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

• epithelium in

membranes

– 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 В 12 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 tissues

:

in organs and

  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, globulins

 1

-acid gycoprotein and • specific proteins-carriers: glucocorticosteroids – transcortin, vitamin ions В

12

– transcobalamin, iron – 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 of erythrocytes – red bone marrow – synthesis • furosemid – endolymph of inner ear – ototoxicity • cephalosporins canalicules – cells of epithelium of kidney – nephrotoxicity • 1% of introduced into organism glycosides distributes into heart cardiac

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 tetracyclins

– in erythrocytes – 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, 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 + O 2 + D Н = ROH + H 2 O + D One atom of О 2 is included into molecule of the substrate, other is reduced to Н 2 О, therefore enzyme performs oxygenase and oxydase functions simultaneously. That’s why monooxygenases ate also called

oxydases of mixed function

calles . Along with this hydroxyl group (-

hydroxylating system

ОН) forms in molecule of substrate, that’s why monooxygenase is also , 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 CY Р-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 CY Р-450 in microsomes of human liver Multiplicity of the enzyme has a group character: one isoform of CY Р-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



paracetamol

- aminoacids:

nicotinic acid,

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 it’s first going through the liver (first pass metabolism) during – 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, pentasocin, organic nitrates, reserpin morphin,

Presystemic elimination

Factors that influence on drug metabolism Factor Reaction type

Age (newborns, children, elderly) Decreasing of metabolism speed Pregnancy Genetic factor Increasing of metabolism speed 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 — chronic Depressing of enzymes that metabolise drugs Induction of enzyme system consumption Smoking Way of excretion 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 Time of introduction of Circade changes in drugs metabolism drugs 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 soluble drugs in the organism – retention of lipid For these patients it’s suitable to correct the dose according to “ideal” body weight :

For men For women ІBW = 50 + [(Н - 150) : 2,5] 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): urosulfan, novokainamid, digoxin ampicillin, gentamicin, • 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

3000 – drugs and their metabolites with relative MM over 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 cholinoreceptos, 2 nd dilates the pupils, 1 st inhibits M – 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

tissues: – the places where drugs bind to macromolecules, transport systems, genes enzymes, channels,

Agonists: adrenalin, isadrine, morphine etc.

Antagonists: atropin, anaprilin, dimedrol

Конкурентні та неконкурентні антагоністи

Agonist-antagonist:

blocker, but activates etc.

labetolol

(  1 ,  1 -adreno  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 Opiate receptors GABAc 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 .)

cholinesterase Receptors - enzymes MAO Cox - Cyclooxygenase ACEangiotensin converting enzyme

RECEPTOR THEORY OF DRUG ACTION

• • • •

Receptors – ionic channels

Na + - channels

– local anesthetics, antiepileptic, antiarrhythmic drugs

Са 2+ - channels

– Nifedipin, Amlodipin, Verapamil, Dilthiazem

Voltage-dependent К + - channels

Ornid (Brethylium tozylat), d-Sotalol – Amiodaron,

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, NaHCO 3 Ca-ions ) neutralize HCl, Trilon B (EDTA) binds salts of heavy metals, Na citrate binds 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

• • • • • • • • •

chemical properties pharmaceutical introduction doses Exogenous structure form and and the physical-chemical ways of its regime of feeding environment rhythm) factors (meteorological, Endogenous age sex pregnancy diseases circadian

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 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 bioavalability

Drugs Spironolactone, hydralazine

absor btion bioaval ability

Anapriline, hydantoine, griseofulvini Furosemid, isoniaside, cefalexine

Drugs and milk

• Glucocorticosteroids: prednisolone, dexamethasone • NSAID: voltaren, butadion, indometacine • Increase of absorption • Decrease of absorption • Antibiotics: tetracyclines, fluoroquinolones • Decrease of absorption

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)

•

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

• •

Decreas of absorption Decreas of therapeutic activity tea

•

Xanthines (Theophyllinum) –

Increase of absorption, Increase of adverse reactions

(insomnia, nervousness)

•

Indirect anticoagulants – decrease of effectivenes

Green tea

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 DOPA It is necessary to exclude and thiramine such products which contain (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-6 phosphatdehydrogenase

: sulfonamides, levomycetinum, drugs for malaria, salicylates, vit C, nitrates lead to hemolysis

Insufficiency of catalase

: H 2 O 2 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