Analytical Toxicology

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics and PharmacodynamicsPharmacokinetic equations describes the relationships between dosage regimen and the profile of drug concentration in the blood over time.Pharmacodynamic equations describe the relationships between the drug concentration-time profile and therapeutic and toxic effects.

Pharmacokinetics and PharmacodynamicsInvolved in Pharmacokinetics and Pharmacodynamics are the aspects of absorption, distribution, excretion, metabolism and compartmental modeling.

Toxicokinetics is a subdivision of pharmacokinetics that is concerned with the impact of toxins on normal body–drug interactions.

Drug Disposition

AbsorptionRoutes of Absorption

OralInhalationIntravenousIntramuscularRectalOral MucosaIntrathecalDermalOcularIntranasally

Bioavailability

For a xenobiotic to have an effect on the body, it must be absorbed into the blood stream.Unless the xenobiotic is administered via the intravenous route, less than 100% of the dose reaches the blood.

Bioavailability

Factors that affect the bioavailability of the administered drug include:

SolubilityConcentrationSurface AreaBlood SupplypH

Bioavailability

pH: The Henderson-Hasselbach equation can be used to calculate the degree of ionization of the drug.

Acid drugs:pH = pKa + log ionized

unionizedBasic drugs:

pH = pKa + log unionized ionized

Absorption Characteristics of

Drugs

First-Pass Metabolism

Some drugs are strongly taken up and metabolized by the liver almost to the point of being fully metabolized in their first pass through the liver. This phenomenon is known as first-pass metabolism. Examples of drugs that are subject to extensive first-pass metabolism include morphine, heroin, and other narcotics.

Distribution

Distribution is the dispersion of the drug among the various organs or compartments within the body.The apparent volume of distribution (Vd), has been devised to describe the distribution of the drug. Vd is the volume into which the drug appears to distribute and it is calculated from the dosage and the concentration of drug in the blood.

Vd = D/(Cp x k)

Volume of Distribution

Example: Assume that 100 g of alcohol are ingested by a man who weighs 70 kg and the blood level is found to equal 2.38 g/L.

Vd = D/(Cp x k)

Vd = 0.100 kg/(0.00238 kg/L x 70 kg)

Vd = 0.60 L/kg or 42 L for this man

Volume of Distribution

Vd values range from about 5% of body volume to as high as 400 L.The latter figure is much higher than anyone’s total volume, so Vd is an artificial concept.

Its importance lies in the fact that it will predict whether the drug will reside in the blood or in the tissue.Water soluble drugs will reside in the blood, and fat soluble drugs will reside in cell membranes, adipose tissue and other fat-rich areas.

Volume of Distribution

Volume of Distribution also relates to whether a drug is protein bound,Drugs that are charged tend to bind to serum proteins.Protein bound drugs form macromolecular complexes that cannot cross biological membranes and remain confined to the bloodstream.

Volume of Distribution

Pathological states may also change Vd.

Because Vd mathematically relates blood concentration to dosage it may be employed in interpretation of laboratory results.

Volume of Distribution

Because Vd may be useful for providing an estimate of dosage, it follows that it can help estimate the amount of antidote to be given.

Vd is able to indicate whether there is any value in trying to enhance elimination as, for example, by dialysis.

Volume of Distribution

Vd is helpful in the context of drug monitoring. It helps to predict whether the practice of drug measurement in blood will have any clinical value.

Psychotropic drugs such as tranquilizers, antidepressants, antipsychotics, mood-altering agents, etc., create their effects by binding at sites within the central nervous system.

Volume of Distribution

Volume of Distribution

Free and Bound DrugsVolume of distribution depends, among other factors, on the extent of the protein binding of a drug.Because only the free form is active but the laboratory result expresses the total drug concentration, the result is misleading if a patient has an abnormal free fraction.

Elimination

The major excretory organs are the liver and the kidney, although other organs also have lesser roles in drug elimination. If a drug is reasonably polar in structure, then it tends to pass into the urine in a more or less efficient manner.

Elimination

The kidney has a high capacity for elimination and so the rate is determined, not by the kidney, but by the toxin’s concentration.

Elimination

Nonpolar drugs are efficiently reabsorbed in the renal tubules and would circulate continuously in the blood, theoretically for weeks or even months. Nonpolar drugs are thus metabolized in the liver.

Elimination

Zero-order elimination is characterized by the plot of concentration vs. time being a straight line. The toxin or drug is eliminated at a constant rate irrespective of whether there are small or large amounts of it. This is characteristic of hepatic elimination, and is call zero-order elimination.

Elimination

Elimination

Some drugs, such as alcohol, follow Michaelis-Menten kinetics, which is a mixture of first-order and zero-order kinetics.At a high concentration of drug the rate of elimination is dictated by the concentration of the fully saturated enzyme.

Calculations on Blood Alcohol and Elimination

The concentration of alcohol in blood may be estimated from a standard pharmacokinetic relationship:

Cp(g/L) = D(g) / Vd(L/kg) × W(kg))

Estimate the blood alcohol concentration in a 200-lb. man who consumes 3 drinks, each of which contains 1.5 oz. of 80-proof whiskey.

Elimination of Alcohol

Social drinkers eliminate alcohol with a rate between 11 and 19 mg/dL/hr, non-drinkers vary from 8 to 16 mg/dL/hr, and alcoholics clear alcohol at a rate of 21 to 39 mg/dL/hr.

Summary

For an ingested drug, bioavailability is that portion of the dose that is actually absorbed. This fraction may be greater or less than normal in overdose situations.Orally ingested drugs are transported by the bloodstream directly to the liver. For those with extensive liver uptake, drug metabolism may be extensive resulting in achievement of very low blood levels. This first-pass effect can be overcome largely by injection or inhalation, rather than oral ingestion, of the drug.

Summary

Volume of distribution is possibly the most important pharmacokinetic parameter. It indicates whether a drug is to be found primarily in the blood or in another bodily site.Volume of distribution is affected by many factors:

It may be higher in overdoseIt suggests that drug testing is worthwhile if the Vd is lowIt enables calculation of a dose from a blood level or vice versa

Summary

Drugs are often found bonded to protein in the blood to some extent. Only the free, nonbonded portion is active. Most laboratory tests give answers for the total drug concentration. The free concentration is important when the patient has protein-binding abnormalities such as a low protein concentration in the plasma.

Summary

Drugs are eliminated from the body according to fairly predictable kinetic models. The sites of elimination are the kidney and the liver. Kinetics of elimination may change in overdose.Half-life, the time during which a drug’s concentration drops by one-half, may change in overdose.