Pharmacokinetic & Pharmacodynamic

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    1

    INTRODUCING

    PHARMACOKINETICS ANDPHARMACODYNAMICS

    Kinanti Narulita D Pharmacology Department

    FACULTY OF MEDICINE – UNISSULA

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    LEARNING OUTCOMES

    Define and discuss pharmacokinetic factors Discuss the factors that affect absorption,

    distribution, metabolism and excretion-howthey affect drug therapy Define and discuss pharmacodynamic mechanisms of drug actions Apply pharmacokinetic and pharmacodynamic concepts to patient scenarios.

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    PHARMACOKINETIC

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    PHARMACOKINETICS : CONSIDERING SUCH TERMS AS

    Route Absorption

    Distribution Protein Binding Hepatic Metabolism

    Metabolic products Renal Excretion Half-life

    Toxicity

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    Route : oral, parenteral, inhalation, rectal, transdermal, injection.

    Absorption entry into body-acidity and solubility.

    First-pass-metabolic change due to liver enzymes : patients with liver disease poor metabolism toxicity. Distribution extent of protein binding important as

    only free (unbound) drug can have effect. Penicillin ishighly protein bound. Two drug co-administered, degree of protein binding can be altered, displaced? Toxicity? Excretion removal or clearance of drug from body. Half-life how long does it take the plasma concentration of drugs to go down to 50%. Toxicity consider the pharmacological routes to adverse drug effects.

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    PHARMACOKINETIC

    Pharmacokinetics is what the body does to the drugs (THE BODIES RESPONSE TO MEDICATION) , pharmacokinetics refers to the handling of a drug within the body. For almost all drugs the magnitude of pharmacological effect depends on its concentration at its site of action. To achieve the pharmacological response desired, the drug must first be in an available and suitable form and then administrated by an

    appropriate route. 6

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    Distribution Metabolism

    Excretion

    Absorption

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    Absorption

    Route

    Enteral Parenteral

    IV Topical

    transdermal inhalationoral sublingual

    Distribution

    Systemic circulation

    Absorption Absorption

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    ABSORPTION

    Process of drug movement from the administration site to the systemic circulation. The amount and rate of absorption are determined by several factors :

    Drug characteristics that affect absorption / physical nature of the dosage form : molecular weight, ionization, solubility, & formulation

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    Disintegration and dissolution of the released drug into the correct part of the GI tract is

    required for the drug to be absorbed. Drugs in liquid dose form require no disintigration and often dissolution are already accomplished and therefore absorb more rapidly with faster effects.

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    ABSORPTION

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    Food effect on some drugs affects the bioavailability.

    GI motility effects the thorough mixing in the GItract which increases the efficacy in which the drug makes contact with surfaces that are available to engage absorption.

    Drug absorption is mainly in the upper small intestine that is facilitated by the large surface area of villi and the rich blood supply.

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    ABSORPTION

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    ABSORPTION

    KEYNOTE Factors affecting drug absorption related to patients :

    Route of administration Gastric or intestinal pH Contents / composition of GI tract

    Presence or absence of food in the stomach Mesenteric blood flow

    Concurrent administration with other drugs

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    BIOAVAILABILITY

    “Bioavailability is the proportion of the administered dose that reaches the systemic circulation. ” = refers to the amount and the rate of appearance of the drug in the blood after administration in its initial

    dose form.Orally administered drug bioavailability is directly related to the individual solubility in body fluids.

    Poor solubility = low bioavailability

    To become affective i.e. produce a therapeuticeffect, a drug must reach an adequate concentration in the blood. Drugs administered by the IV route are bioavailable in 100% of cases as it is administered

    directly into the blood.

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    BIOAVAILABILITY

    Some drugs with the same active principle, made by different manufacturers may differ in the bioavailability, dependant on the degree of

    compression or nature of excipients (addedsubstances), that may affect the disintigration and dissolution of the drug. Drugs licensed for use in the UK (including parallel

    imports) the manufacturing processes are controlled to ensure bioavailability across drug production is consistent. Brand vs generic prescribing . Bioequivalence should be similar with a few exceptions.

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    Time to Peak Concentration

    0 10

    20

    30

    40

    50

    60 70

    80

    90

    100

    0 5 10 20 30 60 120 180

    minutes

    c o n c e n

    t r a

    t i o n

    IV

    Oral

    Rectal

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    EFFECT OF FOOD ON THE ABSORPTION OF DRUGS Bioavailability of some drugs is affected by the presence of food. E.g : penicillin, erythromycin, rifampicin, thyroxine. Some drugs are taken before meals to allow time for drug to act before food is taken. Gastric irritation can be caused by drugs taken on an empty stomach.

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    FIRST PASS EFFECT

    Drugs that are absorbed via the GIT are circulated to the liver first via

    the hepatic portal vein Liver then acts as a filter Only part of the drug is

    circulated systemically The combination of

    processes is termed

    the ‘First Pass’ effect

    http://www.nurse-prescriber.co.uk/education/visual_lib/pp18.jpg http://www.nurse-prescriber.co.uk/education/visual_lib/pp18.jpg

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    All drugs taken orally that are absorbed pass by the hepatic portal vein. This is a defence mechanism to detoxify substances coming into

    the body. The liver protects the body from systemically circulating toxins that are absorbed via the GIT by

    filtering drugs through a range of detoxificationmechanisms seeking for natural toxins. As a result only part of the administered drug reaches the systemic circulation via the hepatic artery.

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    FIRST PASS EFFECT

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    Distribution

    Factors affecting

    Absorption Metabolism

    Low albumin Problems with: Heart

    Circulation Diabetes

    Bound drugs are pharmacologically inactive because the drug-

    protein complex is unable to cross cell membranes.

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    Membrane permeability cross membranes to site of action

    Plasma protein binding bound drugs do not cross membranes malnutrition = albumin = free drug

    Lipophilicity of drug lipophilic drugs accumulate in adipose tissue

    Volume of distribution

    DISTRIBUTION

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    Low Affinity, high capacity binding Proteins : Albumin (e.g. phenytoin) 1-acid glycoprotein (cationic lidocaine) Lipoproteins

    Specific binding Proteins (high affinity low capacity) : cortisol binding globulin, thyroid binding globulin

    PLASMA PROTEINS

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    Protein Berat Molekul

    (Da) Konsentrasi

    (g/L) Obat yang mengikat

    Albumin 65,000 3.5 –5.0 Acid drugs (large variety of drug)

    α1 - acid glycoprotein

    44,000 0.04 – 0.1 Basic drug : propranolol, imipramine and lidocaine.

    Globulins : corticosteroids.

    Lipoproteins 200,000 – 3,400,000 .003-.007 Basic lipophilic drug :chlorpromazine

    α1 globulin

    α2 globulin

    59000