Here is a compilation of essays on ‘Pharmacology’ for class 11 and 12. Find paragraphs, long and short essays on ‘Pharmacology’ especially written for college and medical students.
Essay on Pharmacology
- Essay on Pharmacokinetics
- Essay on Pharmacodynamics
- Essay on the Routes of Administration for Drugs
- Essay on the Factors Modifying Drug Action
- Essay on the Adverse Reactions to Drugs
- Essay on the Adverse Drug Interactions
1. Essay on Pharmacokinetics:
Pharmacokinetics is the study of drug absorption, distribution, metabolism and excretion.
The absorption of a drug molecule depends on its physiochemical properties. To gain access to the site of action, drug molecule must cross one or more barriers- the gastrointestinal mucosa, and the membranes that separate the various aqueous compartments of the body, i.e. plasma, interstitial fluid, intracellular fluid, and trans-cellular fluid.
In general, there are four main ways by which small drug molecules cross cell membranes:
A. Diffusion through Lipid:
Many drugs are highly soluble in lipids and therefore penetrate cell membranes freely, by diffusion. Lipid solubility is one of the most important pharmacokinetic characteristic of a drug, which determines its site of action.
B. Diffusion through Aqueous Channels:
In most parts of the body there are gaps between the endothelial cells of the capillaries, which are large enough to permit small drug molecules to cross by aqueous diffusion, but too small to allow protein molecules to pass through. In central nervous system vascular beds, the capillary endothelium is continuous.
In fact, there are tight junctions between adjacent capillary endothelial cells which, together with their basement membrane and a thin covering from the processes of astrocytes separate the blood from the brain tissue. This blood-brain barrier restricts the passage of lipid insoluble substances from the blood to the brain and cerebrospinal fluid. Lipid insoluble (polar) drugs such as penicillin, methotrexate gain little access to the brain.
C. Carrier Mediated Transport:
Many cell membranes possess highly specific transport mechanism, i.e. a protein molecule incorporated in the cell membrane which binds the drug molecule and ships it to the other side of the membrane in the manner of a ferry. The carrier-mediated drug transport plays an important role in the transfer of drugs at the renal tubule, biliary tract, gastrointestinal tract and blood brain barrier sites.
It involves the transport of a drug molecule across the cell by formation of vesicles. This is applicable to protein and other macromolecules and rarely to drugs.
First Pass Effect (Pre-Systemic Elimination):
Drugs absorbed from the gastrointestinal tract are carried by portal vein to the liver before reaching the systemic circulation. Many drugs are metabolized as they pass through the liver with the result only a portion (about 30%) of the drug absorbed reaches the circulation. Thus, the bioavailability of orally administered drugs is much less as compared to other routes of drug administration. This removal of drug as it passes through liver is called the first pass effect or pre-systemic elimination.
After absorption a drug passes into the circulation. Many drugs are poorly soluble in plasma and are bound to plasma proteins. It is important to know that the free (unbound) fraction of the drug is pharmacologically active and it is the free fraction of the drug that passes from the circulation into body water, e.g. cerebrospinal fluid, transplacentally to the fetus and into breast milk.
The protein bound fraction of the drug acts as a store from where the free drug is released to maintain steady levels of pharmacologically active drug. The distribution of the drug is an important factor in determining its therapeutic usefulness. The drugs initially enter the circulation and highly vascular organs, from where, depending on lipid solubility, diffuse out of the circulation into the tissue spaces and some enter the cells and are bound within the tissues.
Thus, the body can be considered a two compartmental system- a central vascular compartment and a larger peripheral extravascular compartment incorporating interstitial fluid, lymph, intracellular fluid, trans-cellular fluid and fat compartments. The drugs pass in between these compartments, but the entry and elimination is only through the central compartment.
The average volume of the distribution space for an adult is – plasma 3 litres, extracellular space 15 litres and total body water 36 litres. When the volume of distribution exceeds the total volume of body water (e.g. with digoxin), there is substantial uptake and binding of the drug within tissues such as heart muscle.
After distribution has proceeded to the point where the concentration of drug in plasma is in dynamic equilibrium with that in body tissues, the drug levels in plasma and tissue fall in parallel as the drug is eliminated from the body. This is equilibrium phase or elimination phase. Measurement of drug concentration in plasma provides the best reflection of drug levels in tissues during this phase.
The elimination half-life of a drug is the time taken for the circulating concentration of the drug to fall by half. For most of the drugs, the rate of decline in the plasma concentration is constant and directly proportional to the amount present (first order kinetics). The half-life of a drug is useful in predicting its duration of action and frequency of dosing for example, twice a day with elimination half-life of about 12 hours.
Steady State Plasma Concentration:
With repeated dosing, the drug concentration in plasma climbs until a more or less steady level is obtained. During, the steady state, the drug elimination equals the dose administered and the plasma concentration is maintained constant at the optimal therapeutic levels. In general, it takes around five half-lives to reach steady levels for the drugs which follow the first order kinetic clearance.
Clearance denotes the volume of blood from which the drug is completely removed per unit time. The systemic clearance takes place through biodegradation of drugs by the action of liver enzymes and / or renal excretion. Majority of drugs follow first order kinetic laws of clearance – the rate of clearance being constant and directly proportional to plasma concentrations.
A few drugs, notably alcohol, phenytoin, salicylates and theophylline, are inactivated by metabolic degradation and do not obey simple first order kinetic laws of clearance. For them the rate of elimination is independent of the plasma concentrations and this mode of clearance is described as zero order or saturation kinetics, in which a constant amount is cleared per unit time, irrespective of plasma concentrations.
iii. Metabolism (Biotransformation):
The liver is the main site of metabolism for most lipid soluble drugs, where they are broken down or combined with some other chemical so that they are no longer pharmacologically active and become water soluble. Drug metabolism is often a two phase process. The initial metabolic phase consists of oxidation by a family of enzymes – microsomal or non-microsomal. Microsomal enzymes are mainly found in endoplasmic reticulum of hepatocytes and their primary components are cytochrome P-450 reductase and cytochrome P-450. This enzyme system has been termed a mixed-function oxygenase.
Non-microsomal oxidation takes place by soluble enzymes (such as alcohol dehydrogenase, xanthine oxidase, tyrosine hydroxylase and monoamine oxidase) found in the cytosol or mitochondria of cells. Many drugs also undergo a second step (Phase 2) by conjugation in which an endogenous substance such as glucuronic acid or sulphate is attached to the drug or its metabolite.
These are drugs which have been modified so that they are well absorbed or distributed but are pharmacologically inactive. In the body pro-drugs are activated by oxidative processes into pharmacologically active form – for example, cortisone to active form hydrocortisone and levodopa to dopamine.
Although most metabolites (products of drug metabolism) are inactive, some (Phase 1) metabolites of drugs such as paracetamol, halothane, sulphonamides are hepatotoxic. Paracetamol in therapeutic doses, does not cause hepatotoxicity, but is fatal in over dosage. It is oxidized by the P-450 system to a reactive quinone (Phase 1), which is removed by conjugation with glutathione (Phase 2). If the dose of paracetamol is large or glutathione is deficient, the quinone binds irreversibly to the proteins of the hepatocytes causing liver damage. Pro-drug metabolites are pharmacologically active.
The kidney is the most important organ for excretion. Lipid soluble substances are filtered by the glomerulus, but diffuse back into circulation further down the nephron. The extent of back diffusion is less for drugs that are highly ionized or dissociated. Ionization diminishes the lipid solubility and hence tubular reabsorption.
This situation can be exploited in the management of poisoning due to certain drugs by altering urinary pH — for example, alkalization will increase renal excretion of aspirin and barbiturates and acidification that of amphetamine.
Peritubular capillaries of the proximal renal tubule have two nonselective carrier systems one for acidic drugs, e.g. penicillin, cephalosporin’s, salicylates, probenecid, and thiazides, and the other for basic drugs, e.g. amiloride, cimetidine, and procainamide, which transport drug molecules into tubular urine.
These carrier systems can transport drug molecules even when bound to plasma proteins as well as against electrochemical gradients. Rarely, drugs are excreted through lungs and this route is important in the case of volatile anesthetics.
2. Essay on Pharmacodynamics:
Pharmacodynamics is the study of pharmacological properties of a drug and its mechanism of action. Drug effects are the results of physiochemical reactions between the drug and functionally important molecules in the body. They interact with the body’s natural physiological control systems that include receptors, enzymes, carrier molecules and specialized macromolecules such as DNA.
Some of the known mechanisms of drug actions are as follows:
i. Drug Receptor:
The term ‘receptor’ is used to mean any clearly defined cellular protein to which a drug binds to initiate its effects. The drug is thought to fit onto a receptor rather as a key fits a lock. It may then either stimulate the receptor or produce effect similar to that of the naturally occurring (endogenous) substances and is called an agonist or it may occupy the receptor without producing any effect and block the effect of an endogenous agonist and is called an antagonist.
A few drugs have been shown to be partial agonists (antagonist at low concentrations and agonists at high), for example, buprenorphine and pidolol. Receptors may be viewed to consist of two portions – one which binds the drug (drug binding domain) and the other which propagates (transducers) its regulatory signals (effecter domain) to bring about the drug response.
There are four well known transducer mechanisms by which receptors produce a pharmacologic response:
a. Direct Regulated Ion Channels:
The receptors enclose ion channels within their molecules. These are confined to excitable tissue, e.g. central nervous system, neuromuscular junctions, and autonomic ganglia. Most excitatory neurotransmitters cause an increase in sodium and potassium permeability. This results in a net inward current carried mainly by sodium ion which depolarizes the cell and generates an action potential.
b. G Protein Coupled Receptors:
The effecter domain of the receptor consists of a group of guanine nucleotide – binding regulatory proteins (G proteins) which occur within cells and act as intermediaries between receptors and enzyme in the synthesis of a second messenger cyclic-adenosine – 3′,5′-monophosphate (cAMP) which regulates many different kinds of cellular activity. G proteins also regulate intracellular calcium concentrations. Some hormone peptide receptors, neurotransmitter receptors and autacoid receptors depend on G proteins to mediate their actions on cells.
c. Intracellular Receptors:
These are soluble DNA binding proteins that regulate the transcription of specific genes. They are activated by steroid hormones, thyroid hormone, vitamin D and retinoid.
d. Catalytic Receptors:
These are enzymatic proteins. The extracellular agonist-binding domain is connected to an intracellular catalytic domain through a single stretch of trans-membrane stretch of peptide chain. Catalytic receptors regulate cell growth, their differentiation and development and include the receptors for insulin, epidermal growth factor; platelet-derived growth factor and certain lymphocytes.
Receptors exist in a dynamic state. Their number and functional state vary with drug treatment. Continued exposure to an agonist leads to internalization of receptors, thus limiting or reducing efficacy (“down regulation”) and development of tolerance. Tolerance, is a state of decreased responsiveness seen with the long term use of an agonist and may be a consequence of the down regulation of receptors, a homeostatic adaptive response, or the stimulation of the drug’s metabolism.
Tolerance to a selective β2 adrenoreceptor agonist in asthma is due to down regulation and that of nitrates in angina is due to deficiency of reduced sulphydryl groups that nitrates induce in vascular smooth muscle. Intermittent treatment may allow replenishment and restore efficacy. In some disease processes, such as insulin resistance, defects exist not only at the receptor but also within the mechanism coupling or at a post-receptor site.
Long term treatment with an antagonist will lead to an increase in receptor binding sites (“up regulation”). This phenomenon may explain the syndrome associated with rapid withdrawal of some drugs, for example, rebound angina after withdrawing propranolol.
ii. Enzyme Inhibition:
Interaction between drug and enzyme is in many respects similar to that between drug and receptor. Many important drugs owe their action due to inhibition of the enzyme activity, because they structurally resemble a natural substrate and hence compete with it for the enzyme. Examples of enzyme inhibition include angiotensin converting enzyme inhibitors, carbonic anhydrase inhibitor.
These drugs structurally resemble substances which are used by cells for nutrition and, when absorbed, the cells cannot use them and so fail to multiply. Methotrexate, similar in structure to folic acid competes with folic acid for a vital step in the buildup of nuclear material within the cell and blocks the process so that cancer cell dies.
iv. Action on Cell Membranes:
General and local anesthetics appear to act on the lipid, protein or water constituents of nerve cell membranes and interfere with the movements of ions and thus, prevent nerve or muscle function.
v. Replacement of Deficiencies:
Hormone or vitamin therapy controls the disease in deficiency states.
vi. Cytotoxic Effect:
The drugs kill bacteria or malignant cells without undue change to the patient’s cells. The mechanism of action varies between drugs.
vii. Chemical Interaction:
Drugs, extracellularly, react according to simple chemical equation, for example, antacids, acidifying and alkalinizing agents, oxidizing agents and chelating agents.
viii. The Placebo Response:
A placebo or inert treatment may be defined as use of a substance which has no pharmacological action but which, when used, produces a therapeutic effect. In a wide variety of symptoms, e.g. pain, cough, headache, and in some organic disorders, e.g. peptic ulcer, angina. The administration of a placebo will produce satisfactory response in about 30% of patients. The benefit appears to be connected with the powers of suggestion.
3. Essay on the Routes of Administration for Drugs:
Drugs are given in many ways to achieve a systematic response:
The easiest and commonest way to give drugs is by mouth. The absorption of a drug may be delayed by factors which delay emptying of the stomach, for example, food, concomitant disease (migraine), or drug administration (morphine, atropine).
Drugs (e.g. glyceryl trinitrate) given sublingually have a rapid onset of action and escape pre-systemic metabolic degradation as they pass straight into the systemic circulation without entering the portal system.
Certain drugs are absorbed from the rectum and may be given as suppositories or enema.
d. By Injection:
Injections may be given intravenously, intramuscularly, subcutaneously, intradermally or into various body cavities such as the pleura or peritoneum or into the spinal theca. The intravenous route has the advantage of immediate action, 100% bioavailability and can be used for drugs too irritant to be given intramuscularly. However, there is a risk of adverse effects and it is not suitable for oily solutions or insoluble substances.
Intramuscular injection is easier and most widely used. It is suitable for moderate volumes, oily vehicles and some irritating substances. Rarely, it may result in abscess formation. Subcutaneous injection is also widely used. Absorption is slower than intramuscular injection. Intradermal injection is mainly employed for testing sensitivity to allergens and for immunization. Intrathecal injection is used for the drugs, which do not penetrate blood brain barrier.
e. By Inhalation:
Volatile and general anesthetics are given by inhalation. Antiasthmatics, β2 adrenoreceptor agonists, corticosteroids, and cromoglicate are given as aerosol for local action on bronchi, with minimum systemic effects.
A number of drugs, e.g. glyceryl trinitrate, hyoscine, estrogens, fentanyl, can be applied to the skin as a plastic patch holding a container, which releases the drug at a constant rate. One patch may be effective for a relatively long period so replacement can be made infrequently. However, absorption may be variable and skin reaction may occasionally occur.
g. By Local Application:
Drugs are applied locally as solutions, liniments, ointments or creams to the skin, mucous membranes and wound surfaces and produce their action at the site of application.
4. Essay on the Factors Modifying Drug Action:
There are a number of variables that can modify drug response. The main reasons for this variability are pharmacokinetic, pharmacodynamics and a large number of other factors.
i. Pharmacokinetic Factors:
Children, particularly neonates differ from adults in their response to drugs. Special care is needed in the neonatal period and doses should always be calculated with care. At this age, the risk of toxicity is increased by inefficient renal filtration, relative enzyme deficiencies, differing target organ sensitivity and inadequate detoxifying system.
Old people have a reduction in renal clearance. They excrete drugs slowly, and are highly susceptible to nephrotoxic drugs. Metabolism of drugs by the liver may be reduced in the elderly. The net result of pharmacokinetic changes in the elderly is that the tissue concentration of a drug is commonly increased by over 50%.
ii. Pharmacodynamics Factors:
Tolerance leads to decrease in drug response of agonists. Long-term treatment with an antagonist leads to an increase in receptor binding sites (upward regulation) which explains rebound angina after withdrawal of propanolol. The haemostatic and biochemical milieu may also influence the drug response, for example, a depletion of sodium predisposes a patient to lithium toxicity and hypokalemia to digitalis toxicity.
iii. Genetic Factors:
There are a number of inherited variations in the activity of enzymes responsible for the metabolism of drugs (genetic polymorphism). Several primary routes of metabolism, such as acetylation and hydroxylation are subject to strong genetic control. This may explain individual susceptibility to enhanced toxicity or poor efficacy with particular drugs.
A poor capacity for hydroxylation helps to explain why some patients develop profound hypotension with debrisoquine and considerable beta blockade with metoprolol. Throughout the world, there is a much larger variation in acetylation among ethnic group. Fast acetylators are less likely to be cured of tuberculosis by isoniazid. Slow acetylators more often develop peripheral neuropathy when treated with isoniazid and systemic lupus erythematosus when treated with procainamide and hydralazine.
Another example of genetic polymorphism is deficiency in the enzyme glucose-6-phosphate dehydrogenase (G6PD). Quinine, sulphonamides, chloroquine, and Chloromycetin cause hemolysis of red cell in G6PD deficient cells. There are many other examples of inherited differences in response to drugs.
It affects pharmacokinetics of drugs by decreased gastrointestinal activity, increased blood volume, low plasma albumin, increase in body fat and increase in renal blood flow.
v. Life Style:
Hepatic microsomal enzymes may be induced by many dietary factors (high protein low carbohydrate diet), alcohol, hydrocarbons in cigarette smoke, and many insecticides (e.g. DDT), which is an important cause of diminished response to a drug.
vi. Inter-Current Illness:
This may both modify drug elimination and receptor sensitivity and is an important cause of altered response to a drug. The diseases of liver, kidney and heart are commonly associated with the modification of drug response. Loss of liver cells (cirrhosis) may result in a dangerous depression of respiratory centre with therapeutic doses of morphine due to decreased enzymatic inactivation of the drug.
In renal diseases, therapeutic doses of aminoglycoside antibiotics may result in serious accumulation of the drug leading to ototoxicity. In addition, there are a number of other situations when the drug response is altered by pathological state of many organs. Drug response of digoxin and morphine is increased in hypo-thyroids; adrenaline and digoxin in myocardial infarction and morphine in head injury.
Infections, burns and malnutrition are some conditions, which lead to hypo-albuminaemia. The concentration of free drug in plasma, especially those that are highly protein bound, e.g. phenytoin, clofibrate, increases the risk of enhanced responses.
viii. Drug Interaction:
One drug can modify the response to another drug in a number of ways.
ix. Psychological Factors:
Psychological factors may also be important in the patient’s response to a drug. Expectation of a successful outcome may appear to improve the results of treatment. For example, analgesics are more effective if the patient believes they are effective.
5. Essay on the Adverse Reactions to Drugs:
In recent years, adverse reactions to drugs have become increasingly common. This is probably due to the enormous increase in the range and number of drugs, now in use. Though, no drug is completely without side effects, certain group of widely used drugs account for a disproportionate number of reactions – aspirin, digoxin, anticoagulants, diuretics, antibiotics, steroids, antineoplastics, and hypoglycaemic drugs account for 90% of reactions. Adverse reactions can -be divided into two categories – an augmented but qualitatively normal response to a drug (Type A) or a bizarre, unexpected response (Type B).
These reactions occur in patients who are unusually susceptible to the pharmacological effects of the drug. Examples of Type A reactions include postural hypotension with antihypertensive drugs, gynaecomastia with dopamine antagonists and diarrhea with broad-spectrum antibiotics. These reactions are fairly common and can be predicated from the knowledge of their pharmacological action. They are not usually serious and seldom cause death.
These reactions are not related to the drug’s known pharmacological effects and are usually severe and proportionately more often fatal. Some mechanisms of extra-pharmacologic toxicity include direct cytotoxicity, genetic enzymatic defects, and abnormal immune responses.
These are caused by the production of reactive metabolites during drug metabolism, which may covalently bind to hepatic protein causing hepatic necrosis. Examples of cytotoxic reactions are isoniazid hepatotoxicity and paracetamol hepatotoxicity. The risk of hepatic necrosis is increased in patients receiving drugs as phenobarbitone or rifampicin, which increase the activity of microsomal enzymes.
Immunological Mechanism (Allergic Reactions):
This type of reaction implies that the patient has been exposed to the drug on some previous occasion. This exposure has resulted in the production of an antibody against the drug. If the drug is given on a second occasion, the drug and the antibody combine in such a way as to cause damage to tissue and produce symptoms of an allergic reaction. Skin, respiratory, gastrointestinal and cardiovascular systems are the main target of allergic reactions.
Four types of allergic reactions are described:
a. Immediate Type (Acute Anaphylaxis):
The antibody (produced in response to a drug) may become attached to the surface of mast cells or leucocytes. On subsequent administration, the drug combines with antibody, destroys the mast cells, liberating local hormones (autacoids) such as histamine, leukotriene’s, prostaglandins and platelet activating factor, which cause urticaria, acute anaphylactic reaction and asthma. Treatment includes adrenaline, hydrocortisone, antihistamines, and cardiopulmonary resuscitation.
The antibody may become attached to the surface of red cells. On second exposure to the drug, the combination occurs leading to destruction of red cells, which cause blood disorders such as hemolytic anaemia, thrombocytopenia, agranulocytosis and aplastic anemia. Agranulocytosis is a very rare condition which requires withdrawal of the drug and administration of a bacteriocidal drug (penicillin) to prevent infection. Chloromycetin is the most important drug that may cause aplastic anemia.
c. Antigen/Antibody/ Complement Combination:
Antigens (drugs) and antibodies may combine in the blood stream to form immune complexes. They may penetrate various organs where they are deposited, together with a further substance called complement, which is present in the blood. The antigen/ antibody/ complement combination stimulates inflammation which may affect the skin, kidneys and other organs and result in serum sickness, glomerulonephritis, vacuities and pulmonary diseases.
d. Delayed Type (Cell-Mediated):
Drugs acting as antigens may sensitize lymphocyte which on further contact with the drug leads to a local or tissue allergic reaction, e.g. contact dermatitis.
Alteration of Immunologic Status:
Alteration in patient’s immunologic status may result in adverse reactions to drugs. Bone marrow transplant patients may experience cutaneous drug reactions. HIV infected patients run high risk of developing cutaneous reactions to drugs, e.g. cotrimoxazole, dapsone, amoxycillin, clavulanate. They also have a higher risk of the most serious type of allergic reactions, e.g. toxic epidermal necrolysis, Stevens- Johnson syndrome.
These resemble allergic reactions but have no immunological basis. They are largely genetically determined and are due to release of local hormones (histamine or leukotriene’s) by the drug. These pseudo-allergic reactions mimic Type 1, 2, and 3 allergic reactions.
Miscellaneous Adverse Reactions:
Apart from vital organs, toxic reactions on eye can occur on long- term use of certain drugs like chloroquin, corticosteroids and phenothiazine’s. Toxic reactions may be due to the disease during drug treatment. Blackwater fever, a severe and often fatal condition in malaria patients treated with quinine is due to malaria and not quinine.
These are the diseases caused by drugs. Peptic ulcer after long term use of non-steroidal anti-inflammatory drugs or steroids and Parkinsonism by phenothiazine’s is common examples.
Drugs during pregnancy may cross the placental barrier and cause fetal abnormalities. Drugs can produce fetal damage during the first 3 months of pregnancy when cells change into recognizable human beings. Drugs which are known to produce fetal abnormalities are thalidomide, folic acid antagonists, tetracycline’s, androgens, danazol, warfarin, diethylstilbestrol, etretinate, lithium and some anticonvulsants.
Prevention of Adverse Reactions:
Though it may not be possible to prevent adverse reactions, certain guidelines may minimize their incidence.
i. Drugs to be used only when indicated.
ii. Patient’s history for any allergic or idiosyncratic reactions.
iii. Cautious use in extremes of life and pregnancy.
iv. Inform the patient about likely serious allergic reactions.
v. Restrict therapy to few familiar drugs.
vi. Strict vigilance for adverse reactions or any unexpected event with recently introduced drugs.
6. Essay on Adverse Drug Interactions:
Adverse drug interactions have assumed a great importance with the development of potent drugs, the treatment with multiple drugs, and the increasing usage of drugs in aging population that has various degenerative diseases. The number of drug interactions described is very large and many of them are of little or no clinical importance. In general those interactions, which are important, occur when the dose of a drug is critical and a small change in blood concentration or the patient’s sensitivity to the drug results in toxicity or conversely, a lack of therapeutic effect.
Dangerous interactions are particularly liable to occur in patients who take several drugs at the same time as in the case of acute illness or in old age and with drugs which have a narrow margin of safety or are cumulative or have a saturable hepatic metabolism. The risk of interaction is greatest with drugs like warfarin, chlorpromazine, morphine, verapamil, levodopa, lithium, phenytoin, theophylline, beta-blockers, digoxin, rifampicin and erythromycin.
There are two principal types of interactions between drugs – pharmacokinetic interactions resulting from alterations in the delivery of drugs to their sites of actions and pharmacodynamics interactions which modify the responsiveness of the target organ or system.
A. Pharmacokinetic Interactions Causing Diminished Drug Delivery:
Most drugs are absorbed by diffusion through the gut wall. If a well absorbed drug gets attached to poorly or non-absorbed drug, the well absorbed drug will be held in the intestine and its absorption will be decreased. For example, antacids form insoluble complexes with tetracycline’s, iron, and prednisolone and anion exchange resins with digoxin, thyroxin, and warfarin and interfere with their absorption.
Many drugs increase the synthesis of microsomal enzyme protein that metabolizes drugs. As a result, rate of metabolism of inducing drug and/or other drugs is increased, with a reduction in the circulating concentration of the drug and a reduced effect.
Barbiturates, griseofulvin, most anti-epileptics, rifampicin and erythromycin are the most important enzyme inducers in man. Drugs whose metabolism is significantly affected by enzyme induction are oral contraceptives, warfarin, corticosteroids and cyclosporine.
B. Pharmacokinetic Interaction Causing Increased Drug Delivery:
Most inhibitory interactions also affect hepatic enzymes. Many drugs have the potential for interfering with the metabolism of other drugs, usually by competing for binding sites on the appropriate enzymes. Inhibition of the metabolism of the affected drug results in higher plasma concentration with risk of toxicity.
The most dangerous inhibitors are the antibacterial such as erythromycin and cotrimoxazole, cimetidine, and dextropro-poxyphene. Commonly affected drugs are warfarin, anti-epileptics, theophylline and the suphonylureas.
First Pass Metabolism:
Some drugs may suppress the metabolic enzyme activity in the gut wall and liver and increase the oral bioavailability of the affected drug. The antibiotic Chloromycetin is an enzyme suppressor. The best example of interference with first pass metabolism is “cheese reaction” due to inhibition of tyramine breakdown in the gut wall by nonselective monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine that has resulted in severe hypertension.
Displacement of Protein Binding:
Drug displacement from its binding site on plasma protein is normally offset by a compensatory increase in metabolism or excretion, without affecting the free concentration of the drug at the target sites. However, if the displacement is accompanied by metabolic inhibition, toxic reactions would be apparent. This double mechanism explains why phenylbutazone potentiates the effect of warfarin and why the addition of sodium valproate can produce phenytoin toxicity.
Affecting Renal Excretion:
Drugs are eliminated through the kidney both by glomerular filtration and by active tubular secretion. Competition occurs between those which share the same active transport mechanism in the proximal tubule. Thus, probenecid delays the excretion of many drugs including penicillin, some cephalosporin’s, indomethacin and dapsone. Similarly, thiazide diuretics delay the renal excretion of lithium, which may result in serious lithium toxicity.
These are interactions between drugs which have similar or antagonistic pharmacological effects or side effects. They may be due to competition at receptor sites or occur between drugs acting on the same physiological system.
Synergism occurs if two drugs with the same effect, when given together produce an effect that is greater in magnitude than the sum of the effects when the drugs are given individually. For example, the effect of a drug depressing the central nervous system, e.g. benzodiazepine, will be enhanced by another depressant, e.g. alcohol. Synergism of drugs with similar actions may be beneficial also, as with antibacterial components of cotrimoxazole or with combined levodopa and selegiline treatment in Parkinson’s disease.
When one drug decreases or inhibits the action of another drug antagonism occurs. A classic example of antagonism is the suppression of the bactericidal activity of penicillin, which acts on dividing bacteria, by tetracycline which reduces bacterial division.