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Factors Influencing Effect of Drugs
Pharmacokinetics
Factors Influencing Effects of
Drugs
 external
- Characteristic of the drug, way of application, doses and
their intervals...
- They can be easily changed
internal
- Patient´s characteristic
- Change is impossible or very problematic
External Factors
Application
Per os
-
Time of drug dissociation, disolution, stability in GIT
pH in GIT, speed of stomach emptying, motility, size of absorption surface, GIT
diseases, mesenterial flow
Presence of other substances: drugs (antacids, prokinetics, content of ions –
possible chelation), food (possible change of absorption)
Intramuscular application
-
If needed fast effect
If the drug dissolves in GIT (penicilin G)
If high „first pass effect“ (lidocain)
If bad compliance
Influence of liposolubility, pH of solution, muscle perfusion
Rectal application
-
Fast effect, low „first pass“
-
No irritation of stomach mucous membrane
If patient can´t take drugs per os
Pulmonary application
-
Inhalation of gas, aerosol, particles
Quick effect
Application to mucous membrane, skin
-
Sublingual and buccal (quick absorpcion, lower „first pass“)
Intranasal (peptides – vasopressin, calcitonin)
Transdermal – plasters, gels (nitroglycerin, fentanyl,...)
Local application
-
To mucous membrane of the ear, to conjunctival duffel, to
articulation, local application on skin...
Local effect to bronchial stroma ← inhalation
Time of Application
Chronopharmacology
-
glucocortikoids, digoxin, ciklosporin
Xenobiotics, drugs
Internal Factors
Age
Children
-
Absorption (↓ volume of gastric and duodenal liquid, ↓ acidity, ↓
absorption surface)
Biotransformation (immaturity of enzyme systems)
Bigger extracelular space
Incorporation of drug to growing tissues (tetracyclines)
-
↓ glomerular filtration
Geriatric Patients
-
↓ acidity, slower motility, longer time to evacuate stomach,
venostasis in the splanchnic region
↓ activity of biotransformating enzymes, ↓ perfusion of liver
↓ concentration of binding proteins
↓ weight of the body, slower circulation
↓ of kidney function
Gender
Women
-
↓ absorption surface
Competition of estrogens and progesteron with metabolism
↓ glomerular filtration, ↓ weight, ↑ ratio of body lipids
Choice of drugs with respect to gravidity and lactation
Patologic state
absorption
-
GIT diseases (quicker or slower pasage, surgery, inflammation in
the area of application)
distribution
-
States connected with hypoalbuminemia (nephrotic syndrome,
deffect of proteosynthesis in liver)
biotransformation
-
Diseases of liver parenchyma (changes of metabolisation,
presystemic elimination)
excretion
- Kidney deffects, changes of inner space
Genetic factors
genetically dependent changes:
 pharmacodynamics
- resistance to cumarines, decreased effect of β-blockers among
blacks
 pharmacokinetics
- biotransformational polymorfism (slow, fast acetylators,
hydrfoxylators)
Pharmacokinetics
 Study of drug concentration development and its metabolites in time
 Working out of suitable matematic models for interpretation of these
datas
Drug in organism
 Absorption
 Distribution
 Elimination (biotransformation + excretion)
Transport through membranes
-
Always depends on time
Speed of molecule transport through membranes + speed of
molecule changes (biotransformation) → concentration in given place
1.
Pasive transport – in the way of gradient (concentration/electric)
-
Free transfer
Transfer through ion channels
Basic diffusion through lipid membrane
Transfer through intercellular pores
Facilitated diffusion (through carrier, without energy need)
2.
Active transport – against the way of gradient, carrier and energy
needed
3.
Endocytosis – carries out vakuolar aparatus of some cells (e.g.
enterocytes)
 Possibility of molecular transfer through membranes by passive
transport depends mainly on the size, ionisation and
hydrophility/lipophility of the molecule
- Transfer is easier and faster for smaller, electrically neutral and more
lipophilic molecules
Absorption
-
Depends on application form
At i.v. application practically no absorption, drug is instantly distributed
in systemic circulation → the fastes possible effect
The most common is application per os
Factors influencing GIT absorption:
pH (in stomach better absorption of acids, in small intestine of weak
basis), perfusion, motility of intestine, patologic changes of mucosal
membrane (malabsorption), presence of ensymes, other substances
and drugs
Distribution
-
To different compartments
Binding to plasmatic proteins → fixed/not bounded fraction of drug,
effective can be only not bounded fraction!
-
-
Factors influencing distribution:
application form, binding to plasmatic proteins, hydrophility/lipophility
of surrounding, first pass effect, barriers (hematoencephalic,
placenta), special transport mechanisms (transferin)
Bioavailability – part of substances that reaches systemic circulation
I.v. application → bioavailability=1 (100 %)
Biotransformation
-
Many parts of organism, main organ liver, also kidneys, intestine,
lungs
Goal: such a change of applied substance, so it would be eliminated
as fast as possible
Can arise: non-active metabolite; metabolite with stronger effect
(change from „prodrug“ to effective substance); toxic metabolite with
qualitatively changed effect
Basically 2 phases of changes – participating are many ensymes:
I. phase – oxidation and reduction, hydrolysis → ↑ sollubility in water
oxidation– system of composite oxidases, mikrosomal ensyme system of
cytochrome (CY) P450 – many isoensymes
hydrolysis – non-specific esterases
II. phase – conjugation reactions
- sulphatation and glukuronidation
- great influence has induction/inhibition of ensymes of system CYP 450
Excretion
- Many ways, main organ kidneys
- The most important processes influencing renal excretion:
glomerular filtration
passive backward tubullar difusion
active backward tubullar resorption
active tubullar secretion
- pH of urine (with more acid urine are better excreted basic molecules, with
more basic acid molecules)
quantitative description of pharmacokinetic actions uses ph.
parameters
primary
pharmacokinetic parameters
secondary
Primary ph.p.
- directly determined by physiological variables
distributory volume – counted from concentration of substance in blood and
expresses volume that would occupate particles of the whole given dose of
substance, if they would be „inflated“ or „diluted“ the same as in tested
sample Vd = D/C0
- only fictive value – it gives idea about the distribution of substance in
organism
rate constant of absorption (ka) a elimination (ke) inform about speed of these
procceses
clearance – volume of blood (resp. fraction of Vd), which per unit time fictively
completely clears from applied substance
-
clearance can be counted for the whole organism or for individual organs
and compartments
hepatic clearance informs about biotransformation ratio to elimination of drug
renal clearance determines how to reduce doses at kidney disorders
Secondary ph. p.
- derived from primary ph. parameters
biologic half-life – time, after which concentration (ammount) of given drug is
reduced to 50%
- plasmatic half-life – time, after which is reduced to 50% level of drug in blood
- elimination half-life – time, after which is eliminated from organism 50% of
applied drug
- equations: t1/2 = ln2/ke and t1/2 = ln2.Vd/CL, or approximately t1/2 = 0,7/ke and
t1/2 = 0,7.Vd/CL
- biologic half-life values are foundation for determining of intervals between
doses!!
area under the curve (AUC) concentration of drug gives an idea about changes
of concentration in time
bioavailability of drug form – determines quality of drug form
plasma level – informs about concentration of drug in circulation → at many
types of substances determines effect
-
-
Single dose – bolus
Most drugs are given as repeated doses
Too low doses – needed therapeutic effect isn´t reached, too high doses
– risk of cumulation
Administering of the same therapeutic doses – level of drug
progressively increases, till amout of absorbed and eliminated
substance is equal → steady state
This occurs after approximately 4 elimination half-lifes!