Factors that influence drug
effects.
Effect of concomitant diseases
and polypharmacy.
Adverse drug reactions.
Overview of factors
• A. Factors related to drug:
– Physical and chemical properties
– Drug form
– Food administered together with a drug
• B. Factors related to drug and to organism:
– Dose
– Combination of drugs
– Repeated administration
• C. Factors related to organism:
– Age
– Sex
– Weight and body constitution
– Circadian rhytms
– Pathological state of organism
– Genotype/fenotype
– (Race group/ethnic group)
A. Factors related to drug
I. Physical and chemical properties
II. Drug form
III. Food administered together with a drug
I. Physical and chemical
properties of drug
Influence on the transport trough
membranes
• Chemical configuration
• Size and shape of the molecule
• Solubility in water and fats
• Acidobasic properties
Relationship between chemical
structure and character of the
effect
OH
OH
OH
OH
OH
OH
CH
CH
CH
CH
CHCH
CH
NH
NH
3
2 2
2
3
noradrenalin
účinky převážně
mimetickéα
isopropylnoradrenalin
účinky převážně
mimetickéβ α β1 2
Relationship of chemical
structure to PK
• ISDN is more lipophilic than ISMN
• ISDN may be administrated sublingually
• ISMN is almost not subject to the hepatic
FPE
• Another example: atenolol x metoprolol
ISDN
ISMN
Stereoisomerism
• Cis-trans isomerism: only the cis form of
chlorprotixen is efficient
II. Drug form
• definition: a substance or combination of
substances presented as having
therapeutic or preventive properties
administered to set the medical diagnosis.
farmakokinetická
fáze
farmaceutická
fáze
farmakodynamická
fáze
desagregace
desintegrace
disoluce
absorpce
distribuce
eliminace
léčivo-receptor
farmaceut.
dostupnost
biologická
dostupnost
biologický
účinek
Drug form generations
• 1. generation – conventional DF
• 2. generation with controlled release
– with prolongated release (SR,XR...)*
– transdermal therapeutic system
– gastrointestinal therapeutic system
• 3. generation with targeted drug delivery
*SR=sustained release, slow release
LA=long acting, SA=slow acting, XR=extended
release
CR=continuous (controlled) release, retard atd.
Example of transdermal
therapeutic system
krycí vrstva
zásobník s léčivem
membrána (s mikropóry)
řídící uvolňování léčiva
adhezivní povrch
podkožní kapiláry
9,5 - 14,3 mm
0,17 mm
(podle Heilmanna 1978)
• Liposomal vers. conventional drug ( e.g.
amfotericin B)
• Stealth liposomes = PEGylated (daunorubicin,
doxorubicin)
• Nano-liposomes
III. Food intake
FD interactions
- non-selective inhibitors of monoaminooxidase increase the bioavailability
of tyramine from food (fermented food is risky, e.g. some cheese, red wine,
smoked meat, bananas). There is a menace of excessive wash out of
catecholamines and hypertense crisis.
- food with high content of vitamin K (e.g. broccoli) can decrease the effect
of warfarin (vitamin K antagonist)
FK interactions
- more often- influence at the level of absorption, but also
in metabolism and excretion
Farmacokinetic interactions with
food
Food can:
• slow down the absorption without the
change of extension of bioavailability
(inappropriate in analgetics, hypnotics…)
• decrease bioavailability
• inrease bioavailability
Division of factors
• B. Factors related to drug and to organism:
– Dose
– Combination of drugs
– Repeated administration
Dose - dosis
• In preclinical trials
• In clinical trials phase I: MTD (maximal
tolerated dose)
Quantitative test–
dose-effect curve
E
účinek
%
100
95
50
0
podprahové
dávky
prahové
dávky
ED50
submaxim.
dávka
maxim.
dávka
supramaxim.
dávky
log. konc.
Doses in pharmacotherapy
• Dosis therapeutica - pro dosi (singula)
(therapeutic dose) - pro die
• Dosis maxima - pro dosi (singula)
(maximal dose) - pro die
• Dosis curativa – therapeutic dose
(cumulative)
Information about doses
• SPC = summarizing information about LP
(Summary of Product Characteristics)
Available on:
– AISLP -Automated informative system LP
– SÚKL database (State authority for control of drugs)
• Czech pharmacopoeia
II. Combinations of drugs
The effect is
S y n e r g i s m
• Sumation: both drugs have the same (similar) effect
and, if we combine them, the final effect is a total of
effects, which the drugs would have when administered
in monotherapy
one-sided : analgetics anodynes + narcotics
two-sided : combination of cytostatics
• Potenciation
one-sided : Ca2+ + digoxin
two-sided : digoxin + thiazid diuretics
Combinations of drugs
The effect is
A n t a g o n i s m
• pharmakological (ACH + atropin)
• physiological (ACH + adrenalin)
• chemical (heparin + protamin sulfate)
(metals + dimerkaprol, EDTA)
C. Division of factors
• Factors related to organism :
– Age
– Sex
– Weight and body constitution
– Circadian rhytms
– Pathological conditions of organism
– Genotype/fenotype
Age
Administration of medicinal product (MP)
• to children
• to old people
Administration of MP to children
approximate dose for children
=
body surface area (m2) x dose for adult
1,7
Administration of MP to
children
A child is not a miniature of an
adult
• particularities of FD
• particularities of FK
Particularities of PK of drugs
in child
Particularly on newborns (especially premature):
• relatively bigger volume of extracelular liquor
• lower binding on plasmic proteins
• unfinished developement of hematoencephalic barrier
• immaturity of enzymatic systems
• Immaturity of renal functions
Postnatal developement changes of
selected hepatic and renal functions
tubulární sekrece
glomerulární filtrace
konjugace s aminokyselinami
glukuronidace
acetylace
porod
10 20 30 2 3 4 5 6
dny měsíce
• In newborns - activity of majority of the hepatic enzymes is lower
• There is a big risk of cumulation of drugs and of toxicity if the
dosage is not adapted.
Particularities of
pharmacodynamics of drugs in
child
Antihistaminics
• in adult- sedation (somnolency, fatigue )
• In child- even excitation (convulsions)
Administration of MP to old
people
• 60 – 74 older person
• 75 – 89 elderly
• > 90 longevity
• physiological changes
• multimorbidity
• polypragmasia (administration of many drugs
together, risk of drug interaction is increasing)
• higher incidence and severity of adverse effects
Changes of FK of drugs in old
age
• absorption (passive diffusion of subacid
substances thanks to hypoacidity, active
transport is decreasing)
• binding on plasmic proteins
• elimination: decrease of blood flow through
kidneys and GFR, flow through liver and
activity of redox enzymes
=> Prolongation of t1/2
(e.g. digoxin, aminoglycoside atb)
Changes of FD in old age
• Very variable
• Tissue hypoxia
• Dysfunction of regulatory mechanisms
• Change of sensibility of target structures
= hyperergic reaction
Changes of FD in old age
Examples:
• ATB aminoglykosides:
lower doses in case of lower GF (correction according to
CL CR)
• Antihypertensives: orthostatic hypotension, psychical
alternations (confusion)
• Anticoagulants: bleeding from GIT (decreased
absorption of vitamin K and decreased synthesis of
prothrombin)
• NSAID: in 25% hematemesis
• Anticholinergic substances: higher toxicity, depression,
confusion
Sex
• Women are in general more sensitive to effects
of some drugs, e.g. because of lower weight, but
also of lower CL (olanzapin)
• Specific periods are:
– menstruation
– gravidity
– lactation
– menopause
Gravidity
• slowed stomach and intestinal motility
• increased volume of plasma, body water
can be raised up to 8 litres more
• hypoalbuminemia, occupancy rate of
plasmic proteins by hormones
• increased flow through kidneys and
increase of GFR
Weight and body constitution
• In many cases drugs are dosed in consideration
to the weight of the patient (it’s recommended to
use dosing per 1kg of body weight, respecting
the patient’s age)
– Dosage mode: dose per time period
– Dose: mg/kg, mg/kg/age, mg/m2
Infuence of weight and body
constitution
• „muscular type“ needs higher
doses of substances affecting
neuromuscular junction or binding
on muscles
• „obese type“needs higher doses
of substances binding on fats
Circadian rhytms
• are the object of studies of chronopharmacology
a chronotherapy
• Biorhytms of body functions in dependence on
time of day or season
• base = diurnal rhytm of release of hormones and
of activity of some enzymes
• Example: Incidence of asthmathic attacs is the highist in early
morning time, when the tone of sympatikus is low and also the level
of endogene glucocorticoids is low.
Circadian rhytm of secretion of
cortizol
Pathological state of organism
• Influence of lesion/dysfunction of kidneys,
liver and thyroid gland on
pharmacokinetics
• Influence of pathological state on
drug pharmacodynamics
Hypofunction of kidneys
• The most common reason for customisation
of the dosage
• Customisations of dosage in accordance to
the tables – GFR is a clue
• For the majority of drugs, the customisation
of the dosage means prolongation of intervals
(AMG, vankomycin)
• In drugs with very long t1/2 we keep the same
interval, but administer a lower dose (digoxin)
Influence of liver deseases
• No reliable quantitative criteria is available
for measuring disturbed liver elimination
capacity (analogy CLcr in kidney
dysfunctions) empirical attitude
• Liver function tests (aminotransferases,
albumine, blood coagulation factors) are
not a good clue for the dosage of drugs
In persons with liver diseases
• Prefer drugs eliminated mostly by kidneys,
if possible (or those whose kinetics is not disturbed by liver
hypofunction) e.g. atenolol
• Prefer drugs acting directly – without
activation of biotransformations in liver
(lisinopril x enalapril)
• Think about the possibility of increased
biol. availability when drugs with big firstpass
effect are administered p.o
(e.g. metoprolol)
In persons with liver diseases
• Think about the possibility of disturbed elimination of
drugs which are eliminated mainly by liver (over 60 -
70%)
• Reduce the doses when a progressed liver disease is
present: diazepam, paracetamol, fenobarbital, fenytoin,
valproic acid, mesokain, morfin, teofylin, calcium channel
blockers
• Administer carefully: antidiabetics, diuretics,
anticoagulants, antihypertensive drugs (follow the achieved
effect)
• Monitoring of levels is recommended in: antiepileptics,
theofylin, cytostatics (low TI)
Other pathological states
• Heart failure (centralization of the circulation)
– absorption after p.o. administration can be slowed down or
decreased
– biol. availability of the substances with strong FPE can be
increased
– absorption after i.m. administration can be slowed down
• GIT dysfunctions (malabsorption, stomach ulcers a nauseaprovoking
states, vomitting)
• Thyroid gland dysfunctions (by hyperfunction- the intensity of
metabolism is commonly increased) e.g. hyperthyreosis can
intensify the effect of warfarin
• Fever ( GF, acceleration of elimination of gentamicine)
• Edema ( Vd gentamicine)
• Obesity
Genetic factors
• The answer on drugs varies among
individuals qualitatively and quantitatively
interindividual variability – polymorfism
• Genetic factors influence FD and also FK
Genetic factors
• Genetic polymorfism = existence of several (at least
two) alleles for a concrete gene, the least frequent one of
which has the population frequency at least 1%
• Pharmacogenetics
is a field which is focused on studies of genetically
conditioned variability in answering of the organism to a
drug
(Pharmacogenomics investigates the relationship of
drug effect at the level of the whole genome, resp.
transcriptome)
Genetic factors- FK
• Genetic polymorphism of enzymes metabolizing drugs
and transporters for drugs:
In our population, there exist more different fenotypes (slow, middle,
fast, eventually ultra-fast metobolisator)
with a frequencey higher then 1%, which are caused by mutation of
one gene (monogene dependence)
• Genetic tests of deviations in the metabolism and
transport of drugs are not done commonly, although the
findings about the big influence on pharmacokinetics
exist and the methods for examining polymorphism are
available and fast (but expensive).
Monogenní mutace x polygenně podmíněná
Examples of pharmacogenetic
variability
• Polymorphism of N-acetyltransferase
– inactivation of drugs in liver: slow X fast activators
– isoniazid, prokainamid, hydralazin
– peripheral neuropathy (prevention – pyridoxin)
• Polymorphism of thiopurin S-methyl-
transferase
– participates in the metabolism of azathioprine
– there is available a commercially fabricated genetic test for
setting the rate of activity, prevention of severe adverse effects
Examples of polymorphism in
the genes for CYP P450
• CYP2D6 and antidepressants (especially the classical
ones): remarkable pharmacokinetic dirrefences, hardly
titrate dose for slower development of the effect,
long term pharmacoterapy
• CYP2C9 and peroral antidiabetics – derivates of
sulphonylurea (e.g. glimepirid, glipizid a tolbutamid) In
heterozygotes CYP2C9*1/*3 the total clearance is 50%
and in homozygotes CYP2C9*3/*3 20% compared to wt
• CYP2C9 and anticoagulants – (warfarin) In
heterozygotes CYP2C9*1/*3 the total clearance is 70%
and in homozygotes CYP2C9*3/*3 40% compared to wt
Factors affecting interindividual
variability of pharmacokinetics
Clinical pharmacologists …… integrate and
critically look on the findings of preclinical and
clinical trials and in the course of judging the
sources and signification of interindividual
variability in pharmacokinetics …. use methods
of pharmacogenetics and therapeutic monitoring
of drugs.
Drug adverse effects
The term PHARMACOVIGILANCE
Monitoring of adverse effects of drugs in the
common clinical practice/ work experience –
active control of the drug safety
Drug adverse effects
• Adverse Event (may but needn’t to be in
direct relationship with the administered drug)
• Adverse Drug Reaction (is in relationship with
the administered drug)
• Expected / Unexpected
• Severe
• Regulatory Agency : announcement of severe
unexpected adverse effects of drugs
Drug adverse effects
Adverse effects are adversed answers to the
therapeutical doses
They go with the pharmacotherapeutical effects
Drug adverse effects
A – augmented – caused by the same
mechanism as pharmacotherapeutical effects.
• B – bizzare – „pacient’s reaction“ –are caused
by a genetic mechanism (idiosyncrasy) or by an
imunological mechanism (allergies).
• C – chronic – are caused by a long term taking
• D – delayed – show after a longer period of
latency
• E – end-of-use -syndrom caused by
discontinuing a drug
A – augmented
caused by the same mechanism as the
pharmacotherapeutical effects. Induced by
unappropriate dosage or by change in
pharmacokinetics as a result of pathological
process.
• predictable
• directly dependent on the dose
• frequent, seldom fatal
• Insulin > hypoglycaemia
• Anticoagulants> bleeding
• beta-blockers > bronchi-constriction > astmatic attack
B - bizzare
Caused by a genetic mechanism (idiosyncrasy)
or by an imunological mechanism (allergies).
• unpredictable
• do not depend on the dose
• less frequent (1:1 000 až 1:10 000)
• higher mortality
Idiosyncrasy – reaction on the first dose, without previous
sensibilisation (suxamethonium in individuals with atypical
cholinesterase), polymorfisms.
Allergic reaction - reaction after a previous sensibilisation.
C - chronic
• caused by a long term taking
• e.g. analgetics > nefropathy
• prednisolon > iatrogenic Cushing’s syndrome
• laxatives > dysfunction of GIT.
D - delayed
show after a longer period of latency (or in
children of the treated patients)
-mutagenesis, teratogenesis and cancerogenesis
Common characteristics:
• change of the genetic information because of
the effect on DNA
• sensibility of the dividing and growing tissue
• ireversibility of the induced changes
E – end of use
Appears after the administration of a drug is
finished. Like a syndrom caused by
discontinuing a drug
(rebound fenomen, withdrawal syndrome).
up/down-receptors regulation
• Examples:
• Tachykardia after discontinuing betablockers.
• Adrenocortical insufficiency after discontinuing glucocorticoids.
• Attacs after discontinuing antiepileptics.
Drug interaction
Administration of two drugs together influences
the effect of one or even both of them.
↑ probability of interactions:
• Highly efficient drugs
• Inductors or inhibitors of hepatic enzymes
• During administration of more medicaments in
the same time
• Pacients with kidney or liver diseases
• Senioři
Drug interactions
• pharmacokinetic
biotransformation, distribution, absorption, exkretion
• pharmacodynamic
the effect of a drug is influenced
• synergic
• antagonistic