Pharmacokinetics PDF - Drug Absorption, Distribution & Metabolism

Pharmacology Pharmacokinetics Pharmacokinetics is the complex sequence of events that occurs after a drug is administered. It is the effect the body has on the drug after it is administered. The drug must not only reach the desired area, but also...

Pharmacology Pharmacokinetics Pharmacokinetics is the complex sequence of events that occurs after a drug is administered. It is the effect the body has on the drug after it is administered. The drug must not only reach the desired area, but also accumulate in that fluid or tissue in the required concentration to be effective Drugs must be given repeatedly at fixed time intervals to keep the drug at the desired concentration and counteract the body’s breakdown and excretion of the drug Loading dose- high initial administration to rapidly achieve effective concentration Maintenance dose- reduced dose that maintains concentration by replacing the amount loss through elimination Steady state- the point at which drug accumulation equals drug elimination Therapeutic drug level- the effective level of the drug that is not too high resulting in toxicity and not too low resulting in less than effective levels in the tissue Therapeutic Index- the difference between the minimum effective dose and the maximum effective dose. A drug whose maximum and minimum effective dose are close together is said to have a narrow therapeutic index. Therapeutic drug monitoring- drug levels can be measured in the blood, urine, CSF to determine if the therapeutic drug level has been achieved Factors that influence concentrations of a drug o Rate of absorption o Amount of drug absorbed o Distribution of the drug o Drug metabolism or biotransformation o Rate and route of excretion Routes of Administration Influenced by: Available form Properties of the drug (is it irritating?) Desired speed of onset 1  Behavior of patient (can you pill that feral cat?) Condition being treated (would you give oral meds to a vomiting animal?) Oral Many common drugs are given by this route Route lends itself to at home use Drug may given o Directly in the mouth o Nasogastric tube o Orogastric tube Drugs given this route are usually more slowly absorbed than those given by injection o May not be absorbed at all in some species ▪ Ruminants vs. simple stomach o May depend of stomach pH, fill, GI motility, drug solubility Generally produce a longer lasting effect than injected drugs Parenteral Any drug given by injection Intravenous (IV) Intramuscular (IM) Subcutaneous (SQ/SC) Intradermal (ID) Intraperitoneal (IP) Intraarterial (IA) Intraarticular Intracardiac (IC) Intramedullary Epidural/subdural IV- intravenous 2 Generally, the drugs given IV have the fastest effect and, though it would seem contraindicated, most irritating drugs are given IV because of the dilutional effect of blood. Most drugs given IV must be given slowly to avoid adverse reactions With very few exceptions, nothing cloudy, thick, with suspended particles or opaque should be given IV o Exceptions: propofol, pink or blue euthanasia solution, Legend® Drugs meant for IV injection can be very irritating outside the vein- possibly causing tissue necrosis IM-intramuscular Typically slower onset of action, but longer duration of action Can have fast onset with water based (aqueous) drugs Can have very long duration of action if in depot form, sometimes suspended in oil Not a good choice for irritating drugs Aspirate before injection to prevent inadvertent IV injection SQ-subcutaneous Slower onset of action, but slightly longer duration of action Irritating or hypertonic solutions should not be given this route Must avoid quantities that would cause dissection between skin and underlying tissues Hyaluronidase added to a drug may speed absorption ID-intradermal Used for tuberculosis and allergy testing IP-intraperitoneal Used to deliver drugs to abdominal cavity Typically used when other routes are unavailable- especially in small, exotic pets IA-intraarterial Usually inadvertent In horses inadvertent administration of sedative into the carotids instead of the jugular may result in seizures or death IA-intraarticular Used to treat inflammatory conditions in the joint o Antibiotics o Corticosteroids o Hyaluronic acid o Stem cells Must use sterile technique 3  IC-intracardiac Infrequently used for cardiopulmonary resuscitation or euthanasia Intramedullary Injection of a substance directly into the medullary cavity of a long bone Most frequently done in exotics or pediatric patients for rehydration when the IV route is not available Epidural/subdural- aka intrathecal In veterinary medicine this route is used most frequently for anesthesia and pain control Inhalation Medications administered in inspired air made by converting a liquid form to a gaseous form by a nebulizer or vaporizer o Inhaled anesthetics o Bronchodilators o Antibiotics Topical Skin-transdermal Mucosa- sublingual, rectal, mammary glands, uterus, eyes, ears May be affected by drug vehicle or carrier o Dimethyl sulfoxide (DMSO) Drug Absorption The degree to which a drug is absorbed and reaches the general circulation is called bioavailability o Bioavailability is demonstrated by blood level curve which is influenced by: ▪ Manufacturing ▪ Mechanism of absorption ▪ pH/ionization/solubility of the drug ▪ Absorptive surface area and blood supply Drugs absorbed through passive transport via simple diffusion from high concentration to lower concentration 4  o Requires no energy use Drugs absorbed through active transport drug moves from lower concentration to higher concentration o Requires use of energy o Usual mechanism of absorption of sodium, potassium, other electrolytes Finally, drugs may be absorbed by pinocytosis o Is a mode of passive transport, no energy used o Drug is invaginated to form a vesicle that breaks off in the cell interior Rate of absorption is dependent on fat or water solubility, size/shape, degree of ionization Many drugs can pass through cell membrane only if they are nonionized o Acidic drugs in an acidic environment do not ionize well, so they are absorbed readily o Mildly alkaline drugs in an acidic environment become ionized and may become trapped, not absorbed well As the absorptive surface area of the drug increases, so does the rate of absorption The villi of the small intestine maximize surface area Drugs given IM have faster absorption than SQ because of higher blood flow o Reduced with poor circulation o Increased with increased blood flow of fight/flight response o May be increased with heat and massage Solubility of the drug: lipid solubility directly proportional to nonionization o Lipid soluble/nonionized drugs are more quickly absorbed- can cross the cell membrane o Lipid partition coefficient= the degree of lipid solubility Rate of absorption may also depend on formulation o Depot and spansule drugs have binding agents that result in sustained release Drugs given orally depend on the condition of the GI tract Combining certain drugs with others, or with certain foods may alter absorption 5  o Milk or dairy products reduce tetracycline absorption First-pass effect Substances are absorbed by the GI tract into the hepatic portal venous system which delivers the drug to the liver prior the entering the general circulation This allows the enzymes of the liver to remove toxins and potentially dangerous substance before they reach the general circulation Drugs may be metabolized in the liver to altered forms which may make the drug less active or inactive Drugs that are prone to extensive first-pass effect are not recommended for oral administration Drug distribution The process by which the drug is carried from the site of absorption to its site of action Site->plasma->interstitial fluid->into cells->bind with cellular receptors->action Distribution is dependent on: o Perfusion of the tissue ▪ May be changed by temperature, vasoconstriction and vasodilation o Concentration gradient o Degree of protein binding o Lipid soluble drugs move into tissue and may be bound there Barriers to distribution o Placenta o Prostrate o Eye o Brain (the blood-brain-barrier) Plasma Protein Binding some drugs bind to plasma protein that are too large to pass through the fenestrations in the capillary’s endothelium, rendering the bound drug inactive. Only the unbound/free from drug is capable of exerting its effect. o Animals given highly protein bound drugs who are HYPOproteinemic may require lower doses or suffer toxicity. 6  o Some drugs, like cefovecin, are formulated using protein binding to create a depot effect, releasing the drug into the tissues over an extended time. These drugs may then become bound to tissue protein to further extend the effect. P-glycoprotein is an active transport pump in the epithelium of the intestinal wall, liver and blood-brain barrier. Its purpose is to actively pump drugs back into circulation for excretion. o P-glycoprotein defect/ MDR1 gene defect- exists at the blood-brain-barrier in some individuals of some breeds: collies, Old English sheepdogs, Australian shepherds- this is the mechanism of ivermectin toxicity in these animals, also results in potential toxicity from multiple other drugs Reptiles- reptiles may have a renal portal system that distributes toxic levels of drug to the kidney if the drug is given in the posterior 1/3 of the body Biotransformation Metabolism is the body’s ability to change the drug chemically so that it can be eliminated Most biotransformation occurs in the liver Enzymes make the drug water soluble so it may be excreted in the urine When the drug is altered it is a metabolite Most metabolites are inactive, though some are active Some very lipid soluble drugs are eliminated in the bile Four chemical reactions are controlled by the microsomal enzymes of the liver: 1. Oxidation- loss of electrons 2. Reduction- gain of electrons 3. Hydrolysis- splitting of the drug molecule with the addition of a water molecule 4. Conjugation- addition of a glucuronic acid, which makes the drug more water soluble Special cases: Cats have limited ability to form glucuronic acid, so they have difficulty metabolizing aspirin, barbiturates and narcotics Young animals do not have fully formed liver enzyme systems Older animals have decreased ability to form liver enzymes Malnourished animals have decreased raw materials for enzyme production Drug excretion 7  Most drugs are metabolized by the liver then eliminated from the body through the kidneys May be excreted by mammary glands, bile, lungs, intestinal tract, salivary glands and skin Must consider route of excretion during drug selection o For example: ketamine may accumulate to toxic levels in the CNS of cats with urinary tract obstruction because the drug is excreted by this route The liver excretes drugs by incorporating them into bile-> into the small intestine-> becomes part of the feces or is reabsorbed Drugs given orally that are not absorbed may be eliminated in the feces Drugs may convert to a gas state and be eliminated via the lungs Drug may pass from blood into milk- a consideration for nursing offspring or people drinking milk Renal excretion Glomerular filtration: the glomerulus acts like a sieve to remove metabolites out of blood into the glomerular filtrate Tubular secretion: kidney tubules secrete metabolites out of capillaries into the glomerular filtrate If any portion of the system is not functioning well, toxic levels of the drug may accumulate Half-life T ½ = The time required for the amount of the drug in the body to be reduced by one half Drug residue Quantities of drug remaining in animal products when they are consumed in milk, eggs or meat products People may be allergic to the drug Prolonged exposure may result in resistant strains of bacteria Residues may cause cancer in people Food Animal Residue Avoidance Database (FARAD) is a repository of residue avoidance information- provides withholding times for milk and meat http://www.farad.org 8  Pharmacodynamics Pharmacodynamics is the study to the drug’s effect on the body. Drug molecule combines with components of the cell membrane or internal components to alter cell function The drug and receptor must interact exactly- like a lock and key to cause the action o Affinity is the tendency of the drug to bind with its receptor o Agonist is a drug with high affinity and efficacy o Partial agonist is a drug with less affinity and efficacy o Antagonist a drug that blocks another drug from combining with a receptor, thus blocking the effect Dose response curve demonstrates that as the amount of the drug increases, so does the body’s response up to a given plateau or maximum effect No drug has a single effect so some doses may exert different effects Potency the amount of drug needed to produce a desired response Efficacy the degree to which the drug produces the desired response Therapeutic index is the relationship between the drug’s ability to produce a desired response and its tendency to produce toxic effects: Therapeutic index = LD50 / ED50 LD50 the dose at which the drug is lethal to 50% of the animals treated ED50 the dose at which the drug has the desired effect in 50% of the patients Adverse drug reaction ANY undesirable response to the drug. Can result from the drug itself, its quality or purity or the dose of the drug. Can include dermatitis, anaphylactic shock, and photosensitivity. Idiosyncratic drug reactions are unusual or unexpected reactions to a drug. Drug interactions An altered pharmacologic response to a drug that is caused by the presence of a second drug Classified as: 1. Pharmacokinetic interaction where the plasma or tissue level of one drug is affected by the presence of another (calcium’s effect on tetracycline absorption is an example) 2. Pharmacodynamic interaction is when the action or effect of one drug is altered by another (the reversal by an alpha 2 agonist by its antagonist is an example) 9 3. Pharmaceutic interaction is when a physical or chemical reaction takes place because of physically mixing drugs (diazepam may precipitate with drugs when mixed in the same syringe). 10