GENERAL PHARMACOLOGY

Adverse drug reaction

Special aspects of drugs action
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ADVERSE EFFECTS
SIDE EFFECTS
=
OR

ADVERSE AND TOXIC REACTIONS
ADVERSE EFFECTS
all unfavorable actions of drug observed after
therapeutic doses
type and risk depends on margin of safety
some adverse effects, under very specific conditions,
may be sometimes considered as desired
(in different than original indication)

TOXIC EFFECTS all actions of drug observed after
overdosing
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ADVERSE EFFECTS OF DRUGS
PREDICTABLE
directly connected to
the drugs
mechanism of action
GI injury after NSAIDs
hyperkalemia after ACEI
UNPREDICTABLE
independent from
the drugs
mechanism of action
hypersensitivity reactions
after penicillins
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ADVERSE EFFECTS OF DRUGS
on-target
result from drug
binding to its
intended receptor
often class effect
off-target
results from drug
binding to a target
or receptor for which
it is not intended
mediated by the
immune system
idiosyncratic
reactions
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D D
Intended tissue
Unintended tissue
Intended
receptor
Intended
receptor
Unintended
receptor
Unintended
receptor
DX DX
metabolism metabolism
On-target
adverse effects
dose too high
chronic activation
or inhibition effects
On-target
adverse effects
correct receptor,
but incorrect tissue
dose too high
chronic activation
or inhibition effects
Off-target
adverse effects
incorrect receptor
is activated
or inhibited
Off-target
adverse effects
incorrect receptor
is activated
or inhibited
Toxic cellular adverse effects
Principles of pharmacology, LWW, 3rd Ed, 2012
ADVERSE EFFECTS
ALLERGIC
REACTIONS
IMPACT
ON FETUS
CARCINOGENIC
ACTION
most of drugs become antigens after
binding with some macromolecules
more often in patient with some allergic history
reactions are different from therapeutic effects of drug
characteristic for the patient not for a drug
similar reactions, but not Ig-mediated may be due to
direct histamine release
1-8% (3%) congenital defects
first trimester fetal death, spontaneous abortion,
severe congenital malformations teratogenic action
second and third trimesters fetal death, abortion,
biochemical disturbances embriotoxic action
preterm period changes in fetal function e.g. respiratory
depression after opioids
the same drug may cause different defects in various
animals and various drugs may cause the same defects
many differnt compounds may be potentially carcinogenic
great interspecies differences
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TYPE I
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TYPE II
TYPE III
TYPE IV
immediate
IgE-mediated
symptoms within minutes
degranulation of mast cells and basophils
e.g. anaphylaxis, asthma, hay fever, urticaria
formation of Ag-Ab complexes
activation of complement cascade,
membrane attack complex and cell lysis
e.g. blood transfusion reactions or drug-
induced
levels of Ag-Ab complexes; deposition on
basement membranes in tissues and vessels
activation of complement (C5a, C3a, C4a)
symptoms within 3-4 days
e.g. glomerulonephritis, arthritis
delayed-type; responses after 2-3 days
cell-mediated local inflammatory response
with tissue damage and influx of Ag-
nonspecific inflammatory cells
(macrophages)
e.g. contact dermatitis
IDIOSYNCRATIC REACTIONS
state of increased reactivity of organizm to specific
chemical (drug) substance
appear unpredictably
the reaction is quantitatively altered
probably due to altered metabolism of compound
(genetically or acquired)
often the reason is in various enzymopathies
idiosyncratic reaction causing symptoms similar to
allergy is called pseudoanafilactoidal reaction
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TOXIC REACTIONS
OVERDOSE
absolute
toxic doses of drugs
cumulative
due to the accumulation of doses greater than
eliminated
relative
toxic effects after therapeutic doses e.g.
liver and kidney failure
the use of inhibitors of liver metabolism
other drug-drug interactions
effector tissues alterations (disease)
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APOPTOSIS
(programmed cell death)
NECROSIS
(uncontrolled cell death)
ordered
self-destruction
without damage
to surrounding tissue

coordinated
activation of
a number of
dedicated proteins
enzymatic digestion
of cellular content,
denaturation of
proteins, disruption of
cell membranes of

attraction
inflammatory cells
DRUG-INDUCED TOXICITY
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reduce or eliminate
exposure to the drug
administer specific
treatment based on
antagonizing mechanism
or altering metabolism
provide supportive
measures
MONITORED THERAPY
measurements of plasma/serum drug
concentrations
in case of low therapeutic index
in case of the simultaneous use of many drugs with
possible interactions
in case of kidney or liver failure

some examples:
cyclosporine
methotrexate
theophyllin
digoxin
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FACTORS INFLUENCING DRUGS ACTION
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AGE
SEX
BODY
WEIGHT
GENOTYP
PHYSIOLOGICAL
STATE
PATHOLOGICAL
STATE
PREVIOUS DRUG
EXPOSURE
infants
children
geriatric
impact
of sex
hormones
doses for lean
body mass
obesity
pregnancy
pregnancy
lactation
changes in
GI motility
other diseases
e.g. kidney, liver failure
various
enzymopathies
tachyphylaxis & tolerance
allergy
DIET &
ENVIRONMENT
grapefruit juice
herbal roducts
PHARMACOGENETICS
succinylcholine metabolism
1:2000-3000 patients (Caucasians)
1000-fold reduced affinity
prolonged action of drug due to defects in activity
of pseudocholinesterase
artificial respiration is needed until the drug is
cleared
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PHARMACOGENETICS
isoniazid metabolism (also dihydralazine, procainamide)
differences in acetylation (AR trait)
less enzyme (NAT2) rather than abnormal form
slow acetylators
ca. 45% of whites and blacks in the USA
in Europe mainly northern latitudes
fast acetylators
90% of Asians and Inuits in the USA
slow acetylators
blood level of isoniazid is increased 4-6-fold
higher incidents of autoimmune disorders
free drug inhibits P450 enzymes
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PHARMACOGENETICS
warfarin metabolism (CYP2D9)
also phenytoin, losartan and tolbutamide
differences in hydroxylation

clopidogrel (CYP2C19)
loss of activity
re-stenosis and re-thrombosis
polymorphisms decreased amount of active
drug
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PHARMACOGENETICS
hemolysis
glucose-6-phosphate dehydrogenase defficiency
sulfonamides, some antimalarial agents, nitrofurantoin,
chloramfenicol, some antifungal agents
hemoglobinopathies

methemoglobinemia
reduced nicotine adenine dinucleotide (NADH)
diaphorase system defficiency
reduced nicotine adenine dinucleotide phosphate (NADPH)
diaphorase system
local anesthetics (benzocaine, prilocaine), amyl nitrite and
isobutyl nitrite, nitroglycerin, sulfatiazole
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PREGNANCY
critical factors affecting placental drug transfer
physicochemical properties of drugs
rate at which drugs cross the placenta
amount
duration of exposure
distribution in fetal tissues
stage of placental and fetal development
effects of drugs in combination
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PREGNANCY
lipid solubility
lipophilic drugs cross the placenta readily, highly
ionized slowly
e.g. thiopental vs. succinylcholine
molecular weight
drugs with MW > 1000 cross placenta poorly
e.g. heparins vs. warfarin
placental transporters
PgP pumps out many drugs e.g. some anticancer
or anti-HIV agents
may be responsible for transplacental passage of
large molecules e.g. antibodies
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PREGNANCY
protein binding
for highly lipid-soluble drugs protein binding does not
affects transplacental passage
depends more on placental blood flow
differences between maternal (higher) and fetal
(lower) protein binding
placental and fetal drug metabolism
some enzymes are located in placenta
inactivation of drugs or formation of toxic metabolites
drugs go to the fetal circulation via umbilical vein
40-60% of blood from this vein enters the fetal liver
drugs in placental artery may be shunted through the
placenta to the vein
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PREGNANCY
maternal drug action
effects of drugs on the reproductive system
are altered by hormones
therapeutic action in fetus
new area in pharmacology
e.g. glucocorticoids stimulates fetal lungs development
phenobarbital inducing fetal liver enzymes decreases the risk
of jaundice
anti-HIV agents decrease the risk of vertical HIV transmission
some antiarrhythmic
predictable toxic action in fetus
when toxic action is due to a mechanism of action
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PREGNANCY
teratogenic drug action
multifactorial
single-dose effects of cumulative effect
drugs may interfere with oxygen and/or nutrients
transport
direct action on fetal tissues (differentiation)
consequences of deficiency (e.g. folic acid)
drugs may also cause intrauterine growth
retardation, miscarriage, stillbirth, neurocognitive
delay
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PREGNANCY
absorption
constipation
delayed motility of GI tract may cause increase in absorption
of some poorly absorbed drugs
distribution
increased volume of distribution
increased plasma and extracellular volume
additional compartment (fetus)
finally, concentrations of many drugs are decreased
decreased protein binding
physiological hypoalbuminemia
increased free fraction may counter balance decreased
concentrations due to increased Vd
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PREGNANCY
metabolism
increased biotransformation
gestagens induce liver enzymes
however, phase II reactions may be decreased
conjugation with glucoronic acid or sulfuric acid

excretion
increased renal excretion
in the end of pregnancy very often renal excretion
is decreased
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CATEGORIES FOR DRUGS USED IN PREGNANCY
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A
animal studies have revealed no evidence
of harm to the fetus, however, there are
no adequate and well-controlled studies
in pregnant women
or
animal studies have shown an adverse
effect, but adequate and well-controlled
studies in pregnant women have failed to
demonstrate a risk to the fetus
B
adequate, well-controlled studies
in pregnant women have not shown
an increased risk of fetal abnormalities
CATEGORIES FOR DRUGS USED IN PREGNANCY
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C
studies, adequate well-controlled or
observational, in pregnant women have
demonstrated a risk to the fetus;
however, the benefits of therapy may
outweigh the potential risk
D
animal studies have shown an adverse effect
and there are no adequate and well-
controlled studies in pregnant women
or
no animal studies have been conducted and
there are no adequate and well-controlled
studies in pregnant women
CATEGORIES FOR DRUGS USED IN PREGNANCY
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X
studies, adequate well-controlled or
observational, in animals or pregnant
women have demonstrated positive
evidence of fetal abnormalities
the use of the product is contraindicated
in women who are or may become pregnant
LACTATION
most of drugs enter the breast milk, but in low
(subtherapeutical concentrations)
the medication should be taken 30-60 after nursing
and 3-4 hours before the next nursing
examples of drugs achieving high concentration in
breast milk:
tetracyclines
isoniazid
hypnotics and sedatives
opioids
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PEDIATRIC PHARMACOLOGY
two major problem
ethical inability to obtain true informed consent
children rapid growth and development

five groups of children:
preterm infants
term infants till the end of first month
from 1 month to 2 years of age
from 2 years to 12 years of age
from 12 years to 18 years of age
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PEDIATRIC PHARMACOLOGY
absorption
increased membrane permeability in GI tract
drugs are more irritant to GI mucosa
slow increase in gastric acid in preterm children
fluctuations of gastric acid levels
initiation of gastric acid secretion is delayed when children ar
not oral feeding
decreased gastric emptying in the first few hours
after delivery and is slow up to the end of 1 year
impact of food
dramatic increase after 2 years of age (together with
splanchnic blood flow)
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PEDIATRIC PHARMACOLOGY
absorption
variable intestinal motility in infants
often slow in the beginning and then increased
decreased activity of some enzymes in GI tract
lower levels of bile acids and lipase

irregular absorption from muscles in neonates
(esp. preterm infants)
low blood flow through the muscles

exessive percutaneous absorption in preterm
children resulted in higher toxicity
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PEDIATRIC PHARMACOLOGY
distribution
higher total (70-77%) and extracellular (40%) water
amount
small preterm neonates even 85%
loading doses are sometime necessary
different distribution of water-soluble drugs
differences starts to be insignificant after 1 year of age

differences in body fat
preterm (1%) vs. full-term neonates (15%)
different distribution of lipid-soluble drugs
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PEDIATRIC PHARMACOLOGY
distribution
reduced protein binding
decreased albumin level
decreased drug-binding affinity

higher pharmacological effects despite lower plasma
concentration of total drug
competition with bilirubin binding kernicterus (?)
in hyperbilirubinemia displacement of drugs from albumins

easier penetration through the blood-brain barrier
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PEDIATRIC PHARMACOLOGY
metabolism
activities of P450-dependent mixed-function
oxidases, demethylation enzymes and the
conjugating enzymes (with glucuronates) are lower in
neonates (50-70% of the adult value)
glucuronate activity reaches normal value about 3-4 years
of age
sulfate cojugation is greater
some enzymes work normally
various metabolites in children and adults
in older children (12-36 months) half-life of many
drugs is shorter than in adults
e.g. theophyllin, phenytoin
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PEDIATRIC PHARMACOLOGY
excretion
GFR in preterms and neonates in much lower than in
older children
esp. in preterm (before 34 week of gestation) children
in some cases (e.g. penicillin) MIC after single dose is within
therapeutic range 6-times longer than in adults
(administration every 12 hours)
less frequent dosing
GFR reaches the adult value after 6-12 months and
thenafter even exceeds it
tubular secretory function mature at slower rate
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PEDIATRIC PHARMACOLOGY
some drugs are used in children because of very
specific indications e.g.:
indomethacin closure of patent Botals duct
prostaglandin E
1
maintaining the patency of
Botals duct
theophylline apnea of prematurity

some drugs may have altered action in children e.g.:
phenobarbiltal hyperactivity
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PEDIATRIC PHARMACOLOGY
some specific adverse effects of drugs in children:
nephrocalcinosis after furosemid
renal failure and bowel perforation after
indomethacin
growth suppression after glucocorticoids
hyperactivity after phenobarbital
hepatotoxicity after valproic acid
Reys syndrome after aspirin
gray baby syndrome after chloramphenicol
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PEDIATRIC PHARMACOLOGY
problems with appropiate formulation of drugs
lack of suitable for children

during IV administration of small dose by electric
infusion pump a large part of dose may be lost
may adhere to IV tubes, catethers

errors during preparing dilutions
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PEDIATRIC PHARMACOLOGY
children are not small adults
infants are not small children
newborns are not small infants
preemies are not small newborn
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PEDIATRIC DOSING
the most reliable pediatric doses are provided by
manufacurer and are given in mg/kg or mg/body surface
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Youngs rule
Clarks rule
d dose for a child
D dose for adult
age given in years
weight given in kilograms
70 average weight of adult
age + 12

D x age
d =
70

D x weight
d =
PEDIATRIC DOSING
4-years old child weighted 16 kg
calculate single dose according to the recommended dose
of amoxicillin and according to the doses for adults:
adults: daily dose 0.75-1.5 g in 3 single doses
recommended daily dose for 4-years old child: 20-40 mg/kg
in 3 single doses
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single dose for a child:
from 16 kg x 20 mg/kg / 3 doses = 320 mg / 3 106 mg
to 16 kg x 40 mg/kg / 3 doses = 640 mg / 3 212 mg
single dose according to Clarks rule:
from 250 mg x 16 kg / 70 kg 57 mg
to 500 mg x 16 kg / 70 kg 114 mg
single dose according to Youngs rule:
from 250 mg x 5 / (5 + 12) 73.5 mg
to 500 mg x 5 / (5 +12) 147 mg
GERIATRIC PHARMACOLOGY
very often persons over 65 are elder

geriatric pharmacology starts over 75 years of age

for some drugs age-related changes in action
are great for other minimal

many additional diseases may influence drugs
action
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GERIATRIC PHARMACOLOGY
absorption
altered nutritional habits
greater consumption of OTC drugs, herbal
preparations
delayed gastric emptying
esp. in patients with diabetes mellitus
decreased gastric acid secretion
increased absorption of acid-unstable drugs
most of drugs do not have altered GI absorption
decreased splanchnic blood flow
less complete absorption
more slowly absorption

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GERIATRIC PHARMACOLOGY
distribution
reduced lean body mass (muscles)
often increased fat tissue
reduced total water amount
decreased albumin level (about 20%)
reduced hepatic synthesis of albumins
decreased protein binding
increased plasma drug concentration
(but not always increased tissue drug concentration due to
decreased tissue blood flow)
concurrent increase in alpha-acid glycoprotein
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GERIATRIC PHARMACOLOGY
metabolism
reduction of hepatic enzyme activity
reduction of hepatic mass, volume and blood flow
reduced ability of liver to recover after injury
impact of malnutrition of heart failure on liver
function
phase I reactions are decreased
phase II reaction are often unchanged
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GERIATRIC PHARMACOLOGY
excretion
age-related decline in renal function
decreased renal blood flow
CrCl is decreased in about
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of the population
sometimes 12- or 24-hour urine collection is necesarry
not always reflected as increased serum creatinine level
(reduced muscle mass)
decline about 10% per decated (after 20 years of age)
altered tubular secretion and reabsorption
urine is more alkaline

decreased excretion of volatile agents
inhaled anesthesia
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GERIATRIC PHARMACOLOGY
3-5 times greater incidence of iatrogenic
complications
20-40% adverse drug reaction
of hospitalized patients receive unnecessary
drugs
esp. high risk of delirium after many psychoactive
drugs
noncompliance 50% of elder patient
side effects
mental impairment
difficult instructions
inability to pay for a drugs

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Brenner & Stevens: Pharmacology, 3 Ed, 2010
Brody human pharmacology. Molecular to clinical. Mosby, Elsevier, 5th Ed, 2010.
Katzung & Trevors Pharmacology, Examination and Board Review, McGraw Hill,
Lange, 9th Ed, 2010
Modern Pharmacology with Clinical Applications, LWW, 6th Ed, 2004
Principles of pharmacology. The pathophysiologic basis of drug therapy. WK,
LWW, 3rd Ed, 2012
Podstawy farmakologii dla lekarzy, farmaceutw i studentw medycyny, Volumed,
1996
Basic and Clinical Pharmacology, McGraw Hill, Lange, 11th Ed, 2009
Stedmans Medical Dictionary, LWW, 28th Ed, 2006
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Goodman & Gilmans The Pharmacological Basis of Therapeutics, McGraw Hill,
11th Ed, 2006
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REFERENCES