Basic and Clinical Pharmacology Dr. J.M.Nguta, BVM, MSc, PhD, Pharmacol & Toxicol (UON). Notes available at:

Description Broad spectrum antibiotic Produced by Streptomyces genus of Actinobacteria Bacteriostatic (binds to 30S ribosomal subunit) Could also bind to 50S subunit Causes cytoplasmic membrane alterations with Incr. efflux of intracellular bacterial components

Indications Broad spectrum antibiotics: active against gram +ve and gram –ve bacteria. Drugs of choice in: Chlamydophilosis; Ehrlichiosis; Coxiellosis; Rickettsiosis and for some Mycobacterial and Mycoplasmal infections

Pharmacodynamics Reversible binding to 30S subunit Also binds to some extent to 50S subunit Alterations of cytoplasmic membrane inducing leakage of nucleotides from the bacterial cell

Mechanism of Action Diffusion through porin bacterial channels Reversible binding Inhibition of binding of tRNA to the mRNA ribosome complex Interference with protein synthesis

Pharmacokinetics Bioavailability: less than 40% I.M; 100% I.V; 60-80% Oral. Food and /milk reduces GI absorption by 50% or more Upto 67% plasma protein bound Not metabolised Concentrated by the liver in bile &Eliminated in urine and feaces in biologically active form.

Pharmacokinetics (Cont.) LD 50 =808mg/kg (orally in mice) Doxycycline is excreted in feaces

Bacterial resistance Energy dependent efflux Ribosomal protection Chemical modification and enzymatic catalysis

Drug interactions Absorption is decr. By antacids; iron containing prep. Synergism with tylosin in pasteurella Rx Comb. With polymixins incr. their efficacy. Doxycycline is synergistic with rifampicin or streptomycin in brucellosis Rx Doxy. Is synergistic with.pyrimethamine in toxoplasmosis Rx.

Toxicity and adverse effects Relatively safe drugs Toxicity is attributed to their irritant nature; Disturbances of intestinal flora Ability to bind calcium (cardiovascular effects, deposition in teeth and bone); Their toxic effects on liver and kidney cells.

Antineoplastic drugs Drugs used in cancer chemotherapy Goal (remission/palliation) Challenges: Increased toxicity (myelosuppression and git injury). Mostly affected: rapidly dividing cells e.g. bone marrow; intestines; testis; skin Also apoptosis; peripheral neuropathy

Cancerous cells: the target site! Biological similarity with normal ells Neoplastic cells are dividing more rapidly: Quantitative differences

Cell cycle kinetics Important aspect since many antineoplastics target rapidly dividing cells: cell cycle specificity-:G1; S; G2; M; G0 Phase. The question of incr. vulnerability to bone marrow and git cells due to their rapid division arises. Cells in G0: resistant to chemotherapy!

Drug resistance, a chemotherapeutic challenge! Incr. efflux Enzymatic catalysis Rapid DNA repair Decr. Binding to target sites in the tumor cells.

Alkylating agents CCNS agents Substituting an alkyl group for a reactive hydrogen atom in the DNA leading to cross linking of the DNA molecule Include nitrogen mustards and nitrosoureas Dose limiting toxicity: bone marrow suppression Are carcinogenic and mutagenic

Nitrogen mustards Cyclophosphamide: well distributed following oral & I.V adm. Metabolism Toxicity (diarrhoea; vomiting; cysitis); myelosuppression Cystitis minimized by diuresis and Mesna((sodium-2- mercapto-ethane sulfonate),

Nitrogen mustards Others are: Ifosfamide; chlorambucil and melphalan

Nitrosoureas Carmustine and lomustine Highly lipophilic Indicated in brain tumors Toxic to the CNS, liver and kidneys

B). Antimetabolites Folic acid analogues (methotrexate) and pyrimidine analoques (5-fluoro uracil & Cytosine arabinoside ) Methotrxate is a CCS, active against the S phase Inhibits dihydrofolate reductase and thymidylate synthase enzymes for purine and pyrimidine synthesis

Methotrexate Hence interferes with folic acid synthesis in cancerous and normal cells Calls for leucovorin (folate co enzyme) adm. Well distributed to all tissues except CNS

Pyrimidine Analoques 5-fluorouracil, a, CCS, targeting the S phase Inhibits thymidylate synthase activity, thereby inhibiting DNA synthesis. Variable git absorption-adm.i.v Shows enhanced CNS toxicity in cats: hence contraind. Dose limiting toxicity: Bone marrow and git toxicity

C). Mitotic Inhibitors Vinca alkaloids (vincristine and vinblastine,) CCS at the M phase. Well distributed except in the CNS. Adm I.V. Metabolism and excretion Vinblastine is less tolerated in small animals Indicated in transmissible venereal tumors (TVT)

D). Antibiotics CCNS agents, inhibiting DNA and RNA synthesis Include the anthracyclines (doxorubicin, mitoxantrone), dactinomycin and bleomycin. Adm. I.V. Dose limiting toxicity is myelosuppression

E). Enzymes Asparaginase (L-asparagine amidohydrolase) : inhibits protein synthesis G1 phase specific Toxicity includes induction of an anaphylactic reaction, pancreatitis and hepatotoxicity

F). Platinum Co-ordination Complexes Cis-platinum: inhibits DNA synthesis Dse limiting toxicity: nephrotoxicity Use of diuretics Contraindications: in cats due fatal pulmonary vasculitis Carboplatin is better tolerated than Cis-platinum

G). Corticosteroids Incorporated in cancer chemotherapy protocols: are cytotoxic CCNS Metabolized in the liver and excreted in urine Dose limiting toxicity: immunosuppression & git toxicity.

H). Miscellaneous Agents i).Hydroxyurea S phase specific Excreted unchanged in urine Dose limiting toxicity: bone marrow depression

ii). Procarbazine CCNS (a potent carcinogen and teratogen) Well absorbed following oral adm. Leads to DNA damage via incr. generation of reactive free radicals A MAOI: hence containdicated in patients taking tricyclics; sympathomometic amines and tyramine cont. foods Dose limiting toxicity: myelosuppression

Brainy quote Thomas Carlyle Quote: Permanence, perseverance and persistence in spite of all obstacles, discouragement, and impossibilities: It is this, that in all things distinguishes the strong soul from the weak” (Thomas carlyle , Scottish Historian and essayist, Leading figure in the Victorian Era)