Basic and Clinical Pharmacology Dr. J.M.Nguta, BVM, MSc, PhD, Pharmacol & Toxicol (UON). Notes...
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Transcript of Basic and Clinical Pharmacology Dr. J.M.Nguta, BVM, MSc, PhD, Pharmacol & Toxicol (UON). Notes...
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Basic and Clinical PharmacologyDr. J.M.Nguta, BVM, MSc, PhD,
Pharmacol & Toxicol (UON).Notes available at:
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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
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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
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PharmacodynamicsReversible binding to 30S subunit Also binds to some extent to 50S subunitAlterations of cytoplasmic membrane
inducing leakage of nucleotides from the bacterial cell
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Mechanism of ActionDiffusion through porin bacterial channelsReversible bindingInhibition of binding of tRNA to the mRNA
ribosome complexInterference with protein synthesis
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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.
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Pharmacokinetics (Cont.)LD50=808mg/kg (orally in mice)Doxycycline is excreted in feaces
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Bacterial resistanceEnergy dependent effluxRibosomal protectionChemical modification and enzymatic
catalysis
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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.
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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.
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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
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Cancerous cells: the target site!Biological similarity with normal ellsNeoplastic cells are dividing more rapidly:
Quantitative differences
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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!
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Drug resistance, a chemotherapeutic challenge!Incr. effluxEnzymatic catalysisRapid DNA repairDecr. Binding to target sites in the tumor
cells.
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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
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Nitrogen mustardsCyclophosphamide: well distributed following
oral & I.V adm.MetabolismToxicity (diarrhoea; vomiting; cysitis);
myelosuppressionCystitis minimized by diuresis and
Mesna((sodium-2-mercapto-ethane sulfonate),
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Nitrogen mustardsOthers are: Ifosfamide; chlorambucil and
melphalan
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NitrosoureasCarmustine and lomustineHighly lipophilicIndicated in brain tumorsToxic to the CNS, liver and kidneys
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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
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MethotrexateHence interferes with folic acid synthesis in
cancerous and normal cellsCalls for leucovorin (folate co enzyme) adm.Well distributed to all tissues except CNS
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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
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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)
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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
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E). Enzymes
Asparaginase (L-asparagine amidohydrolase) : inhibits protein synthesis
G1 phase specificToxicity includes induction of an anaphylactic
reaction, pancreatitis and hepatotoxicity
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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
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G). Corticosteroids
Incorporated in cancer chemotherapy protocols: are cytotoxic
CCNSMetabolized in the liver and excreted in urineDose limiting toxicity: immunosuppression &
git toxicity.
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H). Miscellaneous Agents
i).HydroxyureaS phase specificExcreted unchanged in urineDose limiting toxicity: bone marrow
depression
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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
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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)