Pharmacokinetics .


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Pharmacokinetics. ผศ.มนุพัศ โลหิตนาวี manupatl@nu.ac.th manupatl@hotmail.com. Outline. Introduction Physicochemical properties Absorption, Bioavialability, routes of admistration Distribution Biotransformation (Metabolism) Excretion Clinical pharmacokinetics.
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Pharmacokinetics ผศ.มนุพัศ โลหิตนาวี manupatl@nu.ac.th manupatl@hotmail.com

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Outline Introduction Physicochemical properties Absorption, Bioavialability, courses of admistration Distribution Biotransformation (Metabolism) Excretion Clinical pharmacokinetics

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Components of pharmacokinetics Input, dosing by utilizing courses of organization Pharmacokinetic forms (figure 1, drawing) Absorption Distribution Biotransformation (Metabolism) Excretion

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Cell film boundary of medication penetration (drawing), with semipermeable property elements influencing drug crosswise over cell layer cell layer properties physicochemical properties of medications

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Cell film physicochemical properties of medications size and shape solvency level of ionization lipid dissolvability

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Cell film Characteristics of Cell layer Lipid bilayer: versatile on a level plane, adaptable, high electrical resistance and impermeable to high polar mixes protein atoms work as receptors or particle channels or destinations of medication activities.

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Diffusion over the cell layer Passive transport (drawing) higher conc to bring down conc range vitality free at unfaltering state both sides have parallel conc.(non electrolye cpds) electrolyte: conc. of every side relies on upon pH (fig 2) feeble corrosive and powerless base

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Diffusion over the cell film Carrier-interceded layer transport (drawing) bring down conc to higher focus territory (agianst fixation slope) structure particular fast rate of dispersion Active and Facillitated transport

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Diffusion over the phone film Active transport vitality subordinate structure particular, repressed by structure-related cpds, saturable Facillitated transport vitality autonomous structure particular, restrained by structure-related cpds, saturable

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Saturable process Drawing all protein-intervened handle in our body can happen this procedure immersion transport framework as well as others, for example, enzymatic response, tranquilize ligand official et cetera. since useful protein atoms are constrained.

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Drug retention Parameters in medication ingestion Rate consistent of medication assimilation (Ka) Bioavialability (F) Anatomical perspectives influencing retention parameters (Drawing) GI tract (metabolzing organ and obstruction of medication development) Liver (entryway and hepatic vien, discharge by means of biliary discharge) aggregate debasement supposed "First pass impact"

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Drug ingestion Factors influencing drug retention (Drawing) Physicochemical properties of medications pH at site of assimilation Concentration at the site of organization Anatomical and physiological elements Blood stream Surface zone

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Routes of organization Enteral and parenteral courses Pros and cons amongst Enteral and parenteral

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Enteral organization Pros most prudent, most helpful Cons high polar cpds couldn\'t be consumed GI aggravating operators enzymatic degradaion or pH impact Food or medication collaboration (accompanying utilized) participation of the patients is required first pass impact because of GI mucosa

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Parenteral organization Pros Rapidly achieved focus Predictable conc by the measurable measurement Urgent circumstance Cons Aseptic method must be utilized Pain restricted self adminstration More costly

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Enteral organization Common utilization of enteral organization Oral organization Sublingual organization Rectal organization

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Enteral organization Concentrion-time course of oral organization (Drawing) Rapid increment in plasma conc until achieving most elevated conc and resulting diminish in plasma conc Drawing (idea of MTC and MEC) Absorption stage Elimination stage

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Enteral organization Prompt discharge: the most well-known dose frame Special arrangement: Enteric-coat, SR, Controlled discharge: Purposes and constraint

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Enteral organization Sublingual organization Buccal ingestion Superior vana cava straightforwardly: no first pass impact Nitroglycerin (NTG): exceedingly removed by the liver, high lipid solvency and high strength (little measure of retained particles have the capacity to demonstrate its pharmacological impacts and calm mid-section torment).

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Enteral organization Rectal adminstration oblivious patients, pediatric patients half go through the liver and half sidestep to the second rate vena cava bring down first pass impact than oral ingestion irregularity of retention example fragmented assimilation Irritating cpds

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Parenteral organization Common utilization of parenteral organization Intravenous Subcutaneous Intramuscular Simple dispersion Rate relies on upon surface of the fine, dissolvability in interstitial liquid High MW: Lymphatic pathway

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Parenteral organization Intravenous exact measurement and dosing interim No ingestion (F=1), all atoms achieve blood flow Pros: Calculable, quickly achieve coveted conc., Irritating cpds have less impacts than different courses Cons: unretreatable, harmful conc, lipid dissolvable can\'t be given by this course (hemolysis), intently observed

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Parenteral organization Subcutaneous appropriate for non-bothering cpds Rate is typically moderate and steady creating delayed pharmacological activities.

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Parenteral organization Intramuscular more quick than subcutaneous rate relies on upon blood supply to the site of infusion rate can be expanded by expanding blood stream (illustration)

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Pulmonary ingestion vaporous or unstable substances and pressurized canned product achieve the absorptive site of the lung. Very accessible range of assimilation Pros: fast, no first pass impact, specifically achieve coveted site of activity (asthma, COPD) Cons: measurement alteration, confounded technique for administrator, disturbing cpds.

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Bioequivalence Pharmaceutical comparability (drawing) Bioequivalence: PharEqui+ rate+ bioavialable medications Factors: Physical property of the dynamic fixing: precious stone shape, molecule estimate Additive in theformulation: disintegrants Procedure in medication creation: constrain

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A case of a nonexclusive item that could breeze through a bioequivalence test: Simvastatin (Parent frame, n=18)

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A case of a non specific item that could finish a bioequivalence test: Ondansetron (n=14)

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A case of a bland item that could finish a bioequivalence test: Clarithromycin (n=24)

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Distribution Drawing conveyance site: all around perfused organs, poor-perfused organs, plasma proteins Well-perfused: heart, liver, kidney, mind Poor-perfused: muscle, instinctive organs, skin, fat

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Distribution Plasma proteins Albumin: Weak acids alpha-corrosive glycoprotein: Weak bases Effects of plasma protein restricting Free division: dynamic, discharged, metabolized the all the more authoritative, the less dynamic medication the additionally official, the less discharged and metabolized: "longer half-life"

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Distribution Effects of well appropriation into the tissues profound tissue as a medication store maintain discharged medication from the repository and redistributed to the site of its activity drag out pharmacologic activities

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Distribution CNS and CSF Blood-Brain Barrier (BBB) one of a kind anatomical example of the vessels providing the cerebrum just exceptionally lipid solvent mixes can move crosswise over to the cerebrum contamination of the meninges or cerebrum: higher porousness of penicillins to the cerebrum.

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Distribution Placental exchange Simple dispersion Lipid solvent medication, non-ionized species initial 3 mo. of pregnancy is extremely basic: "Organogensis"

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Biotransformation Why biotranformed? (Figure 5) Normally, drugs have high lipid dissolvability along these lines they will be reabsorbed when the filtrate achieving renal tubule by utilizing tubular reabsorption procedure of the kidney. Biotransformation changes the parent medication to metabolites which dependably have less lipid solvency (more hydrophilicity) property hence they could be discharged from the body

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Biotransformation to more polar cpds to less dynamic cpds could be more powerful (M-6-G) or more dangerous (methanol to formaldehyde)

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Biotransformation Phase I and II Biotransformation Phase I : Functionization, Functional gathering Phase II: Biosynthetic, Molecule

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Biotransformation Phase I Reactions (Table 2) Oxidation Reduction Hydrolysis

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Biotransformation Phase II Reactions (Table 3) Glucuronidation Acetylation Gluthathione conjugation Sulfate conjugation Methylation

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Biotransformation Metabolite from conjugation response Possibly discharged into bile corrosive to GI Normal vegetation could metabolize the conjugate to the parent shape and therefore reabsorbed into the blood flow. This pheonomenon is supposed "Enterohepatic flow" which can draw out medication half-life.

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Biotransformation Site of biotransformation Mostly occurred in the liver Other medication metabolizing organs: kidney, GI, skin, lung Hepatocyte (Drawing)

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Biotransformation The Liver: Site of biotransformation: for the most part enzymatic response by utilizing the endoplasmic reticulum-abiding enzymes.(Phase I), Cytosolic catalysts are for the most part required in the stage II Rxm. Strategy for study stage I Rxm Breaking liver cells Centrifugation quickly microsomes and microsomal compounds

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Biotransformation Cytochrome P450 monooxygenase framework (figure 6) microsomal proteins Oxidation response utilizing decreasing specialist (NADPH), O 2 System prerequisite Flavoprotein (NADPH-cytochrome P450 reductase, FMN+FAD) fuctions as an electron giver to cytochrome c. Cytochrome P450 (CYP450)

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Biotransformation Steps in oxidative responses (figure 6) Step 1: Parent + CYP450 Step 2: Complex acknowledges electron from the oxidized flavoprotein Step 3: Donored electron and oxygen shaping a mind boggling Step 4: H 2 O and Metabolite arrangement

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Biotransformation CYP450 is a superfamily

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