Pharmacokinetics Lecture PDF

AP Dr Azyyati Mohd Suhaimi Faculty of Pharmacy UniSZA Adapted from: AP Dr Shazia Jamshed, Uni of Alberta, MIT Open Course  Definition of terms Drug A drug is a chemical or substance that causes changes in the structure or function of...

AP Dr Azyyati Mohd Suhaimi Faculty of Pharmacy UniSZA Adapted from: AP Dr Shazia Jamshed, Uni of Alberta, MIT Open Course  Definition of terms Drug A drug is a chemical or substance that causes changes in the structure or function of living organisms Medicine A medicine is the vehicle for administration of the drug (active ingredient) to the human or animal tablet, capsule, injection, ointment, inhaler, suppository Pharmacokinetics The study of kinetics of absorption, distribution, metabolism and excretion (ADME) of drugs and their corresponding pharmacologic, therapeutic, or toxic responses in man and animals  Definition of terms Pharmacology Simply: the science of drug actions and uses Pharmacodynamics Mechanisms of action (what the drug does to the body) Toxicity Manifestation of the harmful effects of the drug after exposure to high levels (intoxication or poisoning) Therapeutics Use of drugs for intended clinical benefits – cure of a disease, relief of symptoms  Therapeutic prescribing Prime goal of drug therapy is to achieve the desired beneficial effects with minimal adverse effects Choice of drug will be governed by mechanism of action (pharmacodynamics) Dose of drug, route, formulation etc. will be determined by how the body handles the drug (pharmacokinetics)  PHARMACOLOGY  Pharmacology - science dealing with actions of drugs on the body (pharmacodynamics) and fate of drugs in the body (pharmacokinetics)  In order for a drug to work, it must enter the body and be distributed to its site of action  In most cases, the site of action is a macromolecular "receptor" located in the target tissue  Most drug effects are temporary, because the body has systems for drug detoxification and elimination  PHARMACOLOGY Pharmacokinetics Pharmacodynamics How body acts on drug How drug acts on body Dose of Drug Body Drug effect concentration Absorption Receptor Binding over time Distribution Biological Effect Metabolism Excretion  Pharmacodynamics Basic Principles Mechanism of action of drugs Specific molecular processes by which drugs work e.g. inhibition of an enzyme or stimulation of a receptor sub-type Mode of action of drugs General description of the type of action e.g. supplements, antihypertensives, analgesics Site of action of drugs Specific organs, tissues or cells affected by the drug e.g. sensory neurons; myocardium, bronchi  Mechanism of Action Fundamental premise of pharmacodynamics is drug-receptor interactions Within the organs of the body are specific receptors with which specific drugs can interact The analogy often used is ‘lock and key’ only drugs (chemicals) with the correct molecular shape can interact with a particular receptor  Example: Morphine Naturally-occurring substance found in the Opium Poppy (Papaver somniferum) One of a family of natural substances known as opiates or opioids (includes codeine) Some synthetic derivatives also available e.g. heroin, methadone, pethidine Been used for both therapeutic and recreational purposes throughout history  Opioid receptors In the 1970s pharmacologists identified a number of ‘endogenous’ (within the body) opioids known as enkephalins and endorphins Found to have a role in pain perception, mood and a number of other physiological functions Also discovered opioid receptors in key areas of the body e.g. brain, spinal cord, gut, eye Only substances with a similar chemical structure to morphine can attach to opioid receptors (‘key-lock’ analogy) These substances are called opioid agonists – when they attach to the opioid receptors they trigger certain responses  Effects of Opioids (Morphine) Relief of pain (analgesia) – main therapeutic use Mood elevation (euphoria) Sedation Constriction of pupil (miosis) Reduction in gut motility (constipation) Suppress cough (anti-tussive) Tolerance to effects, and dependence in some individuals with repeated doses Respiratory depression leading to death in overdose  A Mix of Desirable & Unwanted Effects Because there is a variety of opioid receptors in different parts of the body, it is very difficult to separate desirable and unwanted effects of morphine and other opioid drugs Example – all patients receiving morphine or codeine for ongoing treatment of cancer pain become very constipated But, these drugs can also be used as anti-diarrhoeals!  Agonists and antagonists Agonists = drugs that stimulate receptors Antagonists = drugs that block receptors For example, salbutamol (Ventolin®) is a beta-receptor agonist/stimulant stimulation of beta-receptors in the lungs causes bronchodilation Metoprolol (Betaloc®) is a beta-receptor antagonist/blocker blockade of beta-receptors in the heart will slow rate and be cardioprotective blocking the beta-receptors in the lungs can cause bronchoconstriction in asthmatics  Pharmacokinetics The study of the disposition of a drug The disposition of a drug includes the processes of ADME  Absorption  Distribution  Metabolism Elimination  Excretion ADME  How drug enters the body Routes of drug administration Parenteral Enteral Injection Topical Respiratory Rectal Oral  Absorption The process by which drug proceeds from the site of administration to the site of measurement (blood stream) within the body Necessary for the production of a therapeutic effect Most drugs undergo gastrointestinal absorption. This is extent to which drug is absorbed from gut lumen into portal circulation Exception: Intravenous (IV) drug administration  Absorption If the drug is absorbed from the skin, mouth, lungs or muscle it will go directly into the systemic circulation If drug is injected directly into the bloodstream (e.g. IV injection), 100% of it is available for distribution to tissues If the drug is given orally and swallowed, it must be absorbed from the GI tract into the portal circulation  Absorption Drug which is absorbed via the portal circulation must first pass through the liver which is the primary site of drug metabolism (biotransformation) Some of the drug may therefore be metabolized before it ever reaches the systemic blood In this case, first-pass metabolism reduces the bioavailability to less than 100% IV vs Oral Is the passage of drug through cell membranes to reach its site of action Mechanisms of drug absorption 1. Simple diffusion = passive diffusion 2. Active transport 3. Facilitated diffusion 4. Pinocytosis (endocytosis)  Also known as passive diffusion Drugs diffuse across a cell membrane from a region of high concentration (e.g. gastrointestinal fluids) to one of low concentration (e.g. blood) Diffusion rate is directly proportional to the gradient but also depends on the molecule’s lipid solubility, size, degree of ionization, and the area of absorptive surface Because the cell membrane is lipid, lipid-soluble drugs diffuse most rapidly Small molecules tend to penetrate membranes more rapidly than larger ones  Water soluble drug (ionized or polar) is readily absorbed via aqueous channels or pores in cell membrane  Lipid soluble drug (nonionized or non polar) is readily absorbed via cell membrane itself  Simple diffusion Most drugs exist in unionized and ionized forms in an aqueous environment Unionized form = lipid soluble (lipophilic)  diffuses readily across cell membranes Ionized form = water soluble (hydrophilic)  high electrical resistance, cannot penetrate cell membranes easily The proportion of the unionized/ionized form present is determined by pH and drug’s pKa (acid dissociation constant) pKa = the pH at which concentrations of ionized and un- ionized forms are equal  Simple diffusion pKa = the pH at which concentrations of ionized and un-ionized forms are equal half of the substance is ionized & half is unionized pH of the medium affects ionization of drugs Weak acids - best absorbed in stomach Weak bases - best absorbed in intestine  A type of passive transport No energy required The diffusion of solutes through transport proteins in the plasma membrane Even though it involves transport proteins, it is still passive transport because the solute is moving down the concentration gradient  Active transport Selective Requires energy expenditure Involve transport against a concentration gradient Limited to drugs structurally similar to endogenous substances e.g. ions, vitamins, sugars, amino acids these drugs are usually absorbed from specific sites in small intestine Passive vs Active transport Passive vs Active transport Active transport vs Facilitated diffusion  Pinocytosis In pinocytosis (endocytosis), fluid or particles are engulfed by a cell The cell membrane invaginates, encloses the fluid or particles, then fuses again, forming a vesicle that later detaches and moves to the cell interior Energy expenditure is required Plays a small role in drug transport except for protein drugs Pinocytosis  Bioavailability Fraction of administered dose reaching the systemic circulation Destroyed Not Destroyed Destroyed in gut absorbed by gut wall by liver To Dose systemic circulation  Determination of bioavailability A drug given by intravenous route will have an absolute bioavailability of 1 (F=1 or 100% bioavailable) While drugs given by other routes usually have an absolute bioavailability of < 1. The absolute bioavailability is the area under curve (AUC) non-intravenous divided by AUC intravenous  Factors affecting bioavailability Classified into two general categories Formulation factors excipients (type & concentration) used formulation of a dosage form  particle size of an active ingredient  crystalline or amorphous nature of the drug  hydrous or anhydrous form of the drug  polymorphic nature of a drug Physiological factors  gastric emptying  intestinal motility  changes in gastrointestinal pH  changes in nature of intestinal wall  Distribution After a drug enters the systemic circulation, it is distributed to the body’s tissues Determined by partitioning across various membranes binding to tissue components binding to blood components (RBC, plasma protein) physiological volumes  Distribution All fluid in the body (total body water), in which a drug can be dissolved, can be roughly divided into 3 compartments:  Intravascular (blood plasma found within blood vessels)  Interstitial/tissue (fluid surrounding cells)  Intracellular (fluid within cells i.e. cytosol) The distribution of a drug into these compartments is dictated by its physical and chemical properties  Total body water Intravascular Interstitial Intracellular 3L 9L 28 L 4% BW 13% BW 41% BW  Distribution Apparent volume of distribution (Vd) = Amount of drug in body/plasma drug conc Factors affecting Vd 1. Blood flow rate - varies widely with function of tissue Muscle = slow Organs = fast 2. Capillary structure Most capillaries are “leaky” and do not impede diffusion of drugs Blood-brain barrier (BBB) formed by high level of tight junctions between cells in brain BBB is impermeable to most water-soluble drugs  Protein binding Many drugs bind to plasma proteins in the blood steam limits drug distribution Most important binding proteins are albumin, alpha- 1 acid glycoprotein, lipoproteins Drugs are transported partly in solution as free drug and partly reversibly bound to blood components in blood A drug that binds plasma protein diffuses less efficiently  Blood-Brain Barrier (BBB) Drugs reach the central nervous system (CNS) via brain capillaries and cerebrospinal fluid (CSF) BBB consists of endothelium of brain capillaries and astrocytic sheath Endothelial cells of brain capillaries appear to be more tightly joined to one another than those of general capillaries  limits diffusion of water-soluble drugs The tight junctions between endothelial cells are responsible for the barrier function  Blood-Brain Barrier (BBB) A number of drugs cannot readily enter the brain because of low lipid solubility and are not transported by specific carriers present in the BBB Generally, only lipophilic, positively-charged molecules with a low molecular weight (less than 400 to 600 Da) can cross the BBB Several transport routes have been established to allow for the movement of molecules across the BBB  Blood-Brain Barrier (BBB) Capillary (general) Capillary (brain)  Elimination = The irreversible removal of the parent drugs from the body Elimination Drug Metabolism Excretion (Biotransformation)  Drug metabolism The liver is the principal site of drug metabolism Chemical modification of drugs with the overall goal of getting rid of the drug Enzymes are typically involved in metabolism Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization Metabolism More polar Excretion Drug (water soluble) Drug  Drug Metabolism: Phase I For many drugs, metabolism occurs in 2 phases – Phase I and Phase II reactions Phase I reactions  Convert parent compound into a more polar (hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.)  e.g. oxidation, reduction, hydrolysis  Often these metabolites are inactive  May be sufficiently polar to be excreted readily  Site of drug metabolism Mostly occurs in the liver because all of the blood in the body passes through the liver  Cytochrome P-450 (CYP450) The most important enzyme system of phase I metabolism A microsomal superfamily of isoenzymes that catalyzes the oxidation of many drugs Can be induced or inhibited by many drugs and substances resulting in drug interactions in which one drug enhances the toxicity or reduces the therapeutic effect of another drug  CYP family of enzymes Found in liver, small intestine, lungs, kidneys, placenta Consists of > 50 isoforms Major source of catalytic activity for drug oxidation About > 90% human drug oxidation can be attributed to 6 main enzymes CYP1A2, CYP2D6, CYP2C9, CYP2E1, CYP2C19, CYP3A4 Activity of CYP oxidases differs in different people and different populations  Drug Metabolism: Phase II Main function of phase I reactions is to prepare chemicals for phase II metabolism and subsequent excretion via conjugation The true detoxification step in the metabolism process Glucuronidation = the most common phase II reaction the only one that occurs in the liver microsomal enzyme system  Conjugation reactions Glucuronidation (on -OH, -COOH, -NH2, -SH groups) Sulfation (on -NH2, -SO2NH2, -OH groups) Acetylation (on -NH2, -SO2NH2, -OH groups) Amino acid conjugation (on -COOH groups) Glutathione conjugation (to epoxides or organic halides) Fatty acid conjugation (on -OH groups) Condensation reactions  Phase I and II - Summary End-products of metabolized drugs are generally more water soluble Conjugation makes most drugs more easily excreted by the kidneys Drug metabolism rates vary among patients Some patients metabolize a drug so rapidly Hence therapeutically effective blood and tissue concentrations are not reached Others patients have metabolism rate that are slow Less ability to metabolize drugs, when give usual doses they can get toxic effects  Excretion The main process that body eliminates unwanted substances Most common route - biliary or renal Other routes - lung (through exhalation), skin (through perspiration) Lipophilic drugs may require several metabolism steps before they are excreted  Renal excretion Kidney = most important organ for drug excretion About one fifth of the plasma reaching the glomerulus is filtered through pores in the glomerular endothelium nearly all water and most electrolytes are passively and actively reabsorbed from the renal tubules back into the circulation However, most polar compounds including drug metabolites, cannot diffuse back into the circulation  excreted via kidney Blood cells, platelets, plasma proteins are retained in the blood and not filtered  Renal excretion Active tubular secretion in the proximal tubule is important in the elimination of many drugs Energy-dependent process may be blocked by metabolic inhibitors When drug concentration is high, secretory transport can reach an upper limit (transport maximum) ADME - Summary  Drug R&D 10-15 years to develop a new medicine Likelihood of success: 10% Cost $800 million – 1 billion dollars (US) Why drugs fail  Importance of pharmacokinetic studies Patients may suffer when: Toxic drugs that may accumulate Useful drugs that may have no benefit because doses are too small to establish therapy A drug that can be rapidly metabolized  ?