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Pharmacokinetics
Most drugs are transported in the aqueous phase of blood plasma. To have an effect, a drug must reach cell membrane receptors or enter cells. Absorption, distribution, biotransformation and elimination of drugs all involve transfer across cell membranes, predominantly by passive diffusion of un-ionised drugs down a concentration gradient. The ability of a drug to cross biological membranes is determined primarily by its lipid solubility and degree of ionisation. The degree of ionisation depends on both the acidic dissociation constant (pKa) of the drug and the pH of the surrounding fluid. Most drugs are weak acids or bases that are present in solution in both the ionised and un-ionised forms, with only the latter able to cross membranes.
Pharmacokinetic parameters used for designing dosing regimes
- Bioavailability (F) gives an indication of the extent to which a drug enters the systemic circulation after absorption from its site of administration. Following intravenous (i.v.) administration the bioavailability is 100%
- Volume of distribution (Vd) is the apparent volume in the body in which a drug is dissolved. It is used to indicate how well a drug distributes to the tissues and is constant for any drug, only changing if there are physiological or pathological changes that alter drug distribution. Although a large Vd suggests excellent extravascular distribution, it does not guarantee adequate active drug concentrations at the site of action
- Clearance (CL) is the volume of plasma that is completely depleted of a drug to account for the rate of elimination. It is usually constant for a drug within the desired clinical concentrations but does not indicate how much drug is being removed
- Elimination half-life (t½) is the time required for the drug concentration to decrease by 50%. It is constant for most drugs and determines the timing of repeated doses. It takes around ten half-lives to eliminate 99.9% of a drug from the body
Absorption
Absorption is the rate and extent at which a drug leaves its site of administration. It is influenced by many variables, including the dosage form, e.g. solid forms must first dissolve. If the rate of absorption is very slow, the drug may not reach active concentrations before it is eliminated and, if very rapid unsafe plasma concentrations may be reached.
Distribution
Whether a drug is confined to the vascular space or distributes into the intracellular and extracellular fluid (ECF) compartments depends on its physicochemical properties, e.g. pKa, lipid solubility, molecular size and protein binding. Weakly lipid soluble compounds, e.g. cephalosporins, aminoglycosides and penicillins, generally penetrate poorly into cells: Vd approximates to the ECF volume (adult horse 0.3 litres/kg) and changes in the ECF volume will dramatically affect the plasma concentrations of these drugs.
Highly lipophilic compounds, e.g. ivermectin and moxidectin, are associated with large Vd, implying distribution into a volume greater than the total body water (TBW, adult horse 0.6 litres/kg). These agents reach high concentrations in tissues but relatively low concentrations in plasma and are not usually affected significantly by changes in body water status. Young foals tend to have a relatively high TBW and ECF volume, whereas aged animals tend to have reduced TBW, primarily due to a reduction in ECF volume. Dose rate adjustments may be required to achieve the desired effective (therapeutic) and safe plasma concentrations in these animals.
Metabolism
Biotransformation, mainly in the hepatic smooth endoplasmic reticulum, most commonly detoxifies and/or removes foreign chemicals from the body but can also increase therapeutic activity (metabolic activation). The enzymatic biotransformation of drugs into more polar, less lipid-soluble (more water-soluble) metabolites promotes elimination. Conjugation of drugs, e.g. to glucuronide, further increases their water solubility and hence elimination.
Elimination
The kidney is the most important organ for elimination of drugs and metabolites.
Most organic acids, e.g. penicillin and glucuronide metabolites, are actively transported into the proximal tubule by the same system that is used for excretion of natural metabolites, e.g. uric acid. Organic bases are transported by a separate system designed to excrete bases, e.g. histamine. Although these systems are bi-directional, the main direction of transport is into the renal tubules for excretion. The rate of passage into the renal tubules is dependent on the pKa of the drug and its metabolites, and on urine pH. Increasing urine pH can produce a dramatic increase in excretion of acidic compounds, e.g. salicylate.
Some drugs, e.g. those that remain unabsorbed following oral (per os) administration and hepatic metabolites excreted into the bile by carrier systems similar to those found in the kidney and not reabsorbed, are eliminated via the gastrointestinal tract. Pulmonary excretion is important for the elimination of anaesthetic gases. In lactating mares, excretion of drugs in milk (usually weak bases) may be significant enough to affect sucking foals. Other routes of excretion (skin, sweat, saliva) are generally of minor importance.
Enterohepatic recirculation
Glucuronide conjugated metabolites undergo extensive enterohepatic recirculation: a cycle of absorption from the gastrointestinal tract, metabolism in the liver and excretion in bile, which prolongs elimination.
Protein binding
Many drugs are bound to plasma proteins (mainly albumin) in the circulation. Bound drug is too large to pass through biological membranes, so only free drug is available for delivery to the tissues. The degree of protein binding is only of clinical significance for drugs that are more than 90% protein-bound, e.g. non-steroidal anti-inflammatory drugs (NSAIDs), sulphonamides, aminoglycoside antibiotics and warfarin. For these drugs, conditions that significantly decrease plasma protein concentrations will cause significant increases in the amount of free (active) drug. Protein binding can be involved in drug interactions. Phenylbutazone displaces warfarin from the protein-binding site. A reduction in the amount of protein-bound warfarin from 99% to 98% effectively doubles the plasma concentrations of free warfarin and can lead to bleeding problems.
For more information see Basic Concepts of Pharmacology
References
- Horspool, L. (2008) Clinical pharmacology In Svendsen, E.D., Duncan, J. and Hadrill, D. (2008) The Professional Handbook of the Donkey, 4th edition, Whittet Books, Chapter 12
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