1. PRINCIPLES OF RESEARCH OF MEDICINAL SUBSTANCES. WAYS OF SYNTHESIS OF PHARMACOLOGICAL SUBSTANCES. OBTAINING PREPARATIONS FROM PLANT AND ANIMAL RAW MATERIALS.
The creation of drugs is developing in the following areas: 1) chemical synthesis of drugs 2) obtaining drugs from medicinal raw materials and excretion of individual substances (animal, plant, mineral origin) 3) excretion of substances of waste products of fungi (penicillin), microbes (interferon, interleukins, enzymes) 4) biotechnology (industrial use of biosystems and processes)
Chemical synthesis in two directions: directed synthesis and the empirical path
Directed synthesis: - reproduction of nutrients (adrenaline, norepinephrine received)
- creation of antimetabolites - changing the structure of the molecule, you can get its antagonist
-modification of compounds with known bioactivity (on the basis of hydrocortisone, more active glucocorticoids with fewer side effects were obtained)
- combination of 2 compounds with the required properties - genetic engineering
-the synthesis of lek substances, based on the study of chemical transformations in the body (drugs that change the activity of enzymes)
Empirical way:
Accidental findings, screening are the main method, but very laborious. The scope of the study depends on the nature of the compound being studied. If the structure of a derivative of an already known compound changes, then a comparative characteristic of a specific action is made.
If a new agent changes, then a comprehensive study of its biological activity is carried out.
Valuable drugs were found by screening. However, chance cannot be the main method in the selection and creation of lek substances. Rational search should be based on the study of pathophysiological and pathochemical processes.
2. HISTORY OF DISCOVERY OF ANESTHESIS (MORTON, PIROGOV). THE CONCEPT OF BIOLOGICAL AND MEDICAL ANESTHESIA. CLASSIFICATION OF DRUGS FOR ANESTHESIA. MECHANISM OF ACTION OF INHALATION ANESTHESIC PREPARATIONS. SIDE EFFECTS. CONTRAINDICATIONS. COMPARATIVE EVALUATION OF PREPARATIONS.
1846 - the discovery of anesthesia. Morton (1819-69) was an American dentist who first introduced ether anesthesia into a surgeon's practice. Pirogov (1810-81) - Russian surgeon and anatomist, the main field of military surgery. For the first time he performed an operation under anesthesia on the battlefield (1847).
Classification of drugs for anesthesia.
Inhalation : volatile liquids: ether, fluorothane, sevoflurane, isoflurane, methoxyflurane
Gaseous substances: nitrous oxide, cyclopropane, xenon.
Non-navigational : derivatives of barbituric and thiobarbituric acids: thiopental sodium, thiobutal, hexenal
Steroids: Predion.
GHB salts: sodium oxybutyrate.
Others: propofol, propanidide, ketamine.
Anesthesia is a condition characterized by the shutdown of consciousness, suppression of sensitivity, reflex reactions, and decreased tone of skeletal muscles.
The actions of anesthetic drugs are associated with the fact that they inhibit the interneuronal transmission of excitation in the central nervous system. Dysfunction of the membrane. One of the manifestations of the interaction of drugs for anesthesia with the postsynaptic neuronal membrane is a change in the permeability for ion channels (for example, for K ions), which disrupts the process of depolarization, and, consequently, interneuronal impulse transmission.
Receptor component of the action of drugs for anesthesia. All inhalation (volatile) and non-inhalation drugs (except for ketamine) in narcotic concentrations interact with GABA receptors, potentiating their action. Nitrous oxide does not affect gamk. Ketamine is an NMDA receptor antagonist. These receptors are blocked by xenon.
Ftorotane became widespread. It is characterized by high drug activity, a short stage of arousal. anesthesia is easily controlled, after the patient stops inhaling fluorothane, awakening will occur in 3-5 minutes. In terms of fire, it is safe. Has no irritating effect on the mucous membrane of the respiratory tract (unlike ether)
Respiratory side effects of fluorothane: moderately inhibits the respiratory center.
CCC: weakens myocardial contractility, reduces stroke volume, lowers blood pressure. The mechanism of hypotension is associated with inhibition of the vasomotor center and impaired transmission of vasoconstrictor impulses in the ganglia and the endings of sympathetic nerves., Cardiac arrhythmias are possible.
Kidneys: fluorothane reduces renal blood flow, SKF, diuresis, respectively.
Liver: with a healthy liver does not cause significant changes, is contraindicated in persons with liver disease.
Ether. It has a pronounced narcotic activity, sufficient arcotic breadth, relatively low toxicity. Less manageable. Irritates mucous membranes, causes a pronounced stage of arousal, explosive. Side effects: profuse secretion of the salivary and bronchial glands (the result of irritation of the mucous membranes), aspiration with vomit, which interferes with airway patency, bradycardia and even cardiac arrest due to reflex excitement of the vagus nerve. Ether is administered only against the background of premixing. Ether promotes the release of catecholamines from the adrenal medulla. This can lead to an increase in glycogenolysis, hyperglycemia (therefore, contraindicated in diabetes mellitus)
On the CVS: increased stroke and minute volume of the heart, increased heart rate, moderate narrowing of the peripheral vasculature.
Liver: hepatotoxic (but less than fluorothane),
Kidneys: decreased renal blood flow, skf, urine output.
Metabolism: a pronounced change in metabolism due to hyperglycemia, increased lactic acid, pyruvic acidosis.
In the postoperative period, vomiting is noted.
Nitrous oxide.
Immediate onset of anesthesia, without arousal stage. This is the effect of low plasma solubility. Because of this, a rapid awakening of the patient occurs. Penetrates quickly into the central nervous system. Used for pain relief in myocardial infarction, severe trauma, childbirth, etc. the main disadvantage: low drug activity. Therefore, it is necessary to combine with other anesthetic drugs. Should not be used for long-term analgesia.
In the postoperative period, nausea and vomiting may occur.
Respiration: does not irritate mucous membranes.
CVS: not accompanied by changes in heart function.
Liver: does not cause
Kidney: a transient decrease in urine output is due to constriction of the renal arteries, an increase in the production of ADH.
Metabolism: does not cause
Blood system: use of nitrous oxide for a long time may cause thrombocytopenia, agranulocytosis, megaloblastic anemia.
ANTI-HYPERTENSIVE DRUGS- blood pressure lowering agents.
Classification:
1) Saluretics :, dichlothiazide, furosemide, cyclomethiazide, hygroton, ethacrynic acid, triampur, amiloride.
Mechanism of action: Reduce the volume of extracellular fluid, Reduce cardiac output, gradually reduce OPS, blood pressure decreases. increase the excretion of sodium, chlorine and water ions in the urine.
Side effects: hypokalemia, hypomagnesemia, accumulation of uric acid in the blood.
Contraindications: renal, hepatic failure, hypokalemia.
2) Aldosterone antagonists: spironolactone (veroshpiron)
Mechanism of action: increase urinary excretion of sodium, chlorine, water ions, but does not cause hypokalemia and uric acid accumulation.
Side effects: vomiting, headache, with prolonged use of gynecomastia, allergies.
Contraindications: Addison's disease, severe renal failure, pregnancy.
Dichlothiazide - works for several hours.
Spironolactone - taken orally.
Furosemide - acts when administered intravenously up to 3 hours, inside - 4-8 hours. Active when there is resistance to other diuretics.
Classification:
Organic antiseptics: aromatic (phenol group, nitrofuran production, dyes), aliphatic (formaldehyde group, alcohols, detergents).
Phenol group - phenol, resorcinol, birch tar. Nitrofuran derivatives - furacilin. Dyes - brilliant green, ethacridine lactate, methylene blue. Formaldehyde group - formalin, lysoform. Alcohols - ethyl alcohol. Detergents - chlorhexidine, cerigel, roccal
The mechanism of action of different antiseptics is not the same, it is aimed either at protein denaturation, violation of the permeability of the plasma membrane, inhibition of enzymes important for the vital activity of microorganisms.
Detergents (for example, cerigel) disrupt the structure of the cell membrane, cause denaturation of proteins, inhibition of enzymes. Used for processing hands, tools
Nitrofurans with a broad spectrum of action, are destructive for gram-positive and g- (treatment of wounds, mucous membranes, for washing serous, articular cavities) side: sometimes causes sensitization, dermatitis
Phenols: for vegetative forms of bacteria and fungi. (Disinfection of tools, household items) side: headache, collapse, shortness of breath.
Resorcinol - less antiseptic, keratoplastic and keratolytic action; with skin diseases.
Tar - antimicrobial, keratoplastic, keratolytic, irritating effect; for skin diseases, scabies.
Furacilin - antibacterial action; for treating wounds, washing cavities.
Dyes - antiseptic effect, antidote for cyanide poisoning; outwardly for the treatment of wounds.
Formalin, lysoform - disinfectant and deodorizing for sweating, for washing hands.
Hexamethylenetetramine (urotropine) is an antiseptic for diseases of the urinary tract.
Alcohols - for disinfection of instruments, treatment of the hands of the surgeon and the operating field.
1. After absorption, many medicinal substances nonspecifically and reversibly bind to blood plasma proteins, mainly albumin. In this case, different drugs compete with each other for the same binding zones on the surface of the protein and displace each other. Protein-bound drug fractions do not penetrate into tissues and are virtually devoid of pharmacological action. Only the free fraction of the drug in plasma has the ability to penetrate tissues and act. The binding capacity of the blood decreases significantly with protein starvation, liver diseases, extensive burns, with age, and with the replacement of blood loss with protein-free fluids.
2. A dynamic equilibrium is maintained between the free fraction of the drug and the fraction bound by proteins: as the free substance is released into the tissue, its amount is replenished due to the previously bound proteins.
When administered intravenously, the following steps occur:
- the concentration of the drug in the blood reaches peak concentrations and enters primarily into well-vascularized tissues (heart, brain, kidneys, lungs), which take on the toxic effect - in the next minutes after administration, the drug is distributed throughout the water phase, including organs with slow blood flow (skeletal muscle, subcutaneous tissue)
3. drugs with high lipophilicity are absorbed by the adipose tissue, creating a depot that releases the drug as its concentration in the blood decreases
The significance of biotransformation lies in converting a dangerous substance into a less toxic and water-soluble substance, in order to subsequently remove them with the kidneys, bile, then (excretion routes). This goal is achieved by transferring drug molecules to more polar, more ionized, less lipophilic, less binding to plasma and tissue proteins, less penetrating through biological barriers that are not reabsorbed in the kidneys and intestines.
Biotransformation occurs in the cells of the liver, intestines, lungs, skin and blood plasma. A certain amount is excreted in the urine unchanged.
There are 2 phases of biotransformation: 1) the molecules undergo hydrolysis, oxidation or reduction.
2) When administered orally, the drug begins to undergo biotransformation already in the intestine and during the first passage through the liver, that is, before entering the systemic circulation. This stage of biotransformation is defined as first pass metabolism.
Bioavailability (bioavailability) characterized by the proportion of the drug from the administered dose, which enters the systemic circulation in an active form.
Depends on: presystemic metabolism, properties of the drug form, the rate of absorption, conditions affecting the adsorption of drugs.
Astringents- substances that can interact with proteins, cause partial coagulation of proteins with the formation of insoluble albuminates. At the same time, the physicochemical properties of colloids of cells, extracellular fluid, mucus, exudate change.
Classification: Organic: Tannin, Oak Bark Decoction
Inorganic: lead acetate, bismuth basic nitrate, alum, zinc oxide, zinc sulfate, copper sulfate, silver nitrate.
Astringent properties: anti-inflammatory (the resulting film causes a thickening of the vascular wall and a decrease in permeability)
Analgesic (a film is formed including on the ends of sensitive nerve fibers)
Hemostatic (decreased capillary permeability)
Antimicrobial (mechanical protection with a film and coagulation of microbial proteins)
Antacid and gastroprotective (decrease in the secretion of hydrochloric acid due to the compacted surface of the wall of the gel, weakening of irritating actions, which promotes regeneration)
Indications for use: inflammation of the skin, mucous membranes, used in the form of lotions, text messages, rinses. Tannin and bismuth are used internally for colitis, enterocolitis.
Enveloping - substances that can swell in water with the formation of colloidal solutions-mucus.
Classification:
Organic compounds: Potato or rice starch mucus, flax seed mucus, marshmallow infusion, milk, egg white.
The mucus enveloping the surface of the tissues protects the mucous membranes from irritation, hence reducing inflammation and pain response. Large colloidal particles are able to adsorb toxins on their surface and reduce their absorption.
Inorganic compounds: Aluminum hydroxide, almagel, sucralfate
When taken orally, aluminum preparations neutralize acid, reduce the secretion of pepsin due to a film on the mucous membrane of the stomach, and at the same time have a cytoprotective effect.
Indications: inflammatory diseases of the gastrointestinal tract.
Absorbent agents are the finest, crushed, insoluble, indifferent powders with a large adsorption surface.
Talc, white clay, activated carbon, adsorbents. They are used externally as drying agents for diaper rash, eczema. Inside with diarrhea (absorb toxic substances), flatulence (absorb hydrogen sulfide).
Irritants -substances with the ability to easily penetrate the skin and mucous membranes due to their high lipophilicity and cause irritation of sensitive nerve endings, hyperemia at the site of application. Mustard plaster, turpentine, menthol, ammonia solution, pepper plaster.
Properties and mechanism of action: 1) improvement of tissue trophism due to increased blood supply in the damaged organ - reflexively according to the axon-reflex type, reflexively from the site of irritation according to the type of cutano-visceral reflex, formation in the subcutaneous tissue on the mesh; application of bav (histamine, pg) for this effect: neuralgia, myalgia, sciatica, rheumatoid arthritis, arthrosis, bronchitis, pneumonia
2) distracting - a decrease in pain: a) the imposition of impulses emanating from the diseased organ or parts of the body and from the place of application of the irritating agent, as a result, the irritation from the application drowns out the pain from the pathogen
B) the release of enkephalins indications at the same time: neuralgic, myalgic, joint pain, retrosternal with angina pectoris.
C) antianginal: reflex improvement of coronary blood flow. indications: angina pectoris
Contraindications : not recommended in the acute period of the disease due to possible exacerbation of the process, purulent skin lesions, psoriasis
D) analeptic (ammonia): reflex excitement of the vasomotor and respiratory center due to irritation of the sensitive receptors of the upper pathways. Indication: fainting. Contraindication: reflexive cessation of breathing in case of overdose