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PHARMACOKINETICS II
(An idea on drug distribution, metabolism and excretion with
traditional views.)
Dr. K.J.Karthika,
Fin...
Drug distribution
Drug metabolism
Drug excretion
Contents…
Drug
distribution
Diffusion Tissue
perfusion
Plasma
proteins
Factors
controlling
drug
distribution
Pshysico
chemical
properties
of drugs
Physiological
factors
Cardiac output
Regional ...
Drug administration
Partition of drug b/w blood and body tissue based on.
- Transmembrane pH
- Lipid solubility
Initial di...
Diffusion
Drug absorption or systemic administration.
Diffusion to interstitial or intercellular fluid.
Plasma protein and drug
distribution
- Albumin – Majorly binds with acidic
drugs.
- α1 – acid glycoprotein – binds with ba...
The bound unbound drug
concentration is determined by
- Affinity of binding sites.
- Number of binding sites.
- Existinc P...
Effects of protein binding.
•Limits drug concentration in tissues and site of action.
•Only the unbound drug is in equilib...
Tissue concentration of drugs
-Many drugs accumulate in the tissues at higher
concentrations than those in extra cellular ...
Effects of tissue
concentration of drugs
•local drug toxicity e.g; Gentamicin
in kidney and vestibular system.
Cellular reservoirs
- Fat
- Bones
- Trans cellular fluid
- Sites with active transport of drugs and
tissues with affinity ...
Fat as reservoir
-Many lipid soluble drugs are stored in by physical
solution in neutral fat.
-A stable reservoir due to r...
Bone:
•Tetracycline antibiotics and heavy metals adsorb onto bone
surface and eventually to crystal lattice.
•Reservoir fo...
Therapeutic advantages:
Treatment of osteoporosis by
phosphonates like sodium etidronate
which is resistant to
pyrophospha...
Transcellular fluid reservoir:
•Drugs cross the epithelial cells and accumulate in
the transcellular fluids.
•The major tr...
Redistribution
• The redistribution from site of action to other sites
cause termination of drug effect before drug withdr...
CNS and cerebro spinal fluid.
-Factors preventing transport of drug to brain
1. BBB (brain capillary endothelium and peric...
Lipid soluble
Non ionized
Unbound state
Essential factors for uptake
of drug by brain.
• Meningeal and encephalic inflammation
increases local permeability.
• Recently BBB destruction has emerged as
a strategy...
Volume of Distribution:
-Relates to the amount of drug in the body to the
concentration of drug in blood /plasma depending...
The volume of drug distribution
depends on:
•pKa of drug
•the degree of binding to plasma
proteins
•partition coefficient ...
Drug metabolism
Phase 1- functionalization
• introduce a functional
group to parent compound.
• Loss/ alteration of
pharma...
Site for biotransformation (location):
•Mainly liver
•GIT
•Kidneys
•Lungs
Cell organelles involved
•Mainly smooth endoplas...
Systems involved in drug
metabolism
•Cytochrome P450 mono oxygenase
system.
•hydrolytic enzymes.
•conjugation reactions.
Cytochrome P450 mono oxygenase system
-Heme containing membrane protein found in smooth
endoplasmic reticulum of numerous ...
Hydrolytic enzymes:
- Found in endoplasamic reticulum of human liver
intestine and other tissues.
- The alcohol and amine ...
Conjugation Reactions
- Hallmark of phase 2.
- Most significant is glucuronidation following which
there is increased wate...
Factors effecting drug metabolism
•Genetic variation:
-For an increasing number of enzymes allelic variants
with different...
•Environmental determinants:
The activity of most of the drug metabolizing
enzymes may be modulated by exposure to
certain...
•Disease factors: k
- Hepatitis , alcoholic liver disease, biliary
cirrhosis, fatty liver and hepatocarcinoma can
potentia...
•Age and sex:
•Cytochrome P450 isoforms develop early in foetal
development but levels at birth are lower than those found...
Excretion of drugs
Polar compounds excreted more efficiently than the lipid
soluble drugs.
Drug is excreted as
Unchanged
f...
Routes for
drug
excretion
tear
Renal
(mutra)
Biliary
and
fecal
(sakrut
)
sweat
saliva
Breast
milk
Renal excretion
Involve 3 distinct process
•Glomerular filteration
•Tubular secretion
•Tubular reabsorption
Age and renal ...
Factors determining drug entry to
tubular lumen
•GFR
•Extend of plasma binding(unbound drug
filtered)
•Carrier mediated tu...
Other routes
•sweat
•saliva- some drug concentration here
parallels plasma concentration thus can be
collected when inconv...
Biliary and fecal excretion
•transporters present in the
canalicular membrane of
hepatocytes actively secrete drugs
and me...
Bio availability
It is the term used to indicate the fractional extend to which a
dose of drug reaches its site of action....
In Ayurveda
More biovailability is possibly be in the
order
1. Basthi prayoga.
2. Oral intake
3. Abhyandadi bahya prayoga
...
Pharmakokinetics 2. myppt
Pharmakokinetics 2. myppt
Pharmakokinetics 2. myppt
Pharmakokinetics 2. myppt
Pharmakokinetics 2. myppt
Pharmakokinetics 2. myppt
Pharmakokinetics 2. myppt
Pharmakokinetics 2. myppt
Pharmakokinetics 2. myppt
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Pharmakokinetics 2. myppt

pharmakokinetics 2

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Pharmakokinetics 2. myppt

  1. 1. PHARMACOKINETICS II (An idea on drug distribution, metabolism and excretion with traditional views.) Dr. K.J.Karthika, Final year P.G scholar. Department of R&B, GAVC, Tripunithura.
  2. 2. Drug distribution Drug metabolism Drug excretion Contents…
  3. 3. Drug distribution Diffusion Tissue perfusion Plasma proteins
  4. 4. Factors controlling drug distribution Pshysico chemical properties of drugs Physiological factors Cardiac output Regional blood flow Capillary permeability Tissue volume •Cardiac output •Regional blood flow •Capillary permeability •Tissue volume
  5. 5. Drug administration Partition of drug b/w blood and body tissue based on. - Transmembrane pH - Lipid solubility Initial distribution to well perfused organs(heart, liver, kidney, brain,etc) second phase distribution to large fraction of body mass like muscle, skin, fat etc.(greater time needed to reach equillibrium state)
  6. 6. Diffusion Drug absorption or systemic administration. Diffusion to interstitial or intercellular fluid.
  7. 7. Plasma protein and drug distribution - Albumin – Majorly binds with acidic drugs. - α1 – acid glycoprotein – binds with basic drugs. - Non specific binding forming irreversible covalent binding of reactive drugs like alkylating agents. - Specific binding – sex hormone binding globulin for oestrogen and testosterone.
  8. 8. The bound unbound drug concentration is determined by - Affinity of binding sites. - Number of binding sites. - Existinc Pathology eg; liver diseases, nephrotic syndrome causes hypoalbuminemia. cancer, arthritis, MI, Crohns disease elevate α 1 –acidglycoprotein enhancing binding of basic drugs. Drug- drug interaction – competition or site, alteration of physiology, etc.
  9. 9. Effects of protein binding. •Limits drug concentration in tissues and site of action. •Only the unbound drug is in equilibrium across the membranes. •limits the drugs glomerular filtration. •Drug transport and metabolism are also limited.
  10. 10. Tissue concentration of drugs -Many drugs accumulate in the tissues at higher concentrations than those in extra cellular fluids and blood. -Eg. antimalarial drug quinacrine- liver concentration may exceed several thousand times than blood concentration. -The tissue concentration build up can be due to. •Active transport •Tissue binding( mostly reversible) to - Proteins - Phospholipids - Nuclear proteins, etc
  11. 11. Effects of tissue concentration of drugs •local drug toxicity e.g; Gentamicin in kidney and vestibular system.
  12. 12. Cellular reservoirs - Fat - Bones - Trans cellular fluid - Sites with active transport of drugs and tissues with affinity to drugs. Vary with the type of drug. Eg, liver, kidney, etc
  13. 13. Fat as reservoir -Many lipid soluble drugs are stored in by physical solution in neutral fat. -A stable reservoir due to relatively low blood flow. Difficulty to predict lipophilic drug distribution in obese individuals. Eg, β blockers, barbiturate thiopental.
  14. 14. Bone: •Tetracycline antibiotics and heavy metals adsorb onto bone surface and eventually to crystal lattice. •Reservoir for slow release toxic agents e.g. lead or radium .Their effects persist long after their exposure has stopped. local destruction of bone medulla reduced blood flow prolongation of reservoir effect.
  15. 15. Therapeutic advantages: Treatment of osteoporosis by phosphonates like sodium etidronate which is resistant to pyrophosphatases enzyme thus stabilizes bone matrix.
  16. 16. Transcellular fluid reservoir: •Drugs cross the epithelial cells and accumulate in the transcellular fluids. •The major trans cellular reservoir being the gastrointestinal tract and others are CSF, aqueous humor, endolymph, synovial fluid,etc. •The levels accumulated are not significant.
  17. 17. Redistribution • The redistribution from site of action to other sites cause termination of drug effect before drug withdrawal. •Primarily seen when a highly lipid soluble drug that acts on brain or cardiovascular system is administered rapidly by intravenous injection or inhalation. •As the I V administration is ceased once attaining the peak concentration in the desired tissue, the drug diffuses to other tissues like muscles. Gradually the concentration in desired tissue falls to match the plasma concentration.
  18. 18. CNS and cerebro spinal fluid. -Factors preventing transport of drug to brain 1. BBB (brain capillary endothelium and pericapillary glial cells) 2. Blood CSF barrier (at choroid plexus where epithelial cells are joined by tight junctions.) Drug penetration into the brain depends on trans- cellular transport.
  19. 19. Lipid soluble Non ionized Unbound state Essential factors for uptake of drug by brain.
  20. 20. • Meningeal and encephalic inflammation increases local permeability. • Recently BBB destruction has emerged as a strategy in treatment of certain brain tumors where the intention is to directly deliver the chemotherapy agent to the brain tumor while maintaining the cognitive function that is often damaged by conventional radiotherapy.
  21. 21. Volume of Distribution: -Relates to the amount of drug in the body to the concentration of drug in blood /plasma depending on the fluid volume. The blood plasma volume of a 70kg man is considered to be 3l blood volume is 5.5l. The extracellular fluid volume 12l total body water is 42l.
  22. 22. The volume of drug distribution depends on: •pKa of drug •the degree of binding to plasma proteins •partition coefficient of drug in fat. •Degree of binding to other tissue. Age, gender, disease, body composition.
  23. 23. Drug metabolism Phase 1- functionalization • introduce a functional group to parent compound. • Loss/ alteration of pharmacological activity. • Enzyme system located mainly in endoplasmic reticulum. Pase 2- biosynthetic reaction • Formation of covalent linkage between the functional group of phase 1 metabolite and endogenously derived glucuronic acid, sulphate, glutathione, amino acids or acetates. >> Actively excreted. • Enzymes mainly located in Cytosol.
  24. 24. Site for biotransformation (location): •Mainly liver •GIT •Kidneys •Lungs Cell organelles involved •Mainly smooth endoplasmic reticulum •Cytosol •Mitochondria •Nuclear envelope •Plasma membrane.
  25. 25. Systems involved in drug metabolism •Cytochrome P450 mono oxygenase system. •hydrolytic enzymes. •conjugation reactions.
  26. 26. Cytochrome P450 mono oxygenase system -Heme containing membrane protein found in smooth endoplasmic reticulum of numerous tissues. -catalyzes wide range of oxidative and reductive reactions. -the xenobiotic substrates reacts with the Fe3+ of the cytochrome P450 and form enzyme substrate complex and thereafter further reactions of biotransformation proceeds. Electons from NADPH is utilized by it. - 12 gene families have been identified for cytochrome P450 enzyme and a number of distinct cytochrome P450 exist in a cell.
  27. 27. Hydrolytic enzymes: - Found in endoplasamic reticulum of human liver intestine and other tissues. - The alcohol and amine group exposed following the hydrolysis of esters and amines are the substrates.
  28. 28. Conjugation Reactions - Hallmark of phase 2. - Most significant is glucuronidation following which there is increased water solubility and promotes drug elimination through urine. - conjugation of electrophilic metabolites of xenobiotics with tripeptides of glutathione is the major detoxification pathway for drugs and carcinogens.
  29. 29. Factors effecting drug metabolism •Genetic variation: -For an increasing number of enzymes allelic variants with different catalytic activities have been identified. -The differences involve a variety of molecular mechanisms leading to complete lack of activities, a reduction in catalytic ability or in case of gene duplication enhanced activity.
  30. 30. •Environmental determinants: The activity of most of the drug metabolizing enzymes may be modulated by exposure to certain exogenous compounds. These may result in :- •Inhibition of drug metabolism •Inuction of drug metabolism
  31. 31. •Disease factors: k - Hepatitis , alcoholic liver disease, biliary cirrhosis, fatty liver and hepatocarcinoma can potentially lead to impaired drug metabolism. - The oral availability of drugs that undergo first pass metabolism and reduced bioavailability is increased 2-3 fold. - Severe cardiac failure and shock can result in both decreased perfusion of liver and impared metabolism.
  32. 32. •Age and sex: •Cytochrome P450 isoforms develop early in foetal development but levels at birth are lower than those found post natal. •Both phase 1 and phase 2 enzymes begin to mature gradually following the first two to 4 wks. Thus newborn infants are able to metabolize drugs but slower than adults. •Elderly generally requires moderate reduction in drug dose and awareness of possibility of exaggerated pharmacodynamic responsiveness. •Responsiveness of men and women may be different for certain drugs. some sex related
  33. 33. Excretion of drugs Polar compounds excreted more efficiently than the lipid soluble drugs. Drug is excreted as Unchanged form metabolites
  34. 34. Routes for drug excretion tear Renal (mutra) Biliary and fecal (sakrut ) sweat saliva Breast milk
  35. 35. Renal excretion Involve 3 distinct process •Glomerular filteration •Tubular secretion •Tubular reabsorption Age and renal function Neonates – low renal function low in the beginning which matures rapidly. In adulthood the renal function gradually declines approx 1% per year. Elderly- substantial rate of renal impairment.
  36. 36. Factors determining drug entry to tubular lumen •GFR •Extend of plasma binding(unbound drug filtered) •Carrier mediated tubular secretion in PCT •Reabsorption by membrane transport at DCT •Passive reabsorption non ionized forms of wk acids and bases in PCT and DCT •pH of urine( alterations can result in significant change in drug elimination
  37. 37. Other routes •sweat •saliva- some drug concentration here parallels plasma concentration thus can be collected when inconvenient to collect blood. Ethanol n urea readily enters B.M. •tears •breast milk- slightly more acidic than plasma basic compounds may be accumulated Elimination by these routes depends mainly on diffusion of non-ionized lipid soluble form of drugs through the epithelial cells of the gland based on pH.
  38. 38. Biliary and fecal excretion •transporters present in the canalicular membrane of hepatocytes actively secrete drugs and metabolites into the bile Secretory transporters on the apical membrane of enterocytes causes direct secretion of drugs and metabolites to the intestinal lumen. Absorption from intestine for hepatic clearence
  39. 39. Bio availability It is the term used to indicate the fractional extend to which a dose of drug reaches its site of action. The bioavailability depends on •Nature of drug •Route of administration. •Anatomical site from which absorption takes place •Other anatomical, physiological and pathological factors. When the hepatic Clearence of the drug is more in relation to the hepatic circulation the bioavailability of drug when orally administerd will be low. so is the case of other routes that is subjected to first pass loss.
  40. 40. In Ayurveda More biovailability is possibly be in the order 1. Basthi prayoga. 2. Oral intake 3. Abhyandadi bahya prayoga 4. Nasya 5. Nethra kriyakrama

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