Definition: analysis, assessment, & evaluation of circulating
concentrations of drugs in serum, plasma, or whole blood Purpose: to ensure that a given drug dosage produces maximal therapeutic benefit & minimal toxic adverse effects Used when safe dosage regimens have not been established & a trial & error approach is not appropriate Standard dosage derived from observations in healthy population. Involves quantitative evaluation of circulating drug concentration Key factors: route of administration, rate of absorption, distribution of drug within body, rate of elimination Overview of factors that influence the circulating concentration of an orally administered drug
Intravenous (IV): injected directly into circulation Intramuscular (IM): injected into muscle Subcutaneous (SC): injected just under skin Transcutaneous: inhaled or absorbed through skin Suppository: rectal delivery Oral Administration: by mouth
For orally administered drugs, efficiency of absorption from GI tract depends on many factors: Formulation of drug: tablets, capsules, liquid solutions Uptake by transport mechanisms intended for dietary constituents vs. passive diffusion Changes in intestinal motility, pH, inflammation, food, other drugs Variation among population Age, pregnancy, pathologic conditions
Free vs. Bound Only free (unbound) fraction of drug can interact with site of action & cause biologic response. Percentage free depends on physiologic & biochemical parameters: Inflammation, malignancies, pregnancy, hepatic disease, nephrotic syndrome, malnutrition, acidbase disturbances Concentration of other substances competing for binding sites Drug Distribution Ability of drug to diffuse out of circulation Depends on lipid solubility of drug
Rate of change of drug concentration over time varies continuously in relation to concentration of drug. Elimination equation: C/T = -kC Metabolic Clearance Hepatic mixed function oxidase (MFO) system Converts hydrophobic substances into water-soluble ones Transports them into bile or circulation, eliminates them by renal filtration Renal Clearance
First-order drug elimination
Pharmacokinetics Mathematic modeling of drug concentration in circulation Assists in establishing or modifying a dosage regimen Takes into account all factors that determine concentration of a serum drug & its rate of change (absorption, distribution, elimination, etc.) Sample Collection Timing is critical: trough concentrations, right before next dose; peak concentrations, 1 hour after oral dose Serum or plasma is specimen of choice.
Responders: patients benefitting from therapeutic & desired effects of drug Non-responders: patients not benefitting from therapeutic & desired effects of drug Therapeutic effectiveness of drugs has been attributed to inter-individual variation in genetic polymorphisms of drug metabolism pathways. Cytochrome P450: gene group family that affects drug metabolism
Cardiac Glycosides Digoxin Purpose: used in treatment of congestive heart failure Function: inhibits membrane Na-K-ATPase Absorption: variable, influenced by dietary factors, GI motility, formulation of drug Elimination: renal filtration of plasma free form Half-life (plasma): 38 hours in average adult Measurement: immunoassay to determine total concentration in serum
Antiarrhythmics Quinidine Most common formulations are quinidine sulfate & quinidine gluconate. Procainamide Disopyramide Used as a quinidine substitute when quinidines adverse effects are excessive
Aminoglycosides A group of chemically related antibiotics used for treatment of infections with gram-negative bacteria that are resistant to less toxic antibiotics Most common: gentamicin, tobramycin, amikacin, kanamycin Vancomycin A glycopeptide antibiotic that is effective against gram-positive cocci & bacilli
First Generation Phenobarbital A slow-acting barbiturate that effectively controls several types of seizures Phenytoin A commonly used treatment for seizure disorders Used as a short-term prophylactic agent in brain injury to prevent loss of functional tissue Valproic acid Used as a monotherapy for treatment of petit mal & absence seizures
First Generation Carbamazepine An effective treatment in various seizure disorders Because of its serious toxic adverse effects, it is less frequently used. Ethosuximide Used for control of petit mal seizure Second Generation Felbamate An orally administered drug that is nearly completely absorbed by the GI tract Known for its toxicity & is primarily indicated in severe epilepsies such as Lennox-Gastaut syndrome (children) & refractory epilepsy (adults) Gabapentin May be indicated as monotherapy or in conjunction with other antiepileptic drugs in patients suffering from complex partial seizures with or without generalized seizures Second Generation Lamotrigine Levetiracetam Indicated in partial & generalized seizures Oxcarbazepine A pro-drug that is almost immediately metabolized to licarbazepine Indicated for monotherapy of partial seizures & in secondarily generalized tonic-clonic seizures Second Generation Tiagabine Indicated in partial seizures Topiramate Indicated in partial & generalized seizures Zonisamide Indicated in partial & generalized seizures Lithium: orally administered; used to treat manic depression Tricyclic Antidepressants: a class of drugs used to treat depression, insomnia, extreme apathy, & loss of libido Clozapine: an atypical antipsychotic used to treat otherwise treatment-refractory schizophrenia Olanzapine: a thienobenzodiazepine derivative that effectively treats schizophrenia, acute manic episodes, & recurrence of bipolar disorders
Cyclosporine: Primary clinical use is suppression of host-versus-graft rejection of heterotropic transplanted organs. Tacrolimus: 100 times more potent that cyclosporine Sirolimus: an antifungal agent with immunosuppressive activity; FDA approved for patients receiving kidney transplants Mycophenolic Acid: a lymphocyte proliferation inhibitor; used most commonly as supplemental therapy with cyclosporine & tacrolimus in renal transplant patients Methotrexate One of few antineoplastic drugs in which TDM offers benefits to a therapeutic regimen High-dose methotrexate followed by leucovorin rescue has been shown to be an effective therapy for various neoplastic conditions. Basis of this therapy involves relative rate of mitosis of normal vs. neoplastic cells. Neoplastic cells divide more rapidly than normal cells, have higher requirement for DNA, and are susceptible to deprivation of this essential constituent before normal cells. Efficacy depends on controlled period of inhibition, accomplished by leucovorin.
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