Transcript 19 Common pharmacology

COMMON PHARMACOLOGY
PHARMACOKINETICS
Passive diffusion
Distribution of drugs
Intensity of blood circulation in organs and
tissues:
 Tiopental after intravenous introduction first of all
penetrates into muscular tissue which is well
blood-supplied (there is necessity in repeated
introduction)
 Distribution and pharmacological effects of
drugs can decrease in case of organic blood
supply insufficiency (shock, haemostasis in large
blood circulation circle based on heart
insufficiency)
CONNECTION OF DRUGS WITH BLOOD
PLASMA PROTEINS
• Albumin, lipoproteins, 1-acid gycoprotein and
globulins
• specific proteins-carriers: glucocorticosteroids –
transcortin, vitamin В12 – transcobalamin, iron
ions – transferrin, copper ions – ceruloplasmin
free and bound with proteins forms of a drug stay
in condition of dynamic balance
drug bound with plasma proteins is
pharmacologically inactive !!!
• in case of hypoalbuminemia (liver diseases, kidney
disease, protein starvation, elderly): increasing of free
fraction of a drug, increasing of pharmacological
activity, development of toxic effects
• high level of connection to blood proteins: diazepam,
butamid, difenin, indometacin, furosemid, quinidine
• competition for binding with plasma proteins: sodium
valproate forces out difenin – increasing of free
fraction of the last - toxic effects
• high level of sulfadimetoxin, sulfapirydasin binding
with blood proteins causes prolongation of their action
VOLUME OF DISTRIBUTION
volume of distribution – imaginary volume in which
the drug is distributed in organism, if to let that organism
is a single space (single-camera model), and
concentration of the drug in blood plasma is equal to
concentration in tissues
Distribution volume is calculated according to a formula
Vd %
=
total quantity of the drug in organism
concentration of the drug in blood
plasmа
Vd of acetylsalycylic acid – 8 litter
Vd of rifampicin, lidokain, diazepam, anaprilin, digoxin –
65, 90, 210, 280, 600 litters correspondingly
Metabolism of drugs
Metabolism or
biotransformation complex of processes which provide
decreasing of toxicity and accelerate
excreting of the molecule of a drug or other
foreign substance after its incoming into the
organism
ORGANS OF DRUGS METABOLISM
• liver
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kidneys
muscle tissue
intestinal wall
lungs
skin
blood
The catalytic cycle of cytochrome P450
Drug-Induced Immune-Mediated Liver Injury
- DILI
Metabolism in the intestinal wall
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Synthetic and nonsynthetic reactions take
place
Isadrin – conjugation with sulfate
Hydrlalasin - acetylation
Penicillin, aminazin – metabolism with
nonspecific enzymes
Methotrexat, levodopa – metabolism with
intestinal bacteria
Enalapril, cefuroxim axetil, oseltamivir (tamiflu)
PRESYSTEMIC ELIMINATION
presystemic elimination – extraction of the
drug form blood circulatory system during
it’s first going through the liver (first pass
metabolism) – it leads to decreasing of
bioavailability (and therefore, decreasing of
biological activity) of drugs
propranolol
(anaprilin),
labetolol,
nitroglycerin, aminazin, acetylsalicylic acid,
hydralasin, isadrin, cortizone, lidokain,
morphin,
pentasocin,
organic
nitrates,
reserpin
Presystemic elimination
Factors that influence on drug metabolism
Factor
Reaction type
Age (newborns, Decreasing of metabolism speed
children, elderly)
Pregnancy
Increasing of metabolism speed
Genetic factor Various reactions
Liver pathology Decreasing of excreation speed of drugs, depending on their kinetics, type
and stage of liver disease, increasing of bioavailability and decreasing of
excretion speed of orally administered drugs with high hepatic clearence
GI pathology
Changes in metabolism in GI epithelium
Nutrition
character
Increasing of metabolism speed of certain drugs in case of diet with
dominance of proteins and carbohydrates
Decreasing of metabolism speed in case of heavy digestive disorders linked
with starvation (total or protein)
Environment
Alcohol
— one time
consumption
— chronic
consumption
Smoking
Way of
excretion
Increasing of metabolism speed if in contact
with chlorine insecticides
Depressing of enzymes that metabolise drugs
Induction of enzyme system
Increasing of metabolism of certain drugs (i.e.
theophyllin)
Metabolism in liver before entering system
circulation (first going-through effect) after
peroral administration of drugs
Circade changes in drugs metabolism
Time of
introduction of
drugs
Interaction of Stimulation
drugs
reaction
and
depression
of
enzyme
INTESTINAL-LIVER RECIRCULATION
Biotransformation of drugs into active
(or more active) metabolites
Initial drug
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Allopurinol
Amitriptilin
Acetylsalicylic acid
Butadion
Diazepam
Digitoxin
Codein
Cortizol
Methyldopa
Prednison
Novocainamid
Propranolol
Active metabolite
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Aloxantin
Nortriptilin
Salicylic acid
Oxyfenbutazon
Dismethyldiazepam
Digoxin
Morphine
Hydrocortizon
Methylnoradrenalin
Prednisolon
N-acetylnovocainamid
N-oxypropranolol
Elimination of the drugs
drugs can be excreted in forms of
metabolites or unchanged forms
through different ways: kidneys,
liver, lungs, intestines, sweat and
mammary glands etc.
Elimination through kidneys
filtration, canalicular secretion and
canalicular reabsorption
• filtration (relative molecular weight of drugs is less than 90,
if 90-300 – with urine and bile): ampicillin, gentamicin,
urosulfan, novokainamid, digoxin
• Disorders of filtration – shock, collapse (due to decreasing of blood
circulation and hydrostatic pressure of blood plasma in glomerular
capillaries)
• furosemid (closely connected with plamsa proteins) is not filtrated in
glomerular capilaries
• canalicular secretion – active process (with the aid of
enzyme system and using energy): penicillins, furosemid,
salicilates, chinin
• Disorders of canalicular secretion – in case of disorders of
energetic metabolism in kidneys: hypoxia, infections, intoxications
GENERAL PHARMACOLOGY
PHARMACODYNAMICS
PHARMACOLOGICAL EFFECTS
• Local: astringent, covering, irritating, local anesthesia,
necrotizing, adsorbing
• Reflectory: as a result of local irritating (Sol. Ammonii
caustici, Validolum, Charta Sinapis, expectorants of plant
origin)
• Resorbtive (systemic – after drug absorption or its
introduction to blood): 1) direct (primary) and 2)
indirect (secondary): cardiac glycosides: 1 – on heart,
2 – diuretic effect
• Selective action (salbutamol, celecoxyb, doxazosin)
• Nonspecific action – on all cells of the organism:
drugs for general anesthesia, salts of heavy metals
• Basic (beneficial) action an adverse reaction
• Reversible and irreversible
Receptors – specific cell sites
GABAc receptors
Opiate receptors
steroid-receptor
Serotonine receptor
TYPES OF RECEPTORS
Receptors-enzymes: acethylcholinestherase
(Proserine), monoaminoxydase in neurons of
CNS (Nialamid), angiotensin converting
enzyme (ACE-blockers – Captopril, Enalapril),
K-,Na- ATPase (cardiac glycosides - Digoxin),
H-,K-ATPase (proton pump) (Omeprasol),
COG-1, COG-2 (nonsteroidal antiinflammatory
agents – Diclofenac, Indometacin, Piroxycam,
Meloxicam etc.)
Receptors - enzymes
cholinesterase
Cox - Cyclooxygenase
MAO
ACEangiotensin converting enzyme
Receptors – ionic channels
sodium (Na+) channels
Voltage-dependent potassium channels
calcium channels
thyroid hormone receptor - genes
FOOD - DRUGS
Tea, coffee
Barbiturates
Haloperidolum, theophylline
↑ absorption
↓ absorption
Fructs’ and vegetables’ sour
juices
Calcium chloride,
tetracyclines, isoniazidum
↓ absorption
Milk
Tetracyclines, ampicilline,
griseofulvin, calciferol
↓ absorption
Thyramine-containing
MAO-inhibitors
products (aged cheese,
smoked meat and fish, beans,
bananas, red vine)
Cauli-flower, dogrose
Beans, tomatoes, liver,
kidneys
Indirect anticoagulants
Hormonal contraceptives
↑ toxicity
↓ of action (antagonism)
↓ of action (antagonism)
Food and bioavalability
Drugs
Spironolactone,
hydralazine
Anapriline,
hydantoine,
griseofulvini
Furosemid,
isoniaside,
cefalexine
absor
btion
bioaval
ability
Drugs and milk
• Glucocorticosteroids:
prednisolone,
dexamethasone
• NSAID: voltaren,
butadion, indometacine
• Increase of absorption
• Decrease of absorption
• Antibiotics: tetracyclines,
•
Decrease
of
absorption
fluoroquinolones
Antibiotics and tonic drinks
• Macrolides
(erythromycine,
spiromycine,
klaritromycine)
• Linkosamides
(linkomycine,
clindamycine)
• Tetracyclines
• Decreas of
absorption
• Decreas of activity
Tannin-containing products
• Alkaloids
(papaverine,
platyphylline,
codeine, reserpine)
• Decreas of
absorption
• Decreas of
therapeutic
activity
• Neuroleptics of
phenothiazine and
buthyrophenone
groups (aminazine,
haloperidole etc.)
tea
Green tea
• Xanthines
(Theophyllinum) –
Increase of absorption,
Increase of adverse
reactions (insomnia,
nervousness)
• Indirect
anticoagulants –
decrease of
effectivenes
Drugs and caffeine-containing products
Morphine, papaverine,
codeine, atropine,
aminazine, haloperidol,
hormonal contraceptives,
ergotamine
Decreas of
absorption
Decreas of
therapeutic
activity
Paracetamol,
aspirine
 increase
of
analgesic effect
Grapefruit juice
• Calcium antagonist,
terfenadine,
ciclosporine
• Decrease of
biotransformation in
liver, increase of their
blood concentration,
increase of toxicity
Diet in case of administration of IMAO
It is necessary to exclude such products which contain
DOPA and thiramine (which is formed from casein during the process
of transforming under the influence of bacteria)
Aged cheese, kefir
Marinated herring
Smoked meat and
fish
Red vine, beer, yeast
Beans, oranges,
tangerines,
lemons, grape,
chocolate,
bananas, caviar
(red and black)…
INFLUENCE OF BIOLOGICAL RHYTHMS
• Glucocorticoids are administered between 6
and 8 in the morning
• Theotard (long-acting form of theophylline) is
used in the evening (exacerbation of BA at
night)
• Maximum effect occurs if use diuretics till 10
a.m.
• Toxicity of Haloperidolum changes during the
day in 5 times
• Angina attacks more frequently appears from
2 to 6 p.m.