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

 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
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 CARBENICILLIN
o 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
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
 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 (Merremâ)
 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

Quinolones (inhibits topoisomerase IV [+ve] or DNA gyrase [-ve], Bactericidal at 30 X the MIC)

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

 Nalidixic acid (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)
 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
 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
 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
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
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
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)

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
 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, BURKITTS’S
AND NON-HODGKIN’S LYMPHOMAS
 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
 Fludarabine Phosphate
 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

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, Ewing’s sarcoma, osteosarcoma
o Cardiotoxicity (involves production of free radicals -> use antioxidants)

Natural Products
VInca 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-G 2 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
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

Hormones
Estrogens

 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

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 Cushings’s syndrome
o Lymphoma

Progestins

 Megestrol
o Fluid rentention
o Endometrial cancer

Finasteride (Proscar®)

 5-α-Reductase enzyme inhibitor

 Prostate cancer

Immunotherapy: IL2, Interferon-α

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

Antiviral
Viral 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
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
o 98% PPB
o Low SE, allergic reaction

Interferons-antiviral state promoters (cytokines -> increase antiviral state in cells, 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) (< 1hr, H cyp450)

 Saquinavir
o Variable O
o 98% PPB
o Distributes well in tissue
o SE: nausea, diarrhea, hyperglycemia, hepatotoxic
 Ritonavir
 Indinavir
 Darunavir

Combination therapy – HAART

 Nucleoside analog – zidovudine (AZT)

 Protease inhibitor – saquinavir
 Another nucleoside inhibitor – lavimudine
 OR NNRTI - nevirapine

Antifungals

Ergosterol Disruption Agents

 Amphotericin B (bind to ergosterol causing pore formation in membrane) (very slow R [up to
2mnths], 1-2 days and 15 days
o Streptomyces nodosus
o Topical, poor O, slow IV (lipophillic)
o Colloidal suspension e.g. sodium deoxycholate susp – C-AMB
o Lipid formulations (less toxic) e.g. cholerteryl sulphate
o SE: cytokine release (fever, shaking chills) with 1 st dose preventable by giving aspirin or
glucocortocoid, pain, seizures, phlebitis (prevented by heparin), hypokalemia,
nephrotoxicity (80%)
 o >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
 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
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 newly synthesized 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

Antiprotozoal
Quinoline 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
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)

 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)

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

Pneumocystis carinii: Contrimoxazole

Cryptosporidium: Paromycin, azithromycin

Antihelminthics
Intestinal Nematodes

 Benzimidazoles (bind to b-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)
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 susceptible to gut enzymes, rapid
vermicidal action only) F
o Poor oral (empty GIT, chewable tablet)
o Laxative for full expulsion
o SE: nausea, emesis, diarrhea

[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)
 Phenothiazine-mequitazine
o Phenothiazines
  Promethazine (may inhibit α1-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

Bradykinin
B1

 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
 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
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)
 Modifies release of pituitary hormone

PGF2α: 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

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 α 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

Leukotriene
LTB4 – 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

 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
 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
 Cushing’s 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
 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, GIT epithelial 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
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