08-12-2021-0417 - drafting

M phase – mitosis (ex: vincristine, vinblastine)

Gap 1 or G1 phase (steroids, asparginase)

S phase or DNA synthesis (antimetabolites- methotrexate, fluorouracil, cytarabine)

(topoisomerase –1 inhibitors : topotecan, trinotecan)

Gap 2 or G2 phase or RNA synthesis (bleomycin, etoposide)

G 0 or Resting phase

Interphase between episodes of mitosis

‘proliferation independent’ = can kill both normal and cancer cells

Ex: carmustine, irradiation
Preferentially toxic to cancer cells:
Cell Phase-specific agents- cell cycle- specific (CCS agents)

Ex.: hydroxyurea, cytarabine act on S-phase

Phase nonspecific – but still kill cancer cells preferentially

Cell cycle-nonspecific (CCNS agents)

Ex.: 5-fu, cyclophophamide
‘self-limiting’= Not only phase specific but also block the cell in another phase of cell cycle

Ex.: methotrexate kills cells in S-phase, but also inhibits RNA synthesis in G1 and G2 phases

Alkylating agents :

Nitrogen mustards, Nitrosoureas, Alkyl sulfonates, Triazenes
Antimetabolites:

Folic acid analogues (methotrexate),

Purine analogues (6-mercaptopurine),

Pyrimidine analogues (5-Flurouracil, cytarabine)
Natural products: determined by the source of the drug- plants,lower organisms

Antibiotics: (produced by streptomyces species)

Dactinomycin (actinomycin-D),

Anthracyclines- Doxorubicin, Daunorubicin, Mitoxantrone

Bleomycin, Mitomycin

Periwinkle plant derivatives: vinca alkaloids

Biologic response modifiers: enhance immune responses of the body-

Interleukin –2 (IL-2), Interferons (alpha, beta, gamma)

Enzymes- L-Asparginase

Extract of the mandrake plant-Epipodophyllotoxins-etoposide, teniposide

Western yew tree extract- Paclitaxel
Hormones and antagonists: act on receptors for endogenous hormones required for cell proliferation-

Tamoxifen- estrogen receptor antagonist

Androgens- (in breast cancer) fluoxymesterone, testosterone

Anti androgens- Flutamide

Steroids-Prednisone

Progestins for endometrial cancer
Miscellanious agents:

Hydroxyurea, Procarbazine, Mitotane, Cisplatin Recombinant Interleukin (IL-2)

Drug Profiles (Drug Cards)

Cyclophosphamide/Cisplatin/Procarbazine

Cyclosphosphamide "Cytoxan"

Antineoplastic agent - Alkylator

Nitrogen mustard derivative

Polyfunctional alkylating agent

Cancers of bone, lymphnode, and solid tumors

Leukemias, Hodgkin’s and non-Hodgkin’s Lymphomas, multiple myeloma, sarcomas

Side effects: Bone Marrow Depression (BMD), Hemorrhagic cystitis

Cocci, bacilli, anaerobes, spirochetes, fungi, Mycobacteria, Helminths, Protozoa, Viruses

Bacteriostatic and bactericidal

Antibiotics classification "Magnificient Seven":

1.Sulfonamides

2.Beta-lactam antibiotics

3.Cephalosporins

4.Aminoglycosides

5.Tetracyclines

6.Macrolides

7.Quinolones

Clindamycin

Vancomycin

Chloramphenicol

Sulfonamides:

Inhibit folic acid synthesis by competitively blocking Para Amino Benzoic Acid (PABA) and blocking purine synthesis. "Anti folate drug"

Achieve high concentrations in Kidneys. Used in UTI, Ulcerative colitis

In combination with trimethoprim (co-trimoxazole/ "Bactrim") has synergistic effect.

Group side effects:

Blood: Agranulocytosis, aplastic anemia, hemolytic anemia, and thrombocytopenia

Skin: Necrosis, exfoliative dermatitis, and Stevens-Johnson syndrome, Photosensitivity

GI: Nausea, Vomiting, diarrhea, and pancreatitis

Other: Convulsions, crystalluria, and urticaria

Useful against gram-positive bacteria

Bactrim useful against Pneumocystis carinii

Beta-lactam antibiotics:

Penicillins/Ceohalosporins/Carbapenens/Monobactams

Beta-lactamase inhibitors: Clavulinic acid, Tazobactam, Sulbactam

Ampicillin + sulbactam = "Unasyn"

Amoxicillin + clavulinic acid = "augmentin"

Ticarcillin + clavulinic acid = "timentin"

Piperacillin + tazobactam = "zosyn"
Structure of the penicillins consists of a thiazolidine ring (1) connected to a beta-lactam ring (2), which is attached to a side chain.

Penicillinase inhibitor bacteria have beta lactam inhibiting enzyme and become penicillin resistant strains.

Classification of Penicillins:

1. Naturally occurring- Penicillin G (benzylpenicillin), Penicillin G

2. Penicillinase resistant penicillins- Methicillin, cloxacillin,Nafcillin

3. Amino penicillins ‘Broadspectrum’ – Ampicillin, Amoxicillin, Bacampicillin
‘Antipseudomonas’ penicillins –Caebenicillin,Ticarcillin, piperacillin

MOA of penicillins: Inhibits bacterial cellwall synthesis by binding with cell proteins


MOA of penicillins: Inhibits bacterial cellwall synthesis by binding with cell proteins

Common Adverse effects:

Hematologic: Anemia, increased bleeding time, BMD, leukopenia

GI: Nausea, vomiting, diarrhea, elevated liver enzymes,

abdominal pain, colitis

CNS: Lethargy, hallucinations, anxiety, depression, coma, convulsions

Metabolic: Hyperkalemia, Hypokalemia, Alkalosis

Others: Taste alteration, Sore mouth, sore tongue

Anaphylaxis, Urticaria, Serum sickness

Indications:

Gram positive – strep and staph, Gram negative- meninogcocci

Anthrax, Gas gangrene

Syphilis

First generation –Cephalexin, Cephadroxil – best gram positive coverage,

poor gram negative coverage

Second generation – Cefaclor, Cefoxitin

Third Generation – Cefotoxime, Ceftriaxone, Ceftazidime- best gram negative coverage, but poor gram positive coverage

Fourth Generation – Cefepime, Cefipirome- good gram negative and have same gram negative as 3rd generation

MOA is by inhibiting cell wall synthesis. Active against gram negative and positive bacteria, and anaerobes as well. Side effects similar to that of penicillins

Carbapenems: Imipenem – given in combination with cilastatin to reduce nephrotoxicity. Has the broadest spectrum. Gonococci, Hosp.acquired infections.

Monobactam: Aztreonam – MOA: Inhibits cell wall synthesis. Bio availability 100%

Highly effective against aerobic gram negative, Pseudomonas, H.Infl, strep

Indications: uti, severe skin infections, osteomyelitis, gynec infections

Side effect: Pseudo membranous colitis (PMC)

"Anti Pseudomonas Penicillins"

Carboxy penicillins: Carbenicillin and ticarcillin

Acyl aminopenicillins: piperacillin

Only carbenicillin is administered orally. Others are parenteral only.

AMINOGLYCOSIDES

Streptomycin: plague and tularemia

Neomycin : Gram neg.

Gentamicin : Gram neg, incl. Proteus, Pseudomonas, Entrobacter, Klebsiella

Tobramycin : As above

Amikacin : As above

Netilmycin : As above

Kanamycin : As above, but more toxic

MOA: directly act on bacterial ribosome and inhibit protein biosynthesis and disrupt cell wall membrane, and has rapid bactericidal action. Excreted by kidneys.

Side effects: Oto toxic and nephrotoxic. Daily dose and duration of treatment dependent.

Drug Interactions: Streptomycin has interaction with muscle relaxants like curare causes neuromuscular junction blockade by decreasing ACh sensitivity.

TETRACYCLINES

Tetracycline

Minocycline

Doxycycline

Chlortetracycline

Oxytetracycline

Bacteriostatic drug

Effective against: Mycoplasma, Rickettsiae- Rocky Mountain Spotted fever, Scrub typhus, Chlamydia, Leptospira, Lymphogranuloma venerum, Psittacosis, Trachoma, Brucellosis, Cholera, Shigella, Salmonella and spirochetal Lyme disease – tick borne: borrelia burgdorpheri

Note: they chelate with Mg, Ca, and Al ions and form non-absorbable compounds. Should not be administered with milk, antacids, iron salts, and not to be given to children under the age of 8 years, pregnant women and nursing mothers, because of bone and dental side effects.

Other side effects: skin rash, photosensitivity, nausea, vomiting

Should be administered on empty stomach. Except Mino and Doxycyclines, which are not chelated.

MACROLIDES

Erythromycin

Clarithromycin "Biaxin"

Azithromycin "Zithromax"

MOA: directly act on bacterial ribosome (50S-sub unit) and inhibit protein biosynthesis

Against: Strep, Haemophilus, Lyme disease, Chlamydia, Mycoplasma

Clarithro and azithromycin effective against Mycobacterium avium infections.

Clarithromycin against H.pylori

Side effects:

CNS- headaches, dizziness, vertigo, sleepiness

CVS- Palpitations, chest pain

GI- nausea, vomiting, heart burn, diarrhea, stomatitis, flatulence, anorexia

Cholestatic jaundice

Skin- rash, itching

Other- hearing loss, tinnitus

Chloramphenicol

MOA: directly act on bacterial ribosome (50S-sub unit) and inhibit protein biosynthesis

Bacteriostatic

Indications: typhoid, H Infl., anaerobics

Side effects:

BMD occurs in 1 in 40,000 patients, not dose related

Gray baby syndrome in neonates because their liver and kidneys are premature and cannot handle large doses of chloramphnenicol. Cyanosis, resp.distress, shock, abd. Distension, loose green stools and ash gray color. Fatal.

Clindamycin

MOA: directly act on bacterial ribosome (50S-sub unit) and inhibit protein biosynthesis

B. Fragilis infections

Side effects: Associated with PMC

Vancomycin

MOA: inhibit protein and disrupt cell wall membrane , excreted in urine

A bactericidal glycopeptide

Aginst gram positive bactaria.

Most useful against clostridium difficile cause of PMC.

Side effects: Oto and Nephro toxicity

Quinolones

MOA: inhibit DNA gyrase and are rapidly bactericidal, excretion by kidney

Norfloxacin "Noroxin"- UTI

Lomefloxacin "Maxaquin"– UTI, bronchitis

Ciprofloxacin "Cipro"– UTI, diarrhea, bone, joint infections, LRTI

Ofloxacin "Floxin"– STD(gonorrhea), Chlamydia

Enoxacin "Penetrex"– UTI, STD

ASSESSMENT OF PATIENTS PRIOR TO ADMINISTERING ANTIBIOTICS

H/O DRUG HYPERSENSITIVITY

HEPATIC, RENAL, CARDIAC FUNCTION EVALUATION

CULTURE AND SENSITIVITY TESTS FOR INFECTION BEFORE START OF THERAPY

LIST OTC DUGS BEING USED

CONTRAINDICATIONS AND PRECAUTIONS

PENICILLINS:

Known hpersensitivity to penicillins, cephalosporins, asthma, and procaine hypersensitivity
Cephalosporins:

Known hpersensitivity to it or penicillins. Impaired renal or liver function-use with caution. Drug interaction with – furosemide, ethacrynic acid, colistin, or aminoglycosides
Sulfonamides:

Pregnancy, lactation, hepatitis, nephritis, uremia.

Drug interactions with anticoagulants, oral antidiabetics
Tetracyclines:

Pregnancy, hpersensitivity. NOT for children under 8 years of age

Lacating women, renal, hepatic disease.

Interacts with- antacids, dairy products, penicillins, oral anticcoagulants, barbiturates, oral contraceptives.
Aminoglycosides:

Impaired liver function. Interact with- oral anticoagulants, diuretics, cephalosporins, muscle relaxantas, and GA agents. Oto and Nephro toxic. Renal function studies needed before and during treatment.
Clindamycin:

Ulcerative colitis or enteritis, infants less than 1 month old

Interacts with- muscle relaxants, chloramphenicol, erythromycin
Quinolones:

Epileptics, renal failure cases, pregnant lactating women.

Interaction with-antacids, anticoagulants, antineoplastics, theophylline
Macrolides:

Impaired liver. Interacts with- clindamycin, theophylline, antihistamines, penicillins, oral anticoagulants
Vancomycin:

Oto and nephro toxicity. Impaired reanl function, pregnant /lactating women.

Interacts with- aminoglycosides, cephalosporins, cisplatin, amphotercin.

ANTIFUNGALS

MYCOSIS are fungal infections:

Systemic: Blastomycosis, Coccidioides, Histoplasmosis affect mainly lungs

Cryptococcosis Lungs, and meninges of brain

Cutaneous: Candidiasis due to candida albicans affects skin and mucus membranes

Dermatophytes, tinea -affects scalp and skin

MOA of antifungals depend on their chemical class:

Polyenes bind to fungal ergosterols, open up channels in funcal cell membrane and cell leaks to death.

Flucytopsine acts as antimetabolite, converts to 5-FU inside the plant cell interferes with DNA synthesis.Inhibits enzyme thymidylate synthetase.

Imidazoles interact with cytochrome p-450 of the funcgal cell and prevents formation of ergosterol, but forms lanosterol which is useless for the fungal cell.

Griseofulvin inhibits fungal cell mitosis and prevents reproduction of the cell. Arrests the cell I metaphase. Prevents DNA replication.

Agents for superficial fungal infections:
Nystatin : Polyene

Fungistatic and fungicidal. Not absorbed from GI tract

Indication- candida albicans infection of skin, mucus membrane, Gitract,

Thrush (oral), and vaginits
Griseofulvin: Produced by penicillium griseofulvum

Fungistatic. Has affinity for keratin

Indication- dermatophytal infections of skin, hair, nails.
Naftifine, and terbinafine: Synthetic allylamines

MOA: decrease synthesis of ergosterol by inhibitng enzyme squalene epoxidase

Indication: Tinea infections local application
Miconazole and clotrimazole: Imidazoles

Indication: ringworm treatment, vulvovaginal candidiasis.

Miconazole used for systemic infections with canididasis, coccidioidomycosis, cryptococcosis

Agents used for systemeic infections:
Amphotercin B: Polyene

Poor oral absorption. IV administration has long (24Hrs) plasma half life. Very slow renal excretion.

Broadspectrum antifungal drug.Histoplsama, coccidioido mycoses, Blastomycoses, Aspergillus

Indication: life threatening fungal infections. "Immune compromised patients"

American leishmaniasis

Side effects: Anaphylaxis, fever, chills, headache, GI disturbances, decreased renal function especially when patient is receiving cyclosporine as well.
Flucytosine:fluorinated pyrimidine compound,

Good oral absorption.Corosses blood brain barrier. Unmetabolized Renal excretion.

Indication: Cryptococcus neoformans in combination with amphotercin B.

Side effects: Fatal BMD, GI disturbances, skin rash, liver dysfunction

3. Ketoconazole: substituted imidazole derivative

Oral absorption. Needs acid medium for absorption. Antacids or H2 blockers may inhibit absorption.

Acts slowly. Needs longer pewriod for action. Not useful insevere life threatening infections. Used as oral tablets for skin infections like-candidiasis, dermatophytal infection.

Side effects: Nausea, vomiting, hepato toxicity, urticaria, anaphylaxis, gynecomastia.

Blocks testosterone synthesis, and blocks adreanl response to ACTH. Blocks cytochrome P-450 enzyme, and interacts with drugs using that enzyme system in the liver.
Itraconazole:Synthetic triazole

MOA: Inhibiots cytochrome p-450 and blocks ergosterol synthesis.

Oral availability best when taken with food. Safe in renal impaired patients.

Indication: Histo plasmosis,blastomycosis, aspergillosis,

Side effects: dose related nausea, abdominal distension.

Interaction: when given with terfendrine causes cardiac arrhythmias.
Fluconazole: bis-triazole.

MOA: blocks cytochrome P-450 and prevents ergosterol formation.

Highly bioavailable. Penetrates blood brain barrier. Should be discontinued if there is progressive hepatic dysfunction.

Indications: Aspergillus, Candidiasis, Cryptococcus, Coccidoidis, Histoplasma

Oral or IV

Side effects: Rash, GI disturbances

Interacts with cytochrome P-450 using drugs increases serum concentrations of phenytoin, cyclosporine, oral hypoglycemic drugs, potentiates warfarin.

ANTI TUBERCULAR DRUGS

Incidence of tuberculosis (TB) is increasing because of AIDS, and homelessness.

Principles of Treatment:

Drugs are used in combination chemotherapy to prevent development of drug resistnat strains of mycobacterium tuberculosis
Drug resistance is rising because of poor compliance and may require administration of drugs under direct observation

C. First line drugs include: isoniazid, rifampin, pyrazinamide, ethambutol,

and streptomycin
TB caused by possible resistant strain: treat with 4 drugs-

isoniazid, rifampin, pyrizinamide, ethambutol or streptomycin
TB resistant to isoniazid only treated with rifampin, ethambutol, and pyrizinamide for 12 months
TB patients with HIV, disseminated disease, or meningitis The initial nine months treatment should be continued for another 6 months after

Culture conversion
For multiple drug resistant (MDR) TB three drugs to which the strain is susceptible must be continued for 12-24 months after conversion

PROPHYLAXIS

Isoniazid prophylaxis is given to:

Individuals and children in direct contact with TB patient

Any person converting from a negative to a positive skin test

Isoniazid

Pyridine derivative of isonicotinic acid hydrazide

MOA: Interferes with cell metabolism, blocks synthesis of mycolic acid, a constituent of bacterial cell wall.

Orally well absorbed. Crosses blood brain barrier. Renal excretion. Plasma concentration varies depending on the genetic trait of fast or slow acetylation.

Indication: TB infection, but not against atypical mycobacteria.

Adverse/side effects:

20% have elevated liver enzymes, over the age of 35 liver damage is more likely and is aggravated by daily alcohol consumption. Must be discontinued if liver enzymes are > three times the normal.

Peripheral and CNS Toxicity: due to pyridoxine (vit. B6) deficiency induced by the drug. Therefore B6 must be given with the drug to prevent this side effect.

Blood: B6 deficient anemia, and blood dyscrasias

Interacts with phenytoin- reduces its metabolism and enhances its toxicity

Hypersensitivity- fever and rash.

Rifampin

Complex macrocyclic antibiotic

MOA: Inhibits RNA synthesis by binding to the DNA dependent RNA polymerase in bacteria and chlamydiae.

Orally well absorbed, good tissue distribution and excreted by the liver.

Indication: gram positive and negative organisms

Indications: Tuberculosis, atypical mycobacteria, and leprosy

In meningococcal infection prophylaxis.

Adverse/side effects:

Urine, sweat tears, and contact lenses may take an orange color. Harmless.

Light chain protienurea and impaired antibody response may occur.

Induces hepatic enzymes and affects half life of number of drugs.

Can produce febrile flu like syndrome if therapy is erratic.

Pyrizinamide

Pyrazine analog of nicotinamide

MOA not known

Good tissue distribution after oral intake. Renal excretion.

Indication: short course TB multi drug therapy

Adverse effects: Liver impairment, Liver function tests to be done regularly.

Hyperuricemioa and gout may occur.

Ethambutol

MOA:Unknown

Orally well absorbed. Good tissue distributiobn.

Indication: Combination multi drug therapy for tuberculosis.

Side effects: Visual disturbances, optic neuritits, color blindness for red and green.

Strepto mycin mentioned with aminoglycosides.

LEPROSY

SULFONES:

Chemically related to sulfonamides. Class drug: DAPSONE

Bacteriostatic. PABA blocker.

Orally well absorbed.

Indication: Leprsoy as part of multidrug regimen with rifampin, clofazamine.

Given for 2 years.

Adverse effects: Hemolysis, methemoglobinemia, nausea, vomiting, headache, rash, anorexia. Fatal Stevens Johnson syndrome

CLOFAZAMINE:

Phenazine congener

MOA: Binds to bacterial DNA inhibits cell growth.

Slow oral absorption.(50%). Lipophilic. Accumalates in fat tissue and reticulo endothelial cells. After several oral administration half life is 70 days.

Bactericidal. Useful in atypical mycobacterial infections.

Indication: Combination drug therapy in leprsoy with Rifampin, and Dapsone.

Adverse effects: Pain, nausea, vomiting. Reddish to dark brown discoloration of skin, cornea, and all body fluids. Anticholinergic effects can occur.

AGENTS USED FOR TREATMENT OF PROTOZOAL INFECTIONS AND MALARIA (Fig.53-1 Pg.686, 687)

Drug

Metronidazole"Flagyl":

MOA: Reduced intracelluarly into a short acting cytotoxic agent that binds with DNA and inhibits cell growth.

Well absorbed orally. Good tissue distribution. Metabolized in liver. Renal excretion.

Indications: Active against anaerobes, protozoa- amebiasis

Intreracts with : Alcohol, Warfarin, Anatabuse

Side effects: dizziness, headache, gastric distress, diarrhea, vomiting, taste alterations, dark urine, peripheral neuropathy

Oral dose: 7.5mg?kg to a maximum of 1gm q6h, IV infusion 15mg/kg loading then 7.5mg/kg upto 1 gm q6h IV

Useful in antibiotic associated PMC.

Diloxanide Fuorate:

For treating asymptomatic cyst passers

Suramin:

African trypansomiasis, Onchocerciasis

Nifurtimox:

South American trypanosomiasis

Stibugluconate: Leishmanisis

Pentamidine isethionate:

Leishmaniasis, prophylaxis against Pneumocystis carini pneumonia in AIDS

Antimalarials:

Chloroquine- Acute malaria, and prophylaxis

Primaquine- Cure and prevent relapses of P.Vivax, P.Ovale malaria

Mefloquine- Prophylaxis against chloroquine resistant malaria

Pyrimethamine-sulfadoxine "Fansidar"- Prophylaxis and treatment of chloroquin resistant malaria

Quinine sulfate- Acute uncomplicated malaria due to chloroquin resistant type P.Falciparum

Quinine di hydochloride-Severe illness from chloroquin resistant P. Falciparum malaria.

Anthelminthics:

Diethylcarbamzaine- Filarial worms

Praziquantel- Tapeworms, flukes(Schistosomiasis)

Metrifonate- Schistosoma hematobium

Niridazole- S. hematobium

Mebendazole- Whipworm, hookworm, pinworm, Ascaris(round worm), echinococcosis

Niclosamide-Tapeworms

Pyrantel palmoate- Ascariasis, hookworm, pinworm

Piperazine- Ascariasis, pinworm

Thiabendazole- Strongyloidiasis, trichinosis

Ivermectin- Onchocerciasis (river blindness)

DIETHYL CARBAMAZINE "HETRAZAN":

Oral : 2-3 mg/kg PO tid pc for 6-7 days

Side effects: joint pains, headache, dizziness, nausea , vomiting, facial swelling, tender glands, visual disturbances

Mebendazole "vermox":

Oral: 100 mg PO bid for 3 days

MOA: Blocks glucos uptake by the parasite by degenerating its cellular microtubules.

Oral , metabolized in liver, fecal excretion

Side effects: gastric distress, diarrhea, nausea, vomiting, alopecia, dizziness, headache

Niclosamide "Nicloside":

MOA: Inhibits the mitochondtia of parasite cells

Oral administration. Not absorbed. Acts on intestinal tapeworms. 2 gm daily for 7 days

Side effects: Nausea, vomiting, rectal itching, bad taste in the mouth

Piperazine "Entacyl":

Oral: 3.5 gm PO for 2 dayus Children 75 mg/kg

MOA: muscle paralysis of the parasite, blocks Ach at the neuromuscular junction

Side effect: GI distress, CNS toxic effects-headache, dizziness, tremors, blurred vision

Praziquantel "Biltricide":

Oral: 25 mg/kg tid for 1 day

MOA: Increases cell permeability in the parasite, cells leak intracellular calcium, muscle paralysis in the worm

Side effects: GI distress including bloody diarrhea, head aches, dizziness, drowsiness, fever , sweating

Pyrantel "Combantrin":

Oral: 11 mg/kg single dose

MOA: Depolarizing neuromuscular blocking agent, paralyses parasite’s muscles.

Side effects: GI distress

Thiabendazole "Mintezol":

Oral: 25 mg/kg/PO bid PC x 2days

MOA: Inhibits enzyme fumarate reductase in the helminth

Side effects: gastritis, Stevens –Johnson syndrome, convulsions

Induction or Inhibition of microsomal enzymes:

Mixed –function oxygenases and cytochrome P-450 system

INDUCERS

More than 200 drugs , and large number of dietary, and chemical substances are known inducers.

Barbiturates, glutehemide, phenytoin

Benzopyrene

DDT

Nicotine

Ethanol(chronic ingestion)

INHIBITORS

Organophophorous insecticides

Carbon tetrachloride

Ozone

Carbon monoxide

Cimetidine

Omeprazole

ANTIVIRAL AGENTS

Viruses are intracellular obligatory parasites that require the invaded cell’s metabolic process to survive. Therefore the agents which kill the virus will kil the cell as well.

ACYCLOVIR:

Synthetic purine nucleoside analog

MOA: Inhibits herpes virus DNA synthesis by-
interfering with viral DNA polymerase and inhibits viral DNA replication
Gets incorporated into DNA and leads to premature chain termination
It has great affinity for viral enzyme thymidine kinase and hence 100 times more toxic to the virus than the human cell.

Indication: HSV type 1 and 2, V-Z virus, E-B virus, CMV

IV acyclovir is the choice treatment for seriouis HSV, V-Z infections

Oral for primary HSV infections

Local application for ophtalmic zoster

Prophylactic in transplant patients to prevent HS and CMV infections

Side effects: Crystalline nephropathy, neurologic reactions, local phlebitis, rash, hives. Encepahlopathy in 1% of patients.

Nausea , vomiting , diarrhea, head ache.

Local discomfort and itching

Amantadine and Rimantadine:

Synthetic tricyclic amine, and rimatadine is the alpha methyl derivative of amantadine

MOA: Block the release of viral nucleic acid, block the viral assembly in the cell

Indication: P{rophylkaxis for Influenza A virus infections

Shortens duration of Influenza symptoms

Side effects: Confusion, hallucinations, sizures, coma.

Ganciclovir:

Synthetic nucleoside analog of 2’-deoxyguanosine

MOA: Inhibits viral DNA synthesis similar to acyclovir

Similar action as acyclovir, burt more effective against CMV

Indications: CMV retinbits

Side effects: severe local tissue irritation when given IV. BMD. Headache, psychosis, convulsions, coma 5-15% of patients.

Foscarnet:

Phosphonoformic acid

MOA: Inhibits DNA polymerase of HSV, and reverse transcriptase of FIV

Indications: CMV retinits in AIDFS, HSV, V-Z

Side effects- BMFD, Nephrotoxicity, metabolic abnormalities

Trifluridine:

Fluorinated pyrimidine nucleoside

MOA: Inhibits DNA synthesis

Indication: HSV, adenovirus

Keratoconjunctivitis of HSV 1 & 2

Ophthalmic soln.
Side effect: local buirning, singing, and edema.

Ribavarin:

Synthetic purine nucleoside analog

MOA:

Inhibits enzymes needed for synthesis of guanine nucleotides.

Inhibits viral RNA polymerase

Interferes with viral messenger RNA

Active against RNA and DNA viruses- HSV, inflluenza A & B, Resp. syncitial virus (RSV), HIV

Lassa fever, hemorrhagic fever

Contraindicated in people on ventilators because the aerosol precipitate on valves and rubber tubing and cause the respirator malfunction

ANTIVIRALS USED IN HIV RELATED AIDS OPORUNISTIC INFECTIONS

HIV replicates in CD4+ helper T lymphocytes

ZIDOVUDINE (AZT):

Synthetic thymidine analog

MOA:

Inhibits DNA polymerase (reverse transcriptase) of HIV

Incorporateds into viral DNA and terminates chain growth during synthesis

Good oral absorption, good tissue penetration, rapidly removed from blood . (half life 1 hr) Metabolized in liver, renal excretion.

Indications:

Increases median survival of HIV AIDS patients

Slows progression of symptoms

Side effects:

Anemia, megaloblastic bone marrow. Severe BMD

(Erythropoitn, GM-CSF administration helps BMD patients)

Neurotoxicity: saevere headaches, insomnia, Seizures

Nausea, myalgia

Interaction: with Ribavarin , acetaminophen

DIDANSOINE:

Moa: REVERSE TRANSCRIPTASE INHIBITOR

Indications: similar to AZT

Adverse effects:
Painful neuropathy,acute pancreatitis, liver failure

ZALCITABINE:

MOA: Reverse transcriptase inhibitor

Indications: similar to AZT

Side effect: Peripheral neuropathy

Treatment of opportunistic infections of AIDS:

P. cariniii pneumonia:

Drugs:

Trimethoprim-sulfamethoxazole "Bactrim" IV

Pentamidine isethionate IV

Side effects: hypo and hyper glycemia, renal failure, arrhythmias, hypotension

Dapsone can be combined with oral trimethoprim

CMA infections:

Ganciclovir, foscarnet

Toxoplasmosis:

Intracranial mass lesions

Drugs:

Pyrimethamine+sulfadiazine "Fansidar"

Clindamycin + pyrimethamine

Prophylaxis:Bactrim

Cryptococcois:

Drug: Amphotercin B

HSV and V-Z

Agents as discussed above.


IMMUNOLOGY AND IMMUNOMODIFIERS Chapters 54,55,56

Components of ‘immune system’ page 710-diagram (fig.54-1)

ORGANS: Tonsils, Thymus, Lymphnodes, Small intestinal "Peyers Patches", Spleen

Tissue, cellular components:

Bone marrow: produces various cells – stem cells – transforms to –

Immune response initiators:
Mononuclear T cells in Thymus gland – antigen stimulates T cells to produce cellular immunity
B cells (Bursa of Fabrecius) - small lymphocytes produce antibodies which search and bind with antigens and provide humoral immunity

Inflammatory response effectors:

3. Polymorpho nuclearleukocytes (PMNL) – nonspecific cells along with lymphocytes produce an inflammatory response

T cells - 3 varieties:

1. Cytotoxic T Cells: binds tightly to target cell and kill them – bacilli, cancer cells, viruses, and transplant (foreign tissue) cells

2. Helper T Cells (CD4): Major group of T cells. They activate B cells, Cytotoxic T cells, Suppressor T cells. They also secrete interleukin 2 and other lymphokines. HIV virus destroys this T helper cell, and causes AIDS

Suppressor T Cells: Suppresses cytotoxic and helper T cells, and prevents excessive immune reactions.

B Cells: Are in lymphoid tissues and lymph nodes. Get activated when foreign tissue/substance and start immune responses to the antigen.

Definitions:

Antigen = Invading (foreign) organism or substance which produces a antibody response

Antibody = Gammaglobulin (a type of protein) called immunoglobulin (Ig) and belong to one of these five classes- IgG, JgM, IgA, IgD, and IgE. Usually IgM is the primary response, and IgG is the secondary response.

Active and Passive immunity (ref. Table 54-1 on page 714) : can be acquired by active infection or by administering IgG or custom made vaccines.

IMMUNOSUPPRESSANT DRUGS : Prevent immune response or suppress it.

Major role in preventing "Tissue rejection " after organ transplantation. Revolutionized organ transplant program. Kidney, Liver, Heart, Bone marrow transplants have been successful because of the role played by this group of drugs.

Azthioprine "Immuran"

Cyclosporine "Sandimmune"

Daclizumab "Zenapax"

Muromonab-CD3 "Orthoclone OKT3"

Mycophenolate mofetil "CellCept"

Tacrolimus "FK506" "Prograf"

Corticosteroids

Cyclophosphamide

MOA of immunosuppressants:

Azathioprine –

Suppresses delayed hypersensitivity and antibody responses

Antagonizes purine metabolism- decreased DNA, RNA, and protien synthesis

Blocks cellular metabolism and inhibits mitosis

Cyclosporine –

Inhibits Interlukin-2 (IL-2) release from T-lymphocytes (CD4)

Muromonab-CD3 –

Prevents T cells from recognizing foreign antigens

Tacrolimus –

Inhibits IL-2 release from T-lumphocytes

DRUG PROFILES

Azathioprine "Immuran"

Synthetic analog of physiologic purines likes adenine and guanine. Purine antagonist.

Available strength: 50 mg oral tablet / 100mg injection

Dosage: IV/PO 3.5 mg/kg/day, maintenance PO 1-2 mg/kg/day

Indication: Kidney transplants, Rheumatoid arthritis (RA)

In RA: initial dosage (oral) 1-2 mg/kg/day gradually increased to 2.5 mg/kg/day

Adverse effects: Hemo – BMD,decreased WBC, and platelets Liver- increased enzymes

Cyclosporine "Sandimmune"

Polypeptide antibiotic

Available strength: 25 mg, 100 mg soft gelatin capsules, and 100 mg/ml oral liquid

Dosage: PO 15 mg/kg pre and post op for 14 days, then reduce by 5%/wk to a maintenance dose of 5-10 mg/kg/day. IV DOSE is 1/3 of PO : 5-6 mg/kg as single dose and switch to oral dosing later

Indication: Kidney, Liver, heart transplants

Adverse effects:

Renal- Nephrotoxicity and is dose limiting

Hepatic- Jaundice, liver damage

CNS- (20%) Tremors

CVS- (50%) Hypertension

Others- thickened gums, hirsuitism

Muromonab-CD3 "Orthoclone OKT3"

Immunoglobulin IgG2a monoclonal antibody obtained from mice (murine)

Available strength: Injection only 5mg/mL injection

Dosage: IV 5mg/day single bolus for 10-14 days.

Indication: Reverses tissue rejection, renal transplants, steroid resistant heart and liver transplant rejections

Adverse effects:

CNS- fever, chills, tremors

Respiratory- Shortness of breath, wheezing, lung edema

CVS- Chest pain

GI- Nausea, vomiting, diarrhea

Other- flulike symptoms, fluid retention


https://www.austincc.edu/rmandyam/u3lect_ta.htm