Pharmacokinetics-contd

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Pulmonary Implications: Pharmacokinetics

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

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

Volume of Distribution

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

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

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

-Vd for digoxin is 440 L/70 kg (liters per 70 kg person)
-Vd for chloroquine is 13,000 L/70 kg (liters per 70 kg person)

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

Vd is an apparent volume of distribution, since Vd 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

Factors influencing the volume of distribution:

-drug pKa
-extent of drug-plasma protein binding
-partition coefficient of the drug in fat (lipid solubility)
-Vd may be affected by:

a)patient's gender
b)patient's age
c)patient's disease
d)patient's body composition

Example of a poorly lipid soluble agent with a Vd 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:

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

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

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 kel where Vd = volume of distribution and kel is the elimination rate constant

CL = Vd x (0.693/t1/2) where 0.693 = ln2 and t1/2 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, CLb

plasma clearance, CLp

concentration of unbound or free drug, depending on the concentration measured (Cb, Cp or Cu)

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

CL systemic = CLrenal + CLhepatic + CLother

"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:

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

Tubular secretion (active process)-- important considerations:

Drug/metabolite selectivity

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:

Rate of elimination = CL x C

Other factors affecting renal clearance:

-renal disease
-rates of filtration depend on:

a)volume filtered in the glomerulus
b)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 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 = Vmax � C / (Km + C)

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

Vmax refers to maximum elimination capacity

Km is the drug concentration at which the rate of elimination is 50% of Vmax.

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

Half-life

Introduction

Half-life: (t1/2) -- time required to decrease the amount of drug in body by 1/2 during elimination (or during a constant infusion).

Assumption:

single body compartment size = volume of distribution (Vd)

blood or plasma considered in equilibrium with total volume of distribution

t1/2 = (0.693 � Vd)/CL

t1/2 = (0.693)/kel

0.693 equals the natural logarithm of two. {Since drug elimination is an exponential process, the time required for a twofold decreased is proportional to ln(2)}.

kel = km + kex; where the elimination rate, kel ,constant is the sum of the rate constants due to metabolism, km , and excretion,kex.

Factors affecting t1/2:

disease states-- affects volume of distribution and clearance

example 1:a patient with chronic renal failure--

decreased digoxin (Lanoxin, Lanoxicaps) renal clearance

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

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

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

clearance does not change

volume of distribution changes

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

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

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.

Elimination halftime and anesthesia:

Elimination halftime is important in estimating recovery from anesthetic drug administration.

In the case of IV administered agents, an inconsistency between the elimination halftimes following a single, bolus injection compared to continuous IV infusion, has resulted in the development of an idea of referred to as "context-sensitive or dependent" halftimes.

The definition of "context-sensitive" halftimes is the length of time required for the drug plasma concentration to fall 50% after continuous infusion

For IV anesthetic drug pharmacokinetics, special problems exist because those significant differences in individual drug requirements (up to 2-5 times) as a result of dose-plasma and plasma-effect relationships

By contrast to the above special problems associated with IV anesthetic drug pharmacokinetics and variation between drugs, a similar problem does not exist for the volatile agents were drug-effect relationships appear more predictable.

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:
across the gut wall into the portal circulation
portal blood transports of the drug to the liver
the drug may then reach the systemic circulation
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.

Some Pharmacokinetic Equations

Elimination Rate Constant
kel = km + kex
where kel = drug elimination rate constant
km = elimination rate constant due to metabolism
kex = elimination rate constant due to excretion

Half-Life
t1/2 = ln 2 /kel = 0.693/kel
where t1/2 is the elimination half-life (units=time)

Amount of Drug in Body
Xb = Vd � C
Xb: amount of drug in the body (units, e.g. mg)
Vd: apparent volume of distribution (units, e.g. mL)
C: plasma drug concentration (units, e.g. mg/mL)

Volume of Distribution Calculation (one compartment, i.v. infusion)
Vd = Div / Co
Vd: apparent volume of distribution (units, e.g. ml/kg)
Div: i.v dose (units, e.g. mg/kg)
Co: plasma drug concentration (units, e.g. mg/ml)

Clearance
CL = rate of elimination/C
rate of elimination = CL� C
CL = Vd x kel where Vd = volume of distribution and kel is the elimination rate constant
CL = Vd � (0.693/t1/2) where 0.693 = ln 2 and t1/2 is the drug elimination half-life
note that plasma clearance CLp include renal (CLr) and metabolic (CLm) components
Renal Clearance
CLr = (U � Cur) / Cp ; where U is urine flow (ml/min); Cur is urinary drug concentration and Cp is plasma drug concentration.

Steady-State Drug Plasma Concentration (Css)
The calculation required to determine being steady-state drug plasma concentration illustrates the sensitivity of the plasma concentration to number of factors, in this case for a drug taken orally.
First look at the overall form of the equation:
equation 1: Css= 1/(ke*Vd) * (F*D)/T

The drug elimination rate constant,ke is related to the drug half-life ( t1/2 = 0.693/ke) and thus can be calculated from knowledge of the drug half-life.

The plasma steady-state drug levels also dependent on the dose, D, as well as a fraction of the drug that's actually absorbed following ingestion (F).

"T" is the dosing interval, so the once-a-day dosing would be 1 day or to keep the units consistent, 24 hours.

The steady-state level will also be dependent on the apparent volume of distribution (Vd)

Now let's take an example using the drug phenytoin (Dilantin) which is used to manage epilepsy.

The once-a-day dose is 200 mg.

The drug half-life is 15 hours

For the once-a-day dose, the dosing interval (T) is 24 hours [to keep the units the same as the drug half-life will use "hours"]

Let's say that about 60% of the ingested does is in fact absorbed, giving britain value of 0.6 for "F" in equation 1 above.

The volume of distribution for phenytoin (Dilantin) is 40,000 mls (40 liters)

ke = 0.693/15 hours = 0.0462/hr

Let's now compute the results:

equation 1: Css= 1/(ke*Vd) * (F*D)/T or Css= 1/(0.0462/hour*40000 ml) * 0.6 (200 mg)/24 hours or Css = 0.0027 mg/ml or 2.7 ug/ml

Time to Steady-State
Let's consider the above problem from a little different point of view, that is, How long would it take to reach 50% of the Css (no bolus).

Consider the dose is 300 mg/24h (dosing interval is 24 h or T; dose is 300 mg) but for convenience we'll represent it as 12.5 mg/hr, such that T is now 1 hr. The equation is:

f = 1 - e -keTN or 0.5 = 1 - e -keTN where ke is the elimination half-time of 0.0462/hr, T = 1 and N is the number of doses needed to reach 50% of Css.

Rearranging, 0.5 = e -0.0462/hr * 1 hr * N --(note time (hour) units cancel) so taking antilogs,

-0.693 = -0.0462 * N or N = -0.693/-0.0462 = 15

15 doses at an interval of 1 hour/dose gives the time to 50% of Css equal to 15 hours--a predictable time since drugs reach 50% of their steady-state value in 1 half-life

Constant Infusion Dosing
Next, let's consider the case by which drugs are administered by constant infusion.
The infusion rate is Q or in this example, 150 ug/min and for simplicity, the drug is again phenytoin with a ke of 0.0462/hr; t1/2 of 15 hrs and a Vd of 40000 mls
Css = Q/(ke*Vd ) or 150 ug/min / (0.0462/60min * 40000 ml) = 4.87 ug/ml;
[note that we have been careful to use the same units for ke and Q, i.e. 0.0462/hr = 0.0462/60 min]

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

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

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.

Renal Clearance

Factors affecting renal clearance:

renal disease

rates of filtration depend on:

volume filtered in the glomerulus

unbound drug concentration in plasma (plasma protein-bound drug is not filtered)

drug secretion rates:

extent of drug-plasma protein binding

carrier saturation

drug transfer rates across tubular membranes

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

generally inactive

exception to the rule: morphine glucuronide metabolite-- more potent analgesic then parent compound

rapidly excreted in the urine

High molecular weight conjugates:

excreted in the bile

conjugate bond may be cleaved by intestinal flora

parent drug released back to the systemic circulation

this process, "enterohepatic recirculation":

delayed parent drug elimination

prolongation of drug effect

Principal Organs for Biotransformation

Principal Organ: Liver

Other metabolizing organs:

gastrointestinal tract

lungs

skin

kidney

Sequence I

Oral administration (isoproterenol (Isuprel), meperidine (Demerol), pentazocine (Talwain), morphineisoproterenol)

Absorbed intact (small intestine)

Transported first to the liver (portal system) and

Extensive metabolism -- first-pass effect

Sequence II

oral administration: (clonazepam (Klonopin), chlorpromazine (Thorazine))

absorbed intact (small intestine)

extensive intestinal metabolism -- contributing to overall first-pass effect

Issues in bioavailability: reduced bioavailability

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

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

Microsomes have been used to study mixed function oxidases

Drug metabolizing enzymes:

located in lipophilic, hepatic endoplasmic reticulum membranes

smooth endoplasmic reticulum: contains 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

Oxidation-Reduction Process:

Two important microsomal enzymes:

flavoprotein--NADPH cytochrome P450 reductase

Cytochrome P450: -- terminal oxidase

multiple forms

named cytochrome P450 because:

the reduced (ferrous) form, binds carbon monoxide: -- the resulting complex exhibits of absorption maximum at 450 nm.

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:

conjugation

hydrolysis

oxidation

reduction

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

Non-microsomal enzymes catalyze all conjugation reactions except glucuronidation

Conjugation reactions: Usually "detoxification reaction

Conjugates:

more polar

easily excreted

typically inactive

Conjugation:

Involves "high-energy" intermediates and specific transfer enzymes (microsomal or cytosolic transferases)

Conjugation with glucuronic acid requires cytochrome P450 enzymes.

glucuronic acid: available from glucose

glucuronic acid conjugated to lipid-soluble drug results in lipophilic glucuronic acid derivative:

pharmacologically inactive

more water-soluble; more easily excreted in urine & bile

Transferases:

catalyzes coupling of an endogenous substance with a drug

uridine-5'-diphosphate (UDP) derivative of glucuronic acid with a drug

catalyzes inactivated drug within endogenous substrate

for example: S-CoA derivative of benzoic acid within endogenous substrate.

Toxicity:

Certain conjugation reactions: form toxic reactive species (hepatotoxicity)

Example:

acyl glucuronidation nonsteroidal antiinflammatory drugs

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: now more important

with depletion of hepatic glutathione, hepatotoxic, reactive, electrophilic metabolites are formed

Antidotes: N-acetylcysteine, cysteamine

N-acetylcysteine: protects patients from fulminant hepatotoxicity and death following acetaminophen overdose

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.

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 b-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
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