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Description : ABSORPTION DISTRIBUTION METABOLISM AND EXCRETION

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PHARMACOKINETICS PHL 326 Sem 421 Sep 2020
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PHARMACOKINETICS PHL 326 Sem 421 Sep 2020 Introduction Absorption Distribution Metabolism Excretion
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Pharmacokinetics Pharmacokinetics refers to what the body does to the drug It controls the dose-concentration relationship of a drug Pharmacokinetics determines the Onset, intensity and duration of drug action Four corner stones of Pharmacokinetics A- Absorption D- Distribution M- Metabolism E- Elimination
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Pharmacokinetics processes: ADME Absorption of drug from the site of administration into plasma Distribution; drug reversibly leaves the bloodstream and distributes into the interstitial and intracellular fluids Metabolism; drug may be metabolized by the liver, or other tissues Elimination; drug and its metabolites are removed from the body in urine, bile, feces, sweat and expired air
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ABSORPTION PHL 326 Sem 421 Sep 2020
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ABSORPTION of Drugs Absorption is the transfer of a drug from its site of administration to the bloodstream The rate and efficiency of absorption depends on the route of administration, drug nature and formulation. The rate and extent of absorption influences the clinical effectiveness of a drug Only in IV delivery, absorption is complete, but other routes may result in only partial absorption and, thus, lower bioavailability
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Mechanisms of absorption of drugs from the GIT Passive diffusion Facilitated diffusion Active transport Endocytosis & Exocytosis Filtration
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Mechanisms of Absorption 1. Passive diffusion: The drug moves from high concentration to lower concentration. Passive diffusion does not involve a carrier/energy. The majority of drugs are absorbed by this mechanism Lipid soluble drugs move faster than water soluble drugs. Is Not saturated, Non specific
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Mechanisms of Absorption 2. Facilitated diffusion: Specialized transmembrane carrier proteins that facilitate the passage of drug molecules Drugs move from high concentration to an area of low concentration It does not require energy but it can be saturated. Can be inhibited by compounds that compete for the carrier Drugs resemble naturally occurring peptides, amino acids, or sugars
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3. Active Transport: Specialized trans membrane carrier protein is required. With Drugs that are very similar to structure of natural compounds . Drugs move against concentration gradient (Uphill) i.e from low to high drug concentration Energy is required by ATP hydrolysis, Can be saturated Selective and can be competitively inhibited. Mechanisms of Absorption
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4. Endocytosis and exocytosis This type of absorption is used to transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug filled vesicle. Examples: Vitamin B12 is transported across the gut wall by endocytosis Neurotransmitters are stored in intracellular vesicles in the nerve terminal and released by exocytosis Exocytosis is the reverse of endocytosis. Mechanisms of Absorption
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5. Filtration Small drug molecules move along with fluid through pores in cell walls. No passage through the lipid matrix of cell. Capillary membrane pores act as barriers to only very large drug molecules. Water soluble drugs and some electrolytes are absorbed through tissue pores. Mechanisms of Absorption
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Factors Affecting Absorption Ionization Solubility of the drug Blood flow to the absorption site Surface area available for absorption Contact time at the absorption surface Route of administration
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Ionization Most drugs are Weak Acids or Bases Unionized molecules are more lipid-soluble Ionized molecules have low lipid solubility Only unionized/uncharged drug can pass easily through membranes The extent of ionization is depended on the pKa (ionization constant) of the drug and the pH at the site of absorption The pKa is the pH at which half the drug is in its ionized form, a measure of the extent of dissociation at any given pH The larger the value of pKa, the smaller the extent of dissociation at a given pH
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HA A- B BH+ Acidic drugs Basic drugs Deprotonated Ionized Unabsorbed Protonated Ionized Unabsorbed Ionization
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Ionization Aspirin is weak acid. pKa value is 3.5. Ionized in higher pH >3.5 thus less absorption. Unionized in pH lesser <3.5 (more acidic) thus more absorption. Since stomach pH is acidic, aspirin can be easily absorbed. weakly acid drug will be absorbed from the stomach or upper part of intestine. Act opposite to acidic drugs. Ionized in acidic environment  less absorption. Less absorbed from stomach. More absorption from in Alkaline medium the small intestine. Acidic drugs Basic drugs
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How fast the drug solubilizes and form a solution. Lipid-soluble drugs cross lipid cell membranes more rapidly. In tablets disintegration and dissolution are the rate limiting step for absorption. Solubility Blood flow to the small intestine is much higher than stomach. Absorption from the intestine is more than stomach. Blood flow Factors Affecting Absorption
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The more the surface are the more efficient is the absorption. Microvilli present in the intestine increases the surface area to about 1000 folds that of stomach. Surface area Very important factor to determine the rate of absorption. Some drug absorb only from parenteral route. Example: Insulin Route of administration Factors Affecting Absorption
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The more the time spent in the GIT the more absorption will occur. Drug moves through the GI tract very quickly, as in severe diarrhea, parasympathetic activity; it is not well absorbed. Anything that delays the transport of the drug from the stomach to the intestine (gastric emptying) delays the rate of absorption of the drug as sympathetic activity, anticholinergics, and food. Contact time at the absorption surface Factors Affecting Absorption
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Bioavailability Is the fraction of unchanged drug reaching the systemic circulation following administration by any route if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability 70% For an IV dose, bioavailability is considered 100% (unity) For oral drugs, bioavailability is less than 100% (only part of the administered dose appears in the plasma) due to: Incomplete extent of absorption across the gut wall First-pass elimination
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Bioavailability
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Determination of Bioavailability Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (e.g. oral ) and after IV injection By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC). Total AUC reflects the extent of absorption of the drug
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Factors affecting bioavailability Nature of Drug Formulation: Physical nature of drug formulation /drug (Amorphous / crystal) Solubility Dissolution rate (The rate at which drug undergoes dissolution) Particle size First pass metabolism Gastric emptying rate Chemical Instability Health conditions/disease ( Example: Hepatic or GIT diseases) Enzyme induction/inhibition
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Important definitions Two drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations (same rate and extent of absorption). Bioequivalence Two drugs have the same dosage form, contain the same active ingredients and use the same route of administration. Pharmaceutical equivalence Two drug formulations that are pharmaceutically equivalent and have similar clinical effect and safety profiles. Therapeutic equivalence Therapeutic equivalence = Bioequivalence + Pharmaceutical equivalence Two bioequivalent drugs may not be therapeutically equivalent
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DISTRIBUTION 7/9/2020 PHL 326 Sem 421 Sep 2020
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Distribution Process by which a drug reversibly leaves the bloodstream and distributed throughout the body Drugs can be distributed to Water compartments: plasma, interstitial fluid and intracellular fluid Cellular compartments: binding to lipids, proteins and nucleic acids A prerequisite for most drugs to reach target organs in therapeutic concentrations Distribution plays a significant role in onset, intensity and some times duration of action. Distribution half-life: the time required to distribute 50% of the drug from plasma throughout the body.
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Factors influence distribution Blood flow Capillary permeability Protein binding Lipophilicity
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Blood Flow The rate of blood flow to tissues vary widely Well perfused tissues: kidney, heart, liver, brain  ↑blood flow faster uptake, receive the drug within minutes. Poorly perfused tissues: muscle, adipose tissue, skin ↓ blood flow slower uptake, require longer time 7/9/2020 PHL 326 Sem 421 Sep 2020
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Redistribution Drug effects may also be terminated by redistribution from its site of action to other tissues or sites A highly lipophilic-drug may: Rapidly partition into the brain Act briefly and then redistribute into other tissues often ultimately concentrating in adipose tissue Redistribution is the mechanism responsible for termination of action of thiopental (pentothal) or propofol (Diprivan), anesthetic inducing agents.
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Capillary permeability Physiological Barriers Drugs, once again, must overcome these barriers » simple capillary endothelial barrier » simple cell membrane barrier » Blood-brain barrier » Blood-placental barrier » CSF barrier » Blood-testis barrier
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Blood Brain Barrier - BBB Drugs that are SMALL, lipid soluble and poorly bound to plasma proteins can cross BBB and produce effects in the CNS. Highly ionized and protein bound drugs cannot enter CNS BBB has active transport system pumps drug molecules out of the brain that may have entered by diffusion. Brain capillaries are covered by glial cells (astrocytes) Assist in forming tight junctions Limits the size and type of molecules that can enter the brain Meningitis – active transport fails – large amounts of PCN are allowed to remain in the brain.
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Placental Barrier Non-ionized, lipid soluble drugs readily reach fetus through maternal circulation. Placenta is not a barrier to drugs as once thought. Fetus is exposed to same drug concentrations as those in the mother, possibly higher.
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Capillary permeability Capillary permeability depends on capillary structure and the chemical nature of the drug In liver, capillaries are discontinuous having large slit junctions between endothelial cells Lipophilic drugs can pass through the endothelial cell membrane while hydrophilic substances pass through the slit junctions
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Capillary permeability In brain capillary structure is continuous with no slit junction Brain endothelial cells that are connected by tight junctions, thick basement membrane and astrocytic processes constitute the blood brain barrier BBB To enter the brain, drugs must pass through the endothelial cell membrane (lipophilic) or be actively transported Ionized/polar drugs can not enter the CNS
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Binding to plasma proteins Reversible binding of drug to plasma proteins slows drug distribution As the concentration of the free drug decreases due to elimination, the bound drug dissociates from the protein This maintains the free-drug concentrations a constant fraction of the total drug in the plasma
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Binding to plasma proteins Albumin is the major drug-binding protein and acts as drug reservoir it binds acidic drugs e.g. warfarin , penicillin, sulfonamides Alpha-1-acid glycoproteins bind basic drugs e.g quinidine Only free unbound drugs are available to cross cell membranes to site of action Bound drugs are pharmacologically inactive and cannot be bio-transformed or excreted
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Binding to plasma proteins Percentage of binding in circulation depends largely on chemical nature of the drug. Acetaminophen - ~0% protein bound More drug reaches site of action Short duration of action More frequent administration Warfarin – 99% protein bound – 1% pharmacologically active. Long duration of action Once daily administration A number of disease states alter the concentration of plasma proteins which affects distribution. Eg: Hypoalbuminemia can cause drug toxicity
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Lipophilic/lipid soluble drugs readily move across biologic membranes distributed rapidly. Hydrophilic/lipid insoluble drugs do not readily penetrates biologic membranes and must pass through slit junctions  distributed slowly. Lipophilicity
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Volume of distribution Vd Drug may distribute into any of the following compartments of body water: Plasma compartment Extracellular fluid Total body water 28 liters
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Volume of distribution (Vd) is the apparent fluid volume required to contain the entire amount of drug homogenously in the body at the same plasma concentration. (Q) = the total body content of the drug (Cp) = concentration equal to that present in the plasma Vd varies greatly between drugs, aspirin has a low Vd while digoxin has a very high Vd. Volume of Distribution Vd
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Volume of distribution Vd Vd reflects a balance between binding to tissue and binding to plasma proteins ↑Vd ↑ concentration in extravascular tissue & ↓ plasma concentration (retention outside plasma) ↓ Vd ↓ concentration in extravascular tissue & ↑ plasma concentration (retention within plasma) Loading dose of a drug primarily depends on Volume of Distribution As Vd increases the dose of drug required to achieve certain plasma concentration increases.
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Loading Dose Dose required to immediately achieve a plasma concentration equivalent to steady state concentration Achieves immediate therapeutic concentration For most drugs, the loading dose can be given as a single dose by the chosen route of administration
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Maintenance dose Drugs are administered to maintain a steady state of drug in the body drug is given in each dose to replace the drug eliminated since the preceding dose At steady state, the dosing rate ("rate in") must equal the rate of elimination ("rate out").
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METABOLISM/ BIOTRANSFORMATION
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Biotransformation/Metabolism Biotransformation is the chemical alteration of drugs in the body. Humans are exposed daily to a variety of foreign compounds called xenobiotics Metabolism transforms lipophilic drugs into more polar readily excreted products The primary site for drug metabolism is liver, others are: kidney, intestine, lungs , plasma and skin The process of drug metabolism that leads to elimination plays a major role in diminishing the biological activity of a drug
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Biotransformation Results Biotransformation of drug leads to the following: - Inactivation:- Inactive or less active e.g. ibuprofen, paracetamol, lidocaine - Formation of active metabolite:- Drugs have been found to be partially converted to one or more active metabolite e.g. Digitoxin –> Digoxin - Activation of inactive drug:- Few drugs are inactive (pro-drug) and need conversion in the body to one or more active metabolites e.g. Levo Dopa –> Dopamine - Conversion to highly toxic and carcinogenic metabolites e.g. Acetaminophen (APAP; Paracetamol)- induced hepatotoxicity
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Is the process of drug metabolism before entering the systemic circulation Liver: is the principle organ responsible for first pass metabolism Many drugs are absorbed from small intestine and transported to liver via portal system Intestine: contribute to the overall first-pass effect through metabolizing drugs by enzymes present in gut lumen and gut wall Some drugs are more metabolized in the intestine than liver Drugs can be metabolized also by intestinal microorganisms The hepatic first-pass effect can be avoided by use of intravenous route sublingual tablets and transdermal preparations and rectal suppositories. First-Pass Metabolism
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The kidney cannot efficiently eliminate lipophilic drugs. Lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in the liver via two general sets of reactions, called: Phase I metabolism and Phase II metabolism Biotransformation/Metabolism
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The kidney cannot efficiently eliminate lipophilic drugs. Lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in the liver via two general sets of reactions, called: Phase I metabolism and Phase II metabolism Biotransformation/Metabolism
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Biotransformation/Metabolism Phase I Metabolism Phase II Metabolism Reduction, Oxidation, Hydrolysis Conjugation
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Classification of Metabolism Phase I metabolism Convert the parent drug to a more polar metabolite Introducing or unmasking of small polar group (−OH,−NH2, −SH) Metabolites are often inactive, but sometimes activity is only modified or even enhanced If phase I metabolites are sufficiently polar, they may be readily excreted. Phase II metabolism Addition (conjugation) of large polar group to small functional group as glucuronic acid, sulfate, acetate, or an amino acid (GSH, glycine) Form a highly polar drug conjugate Conjugates are readily excreted and often inactive Parent drug may already have a functional group that can form a conjugate directly. Phase II may precede Phase I
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Phase I Metabolism Definition: modification of the drug molecule via oxidation, reduction, or hydrolysis. Addition of a water molecule with subsequent bond breakage (esterase, oxidases and dehydrogenases enzymes) The key enzymes Cytochrome P450 (P450 or CYP) NADPH- Cytochrome P450 oxidoreductase (P450 reductase) CYP3A4 alone is responsible for the metabolism of over 50% of the prescription drugs metabolized by the liver PHASE I REACTIONS: Oxidations, Epoxidation, Oxidative dealkylation, N-Oxidation, S-Oxidation, Deamination, Desulfuration, Reductions, Hydrolyses.
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Drug metabolizing enzymes Most transformations are catalyzed by certain cellular enzymes These enzymes are versatile and nonspecific They are divided into Microsomal enzymes Non Microsomal enzymes
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Phase I Metabolism They are located in the lipophilic membranes of endoplasmic reticulum (microsomes) of liver and other tissues. These enzymes catalyze oxidative, reductive, hydrolytic and glucuronidation reactions. Microsomal enzymes convert lipid soluble drugs into water soluble metabolites and readily excreted. Non microsomal enzymes present in soluble form in cytoplasm, attached to mitochondria not to endoplasmic reticulum. These are non specific enzymes that catalyze few oxidative, reductive, hydrolytic, and conjugation reactions other than glucuronidation. These enzymes act on relatively water soluble drugs. Microsomal enzymes Non-microsomal enzymes
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Microsomal Enzymes Cytochrome P450 Human P450 liver enzymes The CYPs are a superfamily of enzymes, that contain a heme molecule bound to a polypeptide chain. The liver contains the greatest abundance of CYPs that is responsible for the majority of hepatic drug metabolism. CYP3A4 is the most abundant (30%) liver isoform and is responsible in the metabolism of over 50% of drugs metabolized by the liver. Synthesis of endogenous compounds such as steroids
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Microsomal mixed function oxidase system The important class of enzymes called mixed function oxidases or monoxygenases. Located in the lipophilic endoplasmic reticulum membranes of the liver (microsomes) Responsible for oxidative drug metabolism Mixed function oxidases (MFOs), or monooxygenases Requires both a reducing agent (nicotinamide adenine dinucleotide phosphate [NADPH]) and molecular oxygen Two microsomal enzymes play a key role. The first of these is a flavoprotein: NADPH-cytochrome P450 reductase The second microsomal enzyme is a hemoprotein: cytochrome P450 Microsomal drug oxidations require P450, P450 reductase, NADPH, and molecular oxygen
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Non Microsomal Enzymes Non-microsomal enzymes Hydrolysis in plasma by esterase. Alcohol and aldehyde dehydrogenase in cytosolic fraction of liver (ethanol). Monoamine oxidase in mitochondria (noradrenaline, dopamine). Xanthene oxidase (uric acid production). enzymes for particular drugs (tyrosine hydroxylase, dopa-decarboxylase etc).
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Phase I Metabolism
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Enzyme Induction Enzyme induction is the increased drug metabolizing ability of CYP enzymes by several drugs and chemicals This occurs by either increasing synthesis or decreased degradation Agents which cause this effect are enzyme inducers
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Consequences of enzyme induction Decrease in pharmacological activity of drugs. Shorten action of drugs Increased activity of drugs biotransformed to active metabolites. Altered physiological status due to enhanced metabolism of sex steroids
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Enzyme Inhibition A decrease in drug metabolizing ability of CYP enzymes is called enzyme inhibition Prolongs action of drugs or inhibits action of those biotransformed to active agents (pro-drugs) Enzyme inhibition is more important clinically than enzyme induction for drugs with narrow therapeutic index e.g. anticoagulants, antiepileptics.
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Consequences of enzyme Inhibition Increase in pharmacological activity of drugs. Prolong action of drugs Decreased activity of drugs biotransformed to active metabolites. Altered physiological status due to decreased metabolism of sex steroids
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Phase II Biotransformation Coupling or conjugation reactions with drug molecules to yield drug conjugates. Conjugates are polar molecules that are readily excreted and often inactive Phase II reactions are relatively faster than P450-catalyzed reactions, Thus effectively accelerating drug biotransformation, terminal inactivation or true detoxification Conjugation with endogenous compounds via the activity of many enzymes May follow phase I or occur directly Types of conjugation: Glucuronidation: Morphine Acetylation: Isoniazid (INH) Sulfation: Steroids Glutathione (GSH) conjugation: Acetaminophen
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Phase II Biotransformation Some examples of Phase II enzymes: UDP-glucuronosyltransferases (UGT)-Addition of glucuronic acid. Glutathione-S-transferases (GST)-Addition of glutathione. Sulfotransferases (SULT)-Addition of sulfate. N-acetyltransferases (NAT) -Addition of acetyl group. Methyltransferases (MT)-Addition of methyl group.
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Metabolism of drugs to toxic products Some drugs metabolically transformed to reactive intermediates that are toxic to various organs Due to deficiency of endogenous detoxifying cosubstrates (GSH, glucuronic acid, sulfate toxic pathways) may result in overt organ toxicity or carcinogenesis An example is acetaminophen (paracetamol)-induced hepatotoxicity
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Factors affecting Biotransformation Race Age (reduced in aged patients & children) Sex (women slower ethanol metabolizers) Patient condition Other drug administration Food (charcoal grill ++CYP1A, grapefruit juice --CYP3A) Smoking, cause enzyme induction
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EXCRETION (Clearance)
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Renal elimination of drugs Only ionized, lipid-insoluble drugs are excreted into the urine Unionized, lipid-soluble, reabsorbed into blood. Drugs with large Vd are poorly excreted in urine. Drugs contained in blood compartment show higher clearance rates Drugs bound to plasma proteins or bound to tissues cannot be filtered by glomerulus.
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Renal elimination of drugs Renal elimination is the most important route for drug removal from the body into urine. Glomerular filtration: of free unbound drug and metabolites Affected by plasma protein binding and filtration rate Proximal tubular active secretion: of polar ionized drugs and metabolites, nonselective Distal tubular passive reabsorption of lipophilic unionized drugs back to the blood
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Effect of pH on renal elimination PH affects ionization and therefore, polarity of drugs Alteration of urine pH can be done to increase the fraction of ionized drug thus the clearance of an undesirable drug Weak acids can be eliminated by alkalinization of the urine Weak bases can be eliminated by acidification of the urine In overdose of phenobarbital (weak acidic drug), alkalinization of the urine with sodium bicarbonate infusion will increases urinary excretion. Amphetamine (weak base), acidification of urine (ammonium chloride, cranberry juice) increase ionization thus urinary excretion.
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Drug Elimination sites Kidneys elimination of unchanged drugs in the urine (renal clearance) Liver a) elimination of unchanged drugs by secretion into the bile b) clearance via biotransformation/metabolism of drug to metabolites Lungs gases and volatile liquids e.g. General Anesthetic , paraldehyde, alcohols. Intestine unabsorbed drugs are eliminated through feces Saliva &Sweat- lithium, iodide, heavy metals Breast milk Tears
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Clearance (CL)
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Half-life (t1/2) The time required to eliminate (metabolize and excrete) 50% of the drug from the body. Determines the frequency of dosing required to maintain therapeutic plasma levels of a drug Half-life depends on clearance (CL) and volume of distribution (Vd) t1/2= 0.693 Vd/CL
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REFERENCE: BASIC & CLINICAL PHARMACOLOGY. BERTRAM G. KATZUNG