Bible of Drugs=MUST USE

8/8/2019 Bible of Drugs=MUST USE

1/41

Antibacterial

Antimetabolites

Sulphonamides (analog of PABA, prevent production of folate) - Dihydropteroate

Synthase, bacteriostatic

Absorbed & Excreted rapidly

o SULFISOXAZOLE (5-6 hrs)

o SULFADAZINE (10 hrs)

o SULFAMETHOXAZOLE (11 hrs)

Poorly absorbed-active in bowel lumen

o SULFASALAZINE

Topically used:

o SULFACETAMIDE

o SILVER SULFADIAZINE

Absorbed rapidly & excreted slowly-long acting :

o SULFADOXINE (100-230 hrs)

High BA 70-100% (- topical), 70% PPB, distributed well (including CSF), cross

placenta, metabolized in liver, excreted renally

SE hypersensitivity reactions (SJ syndrome, uticaria, exfoliative dermatitis,

eyrthema multiforme)

Photosentitivity (more with cotrimoxazole) Increase potential for sunburn,

stone formation, opportunistic infection

Contraindication infants: displacement of bilirubin from albumin -> jaundice

-> kernicterus

TRIMETHOPRIN (folate analog) - Dihyrofolate Reductase , bacteriostatic


2/41

Rapidly absorbed from GIT, 42-46 PPB%, Well distributed in all of body water,

Concentrates in tissues, T1/2 =8-10 hrs, Eliminated renal, Minimal

glucoronylation in liver

COTRIMOXAZOLE (sulphamethoxazole and trimethoprim (5:1))

Synergism, well absorbed-peak: blood levels 1-4 hrs

Treats: UTI, Otitis media, Respiratory infections, Pneumocystis carinii

Penicillins (betalactam, inhibition of cell wall formation binding to transpeptidase)

bactericidal

Benzylpenicillin & its long acting parenteral forms:

o

BENZYLPENICILLIN (PEN G) (NB destroyed in stomach, given with K

+

and Na+, 0.5hr, R)

IV, IM

45-65% ppb

UTI, meningitis, Peitonitis

MIC 0.01mg/ml for Strep.4-8 mg/ml Salm

o BENZATHINE PENICILLIN

o PROCAINE PENICILLIN

Orally absorbed penicillins resembling PEN G:

o PHENOXYMETHYLPENICILLIN (PEN V)

Penicillins resistant to staphylococcal beta-lactamase:

o CLOXACILLIN (0.5hr, R)

O, parental

MIC 0.1 mg/ml for Staph

95% PPB

o METHICILLIN


3/41

o NAFCILLIN

o OXACILLIN

Extended spectrum penicillin:

o AMPICILLIN

o AMOXICILLIN (1 1.5hrs, R, B)

O, Parenteral

20% PPB

MIC 2.0 mg/l for Staph

o MECILLINAM

Penicillins active against Pseudomonas:

o CARBENICILLINo TICARCILLIN

o AZLOCILLIN

Given parenterally and orally Lipid insoluble, distributed in body fluids,

crosses placenta, excreted unchanged, some bile

SE allergic reaction (1-5%), superinfections (broad spectrum),hypernatremia, hyperkalemia

Clavulanic acid - inhibitor of Beta-lactamase

Probenecid - competes with Pen at tubular secretory site of kidney

Cephalosporins (betalactam, higher generations less effective against gram +ve,

more against ve)

First Generation (soft skin, tissue infection; O, P)

Cephalothin (Keflin)

Cefazolin (Ancef) (2hrs, R)

o IV, IM

o 74-86% PPB


4/41

o MIC 0.1-0.25 mg/l for Strep.1-2 mg/l Salm

Cephapirin

Cephradine

Cephalexin

Cefadroxil (Duricef)

Second Generation (RTI, otitis media, acute sinusitis, prophylaxis in abdominal

surgery; O, P)

Cefamandole

Cefoxitin

Cefuroxime (Zinnat)

Cefaclor (Keflor) (0.6 0.9 hrs, R)

o O

o 25% PPB

o MIC 0.25 mg/l for Strep. 0.06-0.25mg/l Salm

Third Generation (meningitis, otitis media, ceftazidimine covers pseudomonas; O, P)

accumulates well in CSF

Cefotaxime

Moxalactam

Cefoperazone

Ceftizoxime

Ceftriaxone (Rocephin) (7-8 hrs, R)

o O, Parenternal

o 20% PPB

o MIC 0.03mg/ml Strep, 0.5-1 mg/ml Salml, MIC 2.0 ug/ml for Staph.

Ceftazidime

Cefsulodin


5/41

Cefmenoxime

Cefixime

Fourth Generation

Cefepime

Accumulate well in body tissues and distributed well in body fluids

Excretion same as penicillin

SE: Allergic reaction, superinfection, cholestasis, hepatitis

Penems and Monabactams

Carbapenems

o Imipenem (Primaxin )

o Meropenems (Merrem)

Monobacatms

o Aztreonam (Azactam)

o Moxolactam

Notes: sysnthetic compounds, made due to counteract resistance to betalactams,effective against H. influenza, P. auruginosa, Enterobacteria

VANCOMYCIN (Binds to d-alanyl-d-alanyl terminal subunits through hydrogen

bonding and therefore terminates cross-linking to form cell wall layers) -

Bacteriocidal

Gram positive only, last resort, poor O, IV, 6hrs, 55% BPB, accumulates in body

fluids, R

SE: nephrotoxicity, ototoxicity, macular rash, hypotension, allergic reaction,

flushing, pain at site of injection


6/41

Quinolones (inhibits topoisomerase IV [+ve] or DNA gyrase [-ve], Bactericidal at

30 X the MIC)

1. First Generation (gram +ve x3, gram ve x1 )

Nalidixicacid (NegGram) (1.5 hrs, R reduced by Probenecid)

O, P

High PPB

Cinoxacin (Cinobac)

2. Second Generation

Class I (gram +ve x1, gram ve x2, low serum conc)

Lomefloxacin (Maxaquin)

Norfloxacin (Norflox)

Enoxacin (Penetrex)

Class II (gram +ve x 1, gram ve x3, high serum conc)

Ofloxacin (Floxin)

Ciprofloxacin (Ciproxina) (3.5 - 4.5hrs, M)

O, P

Fluoroquinolone

15-40% PPB

Widely distributed in fluids, CSF

MIC 0.25 1 mg/l for Pseudomonas

2. Third Generation (gram +ve x1, gram ve x3, high liver metab)

Levofloxacin (Levaquin)

Sparfloxacin (Zagam)

Gatifloxacin (Tequin)

Moxifloxacin (Avelox)

3. Fourth Generation (gram +ve x2, gram ve x4)


7/41

Trovafloxacin (Trovan) (3.5-6.5 hrs, M active metabolites)

O, P, 15-40% PPB, CSF

MIC 2-32 mg/l for Pseudomonas

MIC 0.25 1 mg/l for Salmonella

Notes: effective against enterobacteria, not effective gram +ve, anaerobes,

pseudomonas

UTI, Gonorrhea, Chlamydia trachomatis, Respiratory infections, RTI, prostaitis

Accumulates well host tissue

SE: photosensitivity, chelation with metal ions, flu-like symptoms, convulsions

Aminoglycosides ( Binds to receptor site on 30s ribosomal sub-unit: Prevents

translocation of peptidyl-tRNA from A site to P- site, blocks initiation of protein

synthesis, causes misreading of the mRNA codon-incooperation of incorrect blocks

further translation and cause premature termination of protein synthesis)

STREPTOMYCIN

KANAMYCIN (20 days, R)

o P, IM

o MIC 2.0 mg/l for Staph

AMIKACIN (2 - 2.3hrs, R)

o P, IM

o MIC 16 mg/l for Staph. 1.0 Ecoli

TOBRAMYCIN

GENTAMICIN (2-3 hrs, R)

o P, IM

o 20-30% PPB

o UTI, meningitis, peritonitis

o MIC 0.4 mg/l for Staph


8/41

PAROROMYCIN

Mainly anerobic gram-negative, Enterobacterial, Mycobacterial, Staphylococcal

infections

Entry into cell-active transport process. Then pass into cells via a energy transport

process (involving Ca2+ ions). This transport process can be blocked by Ca2+,

Mg2+, acidic pH low redox conditions

Not O! P, high polarity, low PPB, do not penetrate tissue, R

SE: low TI, pain at injection site, nephrotoxic, ototoxic, NMJ blockage, allergic

reaction

Tetracyclines (: Binds to 30s ribosomal unit of the A site and prevents access of

aminoactyl tRNA to the codon. Entry into bacterial cell is energy dependent.)Bacteriostatic

CHLORTETRACYCLINE (Topical, poor oral)

OXYTETRACYCLINE (20hrs, H)

o O (slow, peak 6hrs)

o 20 35 % PPB

DEMECLOCYCLINE (12hrs, H)

o 90% PPB

TETRACYCLINE is the semi-synthetic derivative of Chlortetracycline. (8hrs,

R)

o O (slow)

o 65% PPB

MINOCYCLINE (20 hrs, H)

o O (peak 2hr)

o 95% bioavailability

o Absorption not affected by food

o 20 35% PPB


9/41

DOXYCYCLINE (18 hrs, H)

o 90% PPB

METHACYCLINE are semi-synthetic derivatives of Demeclocycline

Used in RTI, acne, pelvic inflammatory diseases, repiratory

O, IV, well absorbed in GIT, affected by food and metal ions (least minocycline,

doxocycline affected), high lipid solubility, accumulates in tissue and fluids, peak

serum levels in 2 hrs with O, low CSF, cross placenta

SE: emesis, polyurea, phototoxicity, hepatotoxicity in pregnancy (fatal),

superinfections

Chloramphenicol (Bind to site of 50s & prevents the action of peptidyltrasferase:

therefore inhibiting protein synthesis by preventing transpeptidation)

Bacteriostatic

Palminate O

Succinate P

Well distributed in tissue and fluid, CSF

Elimination by glucoronylation

SE: aplastic anaemia by binding to mitochondria ribosomes (bone marrow

suppression)

Gray baby syndrome (2-9 days)

Macrolides (Bind to site of 50s & prevents the action of translocation (i.e.

ribosomal shift to allow A site to become P site inhibited), therefore inhibiting

protein synthesis . Bacteriostatic (may be bacteriocidal at high doses)

ERYTHROMYCIN (1.3 6.5hrs, B)

o Poor acid stability, protective coat used

o 70-90% PPB

o Found in all body fluids, accumulates in liver and spleen


10/41

o MIC 0.01-0.25 mg/l for Strep

AZITHROMYCIN (6-8 hrs, B)

o More acid stable

o Found in all fluids, accumulates in tissues and phagocytes

o 51% PPB

o MIC 0.03-0.1 mg/l for Strep

CLARITHROMYCIN (3-7hrs, 5-9 hrs active metabolite, M)

o Good O, converted to active metabolite 14-hydroxy-clariromycin

o 40-70% PPB

o Accumulates in tissue

Gram +ve, very little gram ve activity

Metronidazole

Ferredoxin used by anaerobes w/o mitochondria, acts as electron donor to

metronidazole which binds to DNA causing destruction

O, peak 1-2 hrs, 8 hrs, R, CSF, placenta, saliva, breast milk

SE: metallic taste, nausea, headache, epigastric pain, parethesia

Anti TB (M. tuberculosis/bovis/leprae)

Isoniazid (Inhibition of mycolic acid synthesis)

o Small, water soluble

o Similar to pyridoxine

o Can penetrate cells

o Bactericidal

o Good O, P

o 5mg/kg oral, or IM + pyridoxine


11/41

o O absorption affected by metal salts

o Distributed well in fluids, CSF

o Acetylation in liver

o SE: peripheral neuropathy, hepatotoxicitym haemolytic anaemia,allergic reaction (drug induced SLE)

RIFAMPIN (Inhibits DNA-dependent RNA polymerase by forming a stable

drug-enzyme complex, inhibiting RNA synthesis. At higher doses inhibit

mammalian mitochodrial RNA synthesis,viral RNA polymerase & reverse

transcriptase)

o Active against Gram+ & Gram- such as E-coli, Pseudomonas,

chlamydia, mycobacteria

o Also used for Meningococci, Haemophilus influenza prophylaxis

o MIC: 3-12 ng/ml for Staph. Aureus, 0.005 -0.2 ug/ml for M. tuberculosis

o Good O

o 600mg once daily, 1hr before or 2hr after meal

o Absorption decreased by aminoslicylic acid

o High PPB, well distributed in organ and tissue

o Orange red colour to all fluids

o INDUCES CYTP450, interacts with ketoconazole, warfarin, estrogens

o Excreted B

o Slowly deacteylated -> active metabolites

o SE: orange urine, sweat, tears, rashes, jaundice, emesis, flu-like

symptoms, hepatitis, anaemia, thrombocytopenia

Pyrazinamide (Converted in mycobacteria by pyrazinamidase, to pyrazinoic

acid, bacteriocidal mechanism unknown)

o Nicotinamide analog, slightly soluble in water

o MIC for M. tuberculosis = 13 ug/ml

o Only intracellular action


12/41

o Inactive at neutral pH, needs pH of 5.5

o Well absorbed orally. 15- 30 mg/kg 3-4x daily.

o Well distributed into tissues.

o Eliminated mainly unchanged by GF. Low TI

o Toxic dose= 40-50mg/kg daily causes severe liver damage = Jaundice,

hepatic necrosis, death

Ethambutol (Inhibition of arabinosyl transferase, responsible for formation

of arabinoglycan (cell wall component) thus disrupting cell wall formation.

Increases lipophilicity of wall increasing the entry of other drugs eg. rifampin)

o Ammonium compound

o

Well O

o 8.5 hrs

o R

o Combination with rifampin, isoniazid

o Optic neuritis, headache, giddiness, mental disturbance

Streptomycin

o aminoglycoside

Antineoplastic Drugs

Non-cycle specific

Alkylating Agents (alkylate DNA within N7 position of guanine, causes miscoding,

cleavage, crosslinking)


13/41

Resistance: decrease membrane transport (cisplatin), drug bound to

glutathione/metalloproteins, metabolized by enzymes (ADH1 -> cyclophosphamide)

Nitrogen Mustards

Cyclophosphamide (3-10hrs and 8hrs)

o O, IV, IM

o Given with MENSA

o SE: Nausea, emesis, bone marrow depression, haemorrhagic cycstitis

(acrolein procduced)

o ACUTE LYMPHOTIC LEUKEMIA, NON-HODGKINS LYMPHOMA

Ifosfamide

Mechlorethamine

Melphalan

Chlormbucil

Alkyl Sulfonates

Busulfan (2-3 hrs)

o O

o SE: Nausea, emesis, myelosuppression, bulsufan lung

Thiotepa: similar to busulfan, should be avoided with cyclophophamide

o OVARIAN CANCER

Nitrosureas (BRAIN TUMOURS)

Carmustine (70 mins)

o Penetrates BBB

o IV

o SE: myelosuppression, pulmonary toxicity, fibrosis

Semustine

Lomustine


14/41

Strptozocin

Platinum analogues (intra strand cross link) (LUNG CANCER, ESOPHANGEAL AND

GASTRIC CANCER, OVARIAN BREAST)

Cisplatin

o Water soluble

o Slow IV

o Nephrotoxic, severe nausea and vomiting, given with ondanserton,

tinnitus, anaphylaxis

Carboplatin

o Derivative of cisplatin w/ less SE

Oxaplatin

Dacarbazine: prodrug, metabolized to active alkylating methyldiazonium ion

(HODGKINS LYMPHOMA)

Procarbazine: methyldrazine derivitave, activated in liver to azo intermediates ->

alkylating azoxyl cmpds (HODGKINS LYMPHOMA)

Cell cycle specific

Antimetabolites

Folate Antagonists (DHF -> THF by DHFR, DHFR inhibited, purine and thymidylate

sysnthesis cease)

Methotrexate (3!, 5 mins, 3hrs, 8-10hrs)

o O, IM, IV, IT

o H

o Nephrotoxicity, mucositis, CNS damage, cirrhosis

o Resistance: decreased drug transport. Altered DHFR, increased lvls of

DHFR

o ACUTE LYMPHOBLASTIC LEUKEMIA, CHORIOCARCINOMA,

OSTEOSARCOME, BURKITTSS AND NON-HODGKINS LYMPHOMAS


15/41

Trimetrexate METASTATIC COLORECTAL CARCINOMA, PANCRETIC

CARCINOMA

Pemetrexed MESOTHELIOMA

Purine Analogues (reduction of purine levels, interferes with DNA synthesis)

Mercaptopurine/6MP (50 mins)

o Inhibits 1st step purine synthesis

o Metabolized by enzyme HGPRT to active 6-thioinosinic acid

o O

o M by xanthine oxidase

o SE: myelosuppression, teratogenesis, mucositis

o Allopurinol prevents activation

Thioguanine/6TG

FludarabinePhosphate

Cladribine

Pyrimidine analogues (5-fluorouracil, cytosine arabinoside)

5-fluorouracil

o Converted to fdUMP inhibits thymidylate

o Colorectal cancer (+ levasimole), breast cancer

o IV

Cytarabine (cytosine arabinoside, ARA-C) (10min, 2hrs?)

o Falsely incorporated in DNA

o IV

o Acute leukemia, non-hodgkins lymphoma (anthracyclines)

o Cerebellar dysfinction


16/41

Antibiotics (Cytotoxic, several mechanisms)

Actinomycin D (Intercalate between strands)

Bleomycin (superoxide generation)

o Pulmonary fibrosis

Doxorubicin (topoisomerase II inhibition)

o Breast, endometrium, ovary, testicle, thyroid, lung, Ewings sarcoma,

osteosarcoma

o Cardiotoxicity (involves production of free radicals -> use antioxidants)

Natural ProductsVInca Alkaloids (binds to tubulin, M specific, arrest mitosis)

Vinblastine

o IV weekly

o Hodgkin disease, lymphomas

o Nausea, emesis, marrow depression, alopecia

Vincristine

Vinorelbine

Podophyllytoxin (cytostatic glucosides blocks cell in late S-G2 phase, inhibit

topoisomerase II, damage to DNA)

Etoposide

Teniposide

O, IV

R

Monocytic leukemia, testicular cancer, oat cell carcinoma of lung)

Camptothecins (interfere topoisomerase I, DNA damage)

Topotecan


17/41

o Prodrug -> SN-38

o Metastatic ovarian cancer (cisplatin resistant)

o Neutropenia, thrombocytopenia, anemia

Irinotecan

o Colon/rectal cancer

o Severe diarrhea, myelosuppression

Taxanes (spindle poison, enhancement of tubulin polymerization)

Paclitaxel (Taxol)

o Ovarian and advanced breast cancer

Docetaxel (Taxotere)

o Advanced breast cancer

HormonesEstrogens

Oestradiol

o

Gynecomastia

o Prostate, testicular cancer

Antiestrogens

Tamoxifen

o Binds to estrogen receptors

o G1 phase, highly protein bound, active metabolite

o SE: hot flashes, fluid retention, nausea, amenorrhoea

o Primary therapy for metastatic breast cancer (men and

postmenopausal women)

Reloxifene

Faslodex


18/41

Androgens

Testosterone

o Masculinisation

o Breast cancer

Antiandrogen

Flutamide

o Antagonizes androgenic effect

o Prostate cancer

GnRH agonist (paradoxic effect on pituitary, stimulate release of FSH and LH, then

inhibits these hormones, results in reduced testicular androgen synthesis)

Leuprolide

Goserelin

Gynecomastia, edema, thromboembolism

Metastatic carcinoma of prostate, hormone receptor-positive breast cancer

Aromatase Inhibitors

Aminogluthethimide

o Inhibit aderenal steroid synthesis

o Inhibits enzyme aromatase

o Dizziness, lethargy, visual blurring, rash

o Positive metastatic breast cancer

Anastrozole

Glucocorticoids

Prednisone

o Cushingss syndrome

o Lymphoma

Progestins


19/41

Megestrol

o Fluid rentention

o Endometrial cancer

Finasteride (Proscar)

5--Reductase enzyme inhibitor

Prostate cancer

Immunotherapy: IL2, Interferon-

Monoclonal antibodies: Trastuzumab (Herceptin) for breast cancer

L-Asparaginase: for acute lymphoblastic leukemia, SE hepatotoxicity

Hydroxyurea: inhibits ribonucleotide reductase, SE: myelosuppression

Mitoxanthrone: topoisomerase II inhibitor

Procarbazine: forms active metabolites which cause DNA breaks, DI with alcohol

Radioactive isotopes: Iodine-131, Cobalt-60

AVASTIN

Inhibits Vascular Endothelial Growth Factor (VEGF) tumour angiogenesis

Genetech

Cervarix HPV vaccine

ABVD

Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine -> Hodgkin's

lymphoma

MOPP

Mechlorethamine, Oncovin (vincristine), procarbazine, prednisone Hodgkin's

lymphoma


20/41

AntiviralViral Uncoating Inhibitors (inhibits influenza A, inhibit M2 protein -> viral

envelope -> enables H+ to enter -> facilitates uncoating)

Amantadine (18hrs, R)

o O (slow), peak 3-4hrs

o Low PPB

o Insomnia, dizziness, dry, mouth, teratogneic

Rimantadine

Enfuvirtide (binds to CD4, prevents HIV gp120) (4hr)

Given in combination

IV, SC 100mg/bid

BA by SC = 84%

92% PPB

DNA polymerase Inhibitors (phosphorylated to tri-phosphate by thymidine

kinase, inhibits DNA polymerase, cause strand termination) -> HSV1/2, VZV, EBV,

CMV

Acyclovir (selectively phosphorylated in viral cells) (2-3 hrs, R)

o Guanine analogue

o Parenternal, poor I 20% BA

o Low PPB, widely distributed, CSF

o SE: inflammation at site of IV, nausea

Valacyclovir (selectively phosphorylated in viral cells) (R)

o Prodrug of acyclovir -> converted by esterases in intestines and liver

o 55% BA

Idoxuridine (R)

o Uridine analogue

o T only, cyototxic


21/41

o Local irritation, edema, itching, corneal clouding

Vidarabine (3.5hrs, R)

o T, IV

o Converted to hypoxanthine arabinoside

o Low lipid soluble but gets in CSF

o SE: anorexia, emesis, peripheral neuropathy, diarrhea, irriatation when

applied to eye

o Contraindication in pregnancy

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) (require phosphorylation,

inhibit reverse transcriptase by being incorporated into newly synthesized viral DNA

preventing elongation, selective)

Zidovudine (ZDV, AZT) (0.9-1.5hrs, M)

o Thymidine analogue

o Good O

o Low PPB, passes into CSF

o Contraindicated in pregnanct

o

HIV, HTLV

o SE: anaemia, granulocytopenia, nausea, fever, headache

Lamivudine (3TC)

Didanosine (ddl)

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (directly binds to enzyme)

Nebirapine (1hr, H)

o Good O, 93%

o 60% PPB

o Low SE, SJ syndrome

Delaviridine (5hrs, R)

o 85% BA


22/41

o 98% PPB

o Low SE, allergic reaction

Interferons-antiviral state promoters (cytokines -> increase antiviral state incells, triggered by abnormal amounts of dsRNA) -> binds to cell -> causes synthesis

of protein kinases that prevent translation + synthesis of endonucleases which

destroy viral mRNA

Alpha produced by WBC

Beta produced by connective tissue fibroblasts

Gamma produced by T-lymphocytes

Broad spectrum: DNA (HSV1/2, HPV, VZV, HBV), RNA (influenza, HCV)

Parenternal only: IM, SC

Also Topical in nasal spray

SE: flu-like symptoms, fatigue, depression, muscle weakness, change in

thyroid finction, bone marrow suppression with high doses

Protease Inhibitors (inhibition of late protein assembling, used in combination) (90% PPB

o SE: hypotension, emesis, headache, labored breathing (1-3 hours after

start of IV, rare)

o Accumulates in tissue, low CSF, increases with inflammation

Nystatin (bind to ergosterol causing pore formation in membrane)

o Streptomyces moursei

o Broad spectrum, superficial only, fungicidal

o Only topical (insoluble in water and plasma

o Only oral, vaginal and intestinal

o SE: nausea, diarrhoea


24/41

Azoles (competitive inhibition of lanosterol demthylase, inhibits ergosterol,

cell membrane integrity)

o Fluconazole (27-37 hrs, R)

O, IV

Fluoride triazole

Drug of choice for cryptococcal meningitis

11% PPB, accumulates in tissue high CSF

SE: GIT upset, nausea, rare hepatitis and SJ syndrome

Negligible inhibition of p450

Nail infection (tinea unguium) 150mg

o Itraconazole

o Ketoconazole (1-4hrs and 6-10hrs, M P450 -> B)

Good O in stomach, IM

Broad spectrum, fungistatic

90% PPB, poor CSF

SE: inhibit steroids (used in prostate cancer), inhibits p450,rashes, pruritus

o Clotrimazole

Topical only, 1% creams, 100-500mg vaginal tablets, lozenges

Vaginal candida, dermatophytes

SE edema, pruritus, urticaria

Terbinafine (reversible non-competitive inhibition of ergosterol synthesis

(squalene epoxidase) (200-400hrs, R)

o O

o 250mg for 6 weeks, toenail and fingernail

o Low BA = 40%, >99% PPB, accumulate in skin, nail, fat


25/41

o Dermatophytes (alternative to griseofluvin)

o SE: inhibit cyp450, neutrapenia, lymphocytopenia, hepatic failure

(contraindication hepatic failure patients

o Tines unguium nail infections, 250mg, qid 6-12 weeks

Flucytosine (prodrug, pyrimidine analog, cytosine deaminase coverts to 5-

fluorouracil, enzyme low in host cell -> 5-FdUMP -> inhibit thymidylate synthase

and disrupts DNA, RNA, protein synthesis) (2.5-6hrs, R)

O, slow absorption

Systemic infection + AMPHOTERICIN B or AZOLES (reduces resistance)

SE: nausea, emesis, bone marrow suppression)

Griseofulvin (from penicillium, specific for dermatophytes, accumulates in newlysynthesized keratinized tissue -> when fungus enters tissue it binds to

microtubules, inhibits mitosis -> no effect on mature infected cells)

O, slow absorption, peak plasma conc 5 hr, give with fatty meal

Dermatophytes only, 1st line

Fungistatic, CROSSES PLACENTA

Induces cytp450

SE: leucopenia, granulocytopenia, photosensitivity, hepatic failure

AntiprotozoalQuinoline compounds (increase pH in plasmodium food vacule, prevent digestion

of haemoglobin, blood schizonticidal drugs)

Chloroquine (30-60 days, M)

o Selectively binds to heme, accumulates in infected cells

o Gametocidal except P. falciparum - First choice

o Rapid O, peak 3-5hrs, IV slowly, loading does required

o 50% PPB


26/41

o SE: pruritis, nausea, blurred visio, discolouration of nails, mucous

membranes, headaches, hypotension, vasodilation, haemolysis in

G6PD diff

o TD: cardiotoxicity, long term: ototoxicity peripheral neuropathy

Mefloquine (20 days, M then F)

o Reserved for chloroquinine resistnace, can be used in pregnancy

o O only, peak 17hrs

o Well distributed in tissue, 98% PPB

o EHC?!

o SE: nausea, emesis, diarrhea, behavioural disturbances

o Contraindicated in epileptics and psychotics

Quinine (11-18hr, M 80%)

o Gametocidal

o Rapid O, peak 3hrs, IV, IM

o 90% PPB

o SE: decrease motor end plate excitability, stimulates insulin, uterine

contraction, allergic reaction, haemolysis, leucopenia, cinchonism:THNDFV, emesis, diarrhea

Artemisin and derivatives/artemether (produces free radicals in plasmodium)

(12hrs, M - active)

Blood schizonticidal drug

O, IM (in coconut oil), peak 2-6hrs

95% PPB

Can prolong QT interval (cardiotoxic)

Emesis

Primaquine (inhibiting electron transport in plasmodium -> generates reactive

species) (6 hrs, M)


27/41

Gametocidal (P falciparum)

Tissue schizonticidal (relapse due to vivax and ovale)

Good O, 1-2 hrs

No IV, causes hypotension

Concentrates in tissues, not in RBC

Haemolysis in G6PD

Abdominal cramps

Folate Inhibitors

Sulphadoxine (sulphonamide, inhibit dihydropteroate synthase) (7-9hrs, M)

o Rapid O, 85% PPB, tubular reabsorption

Pyrimethamine (pyrimidine derivative, inhibits dihydrofolate reductase,

selective for enzyme in protozoa) (80-95hrs M)

o Blood schizonticidal drug

o Slow O, peak 4-6hrs

o

Usually + SULPHADOXINE

o Also used for toxoplasmosis

o May cause anemia

Lumen Dwelling Trophozoites

Diloxanide Furoate (ameobacidal action) (R and glycn)

o Metabolized to diloxanide, 90% absorption

o Rarely causes nausea

o Main SE: flatulence

Chlorotetracycline (inhibit growth of enteric bacteria, inhibit colonization)

Parominycin (inhibit growth of enteric bacteria, inhibit colonization)


28/41

Tissue trophozites (mucosal cells -> intestinal amoeabiasis, liver -> liver

abscesses)

Metronidazole (Flagyl) (nitroimidazole, tissue trophites, anerobic protozoa

and bacteria. Prodrug -> ferredoxin oxidoreductase -> reduced cmp

produced -> DNA strand breakage) 7.5 hrs, M

o Good O, peak plasma 1-3hr

o 20% PPB, dist in body fluids and tissues

o SE: nausea, emesis, diarrhea, thrush, dark urine, ATAXIA, seizures,

METALLIC TASTE

o DISULFIRAM (treat alcoholism)

o Avoided in pregnancy

Emetidine + Dehydroemetine (not drug of choice due to toxicities, blocks

protein synthesis, more selective for protozoa)

o SC, IM, not O

o Lying down

o Concentrates in tissues

o SE: pain at site of injection, diarrhea, nausea, emesis, muscle

weakness, hypotension, CARDIOTOXIC

Chloroquinine (only affective against liver trophozoites, causes DNA and

RNA strand breakage)

Combinations

Amoebiasis (asymptomatic to mild intestinal): 1) diloxanide, 2) Paromomycin +

ciloxanide

Moderate to severe intestinal: 1) metronidazole + diloxanide, 2) chloroquine +

diloxanide

Systematic including abscesses: 1) metronidazole + diloxanide

Toxoplasma gindii: 1) pyrimethamine + clindamycin + folic acid 2) pyrimethamine

+ sulphadoxine


29/41

Pneumocystis carinii: Contrimoxazole

Cryptosporidium: Paromycin, azithromycin

AntihelminthicsIntestinal Nematodes

Benzimidazoles (bind to -tubulin, inhibit microtubule polymerization ->

reduced glucose uptake reduced oxidative phosphorolation, also inhibit

mitochondrial fumarate reductase) vermicidal, larvicidal, ovicidal

o Thiabendazole (Mintezol)

o Mebendazole (Vermox) (2-6 hrs, F + M (high first pass)

Poor O (10%)

90% PPB

SE: nausea, emesis, diarrhea (rare)

Contraindication: pregnancy, infants

o Albendazole (Zentel) (8-12 hrs, F + M)

Poor O (< 5%), increased with fat meal

SE: nausea, diarrhea, insomnia, hypotension, hypersensitivity

Contraindication pregnancy (teratogenic)

Piperazine (GABA receptor agonist flaccid paralysis) (R)

o Citrate salt (Vermizine)

o Good O absorption

o Contraindication: epilepsy

o SE: dizziness, ataxia, visual disturbances

Pyrantel Pamoate (Antiminth) (increase Ach accumulation spastic

paralysis)


30/41

o Poor oral absorption

o SE: nausea, dizziness, headaches

Blood and Tissue nematodes

Ivermectin (opens CL- ion channels -> hyperpolarization -> flaccid paralysis)(16 hrs, H -CYP450)

o Slow oral, peak plasma 4-5 hrs

o Distributes in tissue, does not criss BBB

o 93% PPB

o SE (rare) nausea, emesis, diarrhea

Diethylcarbamazine (Hetrazan) (Renders larva more susceptible to host

destruction) (2-13hrs depending on urine pH, R 50%, M 50%)

o Good oral, peak plasma conc 1-2 hrs

o SE (rare): nausea, emesis, diarrhea

Trematodes

Praziquantel (Biltricide)

Cestodes

Praziquantel (increase membrane permeability to Ca -> spastic paralysis)

(1-3 hrs, high first pass M, R and B)

o Good oral

o Peak Plasma 1-2hrs

o 80% PPB

o SE: headaches, dizziness, nausea, drowsiness

Niclosamide (inhibit oxidative phosphorlation, scolex becomes susceptibleto gut enzymes, rapid vermicidal action only) F

o Poor oral (empty GIT, chewable tablet)

o Laxative for full expulsion

o SE: nausea, emesis, diarrhea


31/41

[Cysticercosis pork tapeworm, larva invade CNS, eye -> praziquantel (prolonged

high dose), albendazole (1st line), infection of eye - prednisolone]

Histamine (L-histidine -> histamine by L-histidine decarboxylase)

H1 endothelium, brain, smooth muscle

Contracts ileum

Increase mucous secretion -> diarrhea

Antagonist epinephrine

Vasodilation

Bronchioconstriction -> asthma

Contraction of uterus -> abortion

Allergy triple response

Antagonists

o Ethanolamines

Diphenhydramine (may inhibit muscarinic receptors)

Sedative, local anesthetic, antimuscarinic, antemetic

Dimenhyrinate

o Ethylenediamines

Mepyramine (weak everything, fail)

o Alkylamines

Chlorphenamine daytime use

o Piperazines (long duration, low sedation, good antimuscarinic, very

good antiemetic)

Cyclizine

Meclizine

Chlrocyclizine

Cetirizine (anaphylaxis, adjunct with epinephrine)


32/41

Phenothiazine-mequitazine

o Phenothiazines

Promethazine (may inhibit 1-adrenoceptors) -> epic win at

everything

o Piperidines

Terfenadine Astemizole

Loratadine

SE: dry mouth, blurred vision, constipatiom, urinary retention, tinnitus,

dizziness, fatigue, excessive produce convulsions excitation in children,

topical can cause allergic dermatitis

H2 mast cells, gastric mucosa, cardiac, muscle, brain

Increase secretion of gastric acid -> peptic ulcers

Increased heart rate + baroreceptor reflex

Antagonists

o Cimetidine

Peptic ulcer

Inhibit CP450

Nausea, emesis, muscle pain, diarrhea

Gynecomastia

o Ranitidine

o Famotidine

o Nizatidine

H3 presynaptic: brain, mesenteric plexus


33/41

BradykininB1

Vascular smooth muscle

Vasodilator 10x > histamine

Chronic pain

Release of cytokines e.g. TNF, IL-1

Bronchioconstriction

B2

Normal cells and tissues, mediate effect of bradykinin in absence of

inflammation

Vasodilator 10x > histamine

Acute Pain

Contract GIT, increase fluid secretion -> diarrhea

Contracts uterus

Serotonin/5HT (derived from tryptophan)

Small intestine -> enterochromaffin cells

Platelets

CNS

Food

Carcinoid/ argentaffinoma syndrome

Receptors (5HT1-7)

o 5HT1

When endothelium intact inhibits norepinephrine

A - Regulates sleep and appetite, pain suppression


34/41

D constricts large intercranial blood vessels -> agonists,

migraine therapy

ABCDE

o 5HT2

A - vasodilation when endoepithelium is intact (platelets), when

endothelium damaged platelet aggregation, vasoconstriction,

brachioconstriction -> asthma, contracts uterus

BC

GIT motility

o 5H3 + 5H4

GIT motility

Increase fluid secretion

Nausea, emesis

Smooth muscles and neurons in stomach

Pain

5HT Agonists

5HT4 agonists

o Cisapride reflux oesophagitis, disorders of gastric emptying, can

cause diarrhea

o Metoclopramide same as above

o tegaserood irritable bowel syndrome

5HT1

o Sumatriptan migraine treatment

5HT2

o Ketanserin, cyproheptadine, pizotifen, ergot alkaloids

(methysegide, dihydroergotamine) prophylactically in migraine

o Pizotifen, Ketotifen extrinsic asthma


35/41

Eicosanoids Prostanoids

o Prostaglandins

o Thromboxanes

Leukotrienes

Synthesized from AA (phospholipase A2), released by cellular injury, c5a,

thrombin on platelets, bradtkinin, antigen-antibody reaction, epinephrine

AA + cox = prostanoids

AA + lipoxygenase = leukotrienes

Cox1 found in most cells, physiological function

Cox2 inducible during inflammation, macrophages + mast cells etc (target

for inflammatory drugs eg rofecoxib)

Prostanoids

PGI2: IP

Vasodilation

Inhibit platelet aggregation

Stimulates rennin release and natriuresis

Inhibits gastric secretion

Hyperalgesia

PGD2: DP (mast cells)

Vasodilation

Inhibits platelet aggregation

Relax GIT smooth muscle

Relax uterine muscles

Bronchioconstriction (TP receptors low affinity)


36/41

Modifies release of pituitary hormone

PGF2: FP (smooth muscle, corpus luteum)

Myometrial contraction, parturition

Dysmenorrhoea, menorrhagia


Vasoconstriction

PGE2: EP1-4 (fibroblasts, macrophages, vasculature, GIT, lungs)

EP1 -> bronchioconstriction, GIT smooth muscle contraction

EP2 -> Vasodilation, bronchiodilation, increased fluid secretion in intestines,

relaxes GIT

EP3 -> decreased gastric secretion, increased gastric mucous, inhibits

lipolysis, autonomic neurotransmitter release, contracts pregnant uterus,

relaxes cervix, dysmenorrhoea + menirrhagia

EP4-> inflammation

Hyperalgesia -> through histamines and branykinin

Pyretic effect

TXA2: TP

Vasoconstriction


Platelet aggregation might precipitate thrombosis

Acute inflammation: PGE2, PGI2, PGD2

Chronic inflammation: PGE2, TXA2

Dolor: PGE2, PGI2

Calor: PGE2

Tumor: PGE2, PGD2, PGI2

PGE2 -> RA, OA, gout


37/41

PGE1 analogue

Gemeprost - abortifacient (IV)

Misoprostol Abortifacient, oxytocic, prevent peptic ulcer when using

NSAIDS (IV)

Alprostadil impotence, maintains ductus arteriosus (indomethacin to

close)

PGE2 analogue

Dinoprostone oxytocic (IV, or O, or extra-amniotically as solution)

PGF2 analogue

Dinoprost oxytocic (cardiovascular collapse if escapes into circulation)

Carboprost postpartum haemorrahge (IM)

PGI2

Epoprostenol inhibit platelet aggregation during haemodialysis (replaces

heparin when contraindicated) -> pulmonary hypertension

SE: nausea, uterine pain

LeukotrieneLTB4 neutrophils

LTC4, LTD4, LTE4, LTF4 eosinophils, mast cells, macrophagesm basophils

LTB4: BLT

Chemotactic neutrophils, macrophages

Stimulates cytokine production

Upregulates adhesion

Increase ROS release from neutrophils

Inflammatory conditions RA, ulcerative colitis

CysteinylLTs: CysLT


38/41

Bronchioconstriction, increase mucous secretion -> asthma

IV injection of LTC4 and D4 -> rapid decrease in BP, short DOA, constriction

coronary vessels

LTD4 topically in nose -> blood flow, vascular permeability

Bronchial lavage fluid -> chronic bronchitis

Inhibitors of Leukotrines

CysLT

o Zafirlukast adjunct to other antiasthmatic

o Montelukast prevent acute attack

5-lipoxygenase

o Zileuton antiinflammatory, antiasthmatic

o Piripost antiinflammatory, antiasthmatic

Immunoreceptors

Selective immunosuppressive

Cyclosporine (inhibition of release and receptor of IL-2 -> lower T helper and CD8+cytotoxic T cell, binds to cyclophilin -> calcineurin) 24hrs, H cp450

O, IV

Acute and chronic suppression of organ rejection (heart, kidney, liver,

pancreas)

Given with PREDINOSOLONE

SE: nephro, neuro, hepato toxicity, hypertension/kalemia, hirsutism, NO BONE

MARROW SUPPRESSION

Tacrolimus (macrolide antibiotic, similar to cyclosporine except binds to FKBPs

instead) 7hr, H CP450

O, IV

X10-100 Greater than cyclosporine


39/41

Used for prophylaxis against liver and kidney

Preferred in liver transplants than cyclosporine

Given with: GLUCOCORTICOID

SE: more toxic than cyclosporine, neuro, nephro hepato toxicity,

hypertension/glycemia, thrombocytopenia, NO HIRSUTISM

Non-selective immunosuppressants

Corticosteroids (H) (decrease IL1-8, binds to GM-CSF, inhibits PGE2 ->

reduced cox2, reduce iNOS, leukotriene synthesis, histamine release from

basophils, IgG production, complement components)

o Prednisolone

O, IV, IM, inhalation

RA, SLE, Myasthenia gravis

Suppress allograft rejection

Infection

Cushings syndrome, osteoporosis, hyperglycemia, glaucoma,

orapharyngeal candidasis

Increase osteoclast activity, decrease osteoblast activity, affect

phosphorous and calcium metabolism. Insulin resistance

o Deamethasone

Cushings syndrome buffalo hump, hypertension, thin skin, thin limbs, muscle

wasting, benign intercranial hypertension, cataracts, moon face, increased

abdominal fat, avascular necrosis of femoral head, easy bruising, poor wound

healing

Cyclophosphamide (alkylating agent) (3 12 hrs IV, metabolized to acrolein ->

phosphoramide, H CP450)

O, IV, IM

Extremely powerful

Ablate lymphoid elements for bone marrow transplant


40/41

SLE, hemolytic anemias, Wegeners granulomatosis

Given with PREDNISONE + ANTILYMPHOCYTE GLOBULIN

SE: bone marrow suppression, thrombocytopenia, hemorrhagic cystitis,

nausea, emesis)

Methotrexate (folate analogue, dihydrofolate reductase) (8-10hrs, H, conversion to

polyglutamates)

O, IM, IV

Given with CYCLOSPORINE for prophylaxis of GvHD, bone marrow

transplant, severe RA

Psoriasis refractory to other drugs

SE: bone marrow suppression, hepatic fibrosis, cirrhosis, pneumonitis, GITepithelial damage

Azathioprine (prodrug to 6MP, S phase specific, inhibits DNA synthesis, inhibits T

and B in induction phase) (10-20mins, 6-MP 50mins in adults, H)

O, IV

Renal transplantation, hemolytic anaemias, acute glomerulonephritis

Amplified by ALLOPURINOL (xanthine oxidase breaks down azathioprine)

SE: bone marrow suppression, hepatotoxicity, nausea, emesis

Mycophenolate Mofetil (synthetic estser from fungus, hydrolyzed in GIT ->

mycophenolic acid, reversible inhibition of monophosphate dehydrogenase ->

purine sysnthesis, inhibits T and B cell and leukocyte recruitment) (18hrs, H)

Good O

Given with CORTICOSTEROIDS + CYCLOSPORINE

Mg(OH)2 and Al(OH)3 impair absorption

Immunosuppressive antibodies

Basiliximab, Daclizumab (monoclonal antibodies against IL-2 receptor)

o IV

o Kidney transplant


41/41

o Serious hypersensitivity, abdominal pain

Muromonab-CD3 (monoclonal antibody against CD3 on T cells)

o IV

o Renal, cardiac allograft rejection

o Anaphylactoid reactions, seizures, high fever

Anti-lymphocyte globulin (destroys T cells)

o Given with ANTIMETABOLITES and CORTICOSTEROIDS

o Allograft rejection kidney

o Aplastic anemia

Documents

Bible of Drugs=MUST USE