PHARMACOKINETICS

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PHARMACOKINETICS

• DR.ABDUL LATIF MAHESAR
• KING Dr.SAUD UNIVERSITY
• October 2008D

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DRUG ABSORPTION

• Is the passage of the drug through body barriers
  or cell membranes to reach its site of action

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Mechanism of Drug Movements Across Cell Membrane

• Passive diffusion ( simple diffusion )
• Active transport
• Facilitated diffusion ( need carrier )
• Pinocytosis (endocytosis)

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Passive diffusion

• Types
• a) Aqueous Diffusion ( filtration through the
  pores) gt water soluble and low molecular weight.
• B) Lipid diffusion gt lipid soluble and low
  molecular weight.

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Characters

1. Commenest
2. Non selective
3. Require no energy
4. Depends on concentration gradient
5. Depends on lipid/water partition coefficient
6. Depends on PKa (of drug) and PH ( of the medium.

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• PKa ( is the dissociation or inization constant)
• is the PH at which half of the substance is
  
• ionized and half is unionized
• PH
• is the ionization of the drug
• weak acids gt best absorbed in stomach(
• because acid wont be ionized lipid soluble
  
• best absorption.
• Note strong acids or bases are fully ionized
  (polarwater soluble)- can not cross cell
  membrane ,given IV infusion

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Active transport

• Relatively not common
• Against concentration gradient
• Requires carrier energy
• Specific e.g iodides
• Saturable with receptor
• Depends on lipid/water coefficient
• Iron absorption
• Uptake of levodopa by brain

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Carrier mediated

• Along concentration gradient
• Requires carrier
• Doesnt need energy
• Selective
• Saturable
• e.g uptake of glucose .vit.B12 and intrinsic
  factor.

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Endocytosis

• High molecular weight drugs
• There is engulfment of the
• substrate by the cell
• e.g vit A,E, D ,K

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Factors affecting Drug absorption

• a) Drugs
• 1. Molecular weight
• 2. PKa
• 3. Lipid water partition coefficient.
• 4. Drug formulation

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• b) Patient
• 1. PH of the gut
• 2. Rate of the gastric emptying
• 3. Presence of the food in the gut
• 4. Intestinal motility (transient time)
• 5. Surface area available for absorption
• 6. Drug interaction

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• c) Food
• 1. Reduces absorption e.g aspirin,pencillin
  v, tetracyclin,
• erythromycin
• 2. Increases absorption e.g propranolol,
  diazepam, dicoumrol

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2. DISTRIBUTION

• 1. ECF (extra cellular fluid)
• Plasma (5 of body weight)
• Interstitial fluid (16 of body weight)
• Lymph (1 of body weight)
• 2. ICF (intracellular fluid)
• 35 sum of fluid contents of all cells in the
  body
• 3. Transcellular fluid (2) cerbrospinal ,
  synovial, peritoneal,pleural, digestive secretion.

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THE MAJOR BODY FLUID COMPARTMENTS

• 1. Intravascular(one compartment)
• in blood (not filtered through endothelium)
• 2. Extra vascular (2 compartments)
• i-e blood and interstitial fluid
• pass endothelium but not cell membranes
• e.g Nitroglycerine.
• 3. Extravascular and intracellular(
  multicompartment)
• pass endothelium and cell membranes.
• e.g physostigmine.

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Factors affecting distribution

1. Cardiac output and blood flow. increased cardiac
   output increases the distribution
2. Physiological properties of the drug
3. Permeablity across tissue barrier
4. Plasma protein binding with drug
5. Tissue binding with drug
6. PH
7. PKa
8. Lipid solubility (fat water partition)

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Volume of distribution(vd)

• It is the amount of drug in the body to the
  concentration of the drug in blood or plasma.
• vd amount of drug in the body
• Cp (concentration
  in plasma)
• Increase in Cp ,decreased is the volume of
  distribution and vice versa

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Drugs with high volume of distribution

• Higher concentration in tissue than in plasma
• Relatively lipid soluble
• Distributed intracellularly
• low molecular weight ? easy to cross barrier.
• not efficiently removed by the hemodialysis
• e.g phenyton ,morphine , digoxin,tricyclic
  anti-depressants
• cross BBB or placental barrier easily

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Drugs with low volume of distribution

• confined to plasma and interstitial fluids(not
  tissues)
• Distributed in extracellular compartment mostly
• High MW ,eg.heparin,insulin ,dextran
• these are polar or lipid insoluble drugs e.g
  carbenicillin, vecuronium,gentamycin
• High plasma protein binding e.g warfarin
• Dont cross BBB or placental barrier? because
  of lipid insolubility
• All skeletal muscle relaxants have low vd.

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Physiological barriers

• Blood brain barrier (BBB)
• Placental barrier

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Placental barrier

• Drugs cross placenta by simple diffusion
• lipid soluble drugs readily (easily) enter the
  fetal blood
• In mother if given
• Morphine ? respiratory
  depression
• in the
  fetus
• Warfarin ? hemorrhage ( if
  taken in the 1st 3months
• ?
  congenital malformation)
• Anti-thyroid drugs ? neonatal
  goiter

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Passage of drugs in to CNS and CSF

• Controlled by BBB
• lipid soluble drugs e.g general anesthetics ,
  CNS depressants, antibiotics chloramphenicol and
  sulphadiazine.
• Inflammation as in meningitis ( in meningitis ?
  permeability is increased e.g penicillin
  ,gentamycin.

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Binding of Drugs

• Tissue binding ( some drugs posses and affinity
  for certain tissues and get accumulated in there
  like
• Bone e.g tetracycline and heavy metals such as
  lead ( which combine with collagen)
• 2. Fat drugs like thiopental and ether
• 3. Salivary and thyroid glands Iodides
• 4. Liver quinacrine ( 300 time more in liver)
  chloroquine with nucleic acid
• 5. Hair and Skin arsenic( combines with keratin)

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Plasma Protein Binding

• Albuminacidic drugs bind with albumin such as
  warfarin,phenetoin, aspirin ,sulphonamides
• Globulin Basic drugs such as quinidine
  ,diazepam

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Drugs exists in

• Bound form
• Unbound or free form
• Bound drugs
• Not available for combination with receptor
• No pharmacological action
• Not available for metabolism
• Not available for excretion
• long duration of action
• may lead to clinically important drug - drug
  interaction

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Unbound Drug

• Pharmacologically active
• Available for metabolism
• Available for excretion
• Has short duration of action.

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Displacement

• some drugs can compete with each other for the
  same site on the plasma protein and displace
  drugs thus increasing their concentrations to
  toxic level.
• e.g. Warfarin-strong tolbutamide- weak ?
  hypoglycemia (warfarin is binding where
  tolbutamide is free effect)
• Aspirin strong warfarin-weak ? bleeding

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Termination of the drug

• Biotransformation
• Excretion
• Redistribution

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• Resdistribution
• resdistribution of the drug from its site of
  action to other tissues
• e.g thiopental

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METABOLISM

• Drug metabol(biotransformation)
• It is the chemical reactions which
• lead to modification of drugs
• Sites of metabolism
• - Hepatic microsomes ,mitochondria,
• cytoplasm
• - Extrahepatic lung ,blood ,skin , GIT,
  
• kidney.

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Microsomes

• Microsomal enzyme system? mixed function oxidase
  ? mono-oxigenase.
• its components
• cytochrome P450
• Flavinoprotein NADPH
• Molecular oxygen, Mg

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• Mitochondria
• mono-amine oxidase enzyme (MAO)
• Acetylation
• Cytoplasm
• Alcohol dehydrogenase
• Blood (plasma)
• Estrases
• Amidases
• Catechol-o methyltransferases(COMT)
• Intestinal Mucosa and Lumen
• GIT floraGlucouronidase ,Asoreductases.
• GIT mucosa Monoamime oxidase (MAO) ,
• Suphatase

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Types of Metabolic Reaction

• Phase I reaction (non-synthetic)
• Phase II reaction (synthetic)

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Phase I Reaction

• Make the drug more polar ? more
• water solulble.(oxidation reduction-
• hydrolysis)
• Oxidarion reaction
• introduces functional group (OH,NH2,SH)
• Can be mirosomal or nonmicrosomal

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Microsomal

• Drug O2 NADPHH?changed drug H2O NADPH
• e.g. 1. Aliphatic hydroxylation
• Phenobarbital?hydroxyphenobarbital
• 2. Aromatic hydroxylation
• Phenacetin? 2-hydroxyphenacitin
  (paracetamol)
• 3. Oxidation of amine
• Aniline ? nitrobenzene
• 4. sulphoxidation
• Parathione ? paroxon

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Non-microsomal

• oxidation by soluble enzyme in cytosol or
  mitochondria of cells
• e.g 1. dehydrogenases and oxidases
• Ethanol ? acetaldehyde ? acetic acid.
• Methanol ? formaldehyde ? formic acid
• CH3CH2OH? CH3CHO?CH3COOH
• 2. monoamide oxidase(noradrenaline)
• 3. Hypoxanthine ? xanthine ? uric acid

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• Reduction Reactions
• Microsomal or non-microsomal
• Microsomasl
• nitrobenzene ? aniline
• NO2 ?NH2
• Non-Microsomal
• Chloral hydrate ? trichloroethanol
• Hydrolysis
• Non-microsomal ONLY
• Ester-C-O and amides-C-N
• Acetylcholine ? choline acetate(ester)
• Procainamide (lidocaine) (amide)

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Characteristics of Phase I Products (Result of
Drug Metabolism)

• 1. Inactivation (abolish the activity
• Oxidation of Phenobarbital and alcohol
• Hydrolysis of acetylcholine
• 2. conversion of active drug to another active
  one.
• Diazepam ?oxydiazepam
• Codeine ,heroin ? Morphine
• Phenylbutazone ? oxyphenylbutazone
• Propranolol ? 4-hydroxypropranolol
• 3. conversion of drug to toxic metabolites
• Paracetamol ? acetaminopen (hepatic toxicity)
• Halothane ? metabolite hepatotoxicity
• 4. Activation of pro-drug
• Chloral hydrate ? trichloral hydrate
• 5. Product might undergo phase II

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Phase II Conjugation Reaction (Synthetic reaction)

• Glucuronide conjugation
• Aminoacid eg.glycine
• Acetylation reaction e.g CO-CH3
• Sulphate conjugation SO4
• Methylation reaction e.g CH3
• Noradrenaline ? adrenaline
• ALL is non-microsomal enzyme Except
  glucouronidation (catalyzed by glucouronyl
  transferase )

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Characteristics of Phase II Products

• Product Conjugate
• Pharmacologically inactive
• More water soluble? to be excreted
• More readily excreted in urine

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Modulation of Liver Microsomal Enzymes

• Induction
• Inhibition
• Liver Microsomal Inducers
• Alcohol
• Barbiturates
• Cigarette smoking
• Phenytoin
• Rifampicin
• Spironalactone
• Griseofulvin

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Enzyme Induction results in

• Increase metabolism of the inducer
• Tolerance decreased pharmacological action of
  the drug
• Increase the metabolism of co-administered drug
  (drug interaction)
• Barbiturate Warfarin
• Phenytoin Oral contraceptives
• Rifampicin Hydrocortisone
• Increased metabolite- mediated tissue toxicity
• Paracetamol and phenacetin
• As therapy ( phenobarbitone hyperbilirubinemia)

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Liver Microsomal Inhibitors

• Cimetidine
• Erythromycin
• ketoconazole
• Metronidazole
• Probenecid
• Enzyme inhibition may
• Retard the metabolism and excretion of the
  inhibitor and co-administered drugs
• Prolong the action of the inhibitor and
  co-administered drugs? increased pharmacological
  activity.

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First Pass Metabolism

• A drug can be metabolized before the drug
  reaches the systemic circulation so the amount
  reaching systemic circulation is less than the
  amount absorbed
• Where ? Liver ,gut wall, lung
• Result
• low bioavailability
• Short duration of action
• How is it given
• e.g
• Morphine
• Salbutamol

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4. EXCRETION

• Main routes of excretion
• Renal excretion
• Biliary excretion
• Minor routes of excretion
• Exhaled air
• Salivary secrtetions
• Sweat
• Milk
• Tears

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Renal excretion

• Glomerular filtration
• Active tubular secretion
• Passive tubular reabsorption
• Alteration in tubular PH
• e.g gentamycin , ampicillin ,benzylpencillin
  ,digoxin
• Contraindicaited
• in case of renal failure
• in case of elderly

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Glomerular filtration

• Only free drug (not bound to albumin)
• Low molecular weight drug( below 20000)
• renal plasma flow 600ml /min
• GFR 20 of renal plasma flow 125 ml/min

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Active Tubular secretion

• Characters
• Selective
• Require energy carrier
• Against concentration gardient
• Clearance to plasma protein bound drugs
• Types
• System for acidic drugs
• System for basic drugs

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• System for Acidic Drugs
• e.g. of acidic drugs salicylates,sulphonamides,
  penicillin,glucouronide conjugate, sulphate
  conjugate.
• Blocked by probenicid (inhibitor)? carrier
  will carry this drug so,
• acidic drugs ? long duration of action
  blocker will excertion.
• System for Basic Drugs
• e.g catecholamines,atropine ,morphine ,quinine
  ,neostigmine.

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Passive tubular reabsorption

• Non ionized form (lipid soluble) can be
  reabsorbed back into systemic circulation and
  excretion will be low
• Ionized drugs are poorly reabsorbed and so
  rapidly excereted.

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• Alteration in urine PH
• Urine is normally slightly acidic and favors
  excretion of basic drugs
• Acidification of urine? increased excretion of
  basic drugs
• Alkalization of urine ? increased excretion of
  acidic drugs.

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• Acidification of urine
• by
• ammonium chloride
• ascorbic acid
• Alkalization of urine
• by
• Sodium bicarbonate
• Sodium lactate
• Sodium citrate.

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• Biliary excretion
• Is important for some drugs that are metabolized
  in the liver
• e.g digoxin
• Biliary excretion is useful in treating biliary
  infection
• It plays a role in the removal of conjugated
  metabolites particularly glucouronides

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• Enterohepatic Circulation
• Bile passes into the intestine where drug if
  lipid soluble is reabsorbed again and cycles is
  repeated.
• Glucouronides are hydrolyzed in intestine
  liberating free drugs that can be reabsorbed back
• This prolongs the action the drug
• e.g. morphine , ethinyl estradiol ,
• thyroxine

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• Drug clearance