Download ELIMINATION OF DRUGS

COMMON PHARMACOLOGY
PHARMACOKINETICS
• Barriers: oral administration - barriers of GI mucous
membrane cells and endothelial cells of the vessels;
intravenous administration – layer of endothelial cells
Main principles of drugs penetration through biological
membranes
• epithelium in small intestine
is well penetrable – it contains
multiple channels (canalicules) through which molecules
with relatively low molecular weight (most of drugs) can
penetrate; stomach has no canalicules – strong epithelium
• penetration of drugs through cellular membranes - universal
mechanisms (role in absorption, distribution, excretion):
passive diffusion, facilitated diffusion (with a help of special
carriers), filtration, active transport and pinocytosis
• Passive diffusion – along with gradient of concentration (from the
zone with higher concentration to the zone with lower concentration ; it
doesn’t need any energy and lasts until concentration of the substance
from both sides of the membrane becomes equal): acetylsalicylic acid,
aminazin, quinine, ether
• Facilitated diffusion – with the help of proteins-transporters: glucose,
aminoacids, vitamins (specific gastromucoprotein synthesized in
stomach is necessary for absorption of vitamin В12 in small intestine)
• Filtration – through pores in membrane, the size of which is around
0,35-0,8 nm. Substances with low molecular weight (water, urea etc.)
penetrate through pores. Ionized particles (cations, anions) practically
do not penetrate through pores (the reason is заряд on the cell
membrane)
• Active transport – is provided by specific transport systems of the
cells and needs energy since happens against gradient of
concentration: cardiac glycosides, glucocortecosteroids, input of
iodine into thyroid gland
• Pinocytosis – in the place of drug molecule contact cell membrane
invagination with formation of a vesicle happens, this vesicle plunges
into cell: proteins, nucleonic acids, fat soluble vitamins
Passive diffusion
Distribution of drugs
size of molecules:
 high molecular substances (heparin, mannitol) or those closely
connected to plasma proteins do not penetrate through
endothelium and stay inside the vessels
 low molecular water soluble drugs penetrate through pores of
capillaries’ walls and enter intercellular space
level of solubility in lipids:
 fat soluble drugs go through cell membranes, HEB, placental and
other barriers, enter all organs and tissues
- drugs for general anesthesia, psychotropic drugs
- levomycitin, metronidazole (for meningitis)
- tubocurarin, ditilin, metacin, cephalosporines – do not go into
cerebral tissue
 creation of depot in fat tissue (ether, other drugs for narcosis –
after-narcosis depression)
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, burn
disease, protein starvation, elderly): increasing of free
fraction of a drug, increasing of pharmacological
activity, development of toxic effects
• high level of connection of 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
Selective distribution of drugs
•
•
•
•
•
•
causes peculiarities of pharmacodynamics
iodine – thyroid gland – synthesis of thyroid
hormones
grizeofulvin – epidermis, keratin – treatments of
dermal and onichomicosis
cyanocobalamin – red bone marrow – synthesis
of erythrocytes
furosemid – endolymph of inner ear – ototoxicity
cephalosporins – cells of epithelium of kidney
canalicules – nephrotoxicity
1% of introduced into organism cardiac
glycosides distributes into heart
VOLUME OF DISTRIBUTION
volume of distribution – imaginative 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 equals 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 plasma
Vd of acetylsalycylic acid – 8 litter
Vd of rifampicin, lidokain, diazepam, anaprilin, digoxin –
65, 90, 210, 280, 600 litters correspondingly
Depositing of drugs
• extra- and intracellular depot of drugs
• in blood plasma and on the ways of their excretion
from the organism
• ethambutol – in erythrocytes
• tetracyclins – in bone tissue, in teeth
• ampicillin, biseptol, nitroxolin, nalidixic
acid – in kidneys
• drugs for general anesthesia – in fat tissue
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
Reactions of
biotransformation
• Nonsynthetic - І phase
• Synthetic - ІІ phase
І phase (nonsynthetic reactions):
(oxydation, reduction, hydrolysis)
• 1) microsomal reactions
• 2) nonmicrosomal reactions
Reactions of І phase - transformation in
molecule with formation of functional
groups with active hydrogen atom
ORGANS OF DRUGS METABOLISM
• liver
•
•
•
•
•
•
kidneys
muscle tissue
intestinal wall
lungs
skin
blood
Microsomal enzyme system
Oxydoreductases, esterases,
enzymes of proteins, lipids,
glycerophosphatides, lipo- and
glycoproteids, bile acids, cholesterol,
prostaglandins biosynthesis, enzyme
systems of biosynthesis of couple
compounds, ethers of glucuronic
and sulfur acids
Oxydoreductases of microsomes (oxygenases of
microsomes, microsomal hydroxydating system, NADPHhydroxylase system,
monooxygenases of mixed functions)
–
these are enzymes which activate molecular oxygen and
catalize including of one (monooxygenase) or two
(dioxygenases) atoms of oxygen into molecule of substrate
(R) Reaction is presented as follows:
R + O2 + DН = ROH + H2O + D
One atom of О2 is included into molecule of the substrate,
other is reduced to Н2О, therefore enzyme performs
oxygenase and oxydase functions simultaneously. That’s
why monooxygenases ate also called oxydases of mixed
function. Along with this hydroxyl group (-ОН) forms in
molecule of substrate, that’s why monooxygenase is also
calles hydroxylating system, and reaction of oxydation –
oxydating hydroxylation
CYP 450
CYP-450 – hemoprotein, which is able to interact
with substrate of oxydation, to activate oxygen and
combine it with substrate. Specifically on CYР-450
reactions of hydroxydation are performed
large amount of isoforms of this enzyme –
possibility of its binding with different substrates
and taking part in their metabolism
There are 24 isoforms of CYР-450 in microsomes
of human liver
Multiplicity of the enzyme has a group character:
one isoform of CYР-450 interacts not only with
one substrate but with a group of substances
The catalytic cycle of cytochrome P450
Main ways of biotransformation of drugs
• I phase
•
Oxydation: diazepam, pentazocin, sydnocarb, phenotiazin,
phenobarbital, aspirin, butadion, lidokain, morphin, codein, ethanol,
rifampicin
• Reduction: hestagens, metronidazol, nitrazepam, levomycetin,
chlozepid
• Hydrolysis: levomycetin, novocain, cocain, glycosides, ditilin,
novocainamid, xycain, fentanyl
• II phase
• Conjugation with sulfate: morphin, paracetamol, isadrin
• Conjugation with glucuronic acid: teturam, sulfonamides,
levomycetin, morphin
• Conjugation with remains of  - aminoacids:
nicotinic acid,
paracetamol
• Acetylation: sulfonamides, isoniasid, novocainamid
• Methylation: morphin, unitiol, ethionamid, noradrenalin
Drug-Induced Immune-Mediated Liver Injury
- DILI
Metabolism in the intestinal wall
•
•
•
•
Synthetic and nonsynthetic reactions take
place
Isadrin – conjugation with sulfate
Hydrlalasin - acetylation
Penicillin, aminazin – metabolism with
nonspecific enzymes
Methotrexat, levodopa – metabolism with
intestinal bacteria
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, aminazin,
acetylsalicylic acid, labetolol, 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
Influence of body weight on kinetics of
drugs
• In exhausted patients – speeding up of elimination,
that’s why it’ s appropriate to introduce the
increased dose – 1+1/3
• In patients with overweighting – retention of lipidsoluble drugs in the organism
• For these patients it’s suitable to correct the dose
according to “ideal” body weight:
For men
ІBW = 50 + [(Н - 150) : 2,5]
For women
ІBW = 45 + [(Н - 150) : 2,5]
where Н – height in cm
• in case of normal body weight the dose is
calculated counting on 1 kg of patient’s body weight
Biotransformation of drugs into active
(or more active) metabolites
Initial drug
•
•
•
•
•
•
•
•
•
•
•
•
Allopurinol
Amitriptilin
Acetylsalicylic acid
Butadion
Diazepam
Digitoxin
Codein
Cortizol
Methyldopa
Prednison
Novocainamid
Propranolol
Active metabolite
•
•
•
•
•
•
•
•
•
•
•
•
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
Canalicular reabsorbtion
(reversed absorbtion)
lipid-soluble drugs are reabsorbed passively
ionized drugs, which are weak acids or alkali are
reabsorbed actively
regulation of level of reabsorbtion
- to speed up elimination of drugs – weak alkalis
(antihistamine drugs, chinin, theophyllin) urine is made
acidic (with ascorbinic acid, ammonium chloride)
- to speed up elimination of drugs – weak acids (NSAID,
including ASA, barbiturates, sulfonamides) urine is made
alkaline (introduction of sodium hydrocarbonate)
ELIMINATION OF DRUGS (continuation)
with bile – drugs and their metabolites with relative MM over
3000
enterohepatic (intestinal-liver) recirculation:
cardiac glycosides, morphine, tetracyclines
are excreted with bile in unchanged condition (previously not
metabolized): antibiotics of tetracyclines group, macrolides
through lungs – gases and volatile substances: ether for
narcosis, ftorotan, N2O, partly – camphor, iodides, ethanol
through intestine: ftalasol, enteroseptol, magnesium sulfate
through sweat glands: iodides, bromides, salicylates
through bronchial, salivary glands: bromides, iodides
with milk: get into organism of the baby – levomycetin, fenilin,
reserpin, lithium remedies, meprotan, tetracyclines,
sulfonamides etc.
USING DRUGS DURING LACTATION
Absolutely contraindicated
• Antibacterial: tetracyclins, levomycetin, fluoroquinolones,
sulfonamides, nalidixic acid, metronidazole
• Antiviral: amantadin, gancyclovir, zidovudin, remantadin
• Cytostatics
• Drugs effecting CNS: difenin, sodium valproate, lithium
preparations, barbiturates, reserpin, opioid analgesics (regularly)
• Drugs of other groups: iodides, antithyroid drugs, undirect
anticoagulants, radiopharmaceutical drugs (radioactive iodine
etc.), Ergot alkaloids, chlorpropramid, cyclosporin
USING DRUGS DURING LACTATION
(continuation)
Undesirable
Bromides, meprobamat, derivatives of benzodiazepine
(diazepam, chlozepid, oxazepam etc.), aminazin,
ethosuximid;
M-cholinoblockers, glucocorticosteroids (if dosage is over
100 mg per day), indometacin, salycylates (large doses),
derivatives of sulfonilurea, theophyllin, chloroquin,
nitrofuran derivatives (furazolidon etc.), isoniazid,
cymetidin, aluminum containing antacids, estrogens,
gold medications, retinoids
GENERAL PHARMACOLOGY
PHARMACODYNAMICS
PHARMACODYNAMICS
Pharmacological effect – clinical manifestation of
drug influence on the organism
Its basis is primary pharmacological reaction –
the result of drug influence on special structures of
the organism
• Pharmacological effects may be identical but caused
by different pharmacological reactions:
atropin and adrenalin dilates the pupils, 1st inhibits Mcholinoreceptos, 2nd – activates adrenoreceptors
• In contrary, different pharmacological effects may
appear due to the same pharmacological reaction:
anaprilinum causes β-adrenoreceptors blockade that
resulted in hypotension, antiarrhythmic action and
antianginal effect
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
RECEPTOR THEORY OF DRUG ACTION
Receptors – the places where drugs bind to
tissues: macromolecules, enzymes, channels,
transport systems, genes
• Agonists: adrenalin, isadrine, morphine etc.
• Antagonists: atropin, anaprilin, dimedrol etc.
Конкурентні та неконкурентні антагоністи
• Agonist-antagonist: labetolol (1, 1-adrenoblocker, but activates 2-adrenoreceptors),
pentazocin (agonist delta- and kappa-opiate
receptors and mu-receptors antagonist)
•
RECEPTOR THEORY OF DRUG ACTION
TYPES OF RECEPTORS
Specific structures of cells:
N- and M-cholinoreceptors, - і adrenoreceptors, dophamine-, opiate-,
histamine-, serotonin-, receptors to
angiotensin II, leucotryenic-, prostaglandine-,
polypeptic and steroid hormones etc.
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
RECEPTOR THEORY OF DRUG ACTION
• Receptors – ionic channels
• Na+ - channels – local anesthetics, antiepileptic,
antiarrhythmic drugs
• Са2+ - channels – Nifedipin, Amlodipin,
Verapamil, Dilthiazem
• Voltage-dependent К+- channels – Amiodaron,
Ornid (Brethylium tozylat), d-Sotalol
• АТP-dependent К+- channels:
- blockers - Butamid, Maninil (stimulate secretion
of insulin by -cells of pancreas)
- activators – Minoxidil, Diazoxid (decrease AP)
• Receptors - Genes
• Thyroid gland hormonal preparations
Receptors – ionic channels
sodium (Na+) channels
Voltage-dependent potassium channels
calcium channels
thyroid hormone receptor - genes
NONSPECIFIC ACTION OF DRUGS
Due to their physical and chemical properties
• Mannit increases osmotic pressure in kidneys
canalicules
• Direct chemical interaction: Antacides (MgO,
NaHCO3) neutralize HCl, Trilon B (EDTA)
binds salts of heavy metals, Na citrate binds
Ca-ions
• Physical-chemical interaction: Protamine
sulfate binds Heparin
• Due to the same structure with metabolites of
the organism drugs interferences with
corresponding metabolic processes :
Sulfonamides (have the same structure to
PABA), Mercaptopurin (to folic acid and purin)
Factors effecting the properties of drugs
Exogenous
structure
and
• chemical
physical-chemical
properties
• pharmaceutical form and the ways of its
introduction
• doses
• regime of feeding
• environment factors (meteorological, circadian
rhythm)
Endogenous
• age
• sex
• pregnancy
• diseases
Chemical structure and physical-chemical
properties
• Degree of ionization: methyl, ethylic group – weak ionization, high
lipidotropic activity; hydroxyl, amino-group – high ionization, high
hydrophilic properties, weak penetration through the membranes
• Fluoric atom in molecules of GCS, neuroleptics increases their
activity
• Space structure: distance between nitrogen-atoms 0,6-0,8 nm –
ganglionblockers, 1,4-1,5 nm – myorelaxants
• weak solubility in lipids – bad penetration through the membranes
(tubocurarini chloridum), high solubility in lipids – penetration
through the HEB (mellictin )
• Large active surface – enterosgel, activated charcoal
• Effecting of cell membranes with detergents
Pharmaceutical form and the routs of
its administration
these factors effecting the bioavailability
Bioavailability of drugs
complex of pharmacokinetic processes that
maintenance active concentration of drug in
the area of specific receptors (part of
administered drug that reaches the systemic
circulation and effects specific receptors)
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.
Influence of sex of the patient on
drug action
• Morphin, nicotine, coffeine – women are
more sensitive
• Changes of theophyllin, paracetamol,
prednisolon metabolism accordingly
different phases of menstrual circle
• Pregnancy – worse absorption and slow
biotransformation of drugs
• During menstruation anticoagulants can
course severe uterus bleeding
Influence of pathological processes
on drug action
• Myocarditis increases the toxicity of cardiac
glycosides
• Cardiac glycosides act only when cardiac
insufficiency
• Paracetamolum and other antipyretics act when
hyperpyrexia
• Pathology of liver leads to inhibition of drugs
metabolism and increases their toxicity
• Inhibition of drugs elimination is observed in
kidney pathology
• Smoking provokes risk of thrombosis during
administration of hormonal contraceptives
PATHOLOGY OF ENZYMES (enzymopathya)
• Decreased activity of glucoso-6phosphatdehydrogenase: sulfonamides,
levomycetinum, drugs for malaria, salicylates, vit C,
nitrates lead to hemolysis
• Insufficiency of catalase: H2O2 is not metabolized
with appearance a foam and can course severe burn of
wound
• Insufficiency of butyrilcholinesterase: duration of
dithylinum action changes to several hours instead of 25 minutes
• Insufficiency of acethyltransferase in liver leads to
violation of isoniazid, sulfonamides, novocainamid
biotransformation