Factors modifying the effects

of drugs in individuals
Variability in response attributed to the biological
system
Levine’s pharmacology, Chapter 11
Kurt Kristiansen
07.10.2010

Factors modifying the response of

drugs in individuals
• The variable attributable to the biological
system (chapter 11):
– Body weight and size
– Age
– Gender
– Genetic polymorphism
– General conditions of health (diseases)
– Placebo effect

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 Body weight and size
• Apparent volume of distribution is directly
proportional to body weight
• The average dose =
– Quantity that will produce a particular effect in 50% of
a population between 18 and 65 years of age and
weighing about 70 kg.
• Dose required = Average dose/70 kg * Weight of
individual (kg)
• Adjustment of dosage for lean and obese
individuals (weight and height, total surface
area)
3

Body weight and size

• Average adult
– Water: Around 58% of body weight
• Abnormal obese individuals
– Water: Around 50% of body weight
• Abnormal lean individuals
– Water: Around 70% of body weight

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 Age
• Reduced elimination of drugs in newborn
babies (neonatals and premature) and
elderly people
– Slower biotransformation of drugs
– Slower renal excretion of drugs
• Dose reduction is therefore required

The effect of drugs in newborn

babies (neonatals)
• Drug biotransformation is slower in newborn babies (neonatals, infant up
to 4 weeks from birth)
– Some reactions do not take place
– Immature microsomal enzyme systems (mature during 1-8 weeks from birth)
• Oxydation
• Glucuronide conjugation
• Renal excretion of drugs is reduced
– Reduced rate of blood flow (-> slow filtration)
– Increased apparent distribution volume (-> slow filtration)
– Incomplete development of active transport systems (slow active secretion)
• Incomplete development of active transporter systems (brain,
gastrointestinal tract, kidneys)
– The blood-brain barrier is incomplete developed
• Increased permeability in the newborn
– Passive absorption from the gastrointestinal tract is facilitated
• Increased permeability of large molecules (proteins)

6
• Drugs given by slow-absorption routes
– Higher peak levels in infants
– Cumulative toxicity with repeated administration is greater than
by fast-absorption routes
– [chloramphenicol (i.v.): grey baby syndrome, slow hepatic
glucuronid conjugation in newborn babies] 7

• Infants less than 6 months old

– More sensitive to chemicals in their environment, e.g.
– Inorganic nitrite (increased fetal hemoglobin->methemoglobin
conversion and toxicity in infants)
8
– Less acid lumen in upper GI tract: Conversion of nitrate to nitrite in
infants
 The effect of drugs in elderly
people
• A linear decline in renal function
– 50% at age 90 years
• Hepatic microsomal enzyme activity declines slowly with age
– slower biotransformation
– increased distribution volume of lipid soluble drugs
• Incidence of disease increased
– Liver disease
• Reduction in elimination of fatty soluble drugs
– Kidney disease
• Reduction in elimination of water soluble drugs (and water soluble
metabolites)
– Hearth disease
• Reduction in elimination of drugs
• More frequent use of therapeutic drugs
– Increased possibility for drug interactions

Gender
• Women may require a smaller doses of drugs
– Body weight
– An increased portion of adipose tissue and a
decreased portion of water of total body weight
• The use of drugs in pregnant women
– Almost any drug in maternal blood may cross the
placental barrier
• Slow elimination of drugs from development embryo/fetus
• Adverse side effects in development embryo/fetus
(teratogenic agents)
– E.g. ACE inhibitors, antiepileptic drugs, thalidomide, lithium,
alcohol, cocaine

10
 Genetic variation in drug
response
• Pharmacogenetics
– The study of the genetic basis for variation in
drug response (caused by single genes)

11

Inheritance of genes: Most drug

responses are multifactoral and show
normal distribution
• Normal distribution with the population
– Normal bell shaped distribution curve
– Most drug responses are multifactoral (many
genes and environment factors contribute to
them)

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Terminology: Genetic traits
• Most traits are multifactoral and caused by many genes
• Inherited trait determined by a single gene
– Sex-linked
– Autosomal trait
• Alleles
– Any alternative form of a gene that could occupy a particular
chromosomal locus
• Homozygous
– An individual possessing a pair of identical alleles
• Heterozygous
– An individual possessing a pair of different alleles

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Inheritance of genes: Idiosyncratic drug

responses are caused by genetic
variations in single genes
• Abnormal, nonallergic drug responses
– extreme sensitivity to low doses or
insensitivity to high doses
– Affects only a (small) proportion of
individuals
– Are genetic determined by a single gene
– Shows discontinuous distribution (e.g.
bimodal or trimodal) within the population
• Genetic abnormal responders (particular
inherited defect)
• Normal responders

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 Genetic variants
• Genetic polymorphism
– Variation in the DNA sequence of a gene
• SNPs, single nucleotide polymorphisms (SNPs) that lead
to missense mutations (amino acid substitutions) in a
protein may affect
– protein folding and expression (e.g. no insertion in plasma
membrane)
– drug binding to receptor, biotransformation enzyme, ion channel
or transporter
– signaling properties of receptor, enzyme activity of
biotransformation enzyme
• Insertions/deletions (indels)
• Functional critical residues: Conserved amino acid
residues
– changes in conserved amino acids are most likely to affect the
property of the protein 15

(Genetic polymorphisms in
enzymes involved in drug
biotransformation)
• Phase I enzymes:
– CYP2D6
– CYP2C9
– CYP2C19
• Phase II enzymes:
– TPMT
– UDPA1A
– NAT2

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 CYP2D6 polymorphism
(multimodal distribution)
• Genetic polymorphism in CYP2D6
– Different individuals have different CYP2D6 activity
(monogenetic trait)
• Poor metabolizers (PM)
– Individuals that have low CYP2D6 activity
– Homozygout for a mutant in CYP2D6 with low enzyme
activity
• Extensive metabolizers (EM)
– Homozygout or heterozygout (hetEM) for the wild type
CYP2D6
– Extensive metabolism of CYP2D6 substrates
• Ultra rapid extensive metabolizers (URM)
– Multiple copies of the CYP2D6 gene in the genome
– More rapid metabolism of CYP2D6 substrates

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Discontinuous distribution (e.g.

bimodal or trimodal) within the
population

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 CYP2D6
• Different ethnic populations have differences in the
amound of PM and UM genotypes:
– PM: 7 % of Caucasians
– URM: 1-2 % of Caucasians, 29% in North-East-African Etiopian
• Bioactivation (Prodrug -> Active drug):
– Codeine (opioid analgesic)-> Morphine (codeine is a prodrug)
– PM: No analgesic effect (No biotransformation of codeine to
morphine)
• Drug inactivation (Active drug -> Inactive metabolite):
– Tricyclic antidepressants, antipsycotic drugs, beta-blockers
– PM: Toxic effects (tricyclic antidepressants), risk of
extrapyramidal side effects (antipsychotics)
– URM: Nonresponders (individuals without no clinical effect of
antidepressants)

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Warfarin
• Warfarin
– Anticoagulant factor (vitamine K dependent) used to treat and prevent
thromboembolic disorders
– low therapeutic index
• Dose adjustment
– Dose adjusted according to the patient’s coagulation rate
• Biotransformed to inactive metabolites by CYP2C9
– PM
• Homozygout and heterozygout for the CYP alleles with reduced activity
• Increased bleeding risk (due to accumulation of drug)
• Allele frequency of PM alleles: 11% and 7%
– EM
• Homozygout for the wild type CYP allele
• Genetic abnormal coagulation factors
– Decreased affinity of warfarin
• Marked decrease in response to drug

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 Proton pump inhibitors like
omeprazol
• Biotransformed by CYP2C19
• PM: better therapeutic responses in
treatment of peptic ulcer
– PM: 3-5 % in Caucasians (splice site mutants)

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N-acetyltransferase (NAT2)
• Isoniazid
– Drug for treatment of tuberculosis
• NAT2 (B: bimodal distribution of plasma concentration)
– Phase II enzyme in liver
– Slow acetylators (“slow inactivators”)
• These have no NAT2 enzyme
• Serious toxic side effects (neurotoxicity) due to accumulation of drug
• 60 % Europeans; Eskimos: 5%
– Rapid acetylators (“rapid inactivators”)
• These have an efficient NAT2 enzyme

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TPMT (Tiopurine methyltransferase)
• Phase II enzyme
• Important for biotransformation of 6-MP (6-
mercaptopurin, an antileukemic drug) and
azathioprine (treatment of immune-related
diseases and autoimmune liver disease)
– PM
• Suppress the production of white blood cells
• 1/300
– EM
• Normal biotransformation
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Genetic factors may also influence

absorption of some drugs and vitamins
• Genetic abnormalities: inherited lack of
intrinsic factor (Juvenile percicious
anemia)
– Secreted by cells in the stomach
– Important for complex formation with vitamin
B12 in stomach
– Absorption of B12 in ileum (important for red
blood cells)

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Genetic polymorphisms in transporters
may influence distribution of drugs
• ABCB1 (also known as MDR1, P-glycoprotein)
– Efflux pump in the brain and in tumor cells
– Important role in transport of toxic xenobiotics out of
cells
– Drug resistant epilepsy (Anti-epileptic agents)
• ABCB1 in tumor cells
– Amplification of the gene
– Many chemotherapeutic agents are substrates

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Genetic polymorphisms in
receptors
β1 adrenergic receptor in hearth
– Target for some antihypertensive drugs (beta-
blockers)
– Constitutive active mutation (individuals who
are homozygous, mutant in both alleles)
• Increased risk of hypertension
• Increased risk of hearth failure
• Increased sensitivity to beta blockers

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 Other examples of idiosyncratic
responses to drugs
• Malign hyperthermia (mutations in ryanodine
receptor in muscles)
– Antipsychotic drugs, inhalation anesthetic drugs,
suxamethonium
• Prolonged action of certain muscle relaxing
drugs (mutations in plasma cholinesterase)
– Suxamethonium
• Mutations in glucose-6-phospate
dehydrogenase
– Susceptibility to hemolysis in response to exposure to
some drugs (like sulfonamides)
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Interspecies variation
• Advantage
– Development of drugs that eliminate microorganisms
• Selective toxicity important (target specific features of the pathogen
without harming human cells)
• Disadvantage
– Other species have
• Different biotransformation pathways (absent of specific
enzyme systems in some species)
• Different rate and extend of biotransformation by specific
enzymes
• Different distribution volume
– Consequence:
• Animal experiments (preclinical studies) do not give information of
efficacy and toxicity of drug in the human
– E.g. formation of toxic metabolites in human (impossible to predict from
experiments using other species)

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 Interspecies variation
• Development of drugs to eliminate undesirable species
(microorganisms)
– Depends on its ability of drugs to cause selective toxicity
• Selective damage the microorganism without harming host cells
• Target features that are unique for the pathogen
• Target pathways that are essential for the pathogen and
nonessential for human cells
• Sulfanilamide
– Competitive inhibitor of an enzyme involved in folic acid
synthesis in bacteria
• Penicillin
– Blocks the formation of the bacterial cell wall by inhibiting the
enzyme involved in cross-linking of subunits within its structure
• Mebendazole
– Inhibits the uptake of glucose in parasite whipworms
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General conditions of health (and

diseases that modify drug responses)
• Drug response may depend on physiological variables
– Temperature
– Volume of distribution (states of dehydration or overhydration/edema)
– pH of compartments
• Diseases in liver
– Slower elimination of drugs, in particular fatty soluble drugs
– Accumulation of toxic metabolites
• Diseases in kidneys
– Slower elimination of drugs, in particular water soluble drugs
– Accumulation of toxic metabolites
• Individuals with hyperthyroidea
– May tolerate larger doses of morphine
– May respond to lower doses of adrenalin
• Migraine
– Slower emptying of stomach
• Diseases
– Multiple drug use and possibility of drug interactions

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 The placebo effect
• The placebo effect
– is the psychic and emotional factors that are
temporally correlated with the administration of a drug
– These effects cannot be attributed to the
pharmacological effects of the drug
– Double blind studies
• Typically, patients do not know whether they are given inert
or active drug
• Administration of a placebo
– produces a variety of positive responses in 30-35% of
the population
– No specific group of individuals that could be
classified as placebo responders
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Summary: Factors that modify the

effects of drugs in individuals
• Age, body weight and gender
• Genetic differences in
– Drug biotransformation enzymes
– Drug targets
• Receptors
• Transporters
• Enzymes
– Transporters
• May change the distribution of drugs
• Diseases and general conditions of health
• Placebo effects
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