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Drug Elimination

Termination of Drug Action


Termination Of Drug Action

• Metabolism (Biotransformation):

Anabolic and Catabolic Reactions

• Excretion

• Redistribution
Drug Biotransformation

• Usually inactivates the drug.


• Can generate active metabolite (PRODRUG)
• Can generate toxic metabolite (isoniazid).
• Often generates polar, highly ionized metabolites.
• Conversion rate influences pharmacological activity.
• Some drugs are eliminated unchanged (digoxin).
Liver Metabolism
Phase I and Phase II
Metabolic Reactions

These are general categories of


reactions and occur in no particular
order.
Biotransformation of Major
Functional Groups
• (-OH) oxidation, methylation, glucuronide
conjugation, sulfate conjugation.

• (-COOH) oxidation, glucuronide conjugation,


glycine conjugation.

• (-NH2) deamination (and aldehyde formation),


glucuronide conjugation, methylation.
• Phase I “functionalization” reactions
(oxidation, reduction, hydrolysis) introduce or
expose a functional group on the parent
compound  result in loss of pharmacological
activity

• Phase II conjugation reactions lead to


covalent linkage of a functional group on the
parent drug or phase I metabolite with
endogenously derived glucuronic acid, sulfate,
methyl, glutathione, amino acids, acetate, etc
 result in highly polar conjugates
Phase I and Phase II Metabolic
Reactions

Absorption Metabolism Excretion

Phase I Phase II

Metabolite with
modified activity
Conjugate
Drug
Inactive metabolite Conjugate

Lipophilic Hydrophilic
Phase I Reactions

Dominated by cytochrome P450


enzymes
Cytochrome P450 Mixed Function
Oxidases (MFOs)
• Smooth endoplasmic reticulum
(microsomes)
• Requires molecular oxygen, NADPH,
cytochrome P450 (hemoprotein),
cytochrome P450 reductase (flavoprotein).
• Hydroxylations
• N-, O-, S-dealkylations
• Deamination, desulfuration, dehalogenation
• Susceptible to induction
Families of Cytochrome P450
Enzymes (“CYPs”) are Based
on Amino Acid Sequence
Similarities
Estimated Contribution of Phase I and
Phase II Enzymes to Drug Metabolism
Mechanism of Drug
Oxidation in the
Cytochrome P450 Cycle
Reaction
Parent drug
product binds ferric
state of
enzyme.
Note the
Fe2+ / Fe3+
valence Electrons
transitions. from
NADPH via
reductase

Molecular
oxygen
NADPH

Reductase

Cytochrome P450
Some Drugs Stimulate and Some
Inhibit the drug metabolizing enzymes

• Stimulation is via induction, which means an


increase in enzyme synthesis (oxidation,
reduction, glucoronide formation).
• Phenobarbital and polycyslic aromatic
hydrocarbon (cigarette smoke) inducers
• Inhibition is via competition, prodrug
inhibition or a decrease in the activity of
existing enzyme.
• Cimetidine  inhibitor
Enzyme Induction

100 No induction
Zoxazolamine (mg/ml)
Plasma Level

Phenobarbital (Classic barbiturate


induction effect)
10

Benzopyrene (Generated from


induction grilling meat)
1
Time (hrs)
Other Types Of Phase I Metabolic
Reactions

• Nonmicrosomal oxidations: alcohol


dehydrogenase, xanthine oxidase.
• Microsomal / nonmicrosomal reductions
• Hydrolysis (amidases, esterases)
Phase II Conjugation Reactions

• Glucuronidation (UDP glucuronosyltransferases)


• Glutathione (glutathione S-transferases)
• Amino acid (glycine, glutamine)
• Sulfate (sulfotransferases)
• Acetylation (N-acetyltransferases)
• Methylation (methyltransferases)
Nonpolar Polar

Very Polar
ACETAMINOPHEN
METABOLISM

1. Oxidation
2. Reactive Intermediate
3. Glutathione Conjugation
4. Hepatic Cell Death
Acetominophen Metabolism

Ac-glucuronide Ac Ac-sulfate
Cytochrome P-450

Reactive electrophilic
compound (Ac*)

Good GSH Bad


Ac*-protein
GS-Ac*

Hepatic cell death


Ac-mercapturate
Elimination Of Drugs

• Metabolism: Liver

• Excretion: Kidney
Liver (bile)
Lungs
Kidney Excretion
Renal Excretion of Drugs

• Filtration (Glomerulus)
• Secretion - Active Transport (Tubule)
– Transporter for Organic Acids
– Transporter for Organic Bases
• Reabsorption - Passive Transport
(Tubule)
Diagram of Nephron

Filtration :

Active secretion

Passive reabsorption
Glomerular Filtration

• Only unbound drug is filtered.


• Plasma Protein Binding of drug prevents
filtration: Thyroxine is 99% bound.
• Molecular Size:
– Albumin (70,000) is not filtered.
– Inulin (5,500) is freely filtered; can be
used to estimate GFR.
Tubular Secretion

Active Transport
• Organic Acids (inhibited by probenecid)
• Organic Bases
• No effect of protein binding on this process
• The clearance of drug eliminated by tubular
secretion is a function of renal blood flow
Tubular Reabsorption

• Passive Transport:
– pH, concentration, size, lipid solubility,
ionization.
– acid urine favors reabsorption of weak
acid, basic urine favors reabsorption of
weak base.
– pH urine is affected by diet,drugs, diurnal,
condition of patients (respiratory and
metabolic acidosis)
Other aspects….
amphetamine (weak base, pKa 10)
– its actions can be prolonged by
ingesting bicarbonate to alkalinize the
urine...
– this will increase the fraction of
amphetamine in non-ionized form,
which is readily reabsorbed across the
luminal surface of the kidney
nephron...
– in overdose, you may acidify the urine
to increase kidney clearance of
amphetamine.
• Others
– Bile
– Lung
– Feces
– Saliva
– Sweat
– Milk
Enterohepatic Cycle

Liver 3
2

Portal vein Common bile duct

1 4

Small intestine
Pulmonary Excretion

Factors:

– Plasma solubility of drug


– Cardiac output
– Respiration
Factors affecting drug metabolism

• reversible binding to plasma proteins


• localization of drugs (e.g., fat)
• hepatic blood flow
• Age
• genetics-related deficiency or alteration in drug
metabolizing enzyme (e.g., acetylator,
pseudocholinesterase deficiency and succinylcholine)
• pathology
• inhibition / inductionof drug metabolizing enzyme (e.g.,
by erythromycin, phenobarbital)
• Diet (carb-protein, vegetables, charcoal-broiled beef)
• Enviromental chemicals (alcohol, cigarette smoking,
other chemicals)
Volume of distribution (Vd) relates
the amount of drug in the body to the
plasma concentration of drug (C).

total drug in body (mg)


Vd = ------------------------------
plasma conc. (mg/ml)
• Clearance (CL): the measurement of
blood cleared of the drug by
elimination per unit time (as in units
of mL/sec). It and the volume of
distribution (Vd) create the
dependent variable T1/2. They are
related by the following formula:

T1/2 = 0.693Vd/CL

T1/2 = time required to reduce the concentration


by 50%
Pharmacokinetics variability-age-
pediatric

• ABSORPTION
• Gastrointestinal pH changes (increase)
• Gastric emptying (decrease)
• Gastric enzymes
• Bile acids & biliary function
• Gastrointestinal flora (low)
• Formula/food interaction
Pharmacokinetics variability-age-
pediatric

• DISTRIBUTION
• Body Composition
–  total body water & extracellular fluid
–  adipose tissue & skeletal muscle
• Protein Binding
– albumin, bilirubin, 1-acid glycoprotein
• Tissue Binding
– compositional changes
Age and Hepatic Metabolic
Activity

Hepatic drug
metabolic activity

Birth Puberty Adulthood Old age

Age
Pharmacokinetics variability-age-
pediatric

• Glomerular filtration matures in relation to


age, adult values reached by 3 yrs of age
• Neonate = decreased renal blood flow,
glomerular filtration, & tubular function
yields prolonged elimination of medications
• Aminoglycosides, cephalosporins,
penicillins = longer dosing interval
Pharmacokinetics variability-age-
pediatric
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY
Pharmacokinetics variability-age-
ELDERLY

START LOW…..GO SLOW


Pharmacokinetics variability-PREGNANCY

• Gastric emptying and small intestine motility are reduced


in pregnancy due to elevation of progesterone. This may
increase Tmax and reduce Cmax, although effccts on total
bioavailability may be relatively minor.
• An increase in gastric pH, due to a reduction in H.
secretion and an increase in mucus production,may
increase the ionization of weak acids, tending to reduce
their absorption more than that of weak bases. Such effects
are unlikely to be important during repeated dosing. They
may, however, reduce the efficacy of a single dose of an
oral drug such as an analgesic or anti-emetic for which
Tmax andCmax are important.
Pharmacokinetics variability-PREGNANCY

• If nausea is reduced in the evening its effects on absorption can


be minimized by deferring dosing until the evening (in the case
of once- daily dosing).
• Absorption of drugs administered by inhalation may be
enhanced due to increased cardiac output and tidal volume
increasing alveolar uptake. For example, dose requirements for
volatile anaesthetic agents, such as halothane, are reduced in
pregnancy.
• Drug absorption from intramuscular delivery is usually
enhanced by increased tissue perfusion secondary to
vasodilation.
Pharmacokinetics variability-PREGNANCY

• During pregnancy there is an expansion of intravascular


(plasma volume) and extra- vascular (breasts, uterus,
peripheral edema) water content. Thus, total body water
increases by up to 8 litres, creating a larger space within
which hydrophilic drugs may distribute, i.e. increasing Vd.
• Body fat increases by approximately 4 kg, creating a larger
volume of distribution for lipophilic drugs ± but this has
little practical importance.
Pharmacokinetics variability-PREGNANCY

• Total plasma concentration of albumin-bound drugs


decreases as a result of haemodilution and the subsequent
fall in plasma albumin concentration. In addition, steroid
and placental hormones displace drugs from their protein-
binding sites.
• Some enzymes of the hepatic cytochrome P-450 system
are induced by oestrogen/ progesterone, resulting in a
higher rate of metabolism (and hence elimination) of
drugs, for example, phenytoin, whereas other isoenzymes
are competitively inhibited by progesterone and oestradiol,
leading to impaired elimination, for example, theophylline.
Pharmacokinetics variability-PREGNANCY

• Renal blood flow is increased by 60±80% during


pregnancy, and glomerular filtration rate rises by 50%,
leading to enhanced elimination of drugs that are normally
excreted unchanged, for example, penicillin and digoxin.
This leads to slightly lower steady-state drug
concentrations, although this rarely necessitates increasing
the dosage.
Feto-placental unit
• Drug transfer occurs mainly via difusion across the placenta,
thus favouring the movement of lipophilic agents, and the rate-
limiting step is placental blood flow.
• Protein-bound drugs, and drugs of large molecular weight, for
example heparin and insulin, do not cross the placenta. Both the
immature fetal liver and the placenta can metabolize drugs.
Immature phase I and phase II metabolism can occur in the fetus
8 weeks post-conception. However, metabolic enzyme activity is
low, and this coupled with the fact that 50% of the fetal
circulation from the umbilical vein bypasses the fetal liver to the
cardiac and cerebral circulations contributes to the problem of
fetal drug accumulation.
Feto-placental unit
• Elimination from the fetus is by diffusion back to the maternal
compartment. Because most drug metabolites are polar, this
favours accumulation of metabolites within the fetus, although
as the fetal kidney develops more drug metabolites are excreted
into the amniotic fluid.
• Another process leading to accumulation of drugs within the
fetus is the phenomenon of `ion trapping'. The basis for this is
the (slightly) more acidic nature of fetal plasma pH compared to
maternal plasma. Weak bases, which are mainly non-ionized
(lipophilic), diffuse across the placental barrier and become
ionized in the more acidic fetal blood, leading to a net
movement from the maternal to fetal systems.
Pharmacokinetics variability-PREGNANCY
Pharmacokinetics variability-age-
GENETIC

• Polymorphism acetylation
• Polymorphism oxidation
Pharmacokinetics variability-disease

Renal disease
• A linear relationship between the renal
clearance of a drug and creatinine clearance
• A linear relationship between half life (t1/2)
of a drug and creatinine clearance
t1/2= 0.693/K
K= (A/V) creatinine clearance + (non renal
clearance/V)
 reducing dosage , lengthening the dosing
interval
• Hemodialysis  drug removal during
hemodialysis
• Some clinically important active or toxic
drug metabolite accumulate in renal failure
• The regeration of parent drug from
glucoronide conjugates that when its
elimination is impared
• Impaired drug binding (result of decreased
serum albumin and an accumulation of
endogenous inhibitors)
Liver disease
• The effects on drug metabolizing
enzymes, drug binding, hepatic blood
flow
Half life 27 hr 106
Clearance 27 ml/min 14
%unbound 2.2 4.7
in plasma
Cardivascular disease

• Hepatic perfusion decreased  the


clearance reduced
• Alter the concentration of drug
binding protein (AAG)
• Affects drug metabolism in the liver
Effect of Disease on Drug
Disposition
• Absorption
– PO/NG administered drugs may have altered absorption
due to:
• Alterations in pH
• Edema of GI mucosa
• Delayed or enhanced gastric emptying
• Alterations in blood flow
• Presence of an ileus
• Coadministration with formulas (I.e. Phenytoin)
Effect of Disease on Drug
Disposition
• Drug distribution may be affected:
– Altered organ perfusion due to hemodynamic
changes
• May effect delivery to site of action, site of
metabolism and site of elimination
• Inflammation and changes in capillary permeability
may enhance delivery of drug to a site
– Hypoxemia affecting organ function
• Altered hepatic function and drug metabolism
Effect of Disease on Drug
Disposition
– Alterations in protein synthesis
• If serum albumin and other protein levels are low,
there is altered Vd of free fraction of drugs that
typically are highly protein bound therefore a higher
free concentration of drug
– Substrate deficiencies
• Exhaustion of stores
• Metabolic stress
Pharmacokinetic Interactions:
• Gut Absorption: binding/chelation, gastric
emptying, gastrointestinal motility
(Anticholinergics, antacide/feroous
sulphate-tetracyclin etc)

• Plasma Protein Binding


Strongly bound drugs displace more weakly
bound drugs.
Drug Interactions Related to Protein
Binding

Moderately bound drugs (e.g., tolbutamide,


methotrexate, warfarin) are displaced by
strongly bound drugs (salicylates,
sulfonamides), which could lead to:
hypoglycemia, blood dyscrasias, and
hemorrhage, respectively, due to elevated
free concentrations of the displaced drugs.
Plasma protein
binding

Metabolic
enzyme
induction or
inhibition

GI absorption
Pharmacokinetic Interactions:
Liver metabolism:
Enhance via induction. *Phenobarbital, phenytoin,
 efficacy decrease, phenylbutazone.
adverse/toxicity
effect increase
*Cimetidine, carbidopa,
MAOI, disulfiram.
Inhibit directly.
 accumulation to
toxic concentration
*Penicillin, salicylates.
Renal tubular secretion:
Inhibit secretion of
weak acids (pH ….)
*Cimetidine.
Inhibit secretion of
weak bases (pH …)
• Drug excretion
modify pH urine (ammonium chlorida-
acidify, sodium bicarbonate – alkalize)
 alter GFR
 alter RBF
 inhibit transport in hepatobiliary
syst/ bile blood flow
Liver Clearance

• Extraction Ratio (ER): the extent to which a


drug is cleared from blood in one liver
passage.
• High ER (close to 1, e.g., propranolol,
meperidine). In this case, overall liver
extraction of the drug is dependent on liver
blood flow.
• Low ER (near 0.1, e.g., warfarin, diazepam,
phenytoin). In this case, changes in liver
blood flow are less critical.
Sum of all process
contributing to dis-
appearance of drug
from plasma

Drug in plasma at Drug concentration


concentration of 2 mg/ml in plasma is less after
each pass through
elimination/metabolism
process

Drug molecules disappearing from


plasma at rate of 400 mg/min

400 mg/min
CL = = 200 ml/min
2 mg/ml
Single-compartment model

ka Vd ke

Absorption Body Elimination

C = D/Vd or Vd = D/C
Single compartment model: no
absorption, first-order elimination
Multicompartment models
• combine kinetics of redistribution and
elimination
• provide best description of drugs with high
lipid solubility and drugs given
intravenously
Two-compartment model
PHARMACODYNAMICS