1. Specify the enteral route of drug administration:

1. intramuscular

2. subcutaneous

3. inhalation

4. inside

5. subarachnoid

2. What is typical for administering drugs by mouth?

1. rapid development of the effect

2. Possibility of use in an unconscious state

3. the possibility of using drugs that are destroyed in the gastrointestinal tract

4. the rate of entry of drugs into the general bloodstream is not constant

5. the need to sterilize injected drugs

3. Indicate the main mechanism of absorption of drugs in gastrointestinal tract:

1. facilitated diffusion

2. passive diffusion

3. active transport

4. pinocytosis

5.filtration

4. Indicate from which dosage form Is the drug absorbed faster when taken orally?

1. solution

2. suspension

3. tablets

4. capsules

5. What are the features child's body should be considered when dosing medications in children?

1. faster absorption of drugs than in adults

2. the permeability of histohematic barriers, including the BBB, is higher than in adults

3. the activity of microsomal liver enzymes is lower than in adults

4.lower speed glomerular filtration than in adults

6. What phenomenon may occur with repeated administration of drugs?

1. addictive

2. idiosyncrasy

3. summation

4. potentiation

5. synergy

7. What is the accumulation of a medicinal substance in the body during repeated administrations called?

1. idiosyncrasy

2. sensitization

3. summation

4. material cumulation

5. functional cumulation

8. What phenomenon can occur when combined use medications?

1. idiosyncrasy

2. functional cumulation

3. addictive

4. material cumulation

5. synergy

9. Which of the following statements is true of a drug that is eliminated according to first-order kinetics?

1. the half-life of a drug is proportional to its plasma concentration

2. the rate of drug elimination is proportional to its plasma concentration

3. the amount of drug that is eliminated per unit of time is a constant value

4. elimination of this drug occurs due to rate-limited enzymatic reactions, which flow at their maximum speed

5. The graph of drug concentration versus time in semi-logarithmic coordinates is a curved line

10. What type of action belongs to drugs that restore the activity of the central nervous system to normal in diseases accompanied by mental and motor agitation?

1. tonic

2. stimulating

3. sedative

4. depressing

5. paralyzing

11. The presence of which genetically determined enzymopathy can lead to hemolytic jaundice when drugs with high oxidative potential (quinine and others) are introduced into the body:

1. deficiency of the enzyme glucose-6-phosphate dehydrogenase

2. methemoglobin reductase deficiency

3. uridine diphosphate glucuronyl transferase deficiency

4. N-acetyltransferase deficiency

5. pseudocholinesterase deficiency

12. Note an example of pharmaceutical incompatibility of drugs when used in combination:

1. calcium chloride forms insoluble complexes with tetracyclines in the stomach, which complicates their absorption

2. when amidopyrine (powder) and acetylsalicylic acid (powder) are stored together, the mixture becomes damp and inactive amidopyrine salicylate is formed

3. the a-adrenergic blocker phentolamine “perverts” the effect of the a-adrenergic agonist epinephrine (adrenaline) on blood pressure

4. bendazole (dibazole), which directly inhibits vascular myofibrils, reduces the vasoconstrictor effect of phenylephrine (mesatone), which stimulates a-adrenergic receptors in the vascular wall

5. furosemide shortens and weakens the effect of many drugs, promoting their excretion

13. Mark an example of pharmaceutical incompatibility:

1. furosemide shortens and weakens the effect of many drugs by promoting their excretion

2. phenobarbital weakens the effect of ethyl biscoumarin (neodicoumarin) by inducing microsomal liver enzymes

3. atropine weakens the effect of the M-cholinomimetic pilocarpine on smooth muscle, blocking M-cholinergic receptors

4. Papaverine hydrochloride forms a precipitate when mixed with solutions of digitalis preparations

5. neomycin enhances the ototoxic effect of streptomycin due to their accumulation in the perilymph

14. The concept of tachyphylaxis means:

1. accumulation of the drug in the body

2. enhancing the effect of one drug under the influence of another

3. weakening of the effect of one drug substance under the influence of another

4. rapid decrease in effect with repeated administration of drugs

5. drug addiction

15. The weakening of the effect of one medicinal substance under the influence of another is called:

1. antagonism

2. idiosyncrasy

3. cumulation

4. synergy

5. addictive

16. Strengthening the effect of one medicinal substance under the influence of another is called:

1. antagonism

2. idiosyncrasy

3. cumulation

4. synergy

5. addictive

17. Note an example of pharmacodynamic incompatibility of drugs when used in combination:

1. Papaverine hydrochloride, when mixed in one syringe with digitalis preparations, forms a sediment

2. furosemide shortens and weakens the effect of many drugs by promoting their excretion

3. Ferrous sulfate forms insoluble complexes with tetracyclines, which complicates their absorption

4. phenobarbital weakens the effect of ethyl biscoumarin (neodicoumarin) by inducing microsomal liver enzymes

5. atropine weakens the effect of the M-cholinomimetic pilocarpine on smooth muscles by blocking M-cholinergic receptors

18. What term refers to the effect of drugs during pregnancy that leads to congenital deformities?

1. mutagenic

2. carcinogenic

3. teratogenic

4. embryotoxic

5. fetotoxic

19. After administration of 100 mg medicine, its steady-state concentration in blood plasma was 10 mg/l. Volume of distribution of this medicine:

1. 10 liters

2. 0.1 liters

3. 90 liters

4. 110 liters

5. 1000 liters

20. How much of the drug will remain in the blood after a single infusion, after 2 half-lives of this drug have passed:

21. With continuous intravenous infusion, to achieve a steady-state concentration of the drug in the blood, a period of time is required that is approximately:

1. 4 half-lives of this drug

2. 3 half-lives of this drug

3. 2 half-lives of this drug

4. 1 half-life of this medicine

5. double the infusion time of this medication

22. The steady-state concentration of a drug in the blood is 10 mg/l, the half-life of this drug is 2 hours. After what period of time, after stopping the administration of the drug, will its concentration in the blood be 1.25 mg/l?

1. in 1 hour

2. in 2 hours

3. in 3 hours

4. in 4 hours

5. in 6 hours

23. Which of the following statements is true:

1. drugs that are administered intravenously undergo first-pass metabolism

2. the disadvantage of the inhalation route of administration is very slow absorption

3. passive diffusion requires the presence of special carrier proteins and is characterized by saturable kinetics

4. bioavailability of drugs administered intravenously is 100%

5. An extremely large volume of distribution value indicates that the drug is rapidly metabolized

24. Conjugation of drugs with glucuronic acid:

1. reduces the hydrophilicity of these products

2. usually leads to inactivation of these agents

3. is an example of phase I reactions of drug metabolism

4. is the leading metabolic pathway in newborns

5. catalyzed by the cytochrome P 450 system

25. All of the following statements are true EXCEPT:

1. acetylsalicylic acid (pK a = 3.5) at pH = 2.5 is 90% in a non-ionized state

2. the weak base promethazine (pK a = 9.1) is more ionized at pH = 7.4 than at pH = 2.0

3. absorption of weak bases from the intestine is faster than from the stomach

4. An increase in urine acidity accelerates the excretion of a weak base with pK a = 8.0

5. non-ionized molecules penetrate cell membranes better than ionized, charged molecules

26. Which of the following statements is correct?

1. weak bases are quickly and completely absorbed through the epithelial cells of the stomach

2. simultaneous oral administration of another drug with atropine accelerates the absorption of this drug

3. a drug with a large volume of distribution can be quickly removed from the body by hemodialysis

4. states of shock may cause slower absorption medicinal product

5. if the volume of distribution of the drug is small, then most of it is located in the extravascular compartment of the body

27. What characterizes such a pharmacokinetic indicator as the half-life?

1. rate of absorption of drugs in the gastrointestinal tract

2. nature and rate of distribution in tissues

3. speed of biotransformation

4. rate of elimination from the body

5. degree of binding to blood proteins

28. The end of the action of the drug implies that...

1. the medicine must be eliminated from the body for its effect to cease

2. drug metabolism always leads to an increase in its solubility in water

3. metabolism of a drug always deprives it of pharmacological activity

4. Hepatic metabolism and renal excretion are the two most important mechanisms that are involved in this process

5. distribution of the drug in the extravascular space ensures the cessation of its action

29. All of the following statements regarding routes of drug administration are correct EXCEPT:

1. the level of concentration of a substance in the blood often increases faster when it is intramuscular injection than when administered orally

2. the first pass effect is the result of the metabolism of the drug after its administration, but before it enters the systemic circulation

3. the prescription of antiasthmatic drugs in the form of inhaled aerosols is usually associated with a large number side effects than taking them orally

4. the bioavailability of most drugs is less when administered rectally in the form of suppositories than when administered intravenous administration

5. The entry of drugs into the body from transdermal films is often slower and is associated with less first-pass metabolism than when these drugs are taken orally

30. All of the following relate to drug transport mechanisms, EXCEPT:

1. water diffusion.

2. water hydrolysis.

3. lipid diffusion.

4. pinocytosis and endocytosis.

5. specialized transport involving vectors.

31. What is characteristic of the rectal route of administration?

1. rapid development of the effect

2. the possibility of drugs entering the general bloodstream, bypassing the liver

4. possibility of administering only suppositories

5. the need to follow a certain diet

32. What is characteristic of the sublingual route of administration?

2. possibility of introducing irritants

3. the need to sterilize injected drugs

4. the possibility of drugs entering the general bloodstream, bypassing the liver

5. Possibility of use in an unconscious state

33. What is characteristic of the inhalation route of administration?

1. slow development of the effect

2. rapid development of the effect

3. possibility of introducing irritants

5. possibility of introducing gases

34. Specify the parenteral route of administration:

1. inside

2. sublingually

3. rectal

4. inhalation

5. using a tube into the stomach

35. What characterizes such a pharmacokinetic indicator as bioavailability?

1. completeness and speed of entry of the drug into the general bloodstream

2. nature of distribution

3. metabolic rate

4. elimination rate

5. degree of binding by blood proteins

36. What characterizes such a pharmacokinetic indicator as clearance?

1. suction speed

2. completeness of absorption

3. nature of distribution

5. rate of drug elimination from the body

37. Indicate the main route of elimination of drugs from the body:

1. kidneys with urine

2. liver with bile

3. lungs with exhaled air

4. sweat glands with sweat

5. mammary glands with milk

38. Increased activity of microsomal liver enzymes most often leads to:

1. acceleration of drug inactivation

2. slowing down the inactivation of the drug

3. increased toxicity of the drug

4. enhancing the main effect of the drug

5. increasing number side effects

39. Indicate the main route of introduction of gases and volatile liquids into the body:

1. inside

2. intramuscularly

3. intravenously

4. inhalation

5. subarachnoid

40. For the purpose of local action, the following dosage forms are applied to the skin and mucous membranes:

1. powders

4. emulsions

5. all of the above are true

41. The pharmacological effect develops most quickly when drugs are administered:

1. subcutaneously

2. intramuscularly

3. intravenously

4. inside

5. sublingual

42. What is typical for administering drugs by injection?

1. faster development of effect than when taken orally

2. the possibility of using drugs that are destroyed in the gastrointestinal tract

3. Possibility of use in unconscious patients

4. the need to sterilize injected drugs

5. all of the above are true

43. Specify an enzyme blocker that blocks the formation of angiotensin II:

1. enoxaparin

2. captopril

3. prozerin

5. protamine sulfate

Absorption of the drug.

Absorption (from the Latin absorbeo - I absorb) (absorption) is the overcoming of barriers separating the site of drug administration and the bloodstream. The completeness of absorption depends on various factors: dosage form, degree of grinding, pH of the medium, enzyme activity, solubility, presence of food in digestive tract etc. Penetration into the blood is a prerequisite for successful pharmacotherapy for most resorptive drugs.

For each medicinal substance, a special indicator is determined - bioavailability. It is expressed as a percentage and characterizes the rate and extent of drug absorption from the site of administration into the systemic circulation and accumulation in the blood in a therapeutic concentration. Determination of bioavailability is a mandatory process when developing and testing new drugs. Bioavailability is affected by the amount of drug released from the tablet, the destruction of substances in the gastrointestinal tract, impaired absorption due to high peristalsis, and the binding of drugs to various sorbents, as a result of which they cease to be absorbed.

Some substances have very low bioavailability (10-20%), despite the fact that they are well absorbed from the gastrointestinal tract. This is due to the high degree of their metabolism in the liver. The higher the bioavailability, the more valuable the systemic drug.

The penetration of a drug into the cells and tissues of the body is associated with its transfer in liquid media and entry from the blood through various cellular barriers. Several physicochemical and physiological mechanisms, the main ones being diffusion and filtration.

Distribution of medicinal substances in the body, deposition.

After the drug enters the bloodstream, it spreads throughout the body and is distributed in accordance with its physicochemical and biological properties. The uniformity or unevenness of distribution is determined by the sensitivity of organs and tissues to substances, as well as their inability to penetrate biological barriers: blood-brain barriers (prevents the penetration of substances from the blood into the central nervous system), hemato-ophthalmological (prevents the penetration of substances from the blood into the tissues of the eye), placental (prevents the penetration of substances from the mother's body into the fetus's body). Special barriers are the skin and cell membranes.

Fig.1 Dependence of drug distribution on physicochemical properties

Wall blood vessel has the character of a porous membrane. Hydrophilic compounds penetrate into the vessel through the pores of the membrane due to filtration, and lipophilic compounds penetrate directly through the membrane structures by simple diffusion. Then from the vessels the substance penetrates into the interstitial (intercellular) fluid surrounding the vessels. Of these, lipophilic substances easily penetrate into nearby cells, while hydrophilic substances have an extracellular location. (Fig.1)

During the process of distribution in the body, part of the drug substance can accumulate (deposit) in organs and tissues. Many substances combine with blood plasma proteins. In this state, they are inactive and do not penetrate well into other organs and tissues. But from these bonds or “depots” part of the active drug substance is gradually released, which has pharmacological action. This ensures prolongation of the action of the drug.

Metabolism of drugs.

Organic substances undergo various chemical transformations (biotransformations) in the body. There are two types of transformations of medicinal substances: metabolic transformation and conjugation. Metabolic transformation is the transformation of substances due to oxidation, reduction and hydrolysis. Conjugation is a biosynthetic process accompanied by the addition of a number of chemical groups to a drug substance or its metabolites. (Fig.2)

Rice. 2 Pathways of biotransformation of drugs in the body

These processes entail the inactivation or destruction of medicinal substances (detoxification), the formation of less active compounds, hydrophilic and easily excreted from the body.

Sometimes, as a result of the metabolism of certain substances, more active compounds are formed - pharmacologically active metabolites. In this case we are talking about a “prodrug”.

The main role in biotransformation belongs to microsomal enzymes of the liver, so we are talking about the barrier and neutralizing function of the liver. In case of liver diseases, biotransformation processes are disrupted and the effect of drugs is somewhat enhanced (with the exception of “prodrugs”).

The release of drugs from the body (excretion).

Medicinal substances are eliminated from the body unchanged or in the form of metabolites after a certain time. Hydrophilic (water-soluble) substances are excreted by the kidneys. Most drugs are isolated in this way. Therefore, in case of poisoning, diuretics are administered to speed up the removal of poison from the body (Fig. 3).

Many lipophilic (fat-soluble) drugs and their metabolites are excreted through the liver as part of the bile that enters the intestine. Drugs and their metabolites released into the intestines with bile can be excreted in feces, absorbed back into the blood, or be metabolized by bile and intestinal enzymes. Thus, the drug remains in the body for a long time.

This cyclic process is called enterohepatic circulation (enterohepatic cumulation) - digitoxin, diphenin. This must be taken into account when prescribing drugs that have a toxic effect on the liver to patients with liver disease.

Medicinal substances can be excreted through the sweat and sebaceous glands (iodine, bromine, salicylates). Volatile drugs are released through the lungs in exhaled air. The mammary glands secrete various compounds in milk (hypnotics, alcohol, antibiotics, sulfonamides), which should be taken into account when prescribing the drug to nursing women.

The process of freeing the body from a drug as a result of inactivation and excretion is designated by the term elimination (from Latin - eliminare - to expel).

Excretion rate constant is the rate at which drugs are eliminated through urine and other routes.

General clearance (from the English clearance - cleaning) of a drug is the volume of blood plasma cleared of drugs per unit of time (ml/min) due to excretion by the kidneys, liver and other routes.

Half-life (T0.5) is the time during which the concentration of a drug in plasma decreases by half from its initial value.

This indicator reflects the relationship between the volume of distribution and clearance of the substance. It is known that when a constant maintenance dose of a drug is administered at equal time intervals, on average, after 4-5 T0.5, its equilibrium concentration is created in the blood plasma (see below). Therefore, the effectiveness of treatment is most often assessed through this period.

The shorter T0.5, the faster it comes and stops therapeutic effect of the drug, the more pronounced are the fluctuations in its equilibrium concentration. Therefore, to reduce sharp fluctuations in equilibrium concentration during long-term therapy, retard forms of drugs are used.

After the drug enters the systemic circulation, it is distributed into the tissues of the body. Distribution is typically uneven due to differences in hemoperfusion, tissue binding (eg, varying fat content), local pH, and cell membrane permeability.

The rate at which a drug penetrates tissue depends on the rate of blood flow into the tissue, the size of the tissue, and the distribution patterns between the blood and the tissue. Balance of distribution (where the rates of penetration and elimination from tissue are the same) between blood and tissue is more quickly achieved in areas of rich vascularity if diffusion across the cell membrane is not a rate-limiting factor. Once equilibrium is reached, drug concentrations in tissue and extracellular fluids are proportional to plasma concentrations. Metabolism and elimination occur simultaneously with distribution, making the process dynamic and complex.

For the interstitial fluids of most tissues, the rate of drug distribution is determined primarily by perfusion. Poorly perfused tissues (eg, muscle, fat) are characterized by very slow distribution, especially if the tissue has a high affinity for the drug.

Volume of distribution

The apparent volume of distribution is the estimated volume of fluid into which the total amount of administered drug is distributed to create a concentration corresponding to that in the blood plasma. For example, if 1000 mg of a drug is administered and the plasma concentration is 10 mg/l, then 1000 mg is distributed in 100 l (dose/volume=concentration; 1000 mg/l=10 mg/l; hence: =1000 mg/10 mg/l=100 l). The volume of distribution has nothing to do with body volume or fluid content, but rather depends on the distribution of the drug in the body. For drugs that readily penetrate tissue barriers, a relatively small dose remains in the circulatory system and thus plasma concentrations will be low and volume of distribution high. Drugs that predominantly remain in the circulatory system often have a low volume of distribution. The volume of distribution characterizes the plasma concentration but provides little information about the specific mode of distribution. Each drug is unique in its distribution in the body. Some end up predominantly in fats, others remain in the extracellular fluid, and others are distributed into tissues.

Many acidic drugs (eg, warfarin, salicylic acid) are highly protein bound and thus have a low apparent volume of distribution. Many bases (eg, amphetamine, pethidine), in contrast, are highly absorbed into tissues and thus have an apparent volume of distribution greater than that of the entire body.

Binding

How a drug is distributed into tissue depends on its binding to plasma and tissue proteins. In the bloodstream, drugs are partially transported in solution as a free (unbound) fraction, and partially as a bound fraction (for example, with blood plasma proteins or blood cells). Of the numerous plasma proteins that can interact with a drug, the most important are albumin, acid glycoprotein and lipoproteins. Drugs whose solutions are acidic usually bind more intensely to albumin. Bases, on the contrary, are with acidic glycoprotein and/or lipoproteins.

Only an unbound drug is capable of passive diffusion into extravascular spaces or tissues where its pharmacological action occurs. Therefore, the concentration of unbound drug in big circle blood circulation usually determines its concentration at the site of the effect and, thus, the severity of the latter.

At high concentrations, the amount of bound drug reaches a maximum determined by the number of binding sites available. Saturation of binding sites is the basis of the displacement effect in drug interactions.

Medicines are able to bind to various substances, not just proteins. Binding usually occurs when a drug interacts with a macromolecule in a liquid medium, but can also occur when it penetrates into adipose tissue body. Since fat is poorly perfused, the time to reach steady state is usually long, especially if the drug is highly lipophilic.

The accumulation of drugs in tissues or areas of the body may prolong their effect because the tissues release the accumulated drug as its plasma concentration decreases. For example, thiopental has significant lipid solubility, quickly penetrates the brain after a single intravenous injection and is characterized by the development of a pronounced and rapid anesthetic effect; its effect then wears off within a few minutes as it is redistributed into slowly perfused adipose tissue. Thiopental is then slowly released from adipose tissue, maintaining subanesthetic plasma concentrations. However, upon repeated administration, these concentrations may become significant, causing the drug to large quantities accumulates in adipose tissue. Thus, this process first shortens the effect of the drug, but then prolongs it.

Some drugs accumulate in cells due to binding to proteins, phospholipids or nucleic acids. For example, the concentration of chloroquine in white blood cells and hepatocytes can be a thousand times higher than in blood plasma. The drug in the cells is in equilibrium with its concentration in the blood plasma and moves there as the plasma fraction is eliminated from the body.

Blood-brain barrier

Medicines reach the central nervous system through the capillaries of the brain and cerebrospinal fluid. Although the brain receives about a sixth cardiac output, the distribution of drugs into brain tissue is limited because the permeability of the brain differs from that of other tissues. Some fat-soluble drugs (for example, thiopental) easily penetrate the brain, but this cannot be said about polar compounds. The reason for this is the blood-brain barrier, which consists of the endothelium of the brain capillaries and the astrocytic-glial membrane. The endothelial cells of brain capillaries, which appear to be more closely connected to each other than the cells of most capillaries, slow the diffusion of water-soluble drugs. The astrocytic-glial sheath consists of a layer of glial connective tissue cells (astrocytes) located near the basement membrane of the capillary endothelium. As we age, the blood-brain barrier can become less effective, leading to increased penetration of various substances into the brain.

Medicines may end up in cerebrospinal fluid ventricles directly through the choroidal plexus, then passively diffuse into the brain tissue from the cerebrospinal fluid. In the choroid plexus, organic acids (for example, benzylpenicillin) are actively transferred from the cerebrospinal fluid into the blood.

As for cells of other tissues, the rate of penetration of a drug into the cerebrospinal fluid is determined mainly by the degree of protein binding, the degree of ionization and the solubility of the drug in fats and water. The rate of penetration into the brain is slow for drugs that are largely protein bound and very little for ionized forms of weak acids and bases. Since the central nervous system is well supplied with blood, the rate of drug distribution is determined primarily by permeability.

Metabolism

The liver is the main organ where drug metabolism occurs. Although metabolism usually results in drug inactivation, some metabolites are pharmacologically active, sometimes even more active than the parent compound. A parent substance that has little or no pharmacological activity but has active metabolites is called a prodrug, especially if it is intended to provide more complete delivery.

Medicines can be metabolized by:

oxidation;

recovery;

hydrolysis;

hydration;

conjugation;

condensation or isomerization.

However, whatever the process, its purpose is to facilitate the elimination process. Enzymes involved in metabolism are present in many tissues, but at the same time are predominantly concentrated in the liver. The rate of drug metabolism varies from person to person. Some patients metabolize drugs so quickly that therapeutically effective blood and tissue concentrations are not achieved. In other patients, metabolism may be so slow that usual doses have a toxic effect. The rate of metabolism of individual drugs depends on genetic factors, the presence of concomitant diseases (especially chronic diseases liver and decompensated heart failure) and drug interactions(especially involving induction or inhibition of metabolism).

The metabolism of many drugs occurs in two phases:

The first phase reactions include the formation of new or modification of existing functional groups, or the cleavage of the molecule (by oxidation, reduction, hydrolysis). These reactions are not synthetic.

Second phase reactions involve conjugation with endogenous substances (eg, glucuronic acid, sulfate, glycine) and are synthetic.

Metabolites formed as a result of synthetic reactions are more polar and are more easily excreted by the kidneys (urine) and liver (bile) than metabolites formed by non-synthetic reactions. Some drugs undergo only phase 1 or phase 2 reactions. Thus, the number of phases reflects a functional rather than a sequential classification.

Speed

For almost all drugs, the rate of metabolism along any pathway has an upper saturation limit. However, at therapeutic concentrations, most drugs occupy only a small fraction of the metabolizing enzyme's potential, and the rate of metabolism increases as drug concentration increases. In such cases, described as first-order elimination (or kinetics), the rate of drug metabolism is a constant fraction of the drug remaining in the body (rather than a constant amount of drug per hour), i.e. the drug has a defined half-life. For example, if 500 mg of a drug is present in the body at the zero point, 250 mg remains as a result of metabolism after 1 hour, and 125 mg after 2 hours (corresponding to a half-life of 1 hour). However, when the majority of enzyme binding sites are occupied, metabolism occurs at a maximum rate and is independent of the drug concentration in the blood, i.e., a fixed amount of drug is metabolized per unit time, which is described by the term “zero-order kinetics.” In this case, if 500 mg of the drug is present in the body at the zero point, then after 1 hour as a result of metabolism, 450 mg may remain, after 2 hours - 400 mg (which corresponds to a maximum clearance of 50 mg/h in the absence of a certain half-life value). As drug concentrations in the blood increase, metabolism, originally described by first-order kinetics, begins to follow zero-order kinetics.

Cytochrome P450

The most important enzymatic system of first-phase metabolism, cytochrome P450, is a family of microsomal isoenzymes that catalyze the oxidation of many drugs. The electrons required for this are provided by NADP H (with the participation of cytochrome P450 reductase, a flavoprotein that transfers electrons from NADP H, which is the reduced form of nicotinamide adenine dinucleotide phosphate, to cytochrome P450). Isoenzymes of the cytochrome P450 family can be induced and inhibited by many drugs and substances, thus causing the interaction of many drugs, when one of them increases the toxicity or reduces the therapeutic effect of another.

With age, the liver's ability to metabolize cytochrome P450 decreases by 30% or more as liver volume and blood flow activity decrease. Thus, in old age, drugs metabolized by these enzymes are characterized by higher concentrations and half-lives. At the same time, since newborns have an underdeveloped liver microsomal enzyme system, they have difficulty metabolizing many drugs.

Conjugation

Glucuronidation is the most common second phase reaction and the only reaction that occurs in liver microsomal enzymes. Glucuronides are secreted in bile and excreted in urine. Thus, conjugation makes most drugs more soluble, which makes them easier to eliminate by the kidneys. As a result of the conjugation of amino acids with glutamine or glycine, products are formed that are easily excreted in the urine and are secreted only in small quantities by bile. The intensity of glucuronidation does not depend on age, but in newborns the process of glucuronide formation occurs more slowly, which in some cases can cause serious undesirable effects.

Conjugation by acetylation and sulfoconjugation is also possible. Sulfated esters are polar and are easily excreted in urine. The intensity of these processes does not depend on age.

Excretion

The kidneys remove water-soluble substances and are the main excretory organs. The biliary system also facilitates the elimination of drugs, provided they are not reabsorbed into the gastrointestinal tract. Typically, the intestines, saliva, sweat, breast milk and lungs have little role in excretion, except for the removal of volatile anesthetic agents. Removal from breast milk, although it does not affect the mother, may affect the breastfed baby.

Metabolism in the liver often makes drugs more polar and thus more water soluble. Metabolites resulting from this process are more easily excreted from the body.

Renal excretion

Excretion of most drugs is accomplished by renal filtration. About 20% of the blood plasma entering the glomerulus is filtered by its endothelium, then almost all water and most electrolytes are passively or actively reabsorbed from the renal tubules back into the bloodstream.

However, polar compounds, which include most drug metabolites, cannot diffuse back into the bloodstream (in the absence of a specific transport mechanism for their reabsorption, for example, as is the case with glucose, ascorbic acid and B vitamins) and are excreted from the body. With age, drug excretion by the kidneys decreases. At the age of 80 years, the clearance value usually corresponds to 50% of the same value at the age of 30 years.

The pathways of drug transport in the kidneys are directly related to the mechanisms of transmembrane transport. Medicines bound to plasma proteins remain in the bloodstream. As a result, the glomerular filtrate contains only an unbound portion of the drug. Non-ionized forms of drugs and their metabolites tend to be readily reabsorbed from the tubular lumen.

Urinary pH, ranging from 4.5 to 8.0, can also have a marked effect on drug reabsorption and excretion by determining whether a weak acid or base is in non-ionized or ionized form. Acidification of urine increases reabsorption and decreases excretion of weak acids and decreases reabsorption of weak bases. Alkalinizing the urine has the opposite effect. In some cases of overdose, these principles are used to enhance the excretion of weak bases or acids, for example, the urine is made alkaline to enhance the excretion of acetylsalicylic acid. The extent to which changes in urine pH affect the rate of drug excretion depends on the extent to which the kidneys participate in the overall elimination of the drug, the polarity of the non-ionized form, and the degree of ionization of the molecule.

Active secretion in the proximal tubules is of great importance in the elimination of many drugs. This energy-dependent process can be blocked by metabolic inhibitors. At high drug concentrations, secretory transport can reach a higher limit (transport maximum). Each substance has a characteristic transport maximum.

The transport of anions and cations is controlled by special mechanisms. Typically, the anionic secretory system removes metabolites conjugated to glycine, sulfate, or glucuronic acid. In this case, the anions ( weak acids) compete with each other for excretion, which can be used for therapeutic purposes. For example, probenecid typically blocks the rapid tubular secretion of benzylpenicillin, resulting in higher plasma concentrations of the latter over a longer period of time. In the cationic transport system, cations or organic bases (eg, pramipexole, dofegilide) are secreted by the renal tubules. This process can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol or ketoconazole.

Excretion in bile

Some drugs and their metabolites are actively excreted in the bile. Since they are transported across the biliary epithelium against a concentration gradient, active transport mechanisms are required. At high concentrations of the drug in the blood plasma, secretory transport may approach the highest limit (transport maximum). Substances with similar physical and chemical properties may compete for excretion.

Drugs with a molar mass greater than 300 g/mol and having polar and lipophilic groups are most likely to be excreted in the bile. Smaller molecules are usually eliminated by this route only in small quantities. Conjugation with glucuronic acid facilitates excretion into bile.

During enterohepatic circulation, the drug secreted in bile is reabsorbed into the bloodstream from the intestine. Biliary excretion removes substances from the body only when the enterohepatic cycle becomes incomplete, that is, when a certain part of the secreted drug is not reabsorbed from the intestine.

Pharmacodynamics

Pharmacodynamics sometimes refers to the effects a drug has on the body, including receptor binding (including receptor sensitivity), post-receptor effects, and chemical interactions. Pharmacodynamics, together with pharmacokinetics (the effect of the body on the drug), allows us to explain the effects of the drug.

The pharmacodynamics of a drug may be affected by changes that occur as a result of disorders in the body, aging, or the effects of other drugs. Conditions that affect the pharmacodynamic response include mutations, thyrotoxicosis, malnutrition, myasthenia gravis, and some forms of non-insulin-dependent diabetes mellitus.

These conditions may affect receptor binding, alter the concentration of binding proteins, or reduce receptor sensitivity. With age, it is also possible that the pharmacodynamic response may change due to changes in receptor binding or post-receptor effects. Pharmacodynamic drug interactions result in competition for receptor binding or changes in the post-receptor response.

Option #1

1. What does the concept of “pharmacodynamics” include?

1. Absorption of drugs. 2. Distribution of drugs in the body. 3. Deposition of medicinal substances. 4. Localization of the action of medicinal substances. 5. Mechanisms of action. 6. Pharmacological effects. 7. Types of action. 8. Biotransformation. 9. Removal of drugs from the body.

1. What is the accumulation of drugs in the body during repeated administration called?

1. Functional cumulation. 2. Material cumulation. 3. Sensitization.

1. With repeated use of drugs, the following may occur:

1. Antagonism; 2. Habituation; 3. Cumulation; 4. Tachyphylaxis; 5. Drug addiction.

Task.

WHAT CHARACTERISTICS (A-B) CORRESPOND TO THE PROPERTIES OF A FULL AGONIST, PARTIAL AGONIST AND ANTAGONIST?

The influence of internal and external environmental factors on the action of medicinal substances. The body's reactions to repeated and combined effects of drugs.

Option No. 2

Answer the test control questions, indicate one or more correct answers:

List 4 main “targets” for medicinal substances:

1. Specific receptors. 2. Structural proteins. 3. Transport systems. 4. Ion channels. 5. Enzymes.

What is characteristic of addiction to a drug upon repeated administration?

1. An irresistible desire to constantly take the drug. 2. Strengthening the effect of the medicinal substance. 3. Weakening the effect of the drug. 4. Abstinence when stopping a drug.

The concept of “pharmacodynamics” includes:

1. Mechanism of action; 2. Types of action; 3. Biotransformation of drugs; 4. Localization of action; 5. Pharmacological effects.

Task.

WHICH SUBSTANCE (A-B) IS A FULL AGONIST, PARTIAL AGONIST, ANTAGONIST?

The influence of internal and external environmental factors on the action of medicinal substances. The body's reactions to repeated and combined effects of drugs.

Option #3

Answer the test control questions, indicate one or more correct answers:

Affinity:

What characterizes physical drug dependence?

1. An irresistible desire to constantly take the drug. 2. Improvement in well-being after taking the drug. 3. Possibility of rapid drug withdrawal in the treatment of drug addiction. 4. The need to gradually reduce the dose of the drug in the treatment of drug addiction. 5. Abstinence.

With combined administration of medicinal substances, the following may be observed:

1. Additive effect; 2. Antagonism; 3. Addiction; 4. Potentization.

Task.

WHAT IS THE CHARACTER OF INTERACTION between SUBSTANCES A and B WHEN THEIR COMBINED APPLICATION (A+B)?

Average values ​​with confidence limits are given.

The influence of internal and external environmental factors on the action of medicinal substances. The body's reactions to repeated and combined effects of drugs.

Option No. 4

Answer the test control questions, indicate one or more correct answers:

Internal activity:

1. The ability of a substance to bind to specific receptors. 2. The ability of a substance to cause an effect when interacting with receptors. 3. The dose at which the substance causes the maximum effect.

What is the term for unusual reactions to drug administration?

1. Sensitization. 2. Tachyphylaxis. 3. Idiosyncrasy.

Medicines are combined to:

1. Reducing the manifestation of negative effects of drugs; 2. Increased therapeutic effect; 3. Increasing the therapeutic concentration of one of the drugs in the blood; 4. Acceleration of the elimination of one of the drugs from the body.

Task.

WHAT IS AN OBSERVED INTERACTION OF TWO DRUGS CALLED?

Registration of changes in the amplitude of contractions of the gastrocnemius muscle during electrical stimulation of the motor nerve. 1 – after the administration of pipecuronium, 2 – against the background of inhalation of ether and subsequent administration of pipecuronium.

The influence of internal and external environmental factors on the action of medicinal substances. The body's reactions to repeated and combined effects of drugs.

a perverted reaction of the body to the administration (even once) of a medicinal substance

increased sensitivity of the body to the drug

23. The accumulation of drugs in the body during repeated administration is called:

material cumulation

functional cumulation

sensitization

24. Sensitization underlies:

1. allergies

2. idiosyncrasies

3. tachyphylaxis

4. cumulation

25. A sign of addiction to drugs is called:

feeling better after taking the medicine

increasing the body's sensitivity to the drug

irresistible urge to take a drug

insomnia

26. Next to the name of the dose, indicate its definition

Dose name Dose determination:

coursework a) amount of substance per dose

single b) dose that has a therapeutic effect

daily d) number of drugs per course of treatment

4. toxic c) the amount of drugs per dose during the day

5. therapeutic e) the amount of drugs causing dangerous

toxic effects on the body

27. The dose of the drug for a 3-year-old child is:

1/24 adult dose

1/12 adult dose

1/3 adult dose

1/8 adult dose

28. Combine:

Negative type of action Definition

1. teratogenic a) fetal deformity

2. mutagenic b) stimulation of malignant growth

3. carcinogenic tumors

4. ulcerogenic c) ulceration of the mucous membrane of the gastrointestinal tract

d) damage to the cell of the genetic appa-

29. Combine:

Term Definition

1. tachyphylaxis a) an irresistible desire to repeat

2. drug addiction taking drugs

3. sensitization b) severe and somatic disorders

4. withdrawal syndrome of the body, after a sudden cessation of

drug administration

c) increasing the sensitivity of the organization

ma to the action of the drug

d) rapid weakening of the drug effect with

its reintroduction

30. Most of the drug is absorbed:

in the oral cavity

in the stomach

in the small intestine

in the large intestine

31. Which substances penetrate the cell membrane more easily:

1. lipophilic

2. hydrophilic

32. Combine:

1. antagonist a) interaction with the receptor, causes

effect less than maximum

2. agonist b) interaction with the receptor, causes

maximum effect

3. partial agonist c) blocks the receptor

4. agonist-antagonist d) interacts with receptors; incentive

lyates one receptor subtype and blocks

there is another subtype

33. The release of drugs from the body is called:

1. elimination

2. excretion

3. metabolism

4. esterification

34. The main ways of removing drugs from the body include:

intestines

mammary glands

35. Predominant implementation of biotransformation of most drugs in the body:

36. A drug undergoes the greatest breakdown in the liver when administered:

into the rectum

37. Oil solutions cannot be administered:

1. intramuscularly

2. intravenously

3. inhalation

4. subcutaneously

38. Side effects of drugs are:

action that the doctor expects

action that depends on dose

undesirable action that interferes with the manifestation of the main action