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1 Pharmacology   Pharmacokinetics
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1 Pharmacology Pharmacokinetics

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- Routes of administration …

- 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
  • 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. 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. 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. 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. 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. Absorption Pharmacokinetics Blood Stream Distribution Tissue Bound Metabolism Protein bound Metabolites Elimination
  • 8. Route of administration 1. Oral 2. Sublingual 3. Rectal 4. Intravascular 5. Intramuscular 6. Subcutaneous
  • 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. First pass metabolism Oral Liver Rest of body
  • 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. First pass metabolism
  • 13. Sublingual route – under tongue • Delivers the drug direct to the bloodstream – Not via the liver and liver metabolism • E.g. Glyceryl trinitrate
  • 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. 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. 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. Intramuscular injection
  • 18. Subcutaneous injection Advantage Disadvantage • Minimises risk • Slower rate of absorption compared with i.v. • E.g. Heparin, insulin
  • 19. Subcutaneous injection
  • 20. Other routes of administration • Inhalation • Intranasal • Topical (ointment/creams) • Transdermal (patches) • Intrathecal (into spinal canal)
  • 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. 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. Bioavailability
  • 24. Bioavailability
  • 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. 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. Endothelial fenestrations
  • 28. Blood brain barrier
  • 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. 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. 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. 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. Volume of distribution: water compartments
  • 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. 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. 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. Drug metabolism pathways
  • 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. 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. 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. 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. Half life
  • 43. Half life
  • 44. Volume of distribution - THC
  • 45. Maintenance of therapeutic dose Single dose
  • 46. Maintenance of therapeutic dose Single dose
  • 47. Maintenance of therapeutic dose Multiple doses
  • 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. 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. Urinary system
  • 51. Urinary system
  • 52. Glomerular filtration
  • 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. 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. 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. 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. 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. 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. Biliary tree
  • 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. 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

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