Drug Distribution PDF

DRUG DISTRIBUTION VPM 61 - Basic Veterinary Pharmacology Philip John S. Sajol Assistant Professor I Department of Anatomy, Physiology, and Pharmacology College of Veterinary Medicine Drug Distribution Overview movement of drug from the plasma compartment into the various uid and tissue com...

DRUG DISTRIBUTION VPM 61 - Basic Veterinary Pharmacology Philip John S. Sajol Assistant Professor I Department of Anatomy, Physiology, and Pharmacology College of Veterinary Medicine Drug Distribution Overview movement of drug from the plasma compartment into the various uid and tissue compartments and sites of action fl Drug Distribution Overview Drug Distribution Factors a ecting drug distribution Dose and route of administration Blood ow to di erent organs Physicochemical properties of drugs lipid solubility, pK, pH, and molecular size determine the rate of distribution of a drug to various body uid compartments ion-trapping also in uences distribution of drugs, where more lipid-soluble drugs distribute more widely in the body than do less lipid-insoluble ones fl ff ff fl fl Drug Distribution Factors a ecting drug distribution Concentration gradient drugs are more transported from compartments where they are more concentrated to those compartments where they are less concentrated (simple di usion) until equilibrium is attained rate of di usion of drugs across the lipid-bilayer is dictated by the drug’s lipid solubility ff ff ff Drug Distribution Factors a ecting drug distribution Binding to tissue constituent some drugs bind to cell membranes and to soluble intracellular components where the binding is restricted to a particular tissue, the distribution is consequently limited binding of drugs (e.g antibiotics) to animal tissues for human food is a major consideration, thus the need for instituting withdrawal periods (time between the last drug administration to the time where drug residues in meat, eggs, or milk becomes safe and acceptable) ff Drug Distribution Factors a ecting drug distribution Binding to plasma proteins only the unbound drug is able to cross cell membranes acidic drugs primarily bind to albumin while basic drugs bind to a1-acid glycoprotein binding slows the rate to which the drug reaches a concentration su cient to produce a pharmacologic e ect binding DOES NOT produce an e ect, but plasma protein binding is a silent interaction where albumin can be classi ed as a silent receptor ff ff ffi fi ff Drug Distribution Factors a ecting drug distribution Binding to plasma proteins a drug with higher percent plasma protein binding may be less potent than a similar drug with lower plasma protein binding bound drugs cannot be ltered, and drug- protein binding limits glomerular ltration as the free-drug concentration is lowered, there is rapid dissociation of drug-protein complex to maintain the amount in free state ff fi fi Drug Distribution Factors a ecting drug distribution Redistribution (sequestration) redistribution of a drug from its site of action to other tissues lowers its concentration at its site of action, terminating the response drugs exhibiting redistribution are highly lipid-soluble (e.g thiopental) ff Drug Distribution Factors a ecting drug distribution Drug interactions may occur when two drugs are used that bind at the same site on the plasma protein, where competition for the same site increases the percent of the drug in free- form, and thereby increasing the pharmacologic-toxicologic response to the displaced drug ff Drug Distribution Distribution of drugs to specialized compartments CNS Distribution Blood-brain barrier is a continuous layer of tight junctions between capillary endothelial cells in the CNS a. drugs must be highly soluble to cross this barrier b. latentiation, or the process of incorporating lipophilic groups to a drug, allows its passage to the BBB c. encephalitis opens the BBB, allowing passage of drugs such as penicillin which normally doesn’t pass through Drug Distribution Distribution of drugs to specialized compartments CNS Distribution active transport exists for organic acids in the choroid plexus allows transport of drugs from CSF into the blood Drug Distribution Distribution of drugs to specialized compartments CNS Distribution CSF dilutes a drug concentration CSF produced circulates through the ventricles and over the surface of the brain and spinal cord to ow directly into the venous drainage system of the brain fl Drug Distribution Distribution of drugs to specialized compartments Transplacental Distribution charged molecules rapidly penetrate placenta depending upon the concentration gradient of the drug between the maternal and fetal circulation Drug Distribution Distribution of drugs to specialized compartments Transplacental Distribution only free drugs cross the placenta sink e ect occurs, where free drug having crossed the placenta will once again be protein bound in the fetal circulation, establishing a concentration gradient between the maternal and fetal circulation ff Drug Distribution Distribution of drugs to specialized compartments Transplacental Distribution Drugs with an e ect on the maternal CNS have physical-chemical characteristics to freely cross the placenta and a ect the fetus anesthetics, analgesics, sedatives, tranquilizers ff ff