1 Pharmacology Pharmacokinetics


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- Routes of administration
- First pass metabolism, bioavailablilty, drug distribution,
- Drug interactions with proteins, Drug metabolism, elimination, Half-life

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1 Pharmacology Pharmacokinetics

  1. 1. Pharmacology Pharmacokinetics
  2. 2. Objectives - understand 1. Pharmacokinetics and pharmacodynamics 2. Different routes of administration of medications (advantages and disadvantages) 3. Terms: ‘First pass metabolism’, absorption, bioavailability, drug distribution . 4. Drug interaction with proteins, drug metabolism, elimination, half-life
  3. 3. What is pharmacology? Includes: 1.Origins, chemical structure, preparation, administration, actions, metabolism, excretion 2.Therapeutics: application of action of drugs and other measures in the treatment of disease
  4. 4. Pharmacology • Pharmacology is the study of the action and use of drugs • Medical pharmacology is the science of chemicals (drugs) that interact with the human body • Drugs are chemical substances which, by interacting with biological systems, are able to change them in some way, or: • A substance, applied to a living system, with the intent of bringing about a change
  5. 5. Pharmacokinetics • Refers to the processes concerned with the distribution of drugs in the body and their: – Absorption – Excretion – Metabolism • Therefore it is it is concerned with the way in which the concentration of a drug varies as per the site of its action and how this is affected by the of administration
  6. 6. Drug at site of Pharmacokinetics administration Absorption Drug in blood Drug in tissue Metabolism Metabolites in tissue Elimination Drugs and/or metabolites in Urine/faeces/bile
  7. 7. Absorption Pharmacokinetics Blood Stream Distribution Tissue Bound Metabolism Protein bound Metabolites Elimination
  8. 8. Route of administration 1. Oral 2. Sublingual 3. Rectal 4. Intravascular 5. Intramuscular 6. Subcutaneous
  9. 9. Oral • By mouth – Common route of administration • Complicated pathway • Some of drug is absorbed: – Stomach – Duodenum – Small intestine • Via the small intestine, it goes via the hepatic portal vein to the liver before the systemic circulation
  10. 10. First pass metabolism Oral Liver Rest of body
  11. 11. First pass metabolism • All drugs absorbed in the gut go via the liver to reach the systemic circulation – In the liver • Some of the drug is metabolised • Therefore not all reaches systemic circulation • E.g. 90% of nitroglycerine is cleared in a single pass through the liver
  12. 12. First pass metabolism
  13. 13. Sublingual route – under tongue • Delivers the drug direct to the bloodstream – Not via the liver and liver metabolism • E.g. Glyceryl trinitrate
  14. 14. Rectal • 50% of blood bypasses the portal circulation and liver metabolism • Avoids stomach and acids/enzymes in GIT • Useful if the drug causes vomiting when taken orally. • E.g. Diazepam (antiepileptic drug)
  15. 15. Intravenous injection Advantages Disadvantages • For days not absorbed • Drugs cannot be recalled orally once injected • Avoids GIT; 1st pass • Site of injection can be metabolism of liver infected with bacteria • Rapid effect • Adverse reaction because of • Maximal degree of control a too rapid delivery of high over circulating levels of concentration of drug to drugs blood and tissues (infusion rate must be controlled)
  16. 16. Intramuscular injection • Must be aqueous preparation or specialised ‘depot’ preparation (suspension in ethylene glycol or peanut oil) – Aqueous suspension • Absorbed quickly – Depot suspension • Absorbed slowly • E.g. Haloperidol – anti-schitzophrenic drug
  17. 17. Intramuscular injection
  18. 18. Subcutaneous injection Advantage Disadvantage • Minimises risk • Slower rate of absorption compared with i.v. • E.g. Heparin, insulin
  19. 19. Subcutaneous injection
  20. 20. Other routes of administration • Inhalation • Intranasal • Topical (ointment/creams) • Transdermal (patches) • Intrathecal (into spinal canal)
  21. 21. Absorption of drugs • Drugs absorbed from gut by – Diffusion (across GIT wall into blood) – Active transport (via carrier proteins in plasma membrane; active process) • pH (acid/alkaline environment) influences drug absorption • Physical factors influencing absorption – Blood flow through the absorption site – Total surface area available for drug absorption – Contact time at absorption site (e.g. Poor absorption with diarrhoea) – Presence of food in stomach • Dilutes drug • Slows stomach emptying
  22. 22. Bioavailability • Fraction of the administered drug that reaches the systemic circulation • E.g. If 100mg of drug is administered and 70mg of drug is absorbed unchanged: • Bioavailability is 70%
  23. 23. Bioavailability
  24. 24. Bioavailability
  25. 25. Bioavailability – affecting factors • 1st pass metabolism • Solubility of drugs – If hydrophilic: poorly absorbed because can’t cross lipid bilayer of plasma membrane – Highly hydrophobic: poorly absorbed because insoluble in aqueous body fluids – Drugs need to be hydrophobic, but have some solubility in aqueous solution • Chemical instability – Penicillin: unstable because of pH in stomach – Insulin: may be destroyed by GIT enzymes – injected • Nature of drug formulation
  26. 26. Drug distribution • Drug distribution refers to the movement of the drug to/from the blood and various tissues of the body (e.g. Fat, muscle, brain) and the relative proportion of the drug in the tissues • This depends on blood flow; – Brain, liver, kidney>skeletal muscle>adipose tissue – Capillary structure – Drug structure(hydrophilic/phobic) – Binding of drugs to blood plasma protein
  27. 27. Endothelial fenestrations
  28. 28. Blood brain barrier
  29. 29. Drugs and blood plasma proteins • Main influence of plasma proteins on drugs is in their distribution • The most important plasma proteins are – Albumin, acid-glycoprotein, β-globulin • Once a drug is absorbed into the circulation, it can become protein-bound • This plasma protein binding can be rapidly reversible and is non-specific – Many drugs can bind to one protein • But the plasma proteins are not the target tissue and drugs that are bound to them cannot bring about a physiological effect, however: • Drug/protein binding can form a reservoir of the drug – Only free (unbound) drug is available to the tissues to exert a therapeutic effect.
  30. 30. Effect of protein binding on drug action? • If protein binding does occur, the behaviour of the drug can be influenced: 1. Extensive protein binding reduced available free (unbound) drug; therefore more drug has to be administered to get therapeutic effect 2. Elimination of a highly bound drug may be delayed • If the free drug is low, the total drug elimination/excretion is delayed – E.g. This is the reason for the prolonged effect of digoxin
  31. 31. Effect of protein binding on drug action? • 3 – Low plasma concentration may result in old age • Can get reduced plasma protein concentration with liver disease (made there), or chronic renal failure causing xs protein loss in urine – Increased free drug; decreased bound drug – Increased free drug; reduced drug dose needed
  32. 32. Effect of protein binding on drug action? • 4 – different drugs can compete for the binding sites on plasma proteins, leading to interactions – E.g. Warfarin (anticoagulant) is highly bound and even a small change in binding will greatly effect the amount of free drug – Therefore if there is administration with (e.g.) aspirin, the aspirin displaces the warfarin causing an increase in free anticoagulant
  33. 33. Volume of distribution: water compartments
  34. 34. Drug metabolism 1 • Metabolism is the enzymic conversion of one compound into another – Mostly occurs in the liver, but also in gut wall, lung and blood plasma • Generally, the metabolism of a drug converts in into a more water soluble compound with more polarity – This is important as it can only be excreted in urine an bile – Few drugs are excreted without being metabolised • Generally, as drug is metabolised, its therapeutic effect decreases
  35. 35. Drug metabolism –2 • Liver hepatocytes have all the necessary enzymes for the metabolism of drugs – Main enzyme involved in drug metabolism belong to the cytochrome P450 group. • These are a large family of related compounds housed in the smooth endoplasmic reticulum of the cell – Metabolism is often divided into phase 1 and phase 2 • Some drugs just need to undergo either phase 1 or 2 • More often need phase 1, then phase 2
  36. 36. Drug metabolism 3 • Phase 1 metabolism can be reduction or hydrolysis of a drug, but is usually oxidation • Oxidation is catalysed by cytochrome P450 – One electron removed • Drug is now oxidised; but even after phase 1 metabolism it can still be chemically active
  37. 37. Drug metabolism pathways
  38. 38. Drug metabolism - 4 • Phase 2 metabolism involves conjugation – an ionised group is attached to the drug • Groups included glutathione, methyl or acetyl groups – Usually occurs in hepatocyte cytoplasm • The attachment of the ionised group makes the drug more water soluble – Facilitates excretion – Decreases pharmacological activity • E.g. Aspirin – Phase 1 undergoes hydrolysis to salicylic acid – Phase 2 is conjugated with either glycine or glucuronic acid • Forming a range of metabolites that can be excreted
  39. 39. Drug metabolism - 5 • Some drugs are administered in inactive form, or prodrug, e.g. Enalapril – It’s metabolite is pharmacologically active • Enalaprilat – antihypertensive • Some drug metabolites can be toxic – E.g. Those produced from paracetamol phase 1 metabolism – These are detoxed by phase 2 conjugation with glutathione • In overdose situations, where the dose of paracetamol is high, not enough glutathione is available to detox the metabolites – accumulates causing toxicity – hepatitis – As a solution, compounds are administered to boost levels of glutathione so that phase 2 can take place; thus paracetamol is metabolised fully and reduces the risk of liver damage
  40. 40. Drug metabolism - 6 • Affecting factors – Age: reduced numbers of hepatocytes and enzymic activity – Diseases that reduce blood flow to liver (heart failure/shock) reduce its metabolic activity – Genetic deficiency – re one enzyme – Other drugs and diet etc that reduce liver function • E.g. Grapefruit juice and St john’s Wort – Inhibit cytochrome P450 • Smoking and brussel sprouts – Increase P450 activity
  41. 41. Elimination and half life - (t½) • The duration of the drug in the body is called its half-life (t½) • The t½ is the period of time for the concentration/amount of a drug in the body to be reduced by half • Usually the t½ is used in reference to its plasma concentration • The drug may not be in the plasma; if it leaves: – may be in another body fluid compartment (intracellular fluid) – Destroyed in plasma • The removal of a drug from the plasma – Clearance • The distribution of a drug in various body tissues – Volume of distribution • The clearance and volume of distribution are important in determining the t½
  42. 42. Half life
  43. 43. Half life
  44. 44. Volume of distribution - THC
  45. 45. Maintenance of therapeutic dose Single dose
  46. 46. Maintenance of therapeutic dose Single dose
  47. 47. Maintenance of therapeutic dose Multiple doses
  48. 48. Elimination • Elimination is the process by which the drug (and its metabolites) is eliminated fro the body without further chemical change • Most drugs are metabolised prior to excretion – Some drugs (e.g. Aminoglycoside antibiotics) are polar compounds (hydrophilic) and are excreted by the kidneys without being metabolised first • The kidneys are the major excretory organs and excrete water soluble drugs • The biliary system contributes to excretion if the drug is secreted in bile and then is not reabsorbed from the GIT • There are small contributions from: – Intestines, saliva, sweat, breast milk and lungs • Excretion via breast milk may not be of importance to the mother, but may be to the suckling child
  49. 49. Renal excretion • Excretion of the drug via the kidneys uses 3 processes, all of which occur in the nephron – Glomerular filtration – Tubular secretion – Tubular reabsorption
  50. 50. Urinary system
  51. 51. Urinary system
  52. 52. Glomerular filtration
  53. 53. Glomerular filtration • The drug goes to the kidney via the blood • From the glomerulus it passes into the glomerular (Bowman’s) capsule as part of the filtrate • Large drugs, e.g. Heparin, or those bound to plasma proteins, cannot be filtered and therefore cannot be excreted
  54. 54. Tubular resorption • Drugs and their metabolites enter the filtrate in the nephron, but some may be resorbed • Resorption occurs as diffusion (not active) • Occurs because water is resorbed by osmosis – The majority of water that enters the nephron is resorbed back in to the blood (to maintain body fluid volume) and the drug follows it by diffusion
  55. 55. Urine pH - 1 • Urine pH has a great influence on how fast a drug is excreted • This can be manipulated in a clinical situation to control the excretion of certain drugs from the body
  56. 56. Urine pH- 2 • Most drugs are either weak acids or bases (alkaline) – In alkaline urine, acidic drugs are more readily ionised – In acidic urine, alkaline drugs are more readily ionised • Ionised substances are more polar and so are dissolved and excreted more readily • This is important in situations like blood poisoning; drug must be excreted rapidly from the body – One strategy is to alter urine pH to increase excretion – E.g. Aspirin poisoning: making the urine more alkaline with sodium bicarbonate increases the ionisation of salicylic acid (aspirin metabolite) and increases it excretion from the body
  57. 57. Tubular secretion - 1 • Most drugs don’t enter the nephron via the glomerular filtrate, but by tubular secretion – Active process: drugs are carried against their diffusion gradient, from the capillary network into the tubular filtrate • Tubular secretion involves 2 carrier systems: – Basic (alkaline) carriers: transport basic drugs (amiloride, dopamine, histamine) – Acidic carriers: transport acidic drugs (frusemide, penicillin, indomethacin)
  58. 58. Tubular secretion - 2 • Tubular secretion can have a big impact on the speed that a drug is eliminated from the body; e.g. Penicillin is readily secreted into the tubular filtrate and rapidly excreted in urine • If the therapeutic effect needs to be prolonged/maintained, agents can be administered that block tubular secretion, thus slowing the excretion of the drug
  59. 59. Biliary tree
  60. 60. Biliary secretion • Drugs and metabolites that are secreted in bile are transported across the biliary epithelium against their concentration gradient (active) – Affecting factors • Blood concentration: if high, bile content will be high • If drugs with similar physiochemical properties are present together, they can compete for the transport mechanisms
  61. 61. Biliary secretion • Drugs that are more likely to be excreted into bile have a molecular weight of >300g/mol – Smaller, only in negligible amounts – Both bipolar and lipophilic are excreted – Conjugation (especially with glucuronic acid) leads to biliary excretion