Pharmacodynamics

==== PHARMACODYNAMIC PROCESSES ====

It is a part of pharmacology that study mechanisms of action, pharmacological, therapeutical and side effects of drugs.

The therapeutic and toxic effects of drugs result from their interactions with molecules in the patient. Most drugs act by associating with specific macromolecules in ways that alter the macromolecules' biochemical or biophysical activities. This idea is embodied in the term receptor. In general, receptor is a structural protein molecule on the cell surface or within the cytoplasm that binds to a specific factor, such as a hormone, antigen, or neurotransmitter. This interaction initiates the chain of biochemical events leading to the agent's observed effects. The receptor's affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors often limits the maximal effect a drug may produce. Many drugs and endogenous chemical signals, such as mediators, regulate the function of receptor macromolecules as agonists (mimetic); i.e., they change the function of a macromolecule as a more or less direct result of binding to it. They possess affinity and intrinsic activity. Based on the maximal pharmacologic response that occurs when all receptors are occupied, agonists can be divided into two classes. Partial agonists produce a lower response, at full receptor occupancy, than do full agonists.

Antagonists (lytics, blockers), however, bind to receptors without directly altering their function. Thus, they prevent the binding of agonist molecules and block their biologic actions. The two classes of receptor antagonism are known. In the presence of a fixed concentration of agonist, increasing concentrations of a competitive antagonist progressively inhibit the agonist response. Conversely, sufficiently high concentrations of agonist can completely surmount the effect of a given concentration of the antagonist. Some receptor antagonists bind to the receptor in an irreversible fashion, i.e., not competitive. The antagonist's affinity for the receptor may be so high that for practical purposes, the receptor is unavailable for binding of agonist.

Mechanisms of drug's action may be connected with enzyme's inhibition. For example, proserine, which inhibits acetylcholinesterase, preserves acetylcholine from enzymatic decomposition, in result - tonus of cholinergic system increases. Mechanism of action of some drugs is connected with blockade of ionic channels in cellular membranes, e.g., for example, antagonists of calcium channels. Another drugs cause the exhaustion of mediator reserves in neural fibers in result of synthesis breach or reverse neuronal seizure (e.g., tricyclic antidepressants).

Types of drug's action.

There are local, reflective, and resorptive action. Under local action one can understand the drug's action in place of administration. It is used seldom. Reflective action appears in result of irritation of neural fibers that transmitted through CNS or by axon-reflexes. It may appear both: during local and resorptive action (e.g., reflective action of mustard plaster and cytitone). Resorptive action is observed after drug achievement of blood.

There are some types of resorptive action: direct and indirect, basic and side, selective and general, convertible and non-convertible. Direct action occurs in the place of drug contact with tissues, e.g., cardiotonic action of cardiac glycosides. Indirect action appears in result function changes, e.g., increased diuresis during administration of cardiac glycosides. Basic action is the main goal of drug's administration, e.g., lowering of blood pressure during administration of octadine. Side action is an additional effect to basic action. As the rule, side effect is unfavorable. For example, octadine can cause dyspeptic disorders.

Selective action alters function of certain organ and system. Usually it is related with action on functionally determined cytoreceptors (e.g., salbutamol, pilocarpine). General action is non-specific action in different organs and tissues (action of narcotic substances and alcohol). Convertible (reversible) action disappears just after drug's elimination. Non-convertible (irreversible) action appears in result of strong connection of drug with receptor (usually covalent) that cause irreversible breaking off it functions (e.g., proserine cause convertible inhibition of acetylcholinesterase, phosphacol causes non-convertible inhibition of acetylcholinesterase).

Factors that influence on drug's action. They may be divided into 3 groups:

1\. Features of drugs;

2\. Factors related with whole organism;

3\. Environmental factors.

To the first group we refer structure of drug, it's physical and chemical features, pharmaceutical form, and doze. Chemical structure of drug determines its mechanism of action and toxicity. The molecular size, shape, and electrical charge of a drug determine whether it will bind to a particular receptor among the vast array of chemically different binding sites available in a cell, animal, or patient. Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease a new drug's affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects. Drug's dissociation, solubility in lipids and water, permeation through biological barriers and membranes as well as pharmaceutical form and way of administration determine drugs action also. Strength and duration of effect, possibility of toxic action depends on the doze of drug. There is direct correlation among doze and drug level in serum. Dose is the quantity of a drug to be taken. It can be expressed in milliliters, grams, and international unites. It can be moment dose (for one time use), daily dose (the total amount of a remedy that is to be taken within 24 hours), curative dose (quantity of any substance required to effect the cure of a disease). Minimal (threshold) therapeutical dose is the smallest amount of a drug that will produce a desired therapeutic effect in an adult; maximal therapeutical dose is the largest amount of a drug that an adult can take with safety; median therapeutical dose is the dose that produces the desired therapeutic effect in majority of patients. Initial (loading) dose is a comparatively large dose given at the beginning of treatment to get the patient under the influence of the drug; maintenance dose supports the effect of drug therapy.

For evaluation of activity and safety of drugs therapeutical index is used. It is a ratio of doze that causes death in 50% of laboratory animals to doze that cause desirable effect in 50% of animals. Also it can be expressed as a ration of dose, which evoke toxic effect in 50% of patients, to dose, which evoke favorable effect in 50% of patients. Another data of drug's safety is wideness of therapeutical action - difference between threshold and maximal therapeutical doses. That drug is safer, which has large wideness of therapeutical action. To factors related with whole organism of patient we consider age, sex, genetic features, condition of patient, and biological rhythms. Age of patient considerable influences on the drug action. This factor is especially important in children and old patients. Most part of protective mechanisms in child organism is poorly developed. It is necessary to refer possibility of cramps, allergic reactions, slow biotransformation and excretion of the drugs, unripeness of biological barriers, high absorptive ability of skin and mucosa coats. In children of first 3 years drugs connection with serum proteins is lowered and level of free fraction is increased. In addition, children possess higher sensitiveness to drugs.

Old patients, especially over 75 years characterized by higher sensitiveness to drugs, which suppress CNS and lower sensitiveness that cause opposite effect. Tonus of vegetative nervous system, endocrine gland lowers. Inclination for thrombus formation increases, and it is dangerous to use coagulants. Level of serum albumins is lower and level of free fraction is higher. Biotransformation in liver and excretion by kidneys are delayed. So, in old patient, dose is smaller and administration is more careful.

Also it is necessary to consider condition of patient. Weakened and exhausted patients are needed for lowering of the dose. During shock and bleeding the sensitiveness for oppressing drugs increases (narcotics, neuroleptics, etc.). It is necessary to consider the additive diseases. For example, hepatic disease has been shown to reduce the clearance and prolong the half-life of many drugs.

Biological rhythmus is alternation of process's activity through determined interval of time. Dependence of drug action from biological rhythmus and their influence on them are studied by chronopharmacology. Biorhythmus may have seasonal, monthly, and daily (circadian) character. Knowledge of rhythmus is necessary for choosing of drug’s optimal regimen. For example, it is ascertained that maximal production of hormones in adrenal cortex occurs in the morning and sensitiveness of tissues for those hormones increases in that time also. So, using of corticosteroids in the morning increases efficacy of therapy and lowers risk of complications.

Some effects of drugs are concerned with genetic factors. These problems are studied by pharmacogenetics, part of medical genetics. For instance, metabolism of isoniazid and apressin occur due to their acetylation in liver. People are divided into “slow acetylators” with slow drug’s acetylation and “quick acetylators”. One of genetically determined reactions is idiosyncrasy, which is appears as abnormal reaction to a drug. It is characterized by redness, edema of skin and mucous, disorders of breathing and blood pressure, fever, and other disorders up to shock. Usually these reactions are related with congenital insufficiency of enzymes (enzymopathies). For example, in case of glucose-6-phosphate dehydrogenase of erythrocytes insufficiency sulfanilamides and derivatives of nitrofurane cause hemolytic anemia and jaundice. Pharmacogenetics is also studying mutagenic effects of drugs. It has great significance for individualization of treatment and prognoses efficacy and safety of pharmacotherapy.

Factors of environment also have determined influence on drug's action. They are social conditions that may cause psycho-emotional strain, strong noises, vibration, radiation, ecological problems, fluctuation of temperature, etc. Prolonged and excessive influence of these factors increases the drug's action on the CNS especially of narcosis substances, soporifics and neuroleptics. Some drugs (sulfanilamides) increase sensitivity of the skin to sunlight that named as photosensitization.

Changes in drug's action while repeated administration. In many cases drugs are used for prolonged therapy that can strengthen or weaken their action. Strengthening of effect may be stipulated by its cumulation both material and functional. Material cumulation is the accumulation of drugs (e.g., digitoxine, strychnine) that are slowly excreted from organism. Functional cumulation is the accumulation of drug's effect (alcohol, caffeine, etc.). It means that after the drug's excretion it effects still present As a result, toxic effects may appear.

Tolerance (accustoming, adaptation) is the ability to endure or be less responsive to the drug, especially over a period of continued exposure. Tolerance can be explained by accelerated of biotransformation and excretion, lowered of receptor's sensitiveness. For overcoming of the tolerance you need to increase doses of the drug that sometimes cause intoxication. Usually tolerance for one drug is accompanied by developed tolerance to pharmacologically similar compounds.
Tachyphylaxis is a rapid appearance of progressive decrease in response following repetitive administration of a pharmacologically or physiologically active substance (e.g., while using ephedrine).

Dependence (drug abuse, addiction) is characterized by constant and repeated wish of drug using. Usually it is indicated by withdrawal symptoms (abstinence) that develop when use of the substance is terminated. Psychologic dependence is manifested by compulsive drug-seeking behavior in which the individual uses the drug repetitively for personal satisfaction. Cigarette smoking is an example. Abstinence is characterized by mental depression that include depressed or irritable mood, loss of interest in usually pleasurable activities, sleep and appetite disturbance, fatigue, suicidal thoughts, hopelessness, and guilt. Physiologic dependence is present when withdrawal of the drug produces symptoms and signs that are frequently the opposite of those sought by the user. It has been suggested that the body adjusts to a new level of homeostasis during the period of drug use and reacts in opposite fashion when the new equilibrium is disturbed. For example, symptoms of opioid withdrawal include lacrimation, sweating, weakness, chills, nausea and vomiting, muscle aches, hyper- or hypotension.

Drugs interaction.

Combined therapy is used for the treatment of majority diseases. Thus, it is necessary to know more about drugs interaction. There are two types of interaction: pharmaceutical and pharmacological. Pharmaceutical interaction may appear between incompatible drugs while their production, storing or mixing in solution. It can lowers components activity and increases their toxicity. For example, it is not recommended to mix in one-syringe vitamins B1, B6, and B12.

Pharmacological interaction occurs on the level of pharmacodynamic and pharmacokinetic processes.

Interaction on level of pharmacokinetic processes can be observed during absorption, transport, biotransformation, and excretion of drugs. For example, activated carbon, which has adsorbentive properties, decreases the extent of intestine absorption of concomitant drug. Competition for binding with serum proteins may develop between drugs, e.g., salicylates replace butamide, which decrease the blood glucose concentration, that may cause hypoglycemic coma. Drugs interaction on the biotransformation level may appear due to inducing or inhibiting effects on microsomal enzymes of the liver. As it is mentioned beyond barbiturates increase the enzyme's activity that is accompanied by hastened biotransformation of other drugs. Cimetidine has opposite effect. Interaction on the stage of excretion may cause hastening and slowing of drug's excretion from organism (see beyond). So, alkaline drugs (sodium bicarbonate) hasten excretion the acid substances (salicylates) and on the contrary. This interaction may be used during poisoning, e.g., administration of sodium bicarbonate during poisoning by salicylates and barbiturates.

Drugs interaction on the pharmacodynamic level appears in form of synergism or antagonism. Synergism is a coordinated or correlated action of two or more agents so that the combined action is greater than the effect of each acting separately. It can be in two forms: summation (additive) and potentiation. First one is a simple sum (addition) of effects, e.g., combination of agents for narcosis. Potentiation is an interaction between two or more drugs or agents resulting in a pharmacologic response greater than the sum of individual responses to each drug or agent, e.g. combination of sedative drugs with alcohol. Synergism may be direct, when drugs act on the same substrate, and indirect, when drugs act on different substrates.

Antagonism is the situation in which the combined effect of two or more agents is smaller than the solitary effect of any one of the factors. It can be physiological, chemical, physico-chemical and physical. Physiological antagonism appears on level of biological substrate. It may be direct and indirect. Interaction of cholinomimetic and cholinolytic is an example of direct antagonism. Indirect antagonism is stipulated by interaction of drugs with different mechanism of action. For example, pilocarpine narrow pupil through the stimulation of M-cholinoreceptors of sphincter pupil; adrenaline widens pupil due to stimulation adrenoreceptors of pupil's radial muscle. Chemical antagonism is a type of chemical reaction that results in loosing of initial pharmacological activity of agents and in formation of non-active substance (e.g., binding of unithiol with metals). Example of physico-chemical antagonism is neutralization of heparin (anticoagulant) by protamine sulfate, in result of electrostatic interaction. Physical antagonism is stipulated by physical features of drug, e.g., activated carbon adsorb on own surface molecules of many substances.

Types of drug's therapy.

Basic types of pharmacotherapy are prophylactic, etiotropic, pathogenic, and symptomatic. Prophylactic drug is an agent that acts to prevent a disease, e.g., chloridine for malaria prevention. Etiotropic therapy is directed against the cause; etiotropic agent is a remedy that attenuates or destroys the causal factor of a disease, e.g., antimicrobe drugs. Pathogenic therapy is directed on the pathologic, physiologic, or biochemical mechanism resulting in the development of a disease or morbid process, e.g., uses of cardiac glycosides during heart insufficiency. Finally, symptomatic therapy is directed on removing of symptoms of a disease (analgesics, stimulators of breathing, etc.).

Complications of drug therapy.

Together with therapeutically action drugs may cause unfavorable side (adverse) effects. There are different types of side effects. It may be complications related with absolute drug’s overdose – exceed of maximal therapeutical dose. Comparative overdose can appear in a result of fast intravenous injection of drug, during hard diseases of the liver, kidneys that delay drug’s elimination and increase drug’s concentration in the blood. Unfortunately, many drugs possess toxic action on human organs and tissues. For example, aminoglycosides are ototoxic (vestibular and auditory damage) and nephrotoxic, levomycetin commonly causes bone marrow depression (anemia, leukopenia).

Mutagenic, teratogenic, embryotoxic, and carcinogenic effects of the drugs engage prominent place in nowadays medicine. Mutagenic effect is a promoting of the changes in the chemistry of a gene that is perpetuated in subsequent divisions of the cell in which it occurs. It may be a result of drug's action on sexual cells (e.g., anticancer drugs). Mutagenic action may lead to congenital diseases like Daune’s syndrome. Teratogenic action of the drugs appears after its administration during pregnancy. It is characterized by the disturbed growth processes of fetus that lead to the formation of growth anomalies and malformed neonate. The most dangerous period is the first trimester of pregnancy (2-3 months) during formation of organs and systems. That’s why, administration of drugs in this period of pregnancy must be especially careful. In 60-s years of XX century it was so-called "thalidomide catastrophe". Using of thalidomide during pregnancy was accompanied by numerous developments of congenital defects in fetus. Nowadays, any drug cannot be proposed for sale and using without observing on teratogenic features.

Negative action on fetus can appear in growth retardation also. If this effect appear during first 12 weeks of pregnancy, it is named embryotoxic, if later - fetotoxic.

Allergic reactions are the most spread complications of pharmacotherapy. They are stipulated by formation of antibodies to the drugs that possess antigen features or to their metabolites. Increasing of organism's sensitivity to drugs is named sensitization. Hypersensitivity can be classified, as immediate or delayed depending on the time required for clinical symptoms to become manifest following exposure of the host to the sensitizing antigen. The most dangerous is anaphylactic shock.