• Absorption

  • Fick's Law

• Routes of Administration

• First-Pass Effect

• Pulmonary Effects

• Pharmacokinetics

  • Volume of distribution

  • Clearance

    • Renal clearance: clearance of unchanged drug and metabolites

      • Other Factors Affecting Renal Clearance

    • Factors Affecting Hepatic Clearance

    • Capacity-Limited Elimination

    • Half-life

    • Drug Accumulation

  • Bioavailablity

    • Extent of Absorption

    • First-Pass Elimination

    • Rate of Aborption

  • Some Pharmacokinetic Equations

  • Placental Transfer

  • Redistribution

  • Drug-Plasma Protein Binding

  • Renal Clearance

• Drug Metabolism

  • Introduction

  • Phase I and Phase II Reaction Overview:

  • Phase I characteristics

  • Phase II characteristics

  • Conjugates

  • Principal organs for biotransformation

    • Sequence I

    • Sequence II

  • Bioavailability

  • Microsomal Mixed Function Oxidase System and Phase I Reactions

    • The Reaction

    • flavoprotein--NADPH cytochrome P450 reductase

    • Cytochrome P450: -- terminal oxidase

    • P450 Enzyme Induction

    • P450 Enzyme Inhibition

    • Human Cytochrome P450

  • Phase II Reactions

    • Toxicities

• Individual Variation in Drug Responses

• Genetic Factors in Biotransformation

• Effects of Age on Drug Responses

• Drug-Drug Interactions

Pharmacokinetics and some IV Anesthetics Agents

• Barbiturates

  • Thiopental

• Benzodiazepines

• Ketamine and Etomidate

• Propofol

• Opioids

  • Membrane Bilayer Structure

•  Placental transfer is a concern because certain drugs may induce congenital abnormalities.

•  If administered immediately prior to delivery, drugs may directly adversely affect the infant.

• Characteristics of drug-placental transfer:

  • Mechanism: typically simple diffusion

  • lipid-soluble,non-ionized drugs are more likely to pass from the maternal blood into the fetal circulation.

    •  By contrast, ionized drugs with low lipid-solubility are less likely to pass through the placental "barrier".

    •  The fetus is exposed to some extent to all drugs taken by the mother.

Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B "The Dynamics of Drug Absorption, Distribution and Elimination". In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp. 3-27

Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17

• Termination of drug effects:

  • Usually by:

    • Biotransformation (metabolism)

    • Excretion

  • Drug effects may also be terminated by redistribution -- from its site of action to other tissues or sites

  • A highly lipophilic-drug may:

    • Rapidly partition into the brain

    • Act for a short period of time 

    • and then redistribute into other tissues -- often ultimately concentrating in adipose tissue.

    • Redistribution is the mechanism responsible for termination of action of thiopental (pentothal),an anesthetic inducing agent.

Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B The Dynamics of Drug Absorption, Distribution and Elimination. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 3-27

• Overview:

  • Most drugs: bound to some extent to plasma proteins

  • Major plasma proteins important for drug binding include:

    •  Albumin

    •  Lipoproteins

    •  α₁ -acidic glycoprotein

  • Extent of protein binding important for drug distribution since only unbound fraction may diffuse across biological membranes

  • Volume of distribution (Vd): inversely proportional to protein binding

  • Drug clearance: influenced by protein binding since only the unbound drug fraction may reach and serve as substrate for drug metabolizing enzymes

  • Small changes in fraction of drug bound significantly influences free plasma concentration for highly plasma protein bound drugs, e.g. warfarin, propranolol, phenytoin, diazepam

    • For example: a drug that is 98% protein-bound --following a decrease to 96% protein-bound results then a twofold increase in plasma drug concentration

• Characteristics of drug-protein binding

  • Extent of protein binding: parallels drug lipid solubility

  • Drug-plasma albumin binding -- often nonselective

    • Many drugs with similar chemical/physical properties may compete for the same protein-binding sites

      • Examples:

        •  Sulfonamides -- displace unconjugated bilirubin from albumin binding sites (may lead to neonatal bilirubin encephalopathy)

  •  Renal failure:

    • May decrease drug bound fraction (may not require changes in plasma albumin or other plasma protein concentration; suggesting elaboration of a metabolic factor from the kidney that competes with drug-plasma protein binding sites)

    • Example:

      • Phenytoin (free fraction increased in renal failure patients)

  • α₁ -acidic glycoprotein concentration increases following surgery, myocardial infarction and in response to chronic pain:

    •   In rheumatoid arthritis patients increased a₁ -acidic glycoprotein concentration resulting increased lidocaine (Xylocaine) and propranolol (Inderal) protein binding.

Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

Factors affecting renal clearance:

• Renal disease

• Rates of filtration depend on:

  1. Volume filtered in the glomerulus

  2. Unbound drug concentration in plasma (plasma protein-bound drug is not filtered)

• Drug secretion rates:

  1. Extent of drug-plasma protein binding

  2. Carrier saturation

  3. Drug transfer rates across tubular membranes

  4. Rate of drug delivery to secretory sites

• Changes in plasma protein concentration

• Blood flow

• Number of functional nephrons

Special concerns: Renal disease in elderly

• The kidney loses about 20% of its mass between ages 40 and 80 with most of the difference reflected in a decrease in renal cortical vasculature, tubular atrophy and dilatation along with interstitial scarring.  The kidney has the ability to compensate to some extent by hyperfiltration and hyperfunction of remaining  nephron units; however, despite these changes GFR declines beginning at about age 35 to 40 -- yearly decline = about 1 ml/per minute

  • Creatinine clearance is a measure of renal function.  The Cockcroft-Gault equation for creatinine clearance takes into account age:

    • (140-age) x body weight (kg) / 72 x serum creatinine (mg per dl)

    • For women, the results above should be multiplied by 0.85 

    • Accordingly, for a serum creatinine of 1.5 mg/dL for two men who weigh 81 kg, an 80 year-old man's creatinine clearance would be 45 ml per minute compared with 90 ml per minute for a 20 year-old.

Pharmacokinetic factors that change with age include:

• Summary

  • Creatinine clearance (reduced)

  • Hepatic blood flow (reduced)

  • Lean muscle mass (reduced)

  • Renal blood flow (reduced)

  • Serum albumin level (reduced)

  • Total body water (reduced)

  • Total body fat (increased)

• Generally the rate and extended drug absorption are not significantly altered by age; however, prescribed drugs such as anticholinergic agents, laxatives, calcium channel blockers influence gastrointestinal motility

• Reduced hepatic function associated with aging decreases the rate at which active metabolites are produced.

• Since total body water decreases and total body fat increases with age, volume of distribution will be altered. 

  •  For example, the more water-soluble drugs will exhibit a reduced apparent volume of distribution, causing an increased plasma concentration.  Examples include digoxin (Lanoxin, Lanoxicaps), cimetidine (Tagamet), and ethanol.

  • For more fat-soluble drugs, the opposite result is observed.  Therefore drugs such as diazepam (Valium) and chlordiazepoxide (Librium) will exhibit extended half lives.

• With age-dependent reduction in serum albumin, drugs that are typically extensively protein-bound, such as propranolol (Inderal), will be more likely found as free drug, accounting for a prolonged and enhanced drug action.

• In conclusion, age related reduction in hepatic function and renal clearance will tend to prolong drug half-life.  It may be necessary therefore to adjust dosages to account for these physiological changes.

Ref: Hassan Ali, Renal Disease in the Elderly in Postgraduate Medicine, 100, 6 December (1996).

Ion Trapping:

• Kidney:

  • Nearly all drugs filtered at the glomerulus:

    • Most drugs in a lipid-soluble form will be reabsorbed by passive diffusion.

    • To increase excretion: change the urinary pH to favor the charged form of the drug:

      • Weak acids: excreted faster in alkaline pH (anion form favored)

      • Weak bases: excreted faster in acidic pH (cation form favored)

• Other sites:

  • Body fluids where pH differences from blood pH favor trapping or reabsorption:

    • Stomach contents

    • Small intestine

    • Breast milk

    • Aqueous humor (eye)

    • Vaginal secretions

    • Prostatic secretions