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Pharmacokinetics 2011
 

Pharmacokinetics 2011

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    Pharmacokinetics 2011 Pharmacokinetics 2011 Presentation Transcript

    • Pharmacokinetics 2011 Maria Luisa D. Delacruz. MD DLS-HSI College of Medicine Department of Pharmacology
    • Pharmacokinetics
      • “ What the body does to the drug?”
      • “ How the body handles the drug?”
    • Pharmacokinetic Processes
      • Absorption
      • Distribution
      • Metabolism / Biotransformation
      • Excretion
    • Routes of Drug Administration
      • Enteral
      • Parenteral
      • Topical
    • Routes of Drug Administration
      • Enteral
        • Oral
        • Sublingual
        • Buccal
        • Rectal
    • Routes of Drug Administration
      • 2. Parenteral
        • Intradermal
        • Subcutaneous
        • Intramuscular
        • Intravenous
    • Routes of Drug Administration
      • 3.Topical
        • Dermal
        • Inhalational
        • Mucous membrane
          • Nasal
          • Ophthalmic/Otic
          • Vaginal
    • Mechanisms of Drug Passage Across Membranes
      • Passive Diffusion
      • Facilitated Diffusion
      • 3. Active Transport
      • 4. Pinocytosis
    • Mechanisms of Passage Across Membranes
      • PASSIVE DIFFUSION
          • higher conc  lower conc
          • driving force – difference in drug conc
          • utilized by majority of drugs
    • Passive Diffusion
    • Mechanisms of Passage Across Membranes
      • Facilitated Diffusion
      • carrier-mediated transport process
      • does not require energy
      • carrier enhances movement of the drug down
      • an electrochemical gradient
      • e.g. GLUT 4 enhances the permeation of glucose across a muscle cell membrane
    •  
    • Mechanisms of Passage Across Membranes
      • ACTIVE TRANSPORT
          • requires carrier
          • energy consuming
          • against a concentration gradient
          • saturability
          • selectivity
          • competitive inhibition by
          • co-transported compounds
    •  
    • Mechanisms of Passage Across Membranes
      • PINOCYTOSIS
          • folding over the part of
          • the cell membrane
          • formation of small vesicle
          • molecules of extracellular contents are trapped
    • Factors that Affect the Drug Passage Across Membranes
      • 1. molecular size and shape
      • 2. degree of ionization
      • 3. relative lipid solubility of its ionized and nonionized forms
      • 4. binding to serum and tissue proteins
    • ABSORPTION
      • is the movement of a drug from its site of administration to the systemic circulation and the extent to which this occurs
    • ABSORPTION
      • For an orally administered drug, Absorption depends on:
          • disintegration
          • dissolution
          • diffusion
    • Factors that Affect the Rate and Extent of Drug Absorption
        • Dosage form / Drug formulation
        • Physicochemical Properties of the Drug
            • molecular weight
            • pH
            • lipophilic vs hydrophilic
        • * Partition coefficient
      • most drugs are weak acids or bases that are present in solution as both the nonionized and ionized forms
      • nonionized substances are usually more lipid-soluble and can diffuse readily across the cell membrane
      • ionized molecules have low lipid solubility and are unable to penetrate the lipid membrane
    • Factors that Affect the Rate and Extent of Drug Absorption
      • 3. Physiologic variables
          • gastric motility
          • pH at the absorptive site
          • area of absorbing surface
          • mesentric blood flow
          • presystemic elimination / first pass
      • Acidic pH
      • weak acid – more unioinized – more lipid soluble
      • weak base – less unionized – less lipid
      • soluble
      • Alkaline pH
      • weak acid – less unionized – less lipid soluble
      • weak base – more unionized – more lipid
      • soluble
      pH at Absorptive site
    • BIOAVAILABILITY
      • measures the rate and extent by which a drug reaches systemic circulation
      • fraction of unchanged drug that reaches systemic circulation
    • Factors that Affect Bioavailability
      • 1. Biopharmaceutical factors
        • Dosage form
        • Physicochemical properties
      • 2. Physiologic factors
        • Gastric motility
        • Presystemic metabolism
      • 3. GIT contents – Food, drugs, fluid
      • 4. Disease states
    • Determinants of Bioavalability 1. Plasma data
    • Determinants of Bioavalability
      • AUC is the most reliable measure of bioavailability.
      • It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation
    • Determinants of Bioavalability
      • 2. Urine data
      • maximum urinary excretion rate
      • time for maximum excretion rate
      • cumulative amount of drug excreted in the
      • urine
      • 3. Pharmacologic effect
    • Bioavailability
      • Bioequivalence:
        • when two related drugs show comparable bioavailability
      • Therapeutic Equivalence:
        • when two similar drugs have comparable efficacy and safety
    • Routes of Administration, Bioavailability, and General Characteristics Route Bioavailability (%) Characteristics Intravenous (IV) 100 (by definition) most rapid onset Intramuscular (IM) 75 to ≤ 100 large volumes often feasible; may be painful Subcutaneous (SC) 75 to ≤ 100 smaller volumes than IM; may be painful; slower onset than IV or IM Oral (PO) 5 to < 100 most convenient; first-pass effect may be significant Rectal (PR) 30 to < 100 less first-pass effect than oral Transdermal 80 to ≤ 100 usually very slow absorption; used for lack of first-pass effect; prolonged duration of action
    • Distribution
      • process by which a drug reversibly leaves the systemic circulation and enters the interstitial space and/or the cells of the tissues
      • once in the blood stream, the drug is distributed to the different tissues
    • DISTRIBUTION
      • Factors that Influence Drug Distribution
      • Plasma Protein Binding
      • Cardiac Output an Regional Blood Flow
      • Permeability and Perfusion of Membranes
      • Diseases
    • Factors that Affect Distribution:
      • 1. Plasma protein binding
        • drugs bound to proteins are not
        • readily distributed
        • and are inactive
        • high protein binding prolongs onset and duration of action
    • Factors that Affect Drug Distribution
      • Plasma protein binding
        • weakly acidic drugs – albumins
        • weakly basic drugs –  -1-acid glycoproteins
        • free, unbound drug is the active form of the drug
    • Factors that Affect Distribution:
      • 2. Cardiac output and blood flow to the tissues
        • highly vascular organs
        • receive more of the drugs
    • Factors that Affect Distribution:
      • 3. Permeability
      • and Perfusion
      • of Membranes
    • Factors that Affect Distribution:
      • Natural barriers
        • Blood brain barrier
        • Placental barrier
        • Blood-ocular barrier
        • Prevent distribution of drug to areas where their effects may be dangerous
    • Blood brain barrier Placental barrier
    • Factors that Affect Drug Distribution
      • 4. Diseases
        • renal, cardiac failure
        • plasma albumin conc: ↓ in malnutrition, hepatic and renal diseases
        • alpha-1-acid glycoprotein conc: ↓ in pregnancy and post MI
    • Volume of Distribution
      • the volume of fluid to which a drug is distributed
      • drugs with large volume of distribution will have a longer half-life and duration of action
    • Volume of Distribution amount of drug administered initial drug concentration VD =
        • relates the amount of a given drug in the body to the concentration of the drug in the blood
    • Metabolism / Biotransformation
      • process by which a drug is altered chemically into another compound called “metabolites” which may be more active or less active than the parent drug
      • primarily occurs in the liver
        • can also occur in the stomach, small intestines, plasma, kidney, lung, skin, other tissues
    • Metabolism / Biotransformation
      • Two Phases:
        • 1. Phase I reaction
          • oxidation, hydrolysis, reduction
          • mediated by cytochrome P450 (drug metabolizing enzymes )
        • 2. Phase II reaction
          • glucuronidation, sulfation, glutathione conjugation, n-acetylation, methylation
    •  
    • Metabolism
      • Significance:
        • defensive mechanism
        • increases polarity of drug molecules
          • restricts penetration thru cellular membrane
          • reduces distribution
          • promotes elimination
    • Factors Affecting Drug Metabolism
        • 1. Non – Genetic
      • Age
      • Sex
      • Liver size / function
      • Diet / Nutrition
      • Environmental
        • 2. Genetic
    •  
    • Factors Affecting Drug Metabolism
      • 2. Genetic
      • e.g.
      • Acetylation – slow and fast
      • Oxidation – poor and extensive
    •  
    • Excretion
      • process by which a drug or its metabolites is eliminated from the body
      • main organ of elimination is the kidneys
      • other organ of excretion include the biliary system, GIT, skin and lungs
    • Renal Excretion
      • Glomerular
      • filtration
      • Tubular
      • secretion
    •  
    • Half- life (T½)
      • time required to decrease the concentration of the drug in the plasma by 50%
      • often used to determine frequency of administration
      • determines the time to attain steady-state concentration
    • Half- life (T½)
      • Drug needs about 4-5 half lives to be completely eliminated from the body
      • E.g. Paracetamol (ACET) 500 mg half-life 4 hrs
      • after 1 st 4 hrs = 250 mg
      • after 2 nd 4 hrs = 125 mg
      • after 3 rd 4 hrs = 62.5 mg
      • after 4 th 4 hrs = 31.25
      • after 5 th 4 hrs = 15. 635
    • Half- life (T½) T ½ = 0.7 x Vd Cl Where: Vd = volume of distribution Cl = clearance
    • Steady State
      • the point where rate of drug availability equals rate of elimination
      • constant drug concentration
      • point where expect maximum drug effect
      • usually attained after 4-5 half lives
    • Steady State
    • Clearance
      • the measure of the ability of the body to eliminate the drug
      • the sum of hepatic metabolism and renal excretion
    • Kinetic Order
      • 1. Zero order
      • 2. First order
    • Zero Order
      • constant
      • independent of the amount of drug
      • linear
      • active transport
    • First Order
      • not uniform
      • proportional to the amount of drug
      • Curvilinear
      • passive diffusion
    • Elimination of Drugs Order of Elimination 1. First Order 2. Zero Order
    • Zero order Elimination Time after Drug Administration Drug in Body (mg) Amount of Drug Eliminated Fraction of Drug Eliminated 0 1000 ---- ---- 1 850 150 0.15 2 700 150 0.18 3 550 150 0.21 4 400 150 0.27 5 250 150 0.38 6 100 150 0.60
    • First order Elimination Time after Drug Administration Drug in Body (mg) Amount of Drug Eliminated Fraction of Drug Eliminated 0 1000 ---- ---- 1 850 150 0.15 2 723 127 0.15 3 614 109 0.15 4 522 92 0.15 5 444 78 0.15 6 377 67 0.15
    • “ The gift of true friendship is that it takes us by the hand and reminds us we are not alone in the journey! “
    •