Basic and Clinical PharmacologyDr. J.M.Nguta, BVM, MSc, PhD,

Pharmacol & Toxicol (UON).Notes available at:

bvm2010@gmail.com

DescriptionBroad spectrum antibioticProduced by Streptomyces genus of

ActinobacteriaBacteriostatic (binds to 30S ribosomal

subunit)Could also bind to 50S subunitCauses cytoplasmic membrane alterations

withIncr. efflux of intracellular bacterial

components

IndicationsBroad 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

PharmacodynamicsReversible binding to 30S subunit Also binds to some extent to 50S subunitAlterations of cytoplasmic membrane

inducing leakage of nucleotides from the bacterial cell

Mechanism of ActionDiffusion through porin bacterial channelsReversible bindingInhibition of binding of tRNA to the mRNA

ribosome complexInterference with protein synthesis

PharmacokineticsBioavailability: less than 40% I.M; 100% I.V;

60-80% Oral.Food and /milk reduces GI absorption by 50%

or moreUpto 67% plasma protein boundNot metabolisedConcentrated by the liver in bile &Eliminated

in urine and feaces in biologically active form.

Pharmacokinetics (Cont.)LD50=808mg/kg (orally in mice)Doxycycline is excreted in feaces

Bacterial resistanceEnergy dependent effluxRibosomal protectionChemical modification and enzymatic

catalysis

Drug interactionsAbsorption is decr. By antacids; iron

containing prep.Synergism with tylosin in pasteurella RxComb. With polymixins incr. their efficacy.Doxycycline is synergistic with rifampicin or

streptomycin in brucellosis RxDoxy. Is synergistic with.pyrimethamine in

toxoplasmosis Rx.

Toxicity and adverse effectsRelatively safe drugsToxicity is attributed to their irritant nature;Disturbances of intestinal floraAbility to bind calcium (cardiovascular

effects, deposition in teeth and bone); Their toxic effects on liver and kidney cells.

Antineoplastic drugsDrugs used in cancer chemotherapyGoal (remission/palliation)Challenges: Increased toxicity

(myelosuppression and git injury).Mostly affected: rapidly dividing cells e.g.

bone marrow; intestines; testis; skinAlso apoptosis; peripheral neuropathy

Cancerous cells: the target site!Biological similarity with normal ellsNeoplastic cells are dividing more rapidly:

Quantitative differences

Cell cycle kineticsImportant 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. effluxEnzymatic catalysisRapid DNA repairDecr. Binding to target sites in the tumor

cells.

Alkylating agentsCCNS agentsSubstituting an alkyl group for a reactive

hydrogen atom in the DNA leading to cross linking of the DNA molecule

Include nitrogen mustards and nitrosoureasDose limiting toxicity: bone marrow

suppressionAre carcinogenic and mutagenic

Nitrogen mustardsCyclophosphamide: well distributed following

oral & I.V adm.MetabolismToxicity (diarrhoea; vomiting; cysitis);

myelosuppressionCystitis minimized by diuresis and

Mesna((sodium-2-mercapto-ethane sulfonate),

Nitrogen mustardsOthers are: Ifosfamide; chlorambucil and

melphalan

NitrosoureasCarmustine and lomustineHighly lipophilicIndicated in brain tumorsToxic 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

MethotrexateHence interferes with folic acid synthesis in

cancerous and normal cellsCalls for leucovorin (folate co enzyme) adm.Well distributed to all tissues except CNS

Pyrimidine Analoques

5-fluorouracil, a, CCS, targeting the S phaseInhibits thymidylate synthase activity,

thereby inhibiting DNA synthesis. Variable git absorption-adm.i.vShows 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 excretionVinblastine is less tolerated in small animalsIndicated 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 specificToxicity includes induction of an anaphylactic

reaction, pancreatitis and hepatotoxicity

F). Platinum Co-ordination Complexes

Cis-platinum: inhibits DNA synthesisDse limiting toxicity: nephrotoxicityUse of diureticsContraindications: in cats due fatal

pulmonary vasculitisCarboplatin is better tolerated than Cis-

platinum

G). Corticosteroids

Incorporated in cancer chemotherapy protocols: are cytotoxic

CCNSMetabolized in the liver and excreted in urineDose limiting toxicity: immunosuppression &

git toxicity.

H). Miscellaneous Agents

i).HydroxyureaS phase specificExcreted unchanged in urineDose 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 radicalsA MAOI: hence containdicated in patients

taking tricyclics; sympathomometic amines and tyramine cont. foods

Dose limiting toxicity: myelosuppression

Brainy quoteThomas 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-1795-1881, Scottish Historian and essayist, Leading figure in the Victorian Era)