• Plasma protein-bound drugs cannot permeate through aqueous pores

• Charged drugs will be influenced by electric field potentials {membrane potentials, important in renal, trans-tubular transport}

• II. Lipid diffusion 

  • Most important barrier for drug permeation due to:

    • many lipid barriers separating body compartments

  • Lipid: aqueous drug partition coefficients described the ease with which a drug moves between aqueous and lipid environments

  • Ionization state of the drug is an important factor: charged drugs diffuse-through lipid environments with difficulty.

    •  pH and the drug pKa, important in determining the ionization state, will influence significantly transport (ratios of lipid-to aqueous-soluble forms for weak acids and bases described by the Henderson-Hasselbalch equation.

      • uncharged form: lipid-soluble

      • charged form: aqueous-soluble, relatively lipid-insoluble (does not pass biological membranes easily)

Henderson-Hasselbalch equation

General Form:  log (protonated)/(unprotonated) = pK_a - pH

1. The lower the pH relative to the pK_a the greater fraction of protonated drug is found.  Recall that the protonated form of an acid is uncharged (neutral); however, protonated form of a base will be charged.

2. As a result, a weak acid at acid pH will be more lipid-soluble because it is uncharged and uncharged molecules move more readily through a lipid (nonpolar) environment, like the some membrane,  than charged molecules

3. Similarly a weak base at alkaline pH will be more lipid-soluble because at alkaline pH a proton will dissociate from molecule leaving it uncharged and again free to move through lipid membrane structures

• Lipid diffusion depends on adequate lipid solubility

  • Drug ionization reduces a drug's ability to cross a lipid bilayer.

Drugs that are weak acids or bases

Figure Developed by Dr. Steve Downing, University of Minnesota

Extent of Absorption

• Incomplete absorption following oral drug administration is common:

  • For example -- only 70% of a digoxin dose reaches systemic circulation. Factors:

    • poor GI tract absorption

    • digoxin (Lanoxin, Lanoxicaps) --- metabolism by gastrointestinal flora

• Very hydrophilic drugs - not be well absorbed --cannot cross cell membrane lipid component

• Excessively lipid-soluble (hydrophobic) drugs may not be soluble enough to cross a water layer near the cell membrane.

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 since charged form cannot be readily reabsorbed (they cannot readily pass through biological membranes)

      • 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

• Weak bases-- amines

  •  N + 1 carbon (R) and 2 hydrogens: primary amine (reversible protonation)

  •  N + 2 carbons (R) and 1 hydrogen: secondary amine (reversible protonation)

  •  N + 3 carbons (R): tertiary amine (reversible protonation)

  •  N + 4 carbons (R): quaternary amine (permanently positively charged)

• Most convenient, most economical

•  Disadvantages:

  • emesis (drug irritation of the gastrointestinal mucosa)

  • digestive enzymes/gastric acidity destroys the drug

  • unreliable or inconsistent absorption due to food or other drug effects

  • metabolism of the drug by gastrointestinal flora

• Factors determining rate of drug effect onset

  • Primary factor:

    • Rate & absorption extent by GI tract

  • Absorption Site:

    • mainly small intestine because of large surface area

  • Drug ionization state:

    • nonionized (lipid-soluble) forms favor absorption

      • weak acids may be highly ionized in the alkaline intestinal pH (not favoring absorption) but this effect is counterbalanced by the large surface-area effect

      • drugs which are weak acids are readily absorbed in the stomach

• First-Pass Effect

  • Drugs absorbed from the GI tract passes through the  portal venous system then through the liver and finally into the systemic circulation when drugs interact with receptors in target tissues.

  • Extensive hepatic metabolism/extraction result in minimal drug delivery to the systemic circulation for certain agents.

  • Drugs with large first pass effect exhibit significant differences in pharmacological effects comparing oral vs. IV administration

    • Examples:

      • propranolol

      • lidocaine

Transdermal Administration

• Advantages:

  • sustained, therapeutic plasma levels (reduced peaks/valleys associated with intermittent drug administrations)

  • Avoids continuous infusion technique difficulties

  • Low side effect incidence (smaller doses)

  • Generally good patient compliance

• Factors contributing to reliable transdermal drug absorption:

  • molecular weight < 1000

  • pH range 5-9 in aqueous medium

  • no histamine-releasing action

  • daily drug requirement <10 mg

• Example of drugs available for transdermal delivery:

  • scopolamine:-tolerance may eventually occur; resulting in loss of therapeutic action

  • fentanyl (Sublimaze)

  • clonidine (Catapres)

  • nitroglycerin-tolerance may eventually occur; resulting in loss of therapeutic action

• Proximal rectum administration: Absorption into superior hemorrhoidal veins then enters the portal venous system  then to the liver (possible first pass hepatic effect) and finally into the systemic circulation

• Low rectal administration of drug may allow the drug to enter the systemic circulation without passing through the liver

•  Generally unpredictable pharmacological responses for the above reasons

• Rectal mucosal irritation possible

• Ensures active drug absorption

• subcutaneously intramuscular injection: more rapid/predictable than oral administration route

• only route of administration acceptable for:

  • uncooperative patients

  • unconscious patients

• Factors the determine rate of systemic absorption:

  • absorbing capillary membrane surface area

  • drug solubility in interstitial fluid

  • aqueous channels (vascular endothelium) promote high diffusion rates of drugs, independent of their lipid solubility

• Advantages of IV administration

  • rapid/precise blood drug levels obtained (e.g., no first-pass effect)

  • Irritant drugs: more comfortably administered (blood vessels relatively insensitive); drug rapidly diluted (particularly if administered into large forearm vein)

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

First Pass Effect

First-pass Elimination:

Transport sequence:

1. across the gut wall into the portal circulation

2. portal blood transports of the drug to the liver

3. the drug may then reach the systemic circulation

4. bioavailability may be affected by steps 1 -- 3

• drug metabolism may occur in the intestinal wall or in the blood

• drug metabolism (potentially extensive) may occur in liver

•  liver may excrete drug into the bile

•  overall process that contributes to bioavailability reduction is the first-pass lost or elimination

Extraction Ratios, Routes of Administration, and the First-Pass Effect

• Some drugs that exhibit high extraction by the liver are given orally. 

  • Some examples -- desipramine (Norpramin), imipramine (Tofranil), meperidine (Demerol), propranolol (Inderal), amitriptyline (Elavil, Endep), isoniazid (INH).

• Some drugs which have relatively low bioavailability are not given orally because of concern of metabolite toxicity -- lidocaine is an example (CNS toxicity, convulsions)

• High extraction ratio drugs show interpatient bioavailability variation because all of sensitivity to:

  • hepatic function

  • blood flow

  • hepatic disease (intrahepatic or extrahepatic circulatory shunting)

• Avoiding the first-pass effect:

  • sublingual (e.g. nitroglycerin)-- direct access to systemic circulation

  • transdermal

  • use of suppositories in the lower rectum {if suppositories move upward, absorption may occur through the superior hemorrhoidal veins, which lead to the liver}

  • inhalation: first-pass pulmonary loss by excretion or metabolism may occur.

Pulmonary Implications: Pharmacokinetics

• Important for uptake of injected/intravenously administered drugs -- particularly lipophilic amines (pKa= 8)

• Pulmonary uptake:

  • Effects peak arterial concentration

  • May serve as a reservoir, enabling transport of drug into systemic circulation

• First-pass pulmonary effect magnitude not affected by:

  • spontaneous respiration

  • controlled ventilation

  • apnea

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

Pharmacokinetics

Volume of Distribution

• Volume of distribution (V_d) is the ratio between the amount of drug in body (dose given) and the concentration of the drug (C) measured in blood or plasma.

• V_d = (amount of drug in body)/C where C is the concentration of drug in blood or plasma.

• V_d as calculated is an apparent volume of distribution. For example:

  • V_d for digoxin is 440 L/70 kg (liters per 70 kg person)

  • V_d for chloroquine is 13,000 L/70 kg (liters per 70 kg person)

  • Such very large V_d would be consistent with very high tissue binding, leaving little free in plasma or blood

• V_d is an apparent volume of distribution, since V_d is the volume needed to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or plasma water.

  • Many drugs have a much higher concentration in extravascular compartments (therefore these drugs are NOT homogeneously distributed)

   

• Physical volumes (L./kg body weight) for some body compartments

  • Water

    • Total Body Water (0.5-0.7 L/kg) or about 35000 to 49000 ml (70 kg individual)

    • Extracellular Water (0.2 L./kg)

    • Blood (0.08 L./kg);

    • Plasma (0.04 L./kg)

  • Fat

    • 0.2 - 0.35 L./kg 

  • Bone

    • 0.07 L/kg

Semilogarithmic plot above illustrates extrapolation to time 0 required to determine the volume of distribution;V_d = dose/C_o- also note that the drug elimination halftime can be directly calculated from the graph. This graph applied for a single compartment model only.  For multiple compartments which will appear as a. non-linear relationship extrapolation back to t = 0 must be performed for each compartment separately.  From Goodman Gilman, A, Rall T, Nies, A, Taylor P, eds Goodman and Gillman:  The Pharmacological Basis of Therapeutics, 8th edn, Oxford: Pergamon, 1990

• Factors influencing the volume of distribution:

  • drug pK_a

  • extent of drug-plasma protein binding

  • partition coefficient of the drug in fat (lipid solubility)

  • V_d may be affected by:

    • patient's gender

    • patient's age

    • patient's disease

    • patient's body composition

  • Example of a poorly lipid soluble agent with a V_d about equal to extracellular fluid volume: nondepolarizing neuromuscular blocking drugs.

Clearance

• Introduction

  • Clearance is especially important for insuring appropriate long-term drug dosing -- correct steady-state drug concentrations

• Clearance of a given drug is usually constant over the therapeutic concentration range because:

  1. Drug elimination systems are not saturated -- therefore the absolute rate of elimination is a linear function of the drug's plasma concentration.

  2.  Drug elimination is therefore usually a first-order kinetic process-- a constant fraction of the drug is eliminated per unit time.

  3.  Some drugs (e.g., ethanol) exhibit zero order kinetics -- a constant amount of drug is eliminated per unit time. {Clearance is variable}

• Clearance: the drug's rate of elimination (by all routes) normalized to the concentration of drug C in some biological fluid:

  • CL = Rate of elimination / C

  • CL = Vd x k_el where V_d = volume of distribution and k_el is the elimination rate constant

  • CL = Vd x (0.693/t_1/2) where 0.693 = ln2 and t_1/2 is the drug elimination half-life

• Clearance:

  • volume per unit time (volume of fluid i.e. blood or plasma that would be completely freed of drug to account for the elimination)

  • may be defined as:

    • blood clearance, CL_b

    • plasma clearance, CL_p

    • concentration of unbound or free drug, depending on the concentration measured (C_b, C_p or C_u)

• Clearance is additive: a function of elimination by all participating organs such as liver or kidney:

  • CL systemic = CL_renal + CL_hepatic + CL_other

    • "Other" sites may include the lungs and other sites of drug metabolism (muscle, blood)

    • The two most important sites for drug elimination: kidneys and liver

  • Renal clearance: clearance of unchanged drug and metabolites

    • Kidneys: most important organs for unchanged drug/drug metabolites elimination

    • Water-soluble compounds exhibit more efficient renal excretion compared to lipid soluble compounds (emphasizing the importance of metabolic conversion of lipid-soluble drugs to water-soluble metabolites)

    • Renal drug clearance is correlated with exogenous creatinine clearance or serum creatinine concentration

    • Factors in renal excretion:

      1. Glomerular filtration-- important considerations:

         • Fraction of free drug (compared to protein-bound drug)--when a drug is bound to protein it is not filtered

         • Glomerular filtration rate

      2. Tubular secretion (active process)-- important considerations:

         • Drug/metabolite selectivity

      3. Passive tubular reabsorption-- important considerations:

         • Enhanced lipid solubility favors reabsorption {lipid-soluble agents more readily cross renal tubular epithelial cell membrane thus entering pericapillary fluid}

         • Example: thiopental (highly lipid-soluble): completely reabsorbed -- minimal unchanged drug excreted in urine

         • Renal tubular reabsorption rate influenced by:

           • pH

           • rate of renal tubular urine flow

           • weak acid or weak base drug/drug metabolite pKa compared to urinary pH

  • Hepatic clearance: drug elimination following metabolic transformation of the parent drug to metabolites

    • Since elimination is not "saturable", elimination is typically first order and directly proportional to drug concentration:

• Other 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

• Factors affecting hepatic clearance:

  •  Drug delivery to hepatic elimination sites may be rate-limiting for certain drugs:

    •  also called flow dependent elimination: in this case most of the drug in the blood is eliminated on the first pass of the drug through the organ

    •  these drugs are termed "high-extraction"

  • extent of plasma protein-bound drug

  • blood flow (affects clearance on drugs with high extraction ratios).

• Changes in the intrinsic clearance (i.e. enzyme induction, hepatic disease: affects clearance of drugs with low extraction ratios): Examples --

  • Social factors: 

    • Tobacco smoke induces some Cytochrome P450 (a.k.a. CYP) hepatic microsomal drug metabolizing enzyme isoforms (CYP1A1, CYP1A2, and possibly CYP2E1)

    • Chronic ethanol use induces CYP2E1

  • Dietary considerations:

    • Grapefruit juice contains chemicals that are potent inhibitors of CYP3A4 localized in the intestinal wall mucosa

    • Cruciferous vegetables such as brussels sprouts, cabbage, cauliflower and hydrocarbons present in charcoal-broiled meats can induce CYP1A2.

    • Calcium present in dairy products can chelate drugs including commonly used tetracyclines  and fluoroquinone antibiotics.

  • Age: Neonates have reduced hepatic metabolism and renal excretion due to relative organ immaturity.  On the other hand, elderly patients exhibit differences in absorption, hepatic metabolism, renal clearance and volume of distribution.

  • Genetic Factors:

    • Genetic polymorphism affecting CYP2D6, CYP2C19, CYP2A6, CYP2C9, and N-acetyltransferase result in significant inter-individual differences in drug-metabolizing abilities (the drug of course must be a substrate for one of the above cytochrome P450 isoforms)

    • Certain genetic polymorphisms are associated with ethic groups.  For instance, 5%-10% of Caucasians are  poor metabolizers of CYP2D6 substrates.  By contrast, the frequency in Asian populations is about 1%-2%.  On the other hand, the incidence of poor metabolizers of CYP2C19 drugs is about 20% in Asian populations, but only about 4% in Caucasian populations.

    • Definition: genetic polymorphism -- "Genetic polymorphism is a type of variation in which individuals was sharply distinct qualities co-exist as normal members of the population" Ford, 1940.

    • Cytochrome P450 isoform naming conventions:

      • Review -- drug biotransformation usually involves two phases, phase I & phase II.  

        • Phase I reactions are classified typically as oxidations, reductions, or hydrolysis of the parent drug.  Following phase I reactions, the metabolites are typically more polar (hydrophilic) which increases the likelihood of their excretion by the kidney.  Phase I metabolic products may be further metabolized

        • Phase II reactions often use phase I metabolites can catalyze the addition of other groups, e.g. acetate, glucuronate, sulfate or glycine to the polar groups present on the intermediate.  Following phase II reactions, the resultant metabolite is typically more readily excreted.

      • Most phase I reactions are catalyzed by the cytochrome P450 system (CYP).  This superfamily consists of heme-containing isoenzymes which are mainly localized in hepatocytes, specifically within the membranes of the smooth endoplasmic reticulum.  The primary extrahepatic site containing CYP isoforms would be enterocytes of the small intestine. 

      • The gene family name is specified by an Arabic numeral, e.g. CYP3. > 40% of sequence homology characterize CYP isoforms within a family.

        • CYP families are subdivided into subfamilies designated by an upper case letter, it e.g. CYP3A .

        • Gene numbers of individual enzymes are noted by a second Arabic numeral following the subfamily letter, e.g. CYP3A4.

      • CYP isoforms not only metabolize many endogenous substances including prostaglandins, lipids, fatty acids, and steroid hormones but also metabolize (detoxify) exogenous substances including drugs

      • Major CYP isoforms responsible for drug metabolism include:CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2, CYP2E1 in in certain cases CYP2A6 and CYP2D6

    •  Important enzymes for phase II reactions include glutathione-S-transferases, UDP-glucuronosyl transferases, sulfotransferases, N-acetyltransferases, methyltransferases and acyltransferases.

• Capacity-limited elimination:

  • Drug examples: ethanol, aspirin.

  • Capacity-limited elimination:

    • saturable, dose-or concentration-dependent

    • nonlinear

    • Michaelis-Menten elimination

  • If blood flow to the organ does not limit elimination, the relationship between the elimination rate and drug concentration,C, is:

    • rate of elimination = V_max · C / (K_m + C)

  • the form of this equation is very similar to the Michaelis-Menten description of enzyme kinetics. Here, however:

    • V_max refers to maximum elimination capacity

    • K_m is the drug concentration at which the rate of elimination is 50% of V_max.

    • As expected from the rectangular-hyperbolic shape of the curve, at high drug concentrations (compared to the K_m), dependency of elimination rate on drug concentration decreases significantly, approximating zero order behavior. see below:

Holford, N. H.G. and Benet, L.Z. Pharmacokinetics and Pharmacodynamics: Dose Selection and the Time Course of Drug Action, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 34-49.

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.

Half-life

• Introduction

  • Half-life: (t_1/2) -- time required to decrease the amount of drug in body by 1/2 during elimination (or during a constant infusion).

  • Assumption:

    1. single body compartment size = volume of distribution (Vd)

    2. blood or plasma considered in equilibrium with total volume of distribution

• Factors affecting t_1/2:

  • disease states-- affects volume of distribution and clearance

    •  example 1:a patient with chronic renal failure--

      1. decreased digoxin (Lanoxin, Lanoxicaps) renal clearance

      2. decreased Vd due to decreased renal and skeletal muscle mass (decreased digoxin tissue binding)

      3. resultant increase in digoxin half-life less than expected based on renal function change

    •  example 2: half-life of diazepam (Valium) increases with age --

      1. clearance does not change

      2. volume of distribution changes

    •  example 3: half-life changes secondary to changes in plasma protein binding.

      1. patients with acute viral hepatitis: half-life of Tolbutamide (Orinase) decreases (opposite of expected?)

      2. Acute viral hepatitis alters plasma and tissue drug-protein binding; the disease does not change volume of distribution but increases total clearance because more free drug (not bound to protein) is present.

• Half-life:

  • Useful in estimating time to steady-state: approximately 4 half-lives are required to reach about 94% of a new steady-state

  • Useful in estimating time required for drug removal from the body

  • means for estimation of appropriate dosing interval

Drug Accumulation

• With repeating drug doses, the drug will accumulate in the body until dosing ceases.

• Practically: accumulation will be observed if the dosing interval is less than 4 half-lives.

• Accumulation: inversely proportional to the fraction of the dose lost in each dosing interval

  • Accumulation factor = 1/Fraction lost in one dosing interval = 1/(1 - fraction remaining)

• For example, the accumulation factor for a drug given once every half-life: 1/0.5 equals 2.

Bioavailability

•  Definition: fraction of unchanged drug that reaches systemic circulation following administration (by any Route of Administration)

• Examples:

  • IV administration: bioavailability = 1

  • Other routes of administration = < 1

• Major factors that reduce bioavailability to less than 100%:

  • incomplete absorption

  • first-pass effect (liver metabolizes drug before drug reaches systemic circulation)

• Extent of Absorption:

  • Incomplete absorption following oral drug administration is common:

  • For example -- only 70% of a digoxin dose reaches systemic circulation. Factors:

    • poor GI tract absorption

    • digoxin metabolism by gastrointestinal flora

  • Very hydrophilic drugs - not be well absorbed --cannot cross cell membrane lipid component

  • Excessively lipid-soluble (hydrophobic) drugs may not be soluble enough to cross a water layer near the cell membrane.

• First-pass Elimination:

  • Transport sequence:

    1. across the gut wall into the portal circulation

    2. portal blood transports of the drug to the liver

    3. the drug may then reach the systemic circulation

    4. bioavailability may be affected by steps 1 -- 3

  • drug metabolism may occur in the intestinal wall or in the blood

  • drug metabolism (potentially extensive) may occur in liver

  •  liver may excrete drug into the bile

  •  overall process that contributes to bioavailability reduction is the first-pass lost or elimination

  • Magnitude of first pass hepatic effect: Extraction ratio (ER)

    • ER = CL liver / Q ; where Q is hepatic blood flow (usually about 90 L per hour

    • Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER):

      • F = f x (1 -ER)

• Absorption rate:

  • rate of absorption:dependent on site of administration and drug formulation

  • zero order: drug absorption rate -- independent of amount remaining in the gut

  • first order: drug absorption rate -- proportional to the drug concentration dissolved in the gastrointestinal tract

• Extraction Ratios, Routes of Administration, and the First-Pass Effect

  • Some drugs that exhibit high extraction by the liver are given orally. Some examples -- desipramine (Norpramin), imipramine (Tofranil), meperidine (Demerol), propranolol (Inderal), amitriptyline (Elavil, Endep), isoniazid (INH). 

  • Some drugs which have relatively low bioavailability are not given orally because of concern of metabolite toxicity -- lidocaine (Xylocaine)  is an example (CNS toxicity, convulsions)

  • High extraction ratio drugs show interpatient bioavailability variation because all of sensitivity to:

    • hepatic function

    • blood flow

    • hepatic disease (intrahepatic or extrahepatic circulatory shunting)

  • Drugs poorly extracted by the liver:

    • phenytoin (Dilantin)

    • diazepam (Valium)

    • digitoxin (Crystodigin)

    • chlorpropamide (Diabinese)

    • theophylline

    • Tolbutamide (Orinase)

    • warfarin (Coumadin)

  • Avoiding the first-pass effect:

    • sublingual (e.g. nitroglycerin)-- direct access to systemic circulation

    • transdermal

    • use of suppositories in the lower rectum {if suppositories move upward, absorption may occur through the superior hemorrhoidal veins, which lead to the liver}

    • inhalation: first-pass pulmonary loss by excretion or metabolism may occur.

Holford, N. H.G. and Benet, L.Z. Pharmacokinetics and Pharmacodynamics: Dose Selection and the Time Course of Drug Action, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 34-49.

 

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

• Placental Transfer

  •  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.

  • Anesthesia correlation: Placental transfer of basic drugs

    • Placental transfer of basic drugs from mother to fetus: local anesthetics

    • Fetal pH is lower than maternal pH

    • Lipid-soluble, nonionized local anesthetic crosses the placenta converted to poorly lipid-soluble ionized drug

      •  Gradient is maintained for continual transfer of local anesthetic from maternal circulation to fetal circulation

      •   In fetal distress, acidosis contributes to local anesthetic accumulation

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

• Redistribution

  • 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 briefly

      • 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

• Drug-Plasma Protein Binding

  • Overview:

    • Most drugs: bound to some extent to plasma proteins

    • Major plasma proteins important for drug binding include:

      •  albumin

      •  lipoproteins

      •  a₁ -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)

    • alpha₁ -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.

• Renal Clearance

  • 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

  • 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

Drug Metabolism: Phase I and Phase II Metabolism

• Introduction:

  • Lipophilic drug properties that promote passage through biological membranes and facilitate reaching site to drug action inhibit drug excretion.

    • Note: renal excretion of unchanged drug contributes only slightly to elimination, since the unchanged, lipophilic drug is easily reabsorbed through renal tubular membranes.

  • Biotransformation of drugs to more hydrophilic molecules is required for elimination from the body

    • Biotransformation reactions produces more polar, hydrophilic, biologically inactive molecules -- that are more readily excreted.

      • Sometimes metabolites retain biological activity and may be toxic.

    • Drug biotransformation mechanisms are described as either phase I or phase II reaction types.

• Phase I and Phase II Reactions -- Overview

  • Phase I characteristics:

    •  Parent drug is altered by introducing or exposing a functional group (-OH,-NH₂, -SH)

    •  Drugs transformed by phase I reactions usually lose pharmacological activity

    •  Inactive, prodrugs are converted by phase I reactions to biologically-active metabolites

    •  Phase I reaction products may:

      • be directly excreted in the urine

      • react with endogenous compounds to form water soluble conjugates.

• Phase II characteristics:

  • Parent drug participates in conjugation reactions that:

    • form covalent linkage between a parent compound functional group and:

      • glucuronic acid

      • sulfate

      • glutathione

      • amino acids

      • acetate

• Conjugates are highly polar, and generally biologically inactive.  One exception to this rule is a morphine metabolite, morphine glucuronide which is a more potent analgesic compared to the parent compound.  Conjugates tend to be rapidly excreted in the urine.

  • High molecular weight conjugates  are more likely excreted in the bile. The conjugate bond may be cleaved by intestinal flora with the parent compound released back to the systemic circulation.  This process, "enterohepatic recirculation" results in delayed parent drug elimination and a prolongation of drug effects.

• The Principal Organ for biotransformation is the liver, although other organs participate in metabolism.  These other systems include lungs, skin, kidney, and the gastrointestinal tract.

  • Other metabolizing organs:

• Sequence I could be as follows:

  1. (1) Oral administration (isoproterenol (Isuprel), meperidine (Demerol), pentazocine (Talwain), morphine)

  2. (2) The drug is absorbed intact by the small intestine.

  3. (3) The drug is transported to the liver (portal system) where it might be extensively metabolized by the liver, an example of a first-pass effect.

• Sequence II might be as follows:

  1.  (1) Oral administration  (e.g. clonazepam (Klonopin), chlorpromazine (Thorazine)) and

  2. (2) the agent is absorbed intact by the small intestine.

  3. (3) Extensive intestinal metabolism might ensue, contributing to overall first-pass effects.

• Issues in bioavailability: Reduced bioavailability might result from several factors including (a) the first pass effect in which the bioavailability of orally administered drugs become so limited that alternative routes of administration must be employed.  (b) Intestinal flora might metabolize the drug.  (c) The drug itself is unstable in gastric acid; an example of this effect would be penicillin.  (d) the drug might be metabolized by digestive enzymes; an example of this effect would be insulin.  (d) Finally, the drug might be metabolized by intestinal wall enzymes; sympathomimetic catecholamines represent examples of this effect.

  • First pass effect: bioavailability of orally administered drugs -- so limited -- alternative routes of administration must be used

  • Intestinal flora may metabolize drugs

  •  unstable in gastric acid-- penicillin

  •  metabolized by digestive enzymes -- insulin

  •  metabolized by intestinal wall enzymes-- sympathomimetic catecholamines

Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 50-61.

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

Mixed function oxidase System (cytochrome 450 System)--Phase I Reactions

• Microsomes have been used to study mixed function oxidases

  • Drug metabolizing enzymes are located in lipophilic, hepatic endoplasmic reticulum membranes.  Smooth endoplasmic reticulum contains those enzymes responsible for drug metabolism.

• The reaction:

  • one molecule oxygen is consumed per substrate molecule

  • one oxygen atom -- appears in the product; the other in the form of water

• Cytochrome P450 Enzyme Induction:

  • Following repeated administration, some drugs increase the amount of P450 enzyme usually by:

    • increase enzyme synthesis rate (induction)

    • reduced enzyme degradation rate

• Cytochrome P450 enzyme inhibition:

  • Certain drugs, by binding to the cytochrome component, act to competitively inhibit metabolism. Examples:

    •  Cimetidine (Tagamet) (anti-ulcer --H₂ receptor blocker) and Ketoconazole (Nizoral) (antifungal) bind to the heme iron a cytochrome P450, reducing the metabolism of:

      • testosterone

      • other coadministered drugs

      • Mechanism of Action: competitive inhibition

  •  Catalytic inactivation of cytochrome P450.

    •  Macrolide antibiotics (troleandomycin, erythromycin estolate (Ilosone)), metabolized by a cytochrome P450:

      • metabolites complex with cytochrome heme-iron: producing a complex that is catalytically inactive.

    •  Chloramphenicol (Chloromycetin): metabolized by cytochrome P450 to an alkylating metabolite that inactivates cytochrome P450

    •  Other inactivators: Mechanism of Action: -- targeting the heme moiety:

      • steroids:

        • ethinyl estradiol (Estinyl)

        • norethindrone (Aygestin)

        • spironolactone (Aldactone)

      • others:

        • propylthiouracil

        • ethchlorvynol (Placidyl)

Phase II Metabolism

• Overview: Phase II reactions involve non-microsomal enzymes

  • Reaction types:

    1. conjugation

    2. hydrolysis

    3. oxidation

    4. reduction

  • Location (non-microsomal enzymes): primarily hepatic (liver); also plasma & gastrointestinal tract

  • Non-microsomal enzymes catalyze all conjugation reactions except glucuronidation

• Nonspecific esterases in liver, plasma, gastrointestinal tract hydrolyzed drugs containing ester linkages, including succinylcholine (Anectine), Atricurium (Tracrium), Mivacurium (Mivacron), esmolol (Brevibloc) as well as ester-type local anesthetics.

• Conjugation reactions are usually "detoxification reaction".  Conjugates tend to be more polar compared to the parent compound, more easily excreted, and usually pharmacologically inactive.

•  Conjugation reactions require "high-energy" intermediates in specific transfer enzymes which include both microsomal and cytosolic transferases.

  •   Conjugation with glucuronic acid:  Glucuronic acid is available from glucose and its conjugation with lipid-soluble drugs results in a lipophilic glucuronic acid derivative which is typically pharmacologically inactive and more water-soluble compared to the parent compound.  Therefore, the glucuronic acid derivative molecule is more readily excreted in both urine or bile.

  • Transferases are enzymes which catalyzes the coupling of an endogenous substance with the drug.

    • For example, transferase which catalyzes the "transfer" of uridine-5'-diphosphate (UDP) derivative of glucuronic acid and a drug.

    • A transferase may catalyze an inactivated drug with an endogenous substrate. For example a S-CoA derivative of benzoic acid with an endogenous substrate.

•  Toxicity:

  • Certain conjugation reactions form toxic reactive species (hepatotoxicity).  For example, acyl glucuronidation of nonsteroidal anti-inflammatory drugs may result in toxicity.  Another example would be N-acetylation of isoniazid.

  •  Drugs metabolized to toxic products:

    • Acetaminophen hepatotoxicity -- normally safe in therapeutic doses

    • Therapeutic doses:

      • glucuronidation + sulfation to conjugates (95% of excreted metabolites); 5% due to alternative cytochrome P450 depending glutathione (GSH) conjugation pathway

    •  At high doses:

      • Glucuronidation and sulfation pathways become saturated

      •  Cytochrome P450 dependent pathway becomes now more important.With depletion of hepatic glutathione, hepatotoxic, reactive, electrophilic metabolites are formed. In this circumstance antidotes would include N-acetylcysteine and cysteamine. N-acetylcysteine protects patients from fulminant hepatotoxicity and death following acetaminophen overdose.

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

2. 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

3. Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 50-61

Basis for individual to individual variation in drug responses

• Response Variation Secondary to Pharmacokinetic Differences

  • Bioavailability

  • Renal function

  • Liver function

  • Cardiac function

  • Patient Age

• Response Variation Secondary to Pharmacodynamic Differences

  • Enzyme activity

  • Genetic differences

• Response Variation Secondary to Drug Interactions

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

Genetic Factors: in Biotransformation of Drugs

• Genetic influences: Variation in drug metabolism rates or in receptor sensitivity:

• Metabolism:

  • Patients can be categorized as either rapid or slow acetylators; a classification which refers to the patients ability to relatively rapidly or slowly catalyze acetylation reactions.  Biotransformation of some drugs are affected by acetylation rates, examples include hydralazine (Apresoline) and isoniazid (INH).:

• Pharmacogenetics: One major concern is that on underlying disease state may not be appreciated until an unexpected reaction to an anesthetic agent in fact occurs.  The anesthetic agent essentially exposes on underlying disease state and then appropriate inner operative responses required.  Examples:

  • Atypical cholinesterase enzyme suggested by prolonged succinylcholine (Anectine) or mivacurium (Mivacron)- induced neuromuscular blockade

  • Succinylcholine (Anectine) or volatile anesthetic induced malignant hyperthermia-Malignant hyperthermia is a very serious reaction requiring a definitive treatment approach including dantrolene (Dantrium).

  • If the patient exhibits glucose-6-phosphate dehydrogenase deficiency certain drugs may induce hemolysis

  • Barbiturates may induce intermittent porphyria attacks.  It is extremely important to determine therefore preoperatively if the patient has history of intermittent porphyria.

Acute intermittent porphyria

Background:  Porphyria is an inherited condition in which too much of the chemical porphyrin is synthesized. Porphyrin is used to make heme, the oxygen-carrying component of blood. Specifically, acute intermittent porphyria is inherited as an autosomal dominant disorder which causes unphysiologic, excessive amounts of urinary aminolevulinic acid and prophobilinogen. Porphyrias are associated with overproduction of  porphyrins and for acute intermittent porphyria the exacerbation is induced by barbiturates, sulfonamides, and the antifungal drug griseofulvin. These drugs induce enzymes (increase the amount of enzymes) that cause increased porphyrins synthesis. Porphyrin The specific defect that leads to acute intermittent porphyria is due to a defect in the specific enzyme called porphobilogen deaminase (PBG deaminase) also called uroporphyrinogen synthesis, or HMB synthase, a heme-synthesizing enzyme HMB synthase catalyzes the conversion of porphobilinogen to hydroxymethylbilane which is the immediate precursor of uroporphyrinogen III. In this autosomal dominant condition (acute intermittant porphyria, there is only 50% normal HMB (hydroxymethylbilane) synthase activity which results in porphobilinogen buildup.   Desnick, Robert J., The Porphyrias in Harrison's Priniciples of Internal Medicine, (Braunwald, E., Fauci, A.S. Kasper, D.L., Hauser, S.L., Longo, D.L. and Jameson, J.L.,eds)  15th Edition, ch. 346, pp 2261-2263.McGraw-Hill, New York, 2001 Pathology: Pathology: biosynthetic byproducts may turn the urine red and even can cause, following deposition, reddish brown teeth. Acute episodes of neuropathic syndromes involving abdominal pain is the most common symptom; paresthesias & paralysis may occur with even death resulting from respiratory paralysis.  Acute attacks can involve psychotic episodes and hypertension, and although these attacks usually do not occur before puberty, they can be precipitated by barbiturates & sulfonamides which induces an early but important rate-determining enzymatic step in heme synthesis, specifically delta aminolevulinic acid synthesis  Other factors known to precipitate acute intermittent porphyria include alcohol, starvation, infection, and hormonal changes -- acute intermittent porphyria exacerbations are more common in females. Clinical management:  supportive treatment dextrose infusion high carbohydrate intake hematin infusion (heme), a feedback inhibitor of heme  synthesis (drug may cause renal damage) For management of abdominal pain associate with acute attacks, narcotic analgesics may be used and relief from nausea, vomiting, anxiety and restlessness may be provided by phenothiazine administration. Safe drugs for use in patients with acute intermittent porphyria, hereditary coproporphyria and  variegate porphyria: narcotic analgesics, aspirin,acetaminophen (Tylenol, Panadol), phenothiazines, penicillin & derivatives, streptomycin, glucocorticoids, bromides, insulin, atropine. Unsafe drugs for use in patients with acute intermittent porphyria, hereditary coproporphyria and  variegate porphyria: barbiturate, sulfonamide antibiotics, meprobamate (Miltown), glutethimide (Doriden), methyprylon (Noludar), ethchlorvynol (Placidyl),carbamazepine (Tegretol), succinamides,carbamazepine (Tegretol), valproic acid (Depakene, Depakote), griseofulvin, ergot alkaloids, synthetic estrogens & progestogens, danazol (Donocrine), alcohol. Prevalence: highest in Sweden, frequency is 1 in 1000 Prevalence based on previous manifestation of acute intermittent porphyria (AIP), about 1 in 50,000; however, this number probably underestimate the number of individuals with latent AIP. Source: National Center for Biotechnology Information (http://www3,ncbi.nlm.nih.gov/Omim/) (http://www3.ncbi.nlm.nih.gov/htbin-post/0mim/dispmim?186000#DIAGNOSIS) Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17. Desnick, Robert J., The Porphyrias in Harrison's Priniciples of Internal Medicine, (Braunwald, E., Fauci, A.S. Kasper, D.L., Hauser, S.L., Longo, D.L. and Jameson, J.L.,eds)  15th Edition, ch. 346, pp 2261-2263.McGraw-Hill, New York, 2001

Influence of Age on Drug Responses

• Variation in drug responses may be due to several factors such as:

  • Diminished cardiac output:

    • A reduction in cardiac output reduces hepatic perfusion which may decrease delivery of drug to the liver for metabolism.  This type of an effect would prolonged duration of action of, for example, lidocaine (Xylocaine) or fentanyl (Sublimaze).

  •  Increased body fat:

    • An increase in body fat tends to increase V_d .  An increased V_d would tend to prolong clearance time.

    • Increased body fat also promotes accumulation of highly lipid-soluble agents such as diazepam (Valium) and thiopental (Pentothal).

  • Altered protein binding can affect drug responses because only the "free", unbound drug is active and for a highly protein-bound drug small changes in the extent of protein binding can substantially influence the free drug concentration [free drug].

  • Decreased or compromised renal function can prolong drug action  if renal excretion is the primary mechanism for clearance.

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

Drug-Drug Interactions

• Definition: Drug interaction -- when one drug affects the pharmacological response of a second drug given at the same time.

• Drug interactions may be due to:

  •  pharmacodynamic effects

  •  pharmacokinetic effects

• Consequences of drug interactions:

  •  increased drug effects; decreased drug effects

  •  desired consequences; adverse or undesired effects

• Examples -- positive, beneficial drug interaction effects:

  • propranolol + hydralazine (reflex tachycardia (undesirable) caused by hypotensive hydralazine-mediated response is prevented by propranolol-mediated β-adrenergic receptor blockade

  • Opioid-induced respiratory depression may be counteracted by administration of the opioid receptor antagonist naloxone

•  Adverse effects -- toxic reactions

  •  one drug may interact with another to impede absorption

  •  one drug may compete with another for the same plasma protein-binding sites

  •  one drug may affect metabolism of another by either enzyme induction or enzyme inhibition

  •  one drug may change the renal excretion rate of the other.

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

2. Dolin, S. J. "Drugs and pharmacology" in Total Intravenous Anesthesia, pp. 13-35 (Nicholas L. Padfield, ed), Butterworth Heinemann, Oxford, 2000