Clinical Pharmacokinetics and Pharmacodynamics

Clinical Pharmacokinetics and Pharmacodynamics



Basic Information image



Overview and Goal(s)




• Pharmacokinetics is what the body does to the drug.


• Pharmacodynamics is what the drug does to the body, cell, or pathogen.



Procedure



Pharmacokinetics



• ADME: Mathematical evaluation of the rates of drug absorption (A), distribution throughout the body (D), along with metabolism (M), and ultimate excretion from the body (E).


• Absorption


image Indicates the process whereby drug is transferred from the site of administration to the systemic circulation.

image An intravenously administered drug is 100% absorbed.

image Bioavailability (F) is the fraction of the dose administered extravascular that reaches intact the systemic circulation.

image Determined by comparing the area under the plasma drug concentration curve versus time (AUC) after extravascular (EV) administration to the AUC after intravenous (IV) administration.

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image If the EV AUC is significantly less than the IV AUC, then the drug dose must be adjusted for the EV route.

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image Reasons for low bioavailability of drugs in horses:

image Extensive “first pass effect”

image Poor dissolution of drug in gastrointestinal fluids

image Drug instability in gastric juices

image Transporter interactions (eg, ABCB1/MDR1/P-glycoprotein in intestine)

image Drug interactions leading to poor solubility, enzyme induction

image For IM or SC injections: Poor circulation at injection site, improper injection technique, insoluble complex formation

image If a drug has a narrow therapeutic margin and the F is low, with substantial variation between horses, then there may be no ideal dose for that formulation.

image The oral F for enrofloxacin in horses is approximately 50%, so suggested oral doses are twice the IV doses.

image The oral F for ciprofloxacin is approximately 6%, so it is not feasible to use oral ciprofloxacin in horses.

• Drug distribution


image Determined by the drug’s ability to cross biologic membranes and reach tissues outside the systemic circulation.

image Volume of distribution (Vd) (L/kg): The apparent volume of the body in which a drug is dissolved, but it does not correspond to any specific physiologic compartment.

image Vd is used to calculate the dose of drug given to produce a desired plasma drug concentration, (eg, a loading dose).

image Vd is determined by transporter function and the physical characteristics of the drug, including:

image Protein binding

image Ionization

image Lipid solubility

image Molecular size

image Although Vd describes the extent of distribution of a drug, it does not confirm penetration of a drug to specific tissues.

image When penetration into specific tissues is unknown, a large Vd drug (Vd > plasma volume) is more likely to distribute there than a low Vd drug.

image Vd can change with specific physiologic or pathologic conditions.

image Any condition that changes extracellular fluid volume affects the plasma concentrations of drugs with low Vd values (eg, competition with endogenous substances for protein binding sites).

image Aminoglycosides and nonsteroidal antiinflammatory drugs (NSAIDs) have low Vd values and plasma concentrations and risks of toxicity are increased in dehydrated horses.

image Drugs with high Vds are not significantly affected by changes in body water status but may be affected by changes in body fat.

image Moxidectin distributes into fat, therefore higher plasma concentrations and a greater risk of toxicity are seen in foals or debilitated adult horses.

• Protein binding


image Many drugs in circulation are bound to plasma proteins.

image Albumin

image Lipoprotein

image Glycoprotein

image If the protein binding is reversible, then a chemical equilibrium will exist between the bound and unbound states:

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image Bound drug is too large to pass through biologic membranes, so only free drug is available for delivery to the tissues and to produce the desired pharmacologic action.

image With few exceptions, only free drug is available for metabolism and excretion.

image Bound drug may act as a drug reservoir or depot, from which the drug is slowly released as the unbound form.

image Responsible for the long dosing interval for ceftiofur compared to other cephalosporins.

image Drug-drug interactions from protein displacement are rarely clinically significant and typically do not require dosage adjustment.

image Increased anticoagulant effects seen with concurrent administration of phenylbutazone and warfarin are due to inhibition of hepatic metabolism of warfarin from phenylbutazone and not from displacement from protein binding sites.

• Lipid solubility and drug ionization (the pH-partition hypothesis)


image The degree of lipid solubility determines how readily a drug will cross biologic membranes.

image Most drugs are weak acids or weak bases.

image Ionized drug is hydrophilic and poorly lipid-soluble.

image Nonionized drug is lipophilic and can cross biologic membranes.

image The degree of ionization for a weak acid or weak base depends on the pKa of the drug and the pH of the surrounding fluid.

image It is calculated from the Henderson-Hasselbach equation:

image For a weak acid: pH = pKa + log (ionized drug/nonionized drug)

image For a weak base: pH = pKa + log (nonionized drug/ionized drug)

image When the pH is equal to the pKa of the drug, then the drug is 50% ionized and 50% nonionized (log 1 = 0).

image Basic drugs can be “ion trapped” when they move from the plasma to sites where fluids are more acidic than plasma such as cerebrospinal fluid, milk, and infected tissues.

• Flip-flop kinetics


image Oral and injectable “long-acting “drug formulations are often slowly absorbed into the systemic circulation.

image This causes the drug elimination rate to be limited by the drug absorption rate.

image Flip-flop kinetics is identified by comparing the plasma concentration versus time curve for the extravascular route of administration to the curve after the drug is given intravenously. If the slopes of the elimination phases are not parallel, then absorption is limiting elimination (Figure 1).

• Drug elimination


image The irreversible removal of drug from the body by all routes of elimination.

image Excretion is the removal of the intact drug.

image Most drugs are excreted by the kidney into the urine.

image Drug can also be excreted into bile, sweat, saliva, or milk.

image Biotransformation or drug metabolism converts the drug in the body to a metabolite that is more readily excreted.

image Enzymes involved in biotransformation are mainly located in the liver.

image Other tissues such as the kidney, lung, small intestine, and skin also contain biotransformation enzymes.

• Clearance (Cl)


image Measure of drug elimination from the body without reference to the mechanism of elimination.

image Cl is the sum of all tissue clearances, where renal clearance (ClR) and hepatic clearance (ClH) are the major routes of elimination.

image The body is considered a compartment of fluid with a definite volume (Vd) in which a drug is dissolved.
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Jul 24, 2016 | Posted by in SMALL ANIMAL | Comments Off on Clinical Pharmacokinetics and Pharmacodynamics

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