Session 7 Pharmacokinetics of drug administration

• What is bioavailability?

  Bioavailability is the proportion of administered drug that reaches the systemic circulation.
• Why is insulin administered intravenously and not orally?

  The bioavailability of insulin is very low and hence wouldn't reach the site of action.
• When a drug is administered orally, there can be a reduction in the concentration of the active drug. This is generally when some of the drug is lost due to the liver and the intestine. (liver metabolises it). This also reduces the bioavailability of the drug - first pass metabolism
• Alternative routes of administration avoid the first-pass effect because they allow drugs to be absorbed directly into the systemic circulation. Or if alternative routes are not suitable, a considerably higher oral dose may be required.
• Oral bioavailability may be increased in patients with severe liver disease or if given alongside another drug undergoing first pass metabolism.
• First pass metabolism drugs

  • N - Nitrates
  • I - Imipramine
  • L - Lidocaine
  • B - Beta blockers
  • M - morphine
• Nitroglycerin is converted by mitochondrial aldehyde dehydrogenase in smooth muscle cells to nitric oxide (NO), a potent vasodilator.
• Sublingual glyceryl trinitrate provides rapid symptomatic relief of angina.
• • Therapeutic index is the quantitative measurement of the safety of a drug.
  • It is the ratio that produces toxicity in 50% of the population (TD50) to the clinically desired effect in 50% of the population (ED50).
• safer drugs have a higher therapeutic index, and more’ dangerous’ drugs have a lower therapeutic index.
• Narrow therapeutic index (NTI) drugs are defined as those drugs where small differences in dose or blood concentration may lead to dose and blood concentration dependent, serious therapeutic failures or adverse drug reactions.

  Examples - Methotrexate, levothyroxine, warfarin, digoxin
• Therapeutic drug monitoring is the measurement of specific drug concentrations in the blood at timed intervals, in order to maintain a relatively constant concentration of the medication in the circulation.
• Types of drug administration and examples?

  • Oral - morphine
  • Sublingual/buccal - nitroglycerin/sublingual glyceryl trinitrate
  • Rectal
  • Vaginal - progesterone
  • Topical - hydrocortisone
  • Transdermal - nicotine patches
  • Ocular - chloramphenicol
  • Inhalation - salbutamol
  • Parenteral - IV, IM etc
• Types of parenteral administration?

  • Intramuscular - penicillin, testosterone, vaccines, Haloperidol Decanoate
  • Intravenous - Vancomycin
  • Subcutaneous - Heparin
  • Intradermal
  • Intrathecal (spinal canal)
  • Epidural
• Intramuscular contraindications?

  • Allergy
  • Myopathies
  • Muscular atrophy-delayed drug absorption
  • Infection at administration site.
• Common sites of intramuscular injections?

  • Deltoid muscle
  • Rectus femoris muscle
  • Gluteus medius muscle
• Epidural vs Intrathecal?

  • Intrathecal administration is delivered directly into the CSF and into the superficial spinal cord
  • epidural administration diffuses through the dura into the CSF.
  • Epidural given at cervical, thoracic or lumbar
  • Epidural involves placement of a catheter into the epidural space which may remain in place.
• Pharmacokinetics is the study of what the body does to a drug.
• Pharmacodynamics is the study of what a drug does to the body.
• Components of pharmacokinetics?

  • A - Absorption
  • D - distribution
  • M - metabolism
  • E - elimination
• Pharmacogenomics looks at how your DNA affects the way you respond to drugs.
• Pharmacogenetics is the branch of pharmacology that examines the relation of genetic factors to variations in response to drugs
• Processes in prescribing?

  • Pharmaceutical process (drug)
  • Pharmacokinetic process (body's reaction to drug - e.g. gut)
  • Pharmacodynamic process (pharmacological effect)
  • Therapeutic process (therapeutic effect)
• Vd is defined as the total amount of drug in the body divided by its concentration in plasma.
• What does it mean for a drug to have a high volume of distribution?

  A drug with a high Vd has a propensity to leave the plasma and enter the extravascular compartments of the body, meaning that a higher dose of a drug is required to achieve a given plasma concentration.
• Low Vd?

  a drug with a low Vd has a propensity to remain in the plasma meaning a lower dose of a drug is required to achieve a given plasma concentration.
• What influences Vd?

  • concentration of drug transporters in blood (binding proteins)
  • pH
  • perfusion
  • body water composition.
  • body fat composition
  • disease conditions
  • pregnancy
• Protein binding interactions are important when object drug?

  • Is highly bound to albumin (>90%)
  • Has a small volume of distribution
  • Has a low therapeutic ratio
• 1st order kinetics?

  Rate of elimination is proportional to drug level. Constant fraction of drug eliminated in unit time. Half life can be defined.
• Zero order kinetics?

  Rate of elimination is a constant.
• During repeated drug administration, a new steady state is achieved in 5 half lives.
• If the half life is long and a rapid effect is desired, use a loading dose. This is often determined by the Volume of distribution.
• Only the free fraction of drug is filtered.
• Passive reabsorption of drug is pH dependent.
• pKaof a drug is the pH at which 50% of its ionisable groups are ionised.
• the extent of ionisation determines the extent of absorption or reabsorption.
• If drug is excreted by kidneys, half lives of drug are longer.