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| − | ==Pharmacokinetics==
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| − | [[Image:Donkey paddock 2.JPG|thumb|right|200px|<small><center>Image courtesy of [http://drupal.thedonkeysanctuary.org.uk The Donkey Sanctuary]</center></small>]]
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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]]'''</big>
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| − | ==Literature Search==
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| − | [[File:CABI logo.jpg|left|90px]]
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| − | Use these links to find recent scientific publications via CAB Abstracts (log in required unless accessing from a subscribing organisation).
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| − | <br><br><br>
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| − | [http://www.cabdirect.org/search.html?q=(title:(pharmacokinetics)+OR+title:(pharmacodynamics))+AND+(ab:(donkey)+OR+title:(donkey))&fq=sc:%22ve%22 Pharmacokinetics/pharmacodynamics in dokeys publications]
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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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| − | {{infotable
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| − | |Maintitle = [[Sponsors#The Donkey Sanctuary|This page was sponsored and content provided by '''THE DONKEY SANCTUARY''']]
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| − | |Maintitlebackcolour = B4CDCD
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| − | }}[[Category:Donkey]]
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| − | [[Category:Pharmacology_-_Donkey]]
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