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