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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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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)
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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
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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)
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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
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[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)
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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
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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
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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
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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)
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Modifies release of pituitary hormone
PGF2: FP (smooth muscle, corpus luteum)
Myometrial contraction, parturition
Dysmenorrhoea, menorrhagia
Bronchioconstriction
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
Bronchioconstriction
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
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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
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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
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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
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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
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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