Download Tetracyclines

Basic and Clinical Pharmacology
Dr. J.M.Nguta, BVM, MSc, PhD, Pharmacol
& Toxicol (UON).
Notes available at: [email protected]
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.)
 LD50=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-2mercapto-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-1795-1881, Scottish
Historian and essayist, Leading figure in the Victorian
Era)