GENERAL GENERAL FARMACOLOGYFARMACOLOGY

Ph D. Ass. Aleksandrova A.V.

General Pharmacology General Pharmacology studies the main studies the main principles of interaction principles of interaction between drug and body.between drug and body.

It has two parts:It has two parts:1. Pharmacokinetics 1. Pharmacokinetics 2. Pharmacodynamics2. Pharmacodynamics

Pharmacokinetics includes the following processes:-Absorption-Distribution-Metabolism-Excretion

The main routes of The main routes of drug drug administrationadministration

Enteral (through gastrointestinal

tract -GIT)

Parenteral (by- passing GIT).

*Oral

*Sublingual

*Transbuccal

*Rectal

*Intramuscular*Intravenous*Subcutaneous*Inhalational*Topical*Transdermal*Intraarterial and other

ORAL administraORAL administration tion - the most simple, natural and - the most simple, natural and comfortable for the patient path, does not require comfortable for the patient path, does not require sterilization and medical assistance. Oral drugs are used in sterilization and medical assistance. Oral drugs are used in various dosage forms: various dosage forms: powders, granules, tablets, capsules, powders, granules, tablets, capsules, dragees, solutions, infusions, decoctions, suspensions.dragees, solutions, infusions, decoctions, suspensions.

Peculiarities of drugs usage insidePeculiarities of drugs usage inside::-- The influence of hydrochloric acid of the gastric juice The influence of hydrochloric acid of the gastric juice (penicillin, erythromycin, epinephrine).(penicillin, erythromycin, epinephrine).- - The influence of food on absorptionThe influence of food on absorption: slowing due to : slowing due to changes in pH, increasing intestinal motility, or formation of changes in pH, increasing intestinal motility, or formation of complexes that are not absorbed.complexes that are not absorbed.- - Low bioavailability as a consequence of first-pass Low bioavailability as a consequence of first-pass metabolmetaboliismsm - inactivation of the mucous membrane - inactivation of the mucous membrane enzymes of small intestine and liver before entering the drug enzymes of small intestine and liver before entering the drug into the systemic circulation.into the systemic circulation.- - Irritant and ulcerogenic effect of drugsIrritant and ulcerogenic effect of drugs on the stomach on the stomach and intestines (non-steroidal anti-inflammatory drugs, and intestines (non-steroidal anti-inflammatory drugs, chlorpromazine, reserpine).chlorpromazine, reserpine).- Impossibility to use inside - Impossibility to use inside (resection of the digestive (resection of the digestive organs, severe diseases that are accompanied by organs, severe diseases that are accompanied by malabsorption syndrome)malabsorption syndrome);; contraindications (peptic ulcer, contraindications (peptic ulcer, gastritis)gastritis); ; vomiting, unconsciousvomiting, unconscious state.state.

Sublingual and Sublingual and transdermaltransdermal-- absorption of drugs very fast (when absorption of drugs very fast (when placing them under the tongue and behind placing them under the tongue and behind the cheek).the cheek).

In this route of administration drugs In this route of administration drugs are not destroyed by digestive enzymes are not destroyed by digestive enzymes and hydrochloric acid. Drugs enters and hydrochloric acid. Drugs enters directly into the systemic circulation directly into the systemic circulation bypassing the liver. bypassing the liver.

In this way prescribed drugs only with In this way prescribed drugs only with high activity and high lipid solubility - high activity and high lipid solubility - (validol, nitroglycerin in relieving angina, (validol, nitroglycerin in relieving angina, nifedipine - with relief of hypertensive nifedipine - with relief of hypertensive crisis).crisis).

RectalRectalA considerable part of the substance A considerable part of the substance (50%) enters the bloodstream, (50%) enters the bloodstream, bypassing the liver, in addition with bypassing the liver, in addition with this route of administration the this route of administration the substance is not destroyed by substance is not destroyed by enzymes of the digestive tract.enzymes of the digestive tract.

Rectally administered drugs in the form of suppositories or as enemas (50-100 ml).

Administration Administration by by injectioninjection

Subcutaneous Subcutaneous important in emergency medical practice important in emergency medical practice (injection of antidotes, during anesthesia), (injection of antidotes, during anesthesia), and vaccination.and vaccination.The volume of solution is administered not The volume of solution is administered not more than 1-2 ml, effect occurs within 15-more than 1-2 ml, effect occurs within 15-20 minutes after injection.20 minutes after injection.

IntramuscularIntramuscularApplied sterile isotonic aqueous or oily solutions, Applied sterile isotonic aqueous or oily solutions, suspensions.suspensions.This route of administration is less painful than an This route of administration is less painful than an injection into the subcutaneous tissue.injection into the subcutaneous tissue.

Effect in 10-15 minutes.Effect in 10-15 minutes.The volume should not exceed 10 ml.The volume should not exceed 10 ml.

The absorption of the drug from muscle can be The absorption of the drug from muscle can be accelerated by applying a body warmer, or accelerated by applying a body warmer, or conversely, slow down, using ice.conversely, slow down, using ice.

Intravenous Intravenous Applied sterile aqueous solutions, permitted Applied sterile aqueous solutions, permitted

introduction of hypertonic solutions (not more than 20-introduction of hypertonic solutions (not more than 20-40 ml). Intravenous injection is carried out by 40 ml). Intravenous injection is carried out by introducing a one-time or drip method. introducing a one-time or drip method.

Within a short time achieves maximum drug Within a short time achieves maximum drug concentration in the heart, high concentration – in CNS concentration in the heart, high concentration – in CNS and only then is the distribution in the body.and only then is the distribution in the body.

To eliminate the toxic effects, injections of potent To eliminate the toxic effects, injections of potent and toxic drugs should be carried out slowly and before and toxic drugs should be carried out slowly and before this, substances should be dissolved in solution of this, substances should be dissolved in solution of sodium chloride or glucose.sodium chloride or glucose.

For intra-arterial administration For intra-arterial administration resorted when you need to make a greater resorted when you need to make a greater concentration of the drug (antibiotic, concentration of the drug (antibiotic, anticancer drugs) or have an effect on the anticancer drugs) or have an effect on the vascular wall (introduction of vasodilators for vascular wall (introduction of vasodilators for treatment of endarteriite limbs).treatment of endarteriite limbs).

Intraarterial

This way makes inhalation anesthesia, for This way makes inhalation anesthesia, for topical use aerosols of bronchodilators, topical use aerosols of bronchodilators, corticosteroids, local anesthetics, antibiotics. corticosteroids, local anesthetics, antibiotics. The depth of penetration into the respiratory The depth of penetration into the respiratory tract depends on the size of the drug tract depends on the size of the drug particles.particles.

Inhalational

Transdermal Transdermal (cutaneous)(cutaneous)Used to direct action on the pathological Used to direct action on the pathological process or to obtain a reflex response of the process or to obtain a reflex response of the internal organs. Therefore, drugs must internal organs. Therefore, drugs must penetrate to a sufficient depth that penetrate to a sufficient depth that determines the basis of ointments, pastes, determines the basis of ointments, pastes, liniments.liniments.

Now began to apply the transdermal therapeutic systems for prolonged drug absorption from surface of skin for the getting of resorptive action.Medicine also administered in eye, nasal s, ear drop, and applied to the nasal mucosa.

Absorption of drugsAbsorption of drugsis the penetration of drug into the blood from is the penetration of drug into the blood from the site of administration.the site of administration.During the absorption drug crosses cell During the absorption drug crosses cell membranes. membranes. There are such kinds of this There are such kinds of this crossing as acrossing as a::- - passive diffusion passive diffusion- - filtrationfiltration-- carrier-mediated active transport carrier-mediated active transport-- endocytosis and exocytosis. endocytosis and exocytosis.

Passive diffusion Passive diffusion - - occurs along the occurs along the concentration gradient of the zone concentration gradient of the zone with a higher concentration in the with a higher concentration in the lower concentration zone lower concentration zone ( penetrate low weight lipid soluble ( penetrate low weight lipid soluble and non ionized molecules).and non ionized molecules).

Filtration - drug through the pores of cell membranes (epidermis or mucous membranes of the gastrointestinal tract, the capillary endothelium) occurs with the flow of water depending on the hydrostatic and osmotic pressures (n this way penetrate the water molecules, urea, glucose, some ions).

Carrier-mediated transport (CMT)-movement of substances across the plasma membrane by protein carrier molecules used when molecule cannot cross membrane or crosses very slowly, protein carrier molecules are embedded in lipid, and have site which specifically binds the molecules).

There are two forms of CMT: active transport and facilitated diffusion

Active transport requires a direct expenditure of energy, whereas facilitated diffusion  is not energy dependent.  Active transportcan   move  substances against a  concentration gradient, facilitated diffusion cannot.

The movement of macromolecules such as proteins or polysaccharides into or out of the cell is called bulk transport. There are two types of bulk transport, exocytosis and endocytosis, and both require the expenditure of energy (ATP).

Endocytosis and exocytosis.

*In exocytosis, materials are exported out of the cell via secretory vesicles. *Endocytosis, on the other hand, is the process by which materials move into the cell. There are three types of endocytosis: phagocytosis, pinocytosis, and receptor-mediated endocytosis.

Bioavailability of a drug Bioavailability of a drug is the fraction is the fraction of administered dose that reaches the systemic of administered dose that reaches the systemic circulation. circulation.

Factors influencing on the bioavailability- Route of administration - The individual organism (age, gender)- The state of the gastrointestinal tract, liver, kidney, cardiovascular system- Pharmaceutical factors (adjuvants, especially of production technologies)

BioavailabilityBioavailability is one of the principal is one of the principal pharmacokinetic properties of drugs. When a pharmacokinetic properties of drugs. When a drug is administered intravenously, its drug is administered intravenously, its bioavailability is 100%, however, when a bioavailability is 100%, however, when a drug is administered by other routes (such as drug is administered by other routes (such as orally), its bioavailability generally decreases orally), its bioavailability generally decreases (due to incomplete absorption and first-pass (due to incomplete absorption and first-pass metabolism) or may vary from patient to metabolism) or may vary from patient to patient. patient.

BioequivalenceBioequivalenceOral formulations of a drug from different manufacturers or different batches from the same manufacturer may have the same amount of the drug (chemically equivalent) but may not yield the same blood levels – BIOLOGICALLY INEQUIVALENT.

Two preparations of a drug are considered BIOEQUIVALENT when rate and extent of bioavailability of the active drug from them is not significantly different under suitable test conditions.

 the intestinal and hepatic degradation or alteration of a drug

or substance taken by mouth, after absorption, removing some of the active substance from the blood before it enters the general circulation.

Distribution of drugs in the Distribution of drugs in the bodybody

Distribution of the drug in tissues and organs Distribution of the drug in tissues and organs depends on various factors:depends on various factors:- The size and shape of the molecule.- The size and shape of the molecule.- Solubility in lipids.- Solubility in lipids.- The intensity of regional circulation.- The intensity of regional circulation.- The degree of protein binding.- The degree of protein binding.- Competition for binding with plasma proteins.- Competition for binding with plasma proteins.- Protein concentrations in plasma.- Protein concentrations in plasma.- Biological barriers (walls of capillaries, cell - Biological barriers (walls of capillaries, cell (plasma membrane), the blood-brain barrier (plasma membrane), the blood-brain barrier and other).and other).

Apparent volume of distribution Apparent volume of distribution (V) (V)

The volume into which the total amount of a drug in the body would have to be uniformly distributed to provide the concentration of the drug actually measured in the plasma.

Factors determining the rate of

distribution of drugs

1. Protein binding of drug: A variable and other significant portion of absorbed drug

may become reversibly bound to plasma proteins. The active concentration of the drug is that part which is not bound, because it is only this fraction which is free to leave the plasma and site of action.

- Free drug leave plasma to site of action - binding of drugs to plasma proteins assists absorption - protein binding acts as a temporary store of a drug and

tends to prevent large fluctuations in concentration of unbound drug in the body fluids

- protein binding reduces diffusion of drug into the cell and there by delays its metabolic degradation

e.g. high protein bound drug like phenylbutazone is long acting. Low protein bound drug like thiopental sodium is short acting.

2. Plasma concentration of drug (PC):

It represents the drug that is bound to the plasma proteins (albumins and globulins) and the drug in free form.

It is the free form of drug that is distributed to the tissues and fluids and takes part in producing pharmacological effects.

The concentration of free drug in plasma does not always remain in the same level e.g.1) After I.V. administration plasma concentration falls sharply2) After oral administration plasma concentration rises and falls gradually.3) After sublingual administration plasma concentration rise sharply and falls gradually

3. Clearance: 3. Clearance: - Volume of plasma cleared off the drug by metabolism and excretion per unit time.

Protein binding reduces the amount of drug available for filtration at the glomeruli and hence delays the excretion, thus the protein binding reduces the clearance.

4. Physiological barriers to 4. Physiological barriers to distributiondistribution: :

There are some specialized barriers in the body dueto which the drug will not be distributed uniformly in all the tissues. These barriers are:a) Blood brain barrier (BBB) permeable only to lipid-soluble drugs or those of very low molecularweight. (thiopental sodium is easily crossed but not dopamine).b) Placental barrier: which allows non-ionized drugs with high lipid/water partition coefficient by a process of simple diffusion to the foetus e.g. alcohol, morphine.

5. Affinity of drugs to certain 5. Affinity of drugs to certain organs: organs:

The concentration of a drug in certain tissues after a single dose may persist even when its plasma concentration is reduced to low.

Thus the hepatic concentration of mepacrine is more than 200 times that of plasma level. Theirconcentration may reach a very high level on chronic administration. Iodine is similarlyconcentrated in the thyroid tissue.

Metabolism of drugsMetabolism of drugsthis is a complex of physical, chemical or biochemical transformations of drugs in the body. The main organ for drug metabolism is the liver. Phase I reactions:

(nonsynthetic)1. Oxidation 2. Reduction 3. Hydrolysis

Phase II reactions: (synthetic)1. Glucuronidation2. Methylation3. Sulfation4.Acetylation

Enzymes responsible for Enzymes responsible for metabolism of drugs:metabolism of drugs:

a) Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and GIT e.g. glucuronyl transferase, dehydrogenase , hydroxylase and cytochrome P450

b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs.e.g. esterases, amidase, hydrolase

Phase - I reactionsPhase - I reactionsa) Oxidation:

Microsomal oxidation involves the introduction of an oxygen and/or the removal of a hydrogen atom or hydroxylation, dealkylation or demethylation of drug molecule e.g.conversion of salicylic acid into gentisic acid.

b) Reduction:

The reduction reaction will take place by the enzyme reductase which catalyze the reduction of azo (-N=N-) and nitro (-NO2) compounds e.g. prontosil converted to sulfonamide.

c) Hydrolysis:

Drug metabolism by hydrolysis is restricted to esters and amines (by esterases and amidases) are found in plasma and other tissues like liver. It means splitting of drug molecule after adding water e.g. drugs which undergo hydrolysis are atropine and acetylcholine.

Phase - II reactions (conjugation Phase - II reactions (conjugation reactions):reactions):

This is synthetic process by which a drug or its metabolite is combined with an endogenous substance resulting in various conjugates such as glucoronide, ethereal sulfate, methylated compound and amino acid conjugates.

Glucuronide conjugation: It is the most common and most important conjugation reaction of drugs. Drugs which containa) Hydroxyl, amino or carboxyl group undergo this process e.g. phenobarbitone.b) Sulfate conjugation: Sulfotransferase present in liver, intestinal mucosa and kidney, which transfers sulfate group to the drug molecules e.g. phenols, catechols, etcHere the source of methyl group is s – adenosyl methionine

Phase - II reactions Phase - II reactions (conjugation reactions):(conjugation reactions):c) Acetyl conjugation: The enzyme acetyl transferase, which is responsible for acetylation, is present in the kupffer cells of liver. Acetic acid is conjugated to drugs via its activationby CoA to form acetyl CoA. This acetyl group is then transferred to-NH2 group of druge.g. dapsone, isoniazid.d) Glycine conjugation: Glycine conjugation is characteristic for certain aromatic acidse.g. salicylic acid, isonicotinic acid, p-amino salicylic acid. These drugs are also metabolized by other path ways.e) Methylation: Adrenaline is methylated to metanephrine by catechol-o-methyl transferase.

*The result of stage I is formation of *The result of stage I is formation of active or inactive products which enter active or inactive products which enter the stage II reactions.the stage II reactions.*Stage II reactions lead to the formation *Stage II reactions lead to the formation of inactive metabolits excreted from the of inactive metabolits excreted from the body.body.

Biotransformation of drugs can Biotransformation of drugs can changes due to various factors:changes due to various factors:

- Features of drug metabolism. - Comorbidities. - Hunger (diet). - Bad habits (smoking, alcohol, drugs). - Age. - Gender. - Genetic features.

Prodrug - an inactive substance that is converted to a drug within the body by the action of enzymes or other chemicals.

Drugs which increase the activity of microsomal Drugs which increase the activity of microsomal enzymes in the liver are named enzymes in the liver are named inductors of inductors of microsomal oxidation. microsomal oxidation. (barbiturates, antiepileptics - benzonal, phenytoin, (barbiturates, antiepileptics - benzonal, phenytoin, carbamazepine, carbamazepine, tranquilizers, corticosteroids, anabolic steroids, testosterone, tranquilizers, corticosteroids, anabolic steroids, testosterone, antibiotics - griseofulvin, rifampicin).antibiotics - griseofulvin, rifampicin).

Drugs which decrease the activity of microsomal enzymes in the liver are named inhibitors of microsomal oxidation. *Result of this can be cumulation or prolongation of action.

*Usage of these drugs will decrease the efficiency of the drugs, which metabolized with the

participation of cytochrome P-450.

(antidepressants, antiarrhythmics – qui.nidine, preparations female sex hormones, contraceptives, anticancer drugs, antibiotics - chloramphenicol, erythromycin, teturam).

EXCRETIONEXCRETION The final stage of the pharmacokinetic process of drug and is occurs through the excretory system of the body:

-Kidney (glomerular filtration, tubular reabsorption, tubular secretion);-Liver (with bile);- Intestines;- Lungs;- Exocrine glands (salivary, sweat, mammary gland).

The majority of drugs are excreted by the kidneys. Hydrophilic may be excreted throught the kidney in unchanged form; lipophilic drugs are converted into hydrophilic metabolites which are excreted with urine.

a) a) Renal excretion:Renal excretion:A major part of excretion of chemicals is metabolically unchanged or changed. The excretion of drug by the kidney involves:1) Glomerular filtration2) Active tubular secretion3) Passive tubular reabsorption.

The function of glomerular filtration and active tubular secretion is to remove drug out of the body, while tubular reabsorption tends to retain the drug.

1) Glomerular filtration: It is a process, which depends on - the concentration of drug in the plasma -molecular size, shape and charge of drug - glomerular filtration rate.

Only the drug which is not bound with the plasma proteins can pass through glomerulus. All the drugs which have low molecular weight can pass through glomerulus e.g. digoxin, ethambutol, etc.

In congestive cardiac failure, the glomerular filtration rate is reduced due to decrease in renal blood flow.

a) a) Renal excretion:Renal excretion:2) Active tubular secretion:

The cells of the proximal convoluted tubule actively transport drugs from the plasma into the lumen of the tubule e.g. acetazolamide, benzyl penicillin, dopamine, pethidine, thiazides, histamine.

3) Tubular reabsorption:

The reabsorption of drug from the lumen of the distal convoluted tubules into plasma occurs either by simple diffusion or by active transport.

When the urine is acidic, the degree of ionization of basic drug increase and their reabsorption decreases.Conversely, when the urine is more alkaline, the degree of ionization of acidic drug increases and the reabsorption decreases.

a) a) Renal excretion:Renal excretion:

b) b) Hepatobiliary Hepatobiliary excretion:excretion:the conjugated drugs are excreted by hepatocytes in the bile.Molecular weight more than 300 daltons and polar drugs are excreted in the bile.

Excretion of drugs through bile provides a back up pathway when renal function is impaired. After excretion of drug through bile into intestine, certain amount of drug is reabsorbed into portal vein leading to an enterohepatic cycling which can prolong the action of drug e.g. chloramphenicol, oral estrogen are secreted into bile and largely reabsorbed and have long duration of action. Tetracylines which are excreted by biliary tract can be used for treatment of biliary tract infection.

c) Gastrointestinal c) Gastrointestinal excretion: excretion:

When a drug is administered orally, a part of the drug is not absorbed and excreted in the faeces. The drugs which do not undergo enterohepatic cycle after excretion into the bile are subsequently passed with stool

e.g. aluminium hydroxide changes the stool into white colour, ferrous sulfate changes the stool into black and rifampicin into orange red.

d) d) Pulmonary Pulmonary excretion: excretion:

Drugs that are readily vaporized, such as many inhalation anaesthetics and alcohols are excreted through lungs.

The rate of drug excretion through lung depends on the volume of air exchange, depth of respiration, rate of pulmonary blood flow and the drug concentration gradient.

e) e) SweatSweat: : A number of drugs are excreted into the sweat either by simple diffusion or active secretion e.g. rifampicin, metalloids like arsenic and other heavy metals.

f) Mammary excretion:

Many drugs mostly weak basic drugs are accumulated into the milk.Therefore lactating mothers should be cautious about the intake of these drugs because they may enter into baby through breast milk and produce harmful effects in the baby e.g. ampicillin, aspirin, chlordiazepoxide, coffee, diazepam, furosemide, morphine, streptomycin etc.

Clearance (Cl)Clearance (Cl) of a drug is the volume of of a drug is the volume of plasma from which the drug is completely plasma from which the drug is completely removed per unit of time. The amount of removed per unit of time. The amount of eliminated drug is proportional to its eliminated drug is proportional to its concentration in the bloodconcentration in the blood

CL=rate of elimination/CCL=rate of elimination/C

Some terms of pharmacokinetics

Half-life (t1/2) of a drug is the time taken for plasma drug concentration to reduce to half its peak level.

Volume of Distribution (Vd) is dose administered i.v divided by plasma concentration. Drugs that are highly lipid soluble have a very high volume of distribution. Drugs that are lipid insoluble remain in the blood, and have a low Vd.