Pharmacokinetics 2 -short PDF

Dr Dina Hamdy Selim The science of the rate of movement of drugs within biological systems. Study of the movement of a drug from its site of administration to the place of its pharmacologic activity. The magnitude of response (good or bad) depends on concentration of the drug at the site of...

Dr Dina Hamdy Selim The science of the rate of movement of drugs within biological systems. Study of the movement of a drug from its site of administration to the place of its pharmacologic activity. The magnitude of response (good or bad) depends on concentration of the drug at the site of action. What the body does to the drug? Study of the biochemical and physiologic processes underlying drug action  Mechanism of drug action  Drug-receptor interaction  Efficacy  Safety profile What a drug does do to the body? Individualize patient drug therapy. Monitor medications with a narrow therapeutic index. Decrease the risk of adverse effects while maximizing pharmacologic response of medications. Evaluate PK/PD as a diagnostic tool for underlying disease states. The extent and rate of Absorption, Distribution,Metabolism and Excretion. This is commonly referred to as the ADME. Recent understanding about the drug-body interactions brought about the inclusion of new term Liberation. Release from the dosage form. Absorption from the site of administration into the bloodstream. Distribution to various parts of the body, including the site of action. Rate of elimination from the body via metabolism or excretion of unchanged drug.  Is the process of release of drug from the formulation. Liberation from dosage form can be 1-simple (powder released from a capsule shell after ingestion) 2-complicated(slow release tablet or transdermal patch matrix) 1-Solubility Before the drug being absorbed it must be in solution. 2-Rate of dissolution The rate of release of drug from the dosage form can be the rate limiting factor in absorption when the rate of dissolution is slower than the rate of absorption of the drug.  The movement of a drug into the bloodstream. Bio-availability of a drug is the amount or percentage of the drug that is absorbed from the given dosage and reaches the systemic circulation A. factors related to the drugs: 1.Lipid solubility 2.Molecular size 3.Degree of ionization 4.Nature of drug (Inorganic Vs Organic cpds) 5.Pharmaceutical form ,Dosage form (Syrup> Suspension > tablet) B. Factors related to the patient 1.Route of administration 2.Absorbing surface (area and vascularity of absorbing surface)  How is the drug transported a cross the cellular membrane? o Simple passive diffusion through lipid bilayer:No energy–No carrier–goes with the concentration gradient of drug–Lipid drugs pass by simple diffusion o Passive transport through protein channels:No energy–No carrier-small water soluble molecules pass through protein channels with the concentration gradient of drug o Passive facilitated transport :No energy–Drug binds to carrier–similar drugs compete for the carrier-goes with the concentration gradient of drug. o Active transport: Needs energy(ATP)-Drug binds to carrier– similar drugs compete for the carrier-goes against the concentration gradient of drug  It is the fraction of unchanged drug reaching systemic circulation following administration by any route. After IV administration bioavailability will be 100% Drug distribution is a process by which the drug reversibly leaves the blood stream and enters the extracellular fluid and/or the cells of the tissues(extacellular fluid). The volume of distribution is the volume of fluids which should be required to contain the amount of drug in the body if it were uniformly distributed in the same concentration in which it is present in the blood.  Vd estimate how well the drug is distributed. Value < 0.071 L/kg indicate the drug is mainly in the circulatory system. Values > 0.071 L/kg indicate the drug has gotten into specific tissues.  Transfer of drug from systemic circulation to tissues. Factors contributing to unequal distribution of drugs 1. Blood flow (Cardiovascular function) Highly perfused organs (e.g.brain,liver,kidney ) receive a larger amount of drug than poorly supplied tissues (e.g.fat depot,tendons). 2. Cellular binding (special affinity to certain tissues) e.g.Calcium is concentrated in bones,iodine is concentrated in thyroid glands 3. Concentration in body fat (Thiopental) Binding to plasma protein 4. Physical barriers Blood-brain and placenta barriers The physicochemical properties of the drug ( lipophilicity, MW, molecular size, degree of ionization). Degree of tissue and protein Binding bound drugs do not cross membranes. Malnutrition = albumin =  free drug. ↑Vd ↓fraction in plasma. Body composition ( Women have less water (54 vs. 60%) and more fat (28 vs18%) than men) Pregnancy. Age  The extent of binding to plasma protein varies greatly from drug to the other. Some drugs are strongly bound to plasma albumin , while others occur mainly in free state. Binding to plasma protein scauses a higher concentration of the drug to be present in the blood than other extracellular or intracellular fluids. It is also provides a depot ,since the bound form of the drug is in equilibrium with the free form. As the unbound fraction is metabolized or excreted, additional amounts are freed from the plasma protein. Protein binding prolong the half life of the drug in the body since the bound fraction is not exposed to metabolism or excretion. The protein-bound fraction of a drug is generally inactive until it becomes free. The protein responsible for binding drugs is usually “albumin”, in case of hypoalbuminemia toxic manifestations of drugs may appear as a consequence of deficiency of binding to albumin. The human body may be represented by one or more compartments or pools in which the drug resides in a dynamic state for a short period of time. 1-Cell membranes 2- Capillaries 3- The Blood-Brain Barrier (BBB 4-The Placental Barrier Elimination occurs by : metabolism Excretion(clearance)  Metabolism takes place in the liver by liver enzymes, It makes the drug more water soluble, The metabolites are usually less active than the parent drug. So,metabolism helps in detoxification (Inactivation) Few drugs are in active and when they are metabolized be come more active. These drugs are called Pro drugs. For example: Levodopa (adrug used in parkinsonism) is metabolized in the body to dopamine, which is the active form of the drug. The blood flow to the liver: The more the drug goes to the liver, the higher the probability that the drug is metabolized and eliminated The activity of the liver enzymes: The more the activity of the liver enzymes , the higher the metabolism of the drug The structure of the liver :If the liver is suffering from fibrosis, the cells are dead and not functioning. So, the drug will not be well metabolized.  Drug metabolism involves two kinds of reaction, known as phase 1 and phase 2, which often occur sequentially. Both phases decrease lipid solubility, thus increasing renal elimination. First phase metabolism e.g. oxidation, reduction or hydrolysis(metabolites are sufficiently polar, they may be readily excreted. ) Second phase metabolism e.g. conjugation with glucuronic acid(newly established functional group to form a highly polar conjugate easily eliminated.) 21 Microsomal enzyme inhibitor Slow other drugs metabolism thus increase the duration of drug action and toxicity. Example: female sex hormones, cimetidine, ketoconazole and starvation. Microsomal enzyme inducer Accelerate their own metabolism and or the rate of metabolism of other unrelated drugs. Accelerate destruction of drugs, decrease the duration, intensity of the drug action and toxicity. Example: barbiturates, phenytoin, griseofluvin, refampicin 23 Oral administration drugs: Some are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism. Some are more extensively metabolized in the intestine than in the liver.  Drug Dose – The higher the plasma concentration of a drug the higher the rate of metabolization (first-order kinetics) for most drugs. – A drug that is easily hepatically metabolized must be given in higher doses. Is a measurment of the overall efficiency of drug elemination from the body It provides an indication of the ability of the body as an eleminating system. Some drugs are excreted via the bile, volatile substances are excreted in the breath however most of the drugs are excreted through the kidneys Concominant use of certain drugs  Plasma protein binding Renal plasma flow Urine pH Renal impairment Time required for serum plasma concentrations to decrease by one-half (50%) 4-5 half-lives to reach steady state.  How much time it takes for blood levels of drug to decrease to half of what it was at equilibrium  Steady State: the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant 1-“Distribution” ½ life = when plasma levels fall to half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs. 2-“Elimination” ½ life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated. Both ½ lives contribute to the effects of the drug on behavior, it is usually the elimination ½ life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug.