COMMON PHARMACOLOGY COMMON PHARMACOLOGYPHARMACOKINETICS

COMMON PHARMACOLOGY COMMON PHARMACOLOGY PHARMACOKINETICSPHARMACOKINETICS

Main principles of drugs penetration through biological membranes

• Barriers: oral administration - barriers of GI mucous membrane cells and endothelial cells of the vessels; intravenous administration – layer of endothelial cells

• 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 diffusionPassive 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 drugsDistribution 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 CONNECTION OF DRUGS WITH BLOOD PLASMA PROTEINSPLASMA 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 free and bound with proteins forms of a drug stay in condition of dynamic balancein condition of dynamic balance

drug bound with plasma proteins is drug bound with plasma proteins is pharmacologically inactive !!!pharmacologically inactive !!!

• in case of hypoalbuminemiain case of hypoalbuminemia ( (liver diseases, burn liver diseases, burn diseasedisease, , protein starvationprotein starvation, , elderlyelderly): ): increasing of free increasing of free fraction of a drugfraction of a drug, , increasing of pharmacological increasing of pharmacological activity, development of toxic effectsactivity, development of toxic effects

• highhigh level of connection of blood proteinslevel of connection of blood proteins: : diazepam, diazepam, butamid, difenin, indometacin, furosemid, quinidinebutamid, difenin, indometacin, furosemid, quinidine

• competition for binding with plasma proteinscompetition for binding with plasma proteins: : sodium sodium valproate forces out difeninvalproate forces out difenin – – increasing of free increasing of free fraction of the last - toxic effectsfraction of the last - toxic effects

• high level high level of sulfadimetoxin, sulfapirydasin binding of sulfadimetoxin, sulfapirydasin binding with blood proteins causes prolongation of their actionwith blood proteins causes prolongation of their action

Selective distribution of Selective distribution of drugsdrugs

causescauses peculiarities of pharmacodynamicspeculiarities of pharmacodynamics • iodineiodine – – thyroid glandthyroid gland – – synthesis of thyroid synthesis of thyroid

hormoneshormones• grizeofulvingrizeofulvin – – epidermisepidermis, , keratinkeratin – – treatments of treatments of

dermal and onichomicosisdermal and onichomicosis • cyanocobalamin cyanocobalamin – – red bone marrowred bone marrow – – synthesis synthesis

of erythrocytesof erythrocytes• furosemidfurosemid – – endolymph of inner earendolymph of inner ear – – ototoxicityototoxicity• cephalosporinscephalosporins – – cells of epithelium of kidney cells of epithelium of kidney

canaliculescanalicules – – nephrotoxicity nephrotoxicity • 1% 1% of introduced into organism cardiac of introduced into organism cardiac

glycosides distributes into heartglycosides distributes into heart

VOLUME OF DISTRIBUTIONVOLUME 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 drugsDepositing 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 METABOLISMORGANS OF DRUGS METABOLISM

• liverliver • kidneyskidneys• muscle tissuemuscle tissue• intestinal wallintestinal wall • lungslungs• skinskin• bloodblood

Microsomal enzyme systemMicrosomal 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, NADPH-

hydroxylase 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 CYP 450450

CYPCYP-450 – -450 – hemoproteinhemoprotein, , which is able to interact which is able to interact with substrate of oxydation, to activate oxygen and with substrate of oxydation, to activate oxygen and combine it with substratecombine it with substrate. . Specifically on CYSpecifically on CYР-450 Р-450 reactions of hydroxydation are performedreactions of hydroxydation are performed

large amount of isoforms of this enzymelarge amount of isoforms of this enzyme – – possibility of its binding with different substrates possibility of its binding with different substrates and taking part in their metabolismand taking part in their metabolism There are There are 24 24 isoforms of CYisoforms of CYР-450 Р-450 in microsomes in microsomes of human liverof human liver

Multiplicity of the enzyme has a group characterMultiplicity of the enzyme has a group character: : one isoform of CYone isoform of CYР-450 Р-450 interacts not only with interacts not only with one substrate but with a group of substancesone substrate but with a group of substances

The catalytic cycle of cytochrome P450The 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 InjuryDrug-Induced Immune-Mediated Liver Injury - DILI- 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 ELIMINATIONPRESYSTEMIC 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 eliminationPresystemic elimination

Factors that influence on drug metabolism

Factor Reaction type Age (newborns, children, elderly)

Decreasing of metabolism speed

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 Increasing of metabolism speed if in contact with chlorine insecticides

Alcohol — one time consumption

Depressing of enzymes that metabolise drugs

— chronic consumption

Induction of enzyme system

Smoking Increasing of metabolism of certain drugs (i.e. theophyllin)

Way of excretion

Metabolism in liver before entering system circulation (first going-through effect) after peroral administration of drugs

Time of introduction of drugs

Circade changes in drugs metabolism

Interaction of drugs

Stimulation and depression of enzyme reaction

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 lipid-soluble 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 kidneysfiltration, 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, undirectanticoagulants, radiopharmaceutical drugs (radioactive iodine etc.), Ergot alkaloids, chlorpropramid, cyclosporin

USING DRUGS DURING LACTATION(continuation)

UndesirableBromides, 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 GENERAL PHARMACOLOGY PHARMACODYNAMICSPHARMACODYNAMICS

PHARMACODYNAMICSPHARMACODYNAMICS

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 M-cholinoreceptos, 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-adreno-blocker, but activates 2-adrenoreceptors),

pentazocin (agonist delta- and kappa-opiate receptors and mu-receptors antagonist)

RECEPTOR THEORY OF DRUG ACTION

TYPES OF RECEPTORSTYPES OF RECEPTORS

Specific structures of cells: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

Opiate receptorsGABAc receptors

steroid-receptor Serotonine receptor

TYPES OF RECEPTORSTYPES 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 - enzymesReceptors - enzymes

cholinesteraseMAO

Cox - Cyclooxygenase 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 channelsReceptors – ionic channels

sodium (Na+) channels

calcium channelsVoltage-dependent potassium channels

thyroid hormone receptor thyroid hormone receptor - genes- genes

NONSPECIFIC ACTION OF DRUGSDue 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 drugsFactors effecting the properties of drugs

Exogenous Exogenous • chemical structure and physical-chemical

properties • pharmaceutical form and the ways of its

introduction • doses • regime of feeding • environment factors (meteorological, circadian

rhythm) EndogenousEndogenous

• 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 - DRUGSFOOD - DRUGS

Tea, coffee Fructs’ and vegetables’ sour juices Milk Thyramine-containing products (aged cheese, smoked meat and fish, beans, bananas, red vine) Cauli-flower, dogrose Beans, tomatoes, liver, kidneys

Barbiturates Haloperidolum, theophylline Calcium chloride, tetracyclines, isoniazidum Tetracyclines, ampicilline, griseofulvin, calciferol MAO-inhibitors Indirect anticoagulants Hormonal contraceptives

↑ absorption ↓ absorption ↓ absorption ↓ absorption ↑ toxicity ↓ of action (antagonism) ↓ of action (antagonism)

Food and bioavalabilityFood and bioavalability

Drugs absorbtion

bioavalability

Spironolactone, hydralazine

Anapriline, hydantoine, griseofulvini

Furosemid, isoniaside, cefalexine

Drugs and milk

• Glucocorticosteroids: prednisolone, dexamethasone

• NSAID: voltaren, butadion, indometacine

• Antibiotics: tetracyclines, fluoroquinolones

• Increase of absorption

• Decrease of absorption

• Decrease of absorption

Antibiotics and tonic drinksAntibiotics and tonic drinks

• Macrolides (erythromycine, spiromycine, klaritromycine)

• Linkosamides (linkomycine, clindamycine)

• Tetracyclines

• Decreas of absorption

• Decreas of activity

Tannin-containing productsTannin-containing products

• Alkaloids (papaverine, platyphylline, codeine, reserpine)

• Neuroleptics of phenothiazine and buthyrophenone groups (aminazine, haloperidole etc.)

• Decreas of absorption

• Decreas of therapeutic activity

tea

Green tea Green tea • Xanthines

(Theophyllinum) –Increase of absorption,

Increase of adverse reactions (insomnia, nervousness)

• Indirect anticoagulants – decrease of effectivenes

Drugs and caffeine-containing productsDrugs 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 juiceGrapefruit juice

• Calcium antagonist, Calcium antagonist, terfenadine, terfenadine, ciclosporineciclosporine

• Decrease of

biotransformation in liver, increase of their blood concentration, increase of toxicity

Diet in case of administration of IMAODiet in case of administration of IMAOIt 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, kefirMarinated herringSmoked meat and

fishRed vine, beer, yeast

Beans, oranges, tangerines,

lemons, grape, chocolate,

bananas, caviar (red and black)…

INFLUENCE OF BIOLOGICAL RHYTHMSINFLUENCE OF BIOLOGICAL RHYTHMS

• Glucocorticoids are administered between 6 Glucocorticoids are administered between 6 and 8 in the morningand 8 in the morning

• Theotard (long-acting form of theophylline) is Theotard (long-acting form of theophylline) is used in the evening (exacerbation of BA at used in the evening (exacerbation of BA at night)night)

• Maximum effect occurs if use diuretics till 10 Maximum effect occurs if use diuretics till 10 a.m.a.m.

• Toxicity of Haloperidolum changes during the Toxicity of Haloperidolum changes during the day in 5 timesday in 5 times

• Angina attacks more frequently appears from Angina attacks more frequently appears from 2 to 6 p.m.2 to 6 p.m.

Influence of sex of the patient on Influence of sex of the patient on drug actiondrug 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 Influence of pathological processes on drug actionon 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)PATHOLOGY OF ENZYMES (enzymopathya)

• Decreased activity of glucoso-6-phosphatdehydrogenase: 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 2-5 minutes

• Insufficiency of acethyltransferase in liver leads to violation of isoniazid, sulfonamides, novocainamid biotransformation