Factors Influencing Effect of Drugs

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Factors Influencing Effect of Drugs
Pharmacocinetics
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Factors Influencing Effects of Drugs

• external
• Characteristic of the drug, way of application,
  doses and their intervals...
• They can be easily changed
• internal
• Patients characteristic
• Change is impossible or very problematic

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• 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

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• No irritation of stomach mucous membrane
• If patient cant 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

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• 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)

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• ? 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 funkcion
• 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

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• 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

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• Genetic factors
• genetically dependent changes
• pharmacodynamics
• - resistance to cumarines, decreased effect of
  ß-blocators among blacks
• pharmacokinetics
• - biotransformational polymorfism (slow, fast
  acetylators, hydrfoxylators)

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• 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)

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• Transport through membranes
• Always depends on time
• Speed of molecule transport through membranes
  speed of molecule changes (biotransformation) ?
  concentration in given place
• Pasive transport in the way of gradient
  (concentrational/electric)
• Free transfer
• Transfer through ion channels
• Basic diffusion through lipid membrane
• Transfer through intercellular pores
• Facilitated diffusion (through carrier, without
  energy need)
• Active transport against the way of gradient,
  carrier and energy needed
• Endocytosis carries out vakuolar aparatus of
  some cells (e.g. enterocytes)

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• 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!

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• 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 ? bioavailability1 (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

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• 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

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• 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

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• 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

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• 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 isnt
  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!

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