Основы фармакологии = Essentials of Pharmacology

  основы ФАРМАКОЛОГИИ


    ESSENTIALS
    OF PHARMACOLOGY

    Допущено
    Министерством образования Республики Беларусь в качестве учебного пособия для иностранных студентов учреждений высшего образования по специальностям «Лечебное дело», «Педиатрия»

    2-е издание, переработанное









         Минск
         «Вышэйшая школа» 2022

УДК 615(075.8)-054.6
ББК 52.81я73
     О-75



   Авторы: В.И. Козловский, В.П. Вдовиченко, О.А. Борисенок, В.В. Гончарук

   Рецензенты: кафедра фармакологии УО «Белорусский государственный медицинский университет» (кандидат медицинских наук, доцент А.В. Волчек); заведующий кафедрой общей и клинической фармакологии с курсом повышения квалификации и переподготовки кадров УО «Витебский государственный ордена Дружбы народов медицинский университет» доктор медицинских наук, профессор М.Р. Конорев; доцент кафедры современных технологий перевода УО «Минский государственный лингвистический университет» кандидат филологических наук, доцент Т.И. Голикова









         Основы фармакологии = Essentials of Pharmacology : учебное О-75 пособие / В. И. Козловский [и др.].—2-е изд., перераб. — Минск :
      Вышэйшая школа, 2022. — 287 с. : ил.
         ISBN 978-985-06-3396-5.

         Учебное пособие представляет собой систематизированную информацию по основным разделам фармакологии: общей фармакологии, нейротропным средствам, средствам, влияющим на функции сердечно-сосудистой, дыхательной и других систем организма, химиотерапевтическим средствам. В пособии даются основные аспекты фармакодинамики и фармакокинетики лекарственных средств, их применения в клинике.
         Предыдущее издание вышло в 2019 г.
         Для иностранных студентов учреждений высшего образования по специальностям «Лечебное дело», «Педиатрия».

УДК 615(075.8)-054.6
ББК 52.81я73

   Все права на данное издание защищены. Воспроизведение всей книги или любой ее части не может быть осуществлено без разрешения издательства.

ISBN 978-985-06-3396-5                  © Оформление. УП «Издательство
“Вышэйшая школа”», 2022

PREFACE


   This edition is an attempt to systematize the pharmacological information taught at Faculties of International Students with the English language instruction at Medical Universities of the Republic of Belarus. The information is organized according to the sequence used at many medical universities: basic principles, autonomic drugs, central nervous system drugs, cardiovascular drugs, and drugs influenced on other systems of the organism, anti-inflammatory drugs, endocrine drugs, chemotherapeutic drugs.
   The information is upgraded to up to date level of knowledge and based first of all on world standards of pharmacology. We used the modern data obtained in clinical and laboratory studies and published in the authoritative journals.
   Within each chapter, the emphasis is placed on the discussion of the drug groups and prototypes of these groups with more detailed information about pharmacological properties and clinical applications of the most important drugs.

     ABBREVIATIONS USED IN THE TEXT


         ACE — angiotensin converting enzyme
         ADHD — attention deficit hyperactivity disorder
         ADP — adenosine diphosphate
         ATP — adenosine triphosphate
         BDNF — brain-derived neurotrophic factor
         BP — blood pressure
         cAMP — cyclic adenosine monophosphate
         cGMP — cyclic guanosine monophosphate
         CNS — central nervous system
         COMT — catechol-O-methyltransferase
         COPD — chronic obstructive pulmonary disease
         CYP - cytochrome P450
         DAG — diacylglycerol
         DMARD - disease-modifying anti-rheumatic drug
         GA - general anesthetic
         GABA - gamma-aminobutyric acid
         GIT - gastrointestinal tract
         GUT - genitourinary tract
         HCV - hepatitis C Virus
         HSV - herpes simplex virus
         IFN - interferon
         IL - interleukin
         IM - intramuscularly
         INN - International Nonproprietary Name
         IP₃ - inositol-triphosphate
         IV - intravenously
         MAC - minimal alveolar concentration
         MAO - monoamine oxidase
         MRSA - methicillin-resistant Staphylococcus aureus
         NMDA - N-methyl-D-aspartate
         NO - nitric oxide
         NSAIDs - non-steroidal anti-inflammatory drugs
         PABA - para-aminobenzoic acid
         PD - Parkinson’s disease
         PTT - partial thromboplastin time
         RSV - respiratory syncytial virus
         SC - subcutaneously
         SNS - sympathetic nervous system
         SSNRIs - selective serotonin and norepinephrine reuptake inhibitors
         SSRIs - selective serotonin reuptake inhibitors
         TCA - tricyclic antidepressant
         TNF - tumor necrosis factor
         USAN - United States adopted name
         Vd - volume of distribution

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                SECTION       1





            PHARMACOLOGY: BASIC PRINCIPLES



        INTRODUCTION

   Pharmacology can be defined as the science studying interaction of the chemical substances (i.e. drugs) with living systems, which is revealed as a change (activation or inhibition) of natural reactions in the organism.
   A drug in pharmacology (pharmaceutical drug) is a chemical substance of any origin (natural or synthetic) which is used for treatment, prevention or diagnosis of diseases. Drugs also include oral contraceptives.
   Each drug possesses International Nonproprietary Name (INN) and trade name.
   Drugs can be divided into original (the drug which is done by the company which developed the drug and which is the owner of the brand name) and generic (i.e. copy of the original drug that is produced by other pharmaceutical company after the expiry of the patent of the original drug).
   Pharmacology consists of pharmacokinetics and pharmacodynamics.
   Pharmacology is also divided into basic pharmacology and clinical pharmacology. Basic pharmacology covers mainly mechanisms and effects of drugs at a molecular, cellular, tissue and organ level, whereas clinical pharmacology applies the knowledge of basic pharmacology in clinical situations.
   Clinical pharmacology is the science about the clinical use of drugs. It is underpinned by the basic science of pharmacology, with the added focus on the application of pharmacological principles and methods in the real world. It has a broad scope, from the discovery of new target molecules to the effects of drug usage on the whole populations.
   Types of drug therapy (medications):
   •     etiotropic (causal), when the action of the drug is directed at the cause of the disease (for example, antibiotics in infectious diseases);
   •     pathogenetic, when the action of the drug is directed at the processes of pathogenesis of the disease (for example, clonidine causes reduction of the tone of vasomotor center in the treatment of essential hypertension);
   •     symptomatic, when the action of the drug is directed at the elimination of some symptoms (manifestations) of the disease (for example, the elimination of cancer pain with opioid analgesics);


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   •      replacement, when the action of the drug is directed at compensate shortage in the body of the hormone, enzyme, etc. (for example, the therapy of diabetes mellitus with insulin);
   •      prophylactic, when the action of the drug is directed at the prevention of the occurrence of disease (for example, the seasonal appointment of salicylates and antibiotics for the prevention of exacerbations of rheumatism).


        PHARMACOKINETICS

        Basic Concepts and Terms

   Pharmacokinetics (literally “movements of the drugs”) consists of 1) absorption, 2) distribution and 3) elimination of the drugs. These processes determine how rapidly the drug will appear at the target organ and how long it will be there. Elimination can be subdivided on metabolism and excretion.
   Absorption — the transfer of the drug from the site of administration to systemic circulation.
   Distribution — the transfer of the drug from the systemic circulation into different organs and tissues of the body.
   Elimination — the removal of the drug from the body which involves either (or both) metabolism or excretion.

    Routes of Drug Administration

   There are following routes of drug administration:
   •   enteral (via GIT):
     —   oral;
     —   sublingual;
     —   transbuccal;
     —   rectal;
   • parenteral (bypassing GIT):
     —   subcutaneous;
     —   intramuscular;
     —   intravenous;
     —   inhalation;
     —   transdermal;
     —   intrathecal (subarachnoid);
     —   topical.
   Oral administration.
   Advantages:
   •  convenient;


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   •   safe;
   •   economic.
   Disadvantages:
   •   slow development of effect due to:
      —  slow absorption in the GIT;
      —  passage of drugs through the liver;
   • low bioavailability due to:
      —  incomplete absorption;
      —  the first-pass effect in the liver;
      —  destruction of drugs by gastric acid and enzymes;
   • some drugs can irritate gastric mucosa.
   Sublingual administration. Rapid action is characteristic because a drug is absorbed directly to the systemic blood circulation without passage through the liver. So this route is used in emergent states.
   Rectal administration. It may be used when drug absorption in the GIT is impaired, in children or unconscious patients. The most of a drug does not pass through the liver. The area of absorption is relatively small, so not all drugs are well absorbed from the rectum.
   Subcutaneous and intramuscular administration. The rapid development of action is characteristic for aqueous solutions, but there are so-called slow-released preparations, that are absorbed slowly, so effect develops slowly but lasts for a long time. Suspensions or oil solutions may be administered by this route. It is not possible to use large volumes of solutions. Irritating drugs can not be injected, especially by subcutaneous route.
   Intravenous administration. The effect develops very rapidly (almost immediately); bioavailability is 100%; duration of action is relatively short; only aqueous solutions may be administered, not suspensions or oil solutions.
   Inhalation administration. Development of an effect is almost immediate; only gases, volatile fluids or aerosols are administered.
   Transdermal administration. In this case, a drug is applied on the skin and is absorbed to the systemic blood circulation through the skin. Slow development and long duration of an effect are typical. The transdermal patch is the most commonly used dosage form.
   Topical administration. A drug is used directly to the site of its action, for example, a drug is administered as an ointment on the skin for treatment of some skin disease.

    Absorption of Drugs

   Mechanisms of absorption (Fig. 1). Absorption (excluding intravenous or intra-arterial route) involves passage through the cell membrane.


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Passive transport

Active transport

Fig. 1. Mechanisms of absorption

   Passive diffusion (passive transport) is the most common mechanism of transportation of drugs. It is realized through the membrane’s phospholipid bilayer according to the concentration gradient, i.e. from the area with the higher concentration of the drug to the area with the lower concentration of the drug.
   Paracellular transport (filtration through membrane pores or through intercellular spaces) — only for small (< 100 Da) water-soluble molecules (for example, lithium). It is a subtype of passive diffusion.
   Active transport needs the carrier (i.e. protein) and energy (ATP) and follows against a concentration gradient (for example, 5-fluorouracil).
   Facilitated diffusion is a subtype of active transport when a drug penetrates through the cell membrane with the help of carrier proteins but without requiring energy.
   Pinocytosis exists only for some macromolecules (like phagocytosis or amoeba feeding).
   These mechanisms can be applied not only to the absorption of drugs but also to the transportation of drugs through a cell membrane and other biological barriers.
   Bioavailability (F) is a fraction (calculated in %) of a drug, which reaches systemic circulation in an unchanged form. The bioavailability indicates the extent of absorption of a drug into the systemic circulation. The highest bioavailability is for intravenous route of administration (100%).

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   The term bioequivalence is used to compare two preparations that contain the same active compound (e.g. generic and original preparation). Two preparations are bioequivalent when they have the same bioavailability, the same peak concentration in plasma, and the same time to achieve this peak concentration.


    Distribution of Drugs

   Volume of distribution (Vd) is a hypothetical volume of body fluids in which the drug is distributed in the same concentration as in the blood. Vd can be calculated as:


Vd =

amount of drug in the body



C

where C — concentration of the drug after distribution.
   If a drug is administered intravenously, the amount of the drug is equal to the dose (D), so the above-mentioned formula can be expressed as:


D

Vd = C'


   Vd may be much more than the real volume of fluid in the body (1000 l and even more), so it is often called as apparent volume of distribution. Large Vd means that the drug is accumulated in some tissues. On the other hand, if a drug has extremely low Vd (approximately 3 l in human of the average body weight), distribution of this drug is restricted only to plasma, because it does not penetrate through vessels.
   Using Vd it is possible to calculate loading dose (Dₗ) of the drug:

D = Vd x Ct

where Cₜ is the target concentration, i.e. the desired plasma concentration of the drug that is necessary to produce the therapeutic effect.
   Compartments are the tissues and organs of the body where the concentration of the drug is equal (where central compartment is blood and peripheral compartment is body tissues — a bicompartmental model of the distribution). But the simplest model is a monocompartmental model, when the body is only one homogenous compartment which presupposes that blood is a true reflection of the drug’s concentration in other fluids or tissues and that the elimination of the drug is directly proportional to the drug’s concentration in the organism (first-order kinetics — see below).


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   Influence of plasma protein binding on the distribution of drugs. Drug + circulating plasma proteins (albumins, etc.) = reversible drug-protein complex. The drugs bound with albumins of plasma can not penetrate through the vessels and do not induce the effect. On the other hand, a relation between bound and free fractions of the drug is a constant value, so when some amount of a free drug leaves the bloodstream, some amount of a bound drug dissociates. Nevertheless, the plasma protein binding slows down the distribution of drugs, and, in general, reduces the rate of development of the effect and its magnitude. The decrease of binding with plasma proteins (in case of hypoproteinemia or due to interaction with other drugs binding with the same proteins) leads to the increase of the effect of a drug and can cause toxic reactions.


    Elimination of Drugs

   After absorption in the GIT, the drugs are metabolized in the liver (first-pass effect or presystemic elimination). Therefore, the oral administration of the drug which undergoes to intensive first-pass effect (if metabolites of the drug are pharmacologically inactive) is impossible.
   First-order kinetics (a feature of the majority of drugs) is a process of elimination when a fixed percentage of the drug is eliminated per one time unit.
   Zero-order kinetics (features of just some drugs: ethanol, phenytoin, aspirin, heparin, etc.) is a process of elimination when a fixed amount of the drug is eliminated per one time unit (Fig. 2).
   Elimination of drugs includes two processes: metabolism and excretion.
   Metabolism converts lipid-soluble drugs, which would be reabsorbed from the kidney tubule, into a water-soluble form, which is not reabsorbed,


Fig. 2. Plots of zero-order (a) and first-order (b) drug elimination versus time

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