infections)
These drugs have REPLACED grseofulvin and ketoconazole for this type of infection

277

Caspofungin (Cancidas)

Echinocandins
2nd line therapy for those who failed amphoB or itraconazole (expensive)
Interferes w/ synthesis of fungal wall
Limited to aspergillus and candida species
ADRs- fever, rash, nausea, phlebitis, and flushing rxn.

278

Micafungin (Mycamine)

Echinocandins
Esophageal candidas
Prophylaxis of invasive candida infections in pts undergoing hematopietic stem cell transplantation
ADRs- fever, rash, nausea, phlebitis, and flushing rxn.