Bez nadpisu

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FACTORS INVOLVED IN
DRUG REACTIONS
( prof. MUDr. Jirina Martínková, PhD., 2006 )
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FACTORS INVOLVED IN DRUG REACTIONS - overview
Age Gender Repeated
(intermittent, continuous) dosing
Co-administration Disease
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• Age
• Gender
• Repeated (intermittent, continuous)
  
• dosing
• Co-administration
• Disease

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FACTORS INVOLVED IN DRUG REACTIONS - AGE

• DRUGS IN INFANTS AND CHILDREN
• Children are not miniature adults in terms of
  drugs handling
• differences in pharmacokinetics
• At birth extracellular volume is rather large
  while all renal mechanisms (filtration, secretion
  and reabsorption) are reduced. Hepatic microsomal
  enzymes system is relatively immature (mainly in
  the preterm infants)
• plasma half-life of gentamicin eliminated by
  the kidney
• 
  t 1/2 hours
• premature infants lt 48 h old
  18
• 5-22days
  old 6
• normal infants 1-4 weeks old 3
• adults
  2
• chloramphenicol can produce gray baby
  syndrome in neonates due to high plasma levels
  secondary to inefficient glucuronidation

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POSTNATAL DEVELOPMENT OF SPECIFIC HEPATIC AND
RENAL FUNCTION (from Gladtke 1979).
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FACTORS INVOLVED IN DRUG REACTIONS - AGE

• differences in pharmacodynamics
• A higher dose of antihistamines can cause
  excitation of the CNS (convulsion) in children
  while sedation in adults
• Breast-feeding
• can lead to toxicity in the child if the drug
  enters the milk in pharmacological quantities.
  Milk is weakly acidic, so drugs that are weak
  bases are concentrated in breast milk.
• Some drugs to be avoided amiodarone, aspirin,
  benzodiazepines.
• The infant should be monitored if betalytics
  (bradycardia), corticoids (
  infantsadrenal functions) or lithium
  (intoxication)
• 
  are prescribed to mother.Others
• Metronidazole gives milk an unpleasant
  taste.
• Bromocriptine and diuretics suppress
  lactation.

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FACTORS INVOLVED IN DRUG REACTIONS - AGE
DRUGS IN ELDERLY differences in
pharmacokinetics in healthy individuals aged over
70, glomerular filtration rate is lt60-70 ml/min.
Tubular function also declines with age. Drugs
that are mainly excreted via the kidney are
likely to a c c u m u l a t e in patients in
their seventies and eighties
if given in doses suitable for young
adults. Examples of drugs requiring dose
adjustment in the elderly aminoglycosides,
atenolol, diazepam, digoxin, oral hypoglycemic
agents, warfarin, NSAIDs
differences in pharmacodynamics clotting factors
synthesis by the liver is reduced and old people
often require lower warfarin doses for effective
anticoagulation than young people.
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• Age
• Gender
• Repeated (continuous) dosing
• Co-administration
• Disease

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FACTORS INVOLVED IN DRUG REACTIONS .
GENDER-pregnancy

• DRUGS IN PREGNANCY
• the use is complicated by the potential for
  harmful effects on the growing fetus, and altered
  maternal physiology.
• What are main conditions?
• In the placenta maternal blood is separated from
  fetal blood flow
• by a cellular membrane. Drugs can cross it by
  active
• transport or mainly by passive diffusion down
  the concentration
• gradient.
• Placental function is also modified by changes
  in blood flow.
• There are multiple placental enzymes, primarily
  involved with
• endogenous steroid metabolism, which may also
  contribute to drug
• metabolism.

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FACTORS INVOLVED IN DRUG REACTIONS .
GENDER-pregnancy

• Factors that can influence the effects
• of drugs on the fetus
• the stage of gestation,
• the type of the placenta
• the age of mother
• properties of drugs

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FACTORS INVOLVED IN DRUG REACTIONS. GENDER
-pregnancy

• the stage of gestation
• fertilization and implantation
• organogenesis/embryonic stage
• fetogenic state
• delivery
• fertilization and implantation ( lt 17 days)
• animal studies suggest that
  interference with the fetus
• causes abortion, i.e. if pregnancy
  continues the fetus is
• unharmed

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FACTORS INVOLVED IN DRUG REACTIONS . GENDER -
pregnancy

• organogenesis/embryonic stage (17 -57 days)
• at this stage the fetus is
  differentiating to form major organs,
• this is the critical period for
  teratogenesis.
• Teratogens cause
• deviations or abnormalities in the development
  to
• embryo that are compatible with prenatal life
  and are
• observable postnatally.
• Drugs that interfere with organogenesis can
  cause gross
• structural defects
  
• confirmed, suggestive and
  potencial teratogens

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FACTORS INVOLVED IN DRUG REACTIONS . GENDER -
pregnancy
C o n f i r m e d teratogens (in h u m a
n s) Thalidomide (phocomelia),
cytostatics-antimetabolites, lithium
(cardiac defects), warfarin (chondrodysplasia
punctata), sex hormones (cardiac defects,
multiple abnormalities) S u g g e s t
i v e teratogens (evidence is inconclusive, the
impact of diseases?) antiepileptics (phenytoin,
carbamazepine- craniofacial defects), P
o t e n t i a l teratogens (in a n i m a l s)
chemotherapeutics (metronidazole),
sulphonamides- trimethoprim
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• FACTORS INVOLVED IN DRUG REACTIONS . GENDER -
  pregnancy
• fetogenic state at this stage the fetus
  undergoes further
• development and maturation. Even if organogenesis
  is almost
• complete, drugs can still have significant
  untoward effects on fetal
• growth and development
• ACEI (fetal and neonatal renal dysfunction),
  tetracycline antibiotics
• (inhibit growth of fetal bones and stain
  teeth), opioids and cocaine
• taken regularly (fetal drug dependence),
  warfarin (intracerebral
• bleeding), aminoglycosides (fetal VIIIth nerve
  damage)
• delivery
• some drugs can cause particular problems.
  Pethidine administered
• as an analgesic can cause fetal apnea, warfarin
  predisposes to
• cerebral haemorrhage during delivery.

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FACTORS INVOLVED IN DRUG REACTIONS . GENDER
-pregnancy
the age of mother the background incidence of
major malformations rises to almost 5 by the age
of 5 years the type of the placenta and dose of
the drug many drugs produce birth defects
when given experimentally in large doses to
pregnant animals. This does not necessarily
mean that they are teratogenic in human at
therapeutic doses great differences in the
structures of the placenta among species
the metabolism and kinetics of drugs at high
doses in other species is
different from that in humans.
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FACTORS INVOLVED IN DRUG REACTIONS . GENDER
-pregnancy

• Summary and recommendations
• Prescribing in pregnancy is a balance between the
  risk of unwanted effects on the fetus and the
  risk of leaving maternal disease untreated.
• The effects on the human fetus are not reliably
  predicted by animal experiments.
• However, untreated maternal disease may cause
  morbidity and /or mortality to mother and/or
  fetus.
• THEREFORE
• MINIMIZE PRESCRIBING
• use tried and tested drugs whenever possible
  to new agents
• use the SMALLEST EFFECTIVE DOSE
• consider pregnancy of all women of CHILDBEARING
  potential
• warn the patient about the risks of smoking,
  alcohol, over-the
• counter drugs -OTC- and DRUGS OF ABUSE

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• Age
• Gender
• Repeated (continuous) dosing
• Co-administration
• Disease

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FACTORS INVOLVED IN DRUG REACTIONS -
REPEATED DOSING
- A decrease in the response (tolerance) - An
increase in the response (accumulation) - Drug
dependence
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
can cause A DECREASE in the response
to a drug due to
tolerance or tachyphylaxis tolerance refers
to a state of diminished responsiveness as a
consequence of prior exposures acquired
tolerance (vs. innate tolerance independent of
prior exposure) The degree (extend to which the
dose-response curve is shifted to the right) can
be moderate (ethanol with a factor of about 2) or
high (in opiates the DRC may shift by a log unit
or more) cross-tolerance - tolerance to
one drug confers tolerance to another (opiates,
tetracyclines)


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QUANTAL DOSE-RESPONSE CURVES
LD50
TI -----
Therapeutic range TD50 - ED50
ED50
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
The m e c h a n i s m s of
tolerance metabolic tolerance (due to enzyme
induction) is drug induced increase in the rate
of its own metabolism
pharmacokinetic mechanisms phenytoin,
rifampicin, hypnotics adaptive changes
(up-regulation)- cellular tolerance
pharmacodynamic mechanisms opiates
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Tachyphylaxis is a term used to describe
tolerance which develops in the
course of a few minutes if
the drug is administered continuously or
repeatedly (prior
the drug is eliminated). T. can be associated
with depletion of an essential intermediate
substance. Drugs such as amphetamines, which
act by releasing noradrenaline and other amines
from nerve terminals
show marked tachyphylaxis
because the releasable stores of
noradrenaline
become depleted.
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
can cause AN INCREASE in the
response to a drug due to
accumulation in the body accumulation
results from the rate of drug dosing being
higher that the rate of its elimination. A. is
usually due to impaired function of the organ
that eliminates the drug
digoxin or lithium in decreased glomerular
filtration intoxication
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Drug dependence according to the World Health
Organization (WHO) definition of drug dependence
is a state, psychic and sometimes physical,
resulting from the interaction between a living
organism and a drug characterized by behavioural
and other responses that always include a
compulsion to take the drug on a continuous or
periodic basis in order to experience its
psychic effects and sometimes to avoid the
discomfort of its absence Tolerance may or may
not be present. Drug addiction is a drive to
seek out and consume the drug of choice as the
priority in ones life. Drug abuse is the
consumption of a drug apart from medical need or
in unnecessary quantities.
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Physical dependence following t e r m i n a t
i o n of the drug of dependence some signs and
symptoms occur, that are collectively termed the
abstinence or withdrawal syndrome. Based on
observation of their respective withdrawal
syndromes, several types of physical dependence
are evident Opioid/narcotic analgesics
Drugs that alter perception Drugs which
produce hallucinations Central stimulants
Central depressants Solvent abuse
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Opioid/narcotic analgesics heroin - for
several seconds following IV inj h. produces an
intense euphoria (rush). Over the next few
hours the user may describe a warm sensation in
the abdomen and chest (flush). On examination
the patient may appear to be alternately dozing
and waking, may be hypotensive with a slow
respiratory rate, the pin-point pupils and
infrequent and slurred speech. The signs can be
reversed with naloxone (an antagonist) For a
dose it is important to look for an increase in
pupil diameter, respiratory rate and depth of
respiration during iv adm.
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OPIOID ANALGESICS
Early and late effects
Op
analgesia
Op
up-regulation tolerance
ex
withdrawal syndrome
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING

• Heroin is mainly obtained on the black market.
• It is
• of variable purity and cut with quinine, talc,
  lactose, etc.
• usually mixed with water, heated until
  dissolved, and strained
• through cotton.
• misused IV (mainlining),
• SC (skin popping) or
• INHALED (snorted/chasing the
  dragon, by heating up on
• foil and
  inhaling the smoke) t1/2 60-90 min
• Methadone is mainstay of drug addiction
  clinics,
• usually given as an
  elixir (t1/2 15-55 h)
• Other opioids all have the potential to cause
  dependence

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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING

• Symptoms of opioid abstinence
• e a r l y i n t e r m e d i
  a t e l a t e
• yawing mydriasis
  fever
• lacrimation flushing
  nausea and vomiting
• rhinorrhoea tachycardia
  abdominal cramps
• perspiration tremor
  diarrhoea
• restlessness
• usually start at the time when the next dose
  would normally be
• given,
• their intensity is related to the usual dose.
• For heroin, symptoms usually reach a maximum
  at 36-72 h and
• gradually subside over the next 5 -10 days.
• withdrawal symptoms can be treated acutely by
  substitution with
• another opioid agonists (e.g. methadone)

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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Drugs that alter perception Cannabis (indian
hemp, marijuana) the most active constituent is
?-9- tetrahydrocannabinol. The pleasurable
effects include a sensation of relaxation,
heightened perception of all the senses and
euphoria. Acute adverse effects dysphoric
reactions, (anxiety or panic attacks). The
impairment of performance of skilled tasks, and
sedation. This may lead to road traffic
accidents. Chronic use personality changes
including amotivational syndrome characterized
by extreme lethargy. Physical dependence only
after extremely heavy and frequent intake.
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Drugs which produce hallucinations and other
alterations of perception lysergic acid
diethylamide, psilocybin, mescaline,
phenyldiclidine, ecstasy
induce perceptual changes. Untoward effects
dysphoric reactions (bad trips)
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Central stimulants Amphetamines, Cocaine, Nicotine
, Xanthines (caffeine), Amphetamines alleviate
tiredness and induce a feeling of cheerfulness
and confidence (in oral or inj forms, free base
amphetamine can be smoked) Repeated use can
produce amphetamine psychosis(delirium, panic,
hallucinations and feeling of persecution).
Prolonged use psychological dependence,
tolerance, hostility, irritation due to lack of
sleep and food.
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Cocaine derived from the Andean coca shrub, has
powerful stimulant properties. As a salt it is
most commonly sniffed up the nose, it can be also
injected. Free base (Crack) is smoked. C.
causes arousal, euphoria, the sensation of having
great physical strenght and mental
capacity. C. is used in binges, where doses may
be taken several times an hour over a
day or several days until lack of money prevents
it. Repeated large doses precipitate an
extreme surge of anxiety and agitation.
Withdrawal symptoms excessive sleep, fatique,
mild depression. Use of cocaine in pregnancy is
associated with damage to the CNS of the fetus
Crack babies
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Nicotine -each puff of cigarette smoke that is
inhaled results in the absorption of 50-150 ug
of nicotine. (absorption reaches 20-25 of the
total nicotine in the cigarette). N. induces
dependence. Treatment substitution of nicotine
via skin patches or nicotine gum. Xanthines
(caffeine) A very wide range of behaviour -
reduction of fatigue, insomnia, improved
concentration and a clearer flow of thought. A
mild withdrawal syndrome manifested by headache,
nervousness, irritability occurs after 12-16 h
after discontinuation.
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Central depressants Barbiturates
Benzodiazepines Alcohol Barbiturates are
sedative and anxiolytic, with tolerance and
marked psychological and physical dependence
occuring after chronic administration. During
withdrawal, convulsions are often
seen. Barbiturate overdoses are commonly fatal
due to respiratory depression, and the risk of
lethality may be increased if alcohol and
barbiturates are co-administrated. Barbiturates
should never be used for patients with anxiety or
insomnia, and their uses today are for certain
types of epilepsy or for anaesthetic
pre-induction
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Benzodiazepines. Dependence is usually caused by
a large dose taken for prolonged periods, but
withdrawal states have also arisen after limited
drug exposure. Withdrawal symptoms visual and
auditory hallucinations, paranoia, feeling of
unreality, depersonalization, blurring of vision
and many others. Withdrawal from
benzodiazepines in patients who have become
dependent should be gradual. If this proved
difficult, then an equivalent dose of a
long-acting benzodiazepine should be given as a
single night-time dose. The dose should then be
reduced in small steps.
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Alcohol is the most important drug of dependence,
and in Western Europe and North America the
incidence of alcoholism is about 5 among the
adult population. Tolerance and marked physical
and psychological dependence occur after chronic
administration. A c u t e e f f e c t s 1.
Nervous system a. produces decrease in learning
ability, association formation, attention span,
concentration, judgement and discrimination, and
reasoning. In individuals who are not heavy
drinkers there is a rough correlation between
blood alcohol concentration and the acute CNS
effects 20 mg/100 mL --- sensation of
relaxation 30 mg/100 mL --- mild
euforia 50 mg/100 mL --- mild
inco-ordination 100 mg/100 mL ---
obvious ataxia, 300 mg/100 mL --- stupor
400 mg/100 mL --- deep anaesthesia (chronic
alcoholics may hold a coherent conversation).
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING

• The central depressant actions of alcohol
  greatly enhance
• the effects of other central depressant drugs.
• 2. Circulatory system
• atrial fibrillation, cardiomyopathy, cutaneous
  vasodilation.
• 3. Other actions
• acute gastritis, nauzea and vomiting,
• accumulation of lactate and other acids produces
  metabolic
• acidosis,
• thiamine deficiency,
• hyperuricaemia (resulting in acute gout in those
  who are
• predisposed to the condition),
• hypoglycemia (children),
• hepatitis

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Ch r o n i c e f f e c t s dependence,
behavioural changes, encephalopathy (dementia,
convulsion), cardiomyopathy, pancreatitis,
gastritis, cirrhosis, hypertension, gout, fetal
alcohol syndrome. Withdrawal syndrome tremor,
sweating, seizures, delirium tremens (state of
acute confusion and disorientation associated
with frightening hallucinations and sympathetic
overactivity).
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING
Long-term management of the alcoholic Alcohol-se
nsitizing drugs these produce an unpleasant
reaction when taken with alcohol
Disulfiram inhibits aldehyde dehydrogenase,
leading to acetaldehyde accumulation if alcohol
is taken, causing
flushing, nauzea,
headache,
tachycardia and hypotension.
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FACTORS INVOLVED IN DRUG REACTIONS - REPEATED
DOSING

• Solvent abuse
• is common predominantly in
  adolescens aged
• between 12 and 16 years.
  
• Solvents such as glues, paints, nail-varnish
  removers, dry-cleaning
• fluids are sniffed, often with the aid of a
  plastic bag (placed over
• the head) to increase the concentration of
  vapour.
• Inhaled solvents rapidly reaches the brain.
• The effects occur almost instantly (because of
  rapid absorption
• of volatile hydrocarbons from the lungs)
• and usually resolve within 30 min.
• Disinhibition can lead to excessively aggressive
  or emotional
• behaviour
• Accidents are common, and if overdose occurs,
  
• coma and asphyxiation may result.

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• Age
• Gender
• Repeated (continuous) dosing
• Co-administration
• Disease

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FACTORS INVOLVED IN DRUG REACTIONS - CO -
ADMINISTRATION

• Drugs can be used in combination
• to enhance their effectiveness - synergy
• combination can induce additive effects
• imipenem, a broad spectrum antibiotic is partly
  inactivated by a dipeptidase in the kidney. This
  is overcome by administering imipenem in
  combination with cilastatin, a specific renal
  dipeptidase inhibitor. This results in more
  prolonged plasma concentrations of imipenem.
• Combinations may have more than additive effects
• (co-administration is more effective than either
  component alone)
• sulphamethoxazole trimethoprim cotrimoxazole
• to decrease their effectiveness - antagonism
• at the same receptor site tubocurarine vs. ACH
  (N-receptor)
• at the different receptor site ACH vs. beta2
  mimetics in the bronchi
• on the pharmacokinetic principle heparine vs.
  protamine sulfate

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• Age
• Gender
• Repeated (continuous) dosing
• Co-administration
• Disease

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FACTORS INVOLVED IN DRUG REACTIONS - DISEASE

• Renal failure
• Cardiac failure
• Liver disease

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FACTORS INVOLVED IN DRUG REACTIONS - DISEASE

• Renal failure
• permeability of the blood-brain barrier (uremia)
  is enhanced
• increased access of drugs to the
  CNS-(cimetidine causes
• confusion)
• renal excretion is reduced in relation to GF
• Drugs (and their metabolites) excreted
  predominantly by the kidney accumulate in renal
  failure
• aminoglycosides, digoxin, lithium, enalapril,
  atenolol, methotrexate
• usual doses can therefore result in elevated
  plasma concentrations and impaired elimination-
  accumulation and intoxication
• CLcr is essential in deciding on an appropriate
  dose regimen

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FACTORS INVOLVED IN DRUG REACTIONS - DISEASE

• Prescribing for patients with renal disease
• consider the possibility of renal impairment
  before drugs are
• prescribed
• check how drugs are eliminated before
  prescribing them. If non-
• renal elimination accounts for less than 50 of
  total elimination,
• than dose reduction will probably be necessary
• monitor therapeutic and unwanted effects and,
  when appropriate,
• drug concentrations in plasma
• use potentially nephrotoxic drugs
  (aminoglycosides, NSAIDs,
• ACEI) with special care

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FACTORS INVOLVED IN DRUG REACTIONS - DISEASE

• Cardiac failure
• condition
• distribution -
• in compounds with large Vd distribution
  decreases (probably
• caused by decreased tissue perfusion and
  impaired elimination).
• Usual doses can therefore result in an
  elevated plasma
• concentrations, producing toxicity
  (lignocaine, chinidine).
• elimination by liver and /or kidney is
  diminished
• decreased hepatic perfusion accompanies
  reduced cardiac output
• (theophylline)
• reduced glomerular filtration
  (aminoglycosides, digoxin)

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FACTORS INVOLVED IN DRUG REACTIONS - DISEASE

• Liver disease
• conditions
• liver is the main site of drug metabolism but
• hepatic necrosis and fibrosis have little
  influence on drug
• metabolism (multiple isoforms of CYP450 with a
  high
• metabolising capacity are available)
• but direct portal tracts to hepatic veins
  -shunts- develop, resulting
• in reduced presentation
• of hepatic portal blood
  to hepatocytes
• increase in
  bioavailability.

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FACTORS INVOLVED IN DRUG REACTIONS - DISEASE

• Conditions
• There is no reliable biomarker describing hepatic
  impairment.
• In chronic liver disease
• serum albumin is the most useful index of drug
  metabolizing capacity or
• prothrombin time also shows a moderate
  correlation with drug clearance of drugs.
• such indices of hepatic function serve mainly to
  distinguish the severly affected from the milder
  cases
• (in contrast to serum cr or Clcr in renal
  impairment).

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FACTORS INVOLVED IN DRUG REACTIONS -
DISEASE

• Prescribing for patients with liver disease
• if possible, use drugs that are eliminated by
  routes other
• than the liver
• response and untoward effects should be
  monitored (and
• therapy adjusted accordingly)
• predictable hepatotoxins (cytostatic drugs)
  should only be used
• for the strongest of indications
• avoid drugs that interfere with hemostasis
  (anticoagulants,
• aspirin)

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References Ritter JM, Lewis LD, Mant TGM
A textbook of clinical pharmacology. 4th ed.
Arnold, 1999 Rang HP, Dále MM, Ritter JM
Pharmacology, 4th ed. Churchill Livingstone,
1999 Lippincotts illustrated reviews
Pharmacology. 2nd ed. Harvey RA, Champe PC, Mycek
MJ, Harvey RA, editors. Lippincott Williams
Wilkins, 2000.