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Lecture 4 - Factors Affecting Drug Action
Lecture 4 - Factors Affecting Drug Action
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Acetylation of
morphine converts
it into heroin
which is stronger
analgesic and
readily passes
through the blood-
brain barrier.
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Dose (cont.)
• There are also daily dose, course dose, loading
dose, maintenance dose.
• ED50 ("median effective dose" ) - the dose that
produces an optimal therapeutic effect in 50% of
the population that takes it or in 50% of animals
tested.
• LD50 (“median lethal dose”) - this is the amount
of drug that causes death in 50% of treated
animals.
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• 3. Fetogenic stage
Delivery
Pharmacokinetics in pregnancy
• Absorption
• Gastric emptying and small intestinal motility are
reduced.
• Distribution
• During pregnancy, the blood volume increases by
one-third, with expansion in plasma volume (from
2.5 to 4L at term) being disproportionate to
expansion in red cell mass, so that haematocrit
falls. There is also an increase in body water
due to a larger extravascular volume. For water-
soluble drugs (which usually have a relatively
small volume of distribution), this increases the
apparent volume of distribution.
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• Metabolism
• Metabolism of drugs by the pregnant liver is
increased, largely due to enzyme induction,
perhaps by raised hormone levels. This may lead
to an increased rate of elimination of some
drugs, e.g. theophylline.
• Renal excretion
• Excretion of drugs via the kidney increases
because renal plasma flow almost doubles and
the glomerular filtration rate increases. This has
been documented for cefalexin, gentamicin, etc.
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Breast-feeding
• Breast-feeding can lead to toxicity in the infant if the
drug enters the milk in pharmacological quantities.
• The milk concentration of some drugs (e.g. iodides)
may exceed the maternal plasma concentration, but
the total dose delivered to the baby is usually very
small.
• However, drugs in breast milk may cause
hypersensitivity reactions even in very low doses.
• Milk is weakly acidic, so drugs that are weak bases
are concentrated in breast milk by trapping of the
charged form of the drug (tetracyclines, opioids).
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DRUGS AND
AGE
OF PATIENTS
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DRUGS IN CHILDREN
• Absorption
• Gastro-intestinal absorption is slower in infancy, but
absorption from intramuscular injection is faster. Infant
skin is thin and percutaneous absorption can cause
systemic toxicity if topical preparations (e.g. of potent
corticosteroids) are applied too extensively.
• Distribution
• Body fat content is relatively low in children, whereas water
content is greater, leading to a lower volume of distribution
of fat-soluble drugs (e.g. diazepam) in infants. Plasma
protein binding of drugs is reduced in neonates due to a
lower plasma albumin concentration and altered binding
properties. The risk of kernicterus caused by displacement
of bilirubin from albumin by sulphonamides is well
recognized. The blood–brain barrier is more permeable in
neonates and young children, leading to an increased risk of
CNS adverse effects.
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• Pharmacodynamics changes
DRUGS IN ELDERLY
• Absorption
• Absorption of carbohydrates and of several
nutrients, including iron, calcium and thiamine, is
reduced in elderly people. Lipid-soluble drugs are
absorbed by simple diffusion down the
concentration gradient, and this is not impaired by
age.
• Distribution
• Ageing is associated with loss of lean body mass, and
with an increased ratio of fat to muscle and body
water. This enlarges the volume of distribution of
fat-soluble drugs, such as diazepam and lidocaine,
whereas the distribution of polar drugs such as
digoxin is reduced compared to younger adults.
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• Renal excretion
• Declining renal function is the most important
cause of drug accumulation.
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Pathological Factors
• Diseases cause individual variation in drug’s response.
Renal and liver insufficiency are the main modulators of
drug’s effects.
• Renal failure decreases drugs elimination. Drugs (and
their metabolites) which are excreted predominantly by
the kidney accumulate in renal failure, e.g. digoxin,
aminoglycosides, penicillins.
• Liver failure decreases drugs metabolism. This causes
altered pharmacokinetics:
• a) increased bioavailability due to reduced first-pass
metabolism;
• b) decreased first-pass activation of pro-drugs;
• c) decreased protein binding due to decreased protein
synthesis in the liver;
• d) decreased hepatic elimination.
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Genetic Factors
• Pharmacogenetics is the study of the relationship between
genetic factors and drug response.
• Examples:
• Acetylation is an important route of metabolism for many
drugs that possess an amine group. Most individuals are
either rapid or slow acetylators but the proportion of each
varies greatly between races.
• Some 90% of Japanese are rapid acetylators whereas in
Western populations the proportion is 50% or less. In slow
acetylator phenotype antimycobacterial drug isoniazid may
cause peripheral neuropathy, in rapid acetylator phenotype –
hepatitis.
• In patients with pseudocholinesterase deficiency depolarizing
neuro-muscular blocking agent succinylcholine leads to
prolonged apnea because the duration of action of this drug is
determined by its metabolism by pseudocholinesterase.
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