Lect 2

• Drug metabolism is the process by which the absorbed compounds stay in the body for a much shorter period of time.
• Drugs have a prolonged activity without drug metabolism.
• An accumulation of drugs in tissues can occur without drug metabolism.
• Drug metabolism in the liver is the major organ for drug metabolism in the body.
• The liver is capable of metabolizing some drugs, although this capacity is only occasionally of clinical importance.
• Hepatic metabolism can be divided into phase I and phase II.
• Lipid-soluble drugs require conversion to a water-soluble form before they can be eliminated by the kidney.
• The majority of drug metabolism occurs in the liver but the liver is not the only site.
• Small Animal Clinical Pharmacology and Therapeutics, Second Edition, Edited by Dawn Merton Boothe, 2012, Elsevier Saunders.
• Various metabolic pathways are involved in drug metabolism.
• The bulk of the Phase I biotransformation reactions are performed by a family of enzymes known as CYPs.
• Many drugs excreted as glucuronide conjugates in other species are characterized by a prolonged clearance and exaggerated pharmacologic responses.
• Aspirin half-life approximates 36 hours in cats compared with 8 hours in dogs.
• Metabolism Phase II involves glucuronosyltransferase, sulfotransferase, N-acetyltransferase and methyltransferase.
• Glucuronidation is the most common phase II reaction.
• Most of the drug is eliminated by glucuronidation and sulfation.
• Glucuronide conjugates are eliminated in the urine and bile.
• Deficiencies in phase I (hydroxylation) as well as phase II glucuronidation lead to much slower elimination of phenols and aromatic acids and amines in the cat compared with other species.
• Deficiencies have long been recognized in cats, with extremely low concentrations of some glucuronosyltransferases.
• Phase II, also known as conjugation, occurs when a large water-soluble molecule is chemically added to either the parent drug or its phase I metabolite.
• The CYPs are hemoproteins and are found mostly in the liver.
• Cytochrome P450 enzymes (CYPs) absorb light at 450 nm.
• The CYPs are principally located on the endoplasmatic reticulum (ER) of the hepatocyte (metabolically active cells) and some are in the small intestine.
• Absorption of volatile anesthetics from the pediatric respiratory tract is rapid because minute ventilation is greater.
• The rate of absorption after IM administration changes with age as muscle mass and its blood flow increase, making SC administration frequently preferred.
• Several pediatric drugs intended for systemic effects are available as rectal suppositories.
• Glomerular filtration and renal tubular function progressively increase in puppies, but adult values may not be reached until approximately 2.5 months of age.
• Patients in a state of hypothermia are more sensitive to the effects of gas anesthetics.
• Isotonic fluids are rapidly absorbed, with up to 70% of RBC cells being absorbed in 48 to 72 hours.
• When the oral administration of a drug is undesirable, such as with antiemetics, rectal administration can be used.
• Both phase I and II reactions are reduced in puppies.
• IP administration can be a lifesaving route of blood and fluid administration.
• Absorption from the rectal mucosa is rapid, making rectal administration of drugs or fluids a viable option for pediatric patients when venous catheterization is difficult.
• Renal tubular reabsorption in puppies appears to be similar to that in adults as long as body fluids and electrolytes are maintained.
• Environmental temperature influences SC absorption, with cold environments likely to reduce SC drug absorption if the neonate is not kept warm.
• The overall clearance ( CL total ) can also be estimated by measuring plasma concentrations at intervals following a single intravenous bolus dose (Q mg).
• Renal clearance ( Cl renal ) is the volume of plasma containing the amount of drug that is removed from the body by the kidneys in unit time.
• Rate of drug elimination is the amount of drug being eliminated per unit time.
• During a constant intravenous infusion at rate X mg/h, the plasma concentration increases from zero to a steady-state value (Css); when the infusion is stopped, C declines to zero.
• Elimination T½ refers to the disappearance of drug from plasma.