Diuretics

Drug That Inhibit the Cell Wall Drugs that inhibit Microbial Protein Synthesis

Attack transpedtidase enzyme envolved in cross linking the cell Act on the bacterial ribosomes. 30s and 50s

wall of bacteria.

Tetracyclines and Doxycycline – end in –cycline

 These drugs are Bacteriocidal. Act on 30s

Can cause Bone and Joint disorders

Penicillin(s) end in –cillin. Vancomycin Tetracycline is the prototype agent and doxycycline is one of several

1. Also target penicillin derivatives.

binding proteins. Involved Toxicity good oral absorbtion. causes tooth discoloration do not use if preg or under 7.

in cell wall integrety.  Nephrotoxicity • Doxycycline – safest for use in patients with renal impairment, but

2. Danger of epileptic has increased risk of photosensitivity and hepatotoxicity than

seizures (intrathecal tetracycline

penicillin G injections) • Hepatotoxic esp. in pregnant women

• Major indications in pulmonary infections are Mycoplasma

pneumonia and Chlamydia

Cephalosporins begin with Cef- or Ceph- • Minor use – H. influenza, S.pneumoniae

1. 1st generation – cephalothin (IV), cefazolin (IM), Cefalexin (Oral)

a. Highly b-lactamase resistant

b. Best for gram + Aminoglycosides

c. Some activity for Klebsiella, M. catarrhalis (gram - ) Act on 30s

2. 2nd generation -- cefamandole, cefoxitin (IM), cefaclor(Oral) Bacteriostatic

a. More active vs. certain gram negatives than 1st generation. Remember GAS – Gentamicin, Aminoglicosides, Streptomycin

b. Less active than 1st generation vs. gram positives • Ototoxicity, vestibular toxicity

i. Klebsiella, H. influenza (only pen-sensitive strains),

M. catarrhalis, Pseudomonas

3. 3rd generation -- Cephalosporins: cefotaxime, ceftazidime,ceftriaxone

(IV or IM)

a. Gram + and Gram – activity Macrolides

b. *Ceftriaxone may be active against strains resistant to other Act on 50s

3rd generation cephalosporins Bacteriostatic

i. S. Aureus (not metR), Strep. Pneumonia, Strep. Remember MACE –

Pyogenes, H. influenza, H. parainfluenza, Klebsiella, 1. Azithromycin, Oral IV take on empty stomach

Pseudomonas (not cefatriaxone) 2. Clarithromycine, Oral

4. 4th generation – Cefepine (IV or IM) 3. Erythromycine. Oral IV

a. Gram + and Gram – activity. Improved

b. Gram + activity compared with 3rd Generation Side effects

photosensitivity

Metabolism is not usually an issue. Drugs are excreted via kidney largely Liver toxicity- risk especially with estolate derivatives of erythromycin

unmetabolized. Erythromycin is safe for use in pregnancy (category B)

Toxicity Risk of superinfection by yeast and C. difficile

– Allergic reactions –rare and rarely serious Inhibit Cyp3A4 Esp.Erythromycin and Clarithromycin

– Dose reductions recommended in patients with impaired renal Cardiac Toxicity – prolonged QT intervals, arrhythmia

function of if given in combo with other nephrotoxic drugs E and C – contraindicated with cisapride, pimozide, astemizole, terfenadine,

– Risk of superinfection with Candida and C. difficile quinidine, disopyramide

(pseudomembranous colitis) high with 3rd and 4th generation

agents. Use cautiously with patients with colitis.

Antimicrobial DNA Synthesis and Replication

Inhibitors



FluoroQuinolones – end in –floxacin Clindamycin

generally bacterialsidal Class of its own

– In gram + micro-organisms, Topoisomerase IV

– In gram – micro-organisms, DNA Gyrase Acts like both a macrolide and aminoglygoside

– Both of these enzymes regulate the topology of DNA during

replication. Inhibition of either enzyme results in DNA strand-

breakage.



 ciprofloxacin

 levofloxacin

 gatifloxacin

 moxifloxacin





The pharmacokinetic properties of the fluoroquinolones are excellent

• Excellent oral absorption and tissue distribution

• Tissues concentrate the drug leading to it’s utility in urinary tract

infections as well as infections in the lung, prostate, bone, cerebral

spinal fluid.

Adverse Side-effects are infrequent with agents found on the DRUG

LIST

• Dose reduction of ciprofloxacin in renal deficits

• Photosensitivity, rash

• Generally not recommended for children under 16 due to possible

adverse effects on joints. However,In serious infections, drug use

is recommended.









Sulfa Drugs

Block folic acid absorption or synthisis

Generally bacreriostatic



 Sulfamethoxazole

 Trimethoprim-

General Pulmonary infections

Acute Bronchitis Pneumonia

Likely infectious agents Likely infectious agents

 Streptococcus pneumoniae  Streptococcus pneumoniae

 Haemophilus influenza  Haemophilus influenza

 Moraxella catarrhalis  Moraxella catarrhalis (smokers)

 Mycoplasma pneumoniae

Manage mild cases in otherwise Management of severe cases  Chlyamydia pneumoniae

healthy persons  Legionella pneumoniae



All 3 (S. pneumoniae, H.influenza, All 3 (S. pneumoniae, H.influenza, Management

M.catarrhalis) M.catarrhalis) active against all

 Trimethoprim-  Amoxicillin+clavulante  Fluoroquinolones

sulfamethoxazole (resistant staph)  Azithromycin

 Fluoroquinolones o not for resistant S.pneumoniae;

S. pneumoniae & H. influenza  Levofloxacin o 1st choice for L. pneumoniae

 Doxycycline  Gatifloxacin

 Moxifloxacin H.influenza, M. catarrhalis

S. pneumoniae ,  2nd Generation Cephalosporins

( pen sensitive strains only)  Azithromycin

variable for S. pneumo.

 Amoxicillin S. pneumoniae

S. pneumoniae ,

 Cephalothin  1st or 3rd Generation Cephalosporins

 Cefotaxime

 Cephalothin (S. Pneumo,

M. pneumoniae, C. pneumonia,L.pneum

pen sensitive)

H. influenza & M. catarrhalis  Doxycycline or Erythromycin.

 Cefaclor

If unresponsive:

H. influenza & M. catarrhalis

3rd Generation Cephalosporin + Macrolide (erythromycin or

Cefaclor

azithromycin)









Pneumocystis (carinii)



• Prophylaxis in HIV+ – 3 months of Trimethoprim-

sulfamethoxazole if CD4+ Caffeine>Theobromine • Ipratropium

• Oxitropium

Relaxes airway smooth muscle • Tiotropium

Inhibits synthesis & secretion of inflammatory mediators in mast cells & basophils Caution must be used in context of prostatic symptoms or glaucoma

Narrow therapeutic range of 8-14 mg/dl Tiotropium Bromide in COPD

First order elimination in therapeutic range • Long term, once daily

• If this range is exceeded, zero order kinetics predominate • Currently considered first line treatment

Metabolized by cyp2PA2 • Contraindicated in patients with history of hypersensitivity to

• Clearance induced by cigs, phhenytoin, rifampin barbs, and contraceptives. atropine.

• Reduced by erythromycin, cimetadine, interferon ect. Methylxanthines in COPD

Rapid IV administration can result in sudden death (arrhythmia) Oral dosing only

Drug should be injected slowly over 20-40 min to avoid toxic symptoms • Theophylline

• Occur at plasma concentrations > 20 mg/ml, Seizures > 40 mg/ml • Aminophylline

• Therapeutic levels are 8-14 mg/dl

Theophylline overdose. • Plasma drug monitoring critical

Prophylactic – diazepam • Significant drug interactions

Add phenytoin or phenobarbital Glucocorticoids in NOT indicated in COPD

Lidocaine for arrhythmia

Prevent further absorption with activated charcoal or sorbitol as a cathartic Recent clinical evidence suggests that exacerbations per year and rate of

deterioration may be reduced by inhaled corticosteroids

Try on individual basis



Mucolytic/Antioxidant Therapy in COPD

Pediatric asthma N-Acetyl cysteine may be particularly effective

Leukotriene Inhibitors, First line

Nedocromil or Cromolyn a-Trypsin Therapy in COPD

Reduce potential effects of glucocorticoid use in children Some COPD patients may have a1-antitrypsin deficiency

In US, these patients are eligible for IV infusion of purified protein

Emergency room (Prolastin) 2x/wk

Only b agonists shown effective in immediate treatment

Systemic glucocorticoids (prednisone) warranted but will take 6-12 hrs for effect.



Hospitalized patients

Regular inhaled β agonists

Systemic glucocorticoids (30-120 mg)

INHIBITION OF FUNGAL REPLICATION PATHS

AntiFungals Flucytosine

 Pyrimidine antimetabolite

Ergosterol biosynthysis inhibitors  Fungal cytidine deaminase converts flucytosine to 5-fluorouracil which is further

Inhibition of ergosterol production results in abnormal metabolized to the nucleoside monophosphate that inhibits thymidylate synthase. Also,

functioning of fungal membrane protein systems. metabolized to the nucleotide triphosphate and incorporated into RNA

Fungistatic or fungicidal depending upon the specific drug –

infectious organism combination. Drug Targets – Thymidylate synthase and RNA

Fungistatic

Allylamines And Tolnaftate

act on Squalene epoxidase preventing the conversion of Used only in combination due to rapid development of fungal resistance when used as a single

squalene to squalene-2,3-epoxide. agent

 Allyamines are non-competitive inhibitors of this

enzyme Griseofulvin

 Fungicidal Antimitotic agent

Drug target – fungal mitotic spindle apparatus causing failure of fungi to complete mitosis.

Azoles act on Lanosterol-14a demethylase preventing the Fungistatic

conversion of lanosterol to ergosterol.





Cell membrane inhibitors

Polyenes act on ergosterol.

Binding of drug to membrane ergosterol results in DRUG TOXICITIES ARE A MAJOR CONCERN FOR SYSTEMIC ANTI-FUNGAL

transmembrane pore formation and leaky cell membranes CHEMOTHERAPEUTICS

Fungicidal

Amphotericin B

 Kidney toxicity- common

 Amphotericin B

 Nystatin  Decreases tubular reabsorption of Mg and K and can predispose to cardiac

arrhythmia

Amphotericin B also causes oxidative damage to membrane  Pregnancy Category B –generally regarded safe

lipids

Flucytosine

FUNGAL CELL WALL INHIBITORS  Bone marrow suppression with neutropenia.

Echinochandins  Diarrhea, ulcerative colitis, bowel perforation possible.

Act on 1,3-beta glucan synthase.  excreted primarily via kidneys

 This enzyme is critical to cell wall formation.  Contraindicated in Pregnancy (category C)

 The product polysaccharide in conjunction with

chitin maintains the osmotic integrity of the fungal Itraconazole

cell wall.  inhibition of P450 CYP3A4

 Drug is a non-competitive inhibitor of this enzyme.

Fungicidal or Fungistatic depending upon microbe



 Caspofungin acetate

Systemic fungal infections

Treatment of fungal infections Amphotericin B

 considered a “broad-spectrum” antifungal agent

 resistant strains are emerging.



Tinea infections (superficial) CLINICAL INDICATIONS FOR CASPOFUNGIN

Athlete’s foot (Tinea pedis) and related cutaneous Tinea sp. IV administration

 Azoles

 Undecylenic acid  Esophageal candidiasis (advanced HIV+ infections)– cytocidal, broad-spectrum

 allyamines (the most efficacious but the most  Aspergillosis (Bone Marrow Transplant patients)– cytostatic

expensive)

Tinea infections of nails Use in fungal infections resistant to azoles &/or Amphotericin B.

 Terbinafine Use in patients with renal insufficiency in which Amphotericin B is too toxic.

 Itraconazole Can be used in combination with azoles for highly disseminated infections.

Tinea infections of scalp/hair

 systemic griseofulvin Potential activity in Pneumocystis carinii



DERMATOPHYTOSIS (RINGWORM) CLINICAL INDICATIONS FOR ITRACONAZOLE-

 Topical azoles used a lot even tho drug interactions are a problem

 Allylamines  Candida

 Undecylenic acid  Used to treat non-CNS disease

 Prophylactic therapy in HIV+ patients receiving HAART

SUPERFICIAL CANDIDIASIS

o C. neoformans if CD4+ HSV-2 > VSV >>>CMV

There is cross resistance between these two antivirals.  Acyclovir is safe for use in pregnancy

Foscarnet

Influenza A and B (viral neuraminidase inhibitors) Inorganic pyrophosphate compound that is

CMV

 Oseltamivir Ganciclovir (better id IV) active against all Herpesvirus infections.

 Zanamivir Valganciclovir (prodrug, better absorption)  Given IV in combo with ganciclovir

CMV > HSV for CMV

Prevents the release of the viral particals from the cell membrane.  CMV retinitis in AIDs patients  As a single agent to treat acyclovir-

 CMV pneumonia, GI infection in resistant HSV and ganciclovir-

safe for working age adults and children resistant CMV

bone marrow transplant patients

 Suppress Hepatitis B  Binds to viral DNA polymerase

Oseltamivir with 100x’s greater affinity than

Bone marrow toxicity Caution if used in

orally active; mild GI upset prevented by co-administration with meals to cellular DNA polymerase-

combination with Zidovudine in HIV.

Safety during pregnancy has not been established alpha. Resulting in chain

Contraindicated in Pregnancy (Pregnancy

Category C) termination

Zanamivir

active by inhalation only. Nephrotoxicity

Cautious use in patients with pre-exising broncho-pulmonary Ionic imbalances

disorders.

NNRTI – Non-Nucleoside Reverse Transcriptase Inhibitors

HIV Drugs Nevirapine

NRTI – Nucleoside Reverse Transcriptase Inhibitors  can cause rapid liver failure

Zidovudine Bone marrow Toxicity  P450 inducer

Lamivudine Efavirenz

Abacavir Hypersensitivity, (Sulfa) fatal Toxicity  CNS Toxicity

 Mixed P450 3A inducer/inhibitor

Pyrimidine antimetabolite

 Activated by thymidine kinase and thymidylate kinase Does not undergo metabolic activation in the host cell

 Targets retroviral POL Geen producing RNA-dependent DNA Drug target – viral reverse transcriptase (RT).

polymerase Allosteric inhibitor of RT. Inhibits viral DNA synthesis.

 Incorperated into viral DNA causing termination and inhibition of

viral DNA synthesis Activity : HIV-1

Activity: HIV-1 and HIV-2

Hepatotoxicity

Lactic acidosis Skin rash

Mitochondrial toxicity may also contribute to peripheral neuropathy, P450 Mediated Drug Interactions

myopathy, cardiomyopathy and lipodystrophy

Efavirenz + Clarithromycin is not recommended due to marked elevations in

PI –Protease Inhibitors clarithromycin levels

Nelfinavir

HIV + Pregnancy

 Snack only

All HAART agents are FDA Pregnancy category B and C.

Ritonavir

Zidovudine is Category C

 Parathesias, Hepatitis, increased TG and uric acid

Indinavir

Chemoprophylaxis with Zidovudine to prevent transmission to fetus:

 CNS: heachache Dizziness,blurred vision, rash ,thrombocytopenia,

 Oral beginning at week 14 of gestation;

allopecia

 iv during labor,

 Hemolytic anemia

 treat newborn for first 6 weeks.

 Kidney stones

 Nevirapine may be superior and easier to use for chemoprophylaxis than

Lopinavir

Zidovudine

 Parathesias

 Elevated liver enzymes

Structurally related class of drugs called peptidomimetics Treatment Regimen Recommendations for Asymptomatic Patients

Drug Target: the HIV-1 protease NNRTI (efavirenz) + 2 NRTI (A HAART regimen)

• competitively inhibits the cleavage of the viral substrate, the gag-pol Single PI therapy = indinavir, nelfinavir

gene. Combo PI therapy = ritonavir + indinavir or ritonavir + lopinavir

• Protease inhibitors block viral maturation

70-90% of patients achieve their maximum control of viremia within the first 6-12

Hyperglycemia months of HAART

Increased bleeding risk in hemophiliacs

These all inhibit P4503A especially Ritonavir 2 NRTI + PI- “PI-based” regimen. Difficult to tolerate but minimizes emergence of

• Indinavir, Ritonavir, - will elevate ketoconazole levels drug-resistant HIV

• Ritonavir – will elevate clarithromycin

• All PI except Saquinavir will disrupt actions of oral contraceptives