Pharmacodynamics

Filed under: General,Pharmacology |

Pharmacodynamics is concerned with the actions, interactions and the mode of action of drugs. It deals with: Quantitative study of the biological and therapeutic effects of drugs,  The mechanism of action of a drug, Correlation of drug actions with the chemical structure.

An effect on a tissue is the end result of an interaction between drug molecules and some part of the tissue cells. So the terms ‘action’ and ‘effect’ are not synonymous. The action deals with the initial consequences of drug molecules-cell interaction and effect includes the remaining events. Interaction between drug molecules and some part of the tissue cell may be specific or non-specific. In former, the drugs act on pharmacological receptors situated on or within the cells while in case of later receptors are not involved.

Targets of Drug Action in Pharmacodynamics

Mostly drugs produce their effects by acting on specific macromolecular elements. Thus they alter their biochemical or biophysical activity. The following are important targets for drug action on mammalian cells.

Receptors: The functions of all the different cells in the body are regulated through their system of chemical communications. Receptors are the sensing elements of these chemical communications and the hormone or transmitter substances are chemical messengers. Receptor-mediated actions can indirectly activate or inhibit ion channels, enzymes and carrier molecules.

Carrier molecules: These are carrier proteins which have “recognition sites”. These sites act as targets for a drug. These carrier molecules transport ions and small organic molecules across cell membrane. Some carrier proteins are of proton pump, nor-adrenaline uptake and Na/K pumps.

Ion channels: Mostly drugs modulate ion channels by binding with parts of the channel protein. However, some are ligand-gated receptor mediated ion channels while others are indirectly modulated through C-proteins or other intermediates. Nat, K, Ca, and CE are common ion channels.

Enzymes: Mostly drug molecules produce their effects by competitively inhibiting the enzymes.

A few drugs produce their effect acting on structural proteins, e.g. colchicine on tubulin.

Drug-Receptor Interactions in Pharmacodynamics

In the beginning of this century, Paul Ehrlic developed the concept of receptor. According to him the drug-receptor interaction is a lock (receptor) and key (drug) system. Most drug receptors (pharmacological receptors) are macromolecular proteins. They are specific in size, shape and structure. They occur at specific sites to which specific substances, i.e. drugs (sometimes called ligands) interact. Drug-receptor binding leads to a change in the macromolecule. This in turn triggers a sequence of events (transduction mechanisms or the signaling mechanisms) resulting in a biological response of the tissue or organ. Signaling mechanisms are different at different sites. So far four signaling mechanisms have been well understood.

1. Ligand-gated channels: GABA, n-ACh and the excitatory amino acids are natural ligands and synaptic transmitters. They produce their effects by regulating transmembrane flow of ions along with concentration gradient acting on specific receptor ion channel and opening the gate for relevant ion flow. ACh opens Na channel and glutamate K channel. There occurs depolarization of cell membrane due to the flow of ions.

2. C-protein coupled receptors: Most of the receptors (m-ACh, adrenergic, H2, 5HT, opiate and many peptide hormones) in the body belong to this family. They are situated on the cell membrane. They are linked to the effector (enzyme/channel) carrier protein through one or more CTP activated proteins (C-proteins) for response effectuation. Among number of C-proteins, Cs and Ci are the two important ones. Cs and Ci produce opposite effects by causing stimulation and inhibition of adenylyl cyclase respectively. Stimulation of adenylyl cyclase enzyme leads to accumulation of cAMP while its inhibition is associated with decrease in concentration of cAMP. Cs protein is stimulated by I3 adrenergic amine, H2-agonists, 5-HT1 agonists and polypeptide hormones while Ci protein is activated by f2 adrenoceptor agonists, M2-ACh and &opioid receptor agonists. There are four major effector pathways through which G-protein coupled receptors function:

i. Adenylyl cyclase cAMP pathway: This system has a wide variety of receptor population and produces diverse effects. Activation of adenylyl cyclase leads to intracellular accumulation of second messenger cAMP, which functions almost exclusively through cAIVIP dependent protein kinase (PKa). Phosphodiesterases terminate the intracellular effects of cAMP by degrading it to 5-AMP. Methoxamines prolong the effects of cAMP by competitively inhibiting phosphodiesterases. As observed there are different signaling mechanisms at a molecular level. These mechanisms modulate different cellular function or sometimes even the same cellular function. It means the effects may be complement or oppose each other. Examples are: There occurs release of glucose from liver by 2 different signaling mechanisms, i.e. stimulation of cAMP (beta-adrenoceptors) and phos phoinositid (a1—adrenoceptors) second messengers. Vasopressor drugs contract smooth muscles by IP3-mediated mobilization of Ca (alpha adrenoceptors) whereas vasodilators act by elevation of cAMP (beta—adrenoceptors.

ii. Phospholipase C-Ca/phosphoinos itide system: This system is more complex than the cAMP pathway due to two second messengers (inositotriphosphate, 1P3 and diacylglycerol, DAG) and multiplicity of protein kinases. This pathway is stimulated by 5HT2, TRH, ACh(M1), catecholamine (a1), vasopressin and angiotensin.

iii. cGMP pathway: This pathway is limited to a few cell types. It is stimulated by ACh, histamine, peptide hormone, atrial natriuretic factor (ANF) and vascular endothelial nitric oxide. Activation of membrane bound guanylate cyclase leads to generation of cGMP. In turn it acts by stimulating a cGMP – dependent protein kinase.

iv. Channel regulation: The activated Gproteins can also open or close ionic channels specific for Ca, K, or Na, without involving any second messenger. In turn there occurs hperpolarization/depolarization/changes in intracellular mACh receptors enhance K permeability in cardiac muscle, and opiate analgesics open K channels reducing neuronal excitability.

3. Catalytic receptors (tyrosine kinaselinked receptors): These receptors are enzymatic proteins themselves. The agonist binding site and the catalytic site lie respectively on the outer and inner face of the plasma membrane. Two sites are interconnected through a single transmembrane stretch of peptide chain. These receptors mediate the actions of insulin, a variety of growth factors and peptide mediators which stimulate mitogenesis.

4. Receptors regulating gene expression in Pharmacodynamics:

These receptors are intracellular (cytoplasmic or nuclear) soluble proteins. They respond to lipid soluble chemical messengers that penetrate the cell, e.g. steroid and thyroid hormones. The stimulation of these receptors results in stimulation of transcription of selected genes that in turn leads to the synthesis of particular proteins or enzymes. In turn, these proteins or enzymes produce the cellular effects. In this system, effect lasts for hours or days because of slow turnover of newly synthesized protein or enzyme.

Response of Drug-Receptor Interactions in Pharmacodynamics

Depending on the nature of drug molecule, the drug receptor interaction leads to a variety of responses. The ability of a drug to interact with a receptor is due to its affinity and the ability to produce a response (contraction of muscle or secretion from a gland) is called its ‘intrinsic activity’ or ‘intrinsic efficacy’.

An agonist is a drug (neurotransmitter or hormone) which has affinity and intrinsic activity such as acetylcholine, noradrenaline, histamine, etc.

An antagonist is a drug which binds to the receptor but does not activate it. It means it has affinity but no intrinsic efficacy such as atropine. These drugs, however, compete with the endogenous ligand or exogenous agonists and prevent their receptor occupancy and response.

Some drugs have affinity but very low intrinsic efficacy. They are called partial agonists. They competitively block the effects of a full agonist. They produce a response by themselves which is much lower than that of a full agonist even at full receptor-occupancy. Examples are pindolol (a beta blocker), saralasin, etc.

Inverse agonists are drugs which produce responses that are paradoxical in nature. For example, p-carbolines act on benzodiazepine receptors and produce anxiety, increased muscle tone and convulsions. On the other hand, the agonist benzodiazepines binding with same receptors produce sedation, anxiolysis, muscle relaxation and control of convulsions. Both the responses are mediated by modulating the effects of the neurotransmitter GABA.

A mixed agonist-antagonist has also been described. It should not be confused with partial agonist. This type of drug acts simultaneously on a mixed group of receptors with an agonistic action on one set and with an antagonist action on another set. Examples are seen among the opioids.

There are binding forces in drug-receptor interactions such as covalent bonds (usually the strongest, producing almost irreversible effects), ionic bonds, hydrogen bonds and van der Waals forces (weakest attractive bonds producing a readily reversible effect).

It is also important to determine quantitative aspects of drug action. They help in deciding the mode of use of a drug. The most important aspects of quantitative nature is dose/concentration—effect/response relationship.

1. Drug responses are of two types in Pharmacodynamics:

i. Graded response in Pharmacodynamics: This effect can be seen on a single subject, or discrete organ or tissue. In this case, the pharmacological response increases with an increase in the dose and it is measurable, e.g. contraction or relaxation of muscle, change in blood pressure, blood sugar, etc. The graded dose-response relation is partially a reflection of extent of occupancy of the receptors by the drug. However, the degree of pharmacological effect produced by increasing doses of a drug eventually reaches a steady level. This is termed as “ceiling effect” and the dose which produces this effect is called “ceiling dose”. At this stage, there is no increase in therapeutic effect even if the dose of drug exceeds the ceiling dose. On the contrary, there may occur undesirable effects or different responses. Ceiling dose also helps in comparing the therapeutic efficacy of various pharmacologically active compounds.

The graded dose response curve is usually sigmoid in shape. However, it is almost a straight line when drug response is plotted against the logarithm of the drug dose. The latter is useful for the comparison of the activity of various compounds, e.g. in bioassays.

ii. Quanta! response: It is an ‘all or none response’. It cannot be measured. Examples are analgesic, anticonvulsant or convulsant activity, death, etc. In this case also the log dose response curve is sigmoid in character. To make the relationship more linear, the responses are converted into probits (probability units) from statistical table and logdose-probit response curve is plotted. This type of curve helps in determining LD% or ED50 more accurately.

2. Spare receptors: Drug response is not directly proportional to the rate of receptor occupancy. A pure agonist may produce maximal response just by occupying even duly 1% of receptors. On the contrary, a partial agonist will not produce maximal response even after 100% receptor occupancy. So when the maximal response is produced by a pure agonist without occupying all the available receptors, the left over receptors are called spare receptors. Higher the spare receptor population, greater is the tissue sensitivity for the drug.

3. Potency and efficacy in Pharmacodynamics: A drug is said to be potent when it possesses high intrinsic activity at low unit weight doses. It depends on affinity of receptors and the efficiency of drug receptor coupling. The potency is determined by finding out ED50 or EC50. Lower the ED50 or EC5c1, higher is the potency. However, in drug selecting process efficacy of a drug plays more important role than potency. Efficacy refers to the maximum response or peak response produced by a drug. If a drug is more potent and has high efficacy than the older drug, it is certainly a better alternative. However, if it is more potent but has low efficacy than the older drug, it is not a suitable alternative.

4. Quantitative variation in drug response:

Due to normal “biological variations”, responses to drugs vary from animal to animal, human to human. Sometimes a quantitative change in drug response may be observed in the same individual during the course of therapy. It is of great clinical importance. Depending on the change, a physician has to change either the dose or the drug itself. This may occur in the following circumstances:

a. Down regulation in Pharmacodynamics: On continuous exposure of tissues to an agonist, the number of receptors decreases (down regulation). This results in loss in efficacy. Down regulation of receptor occurs due to accelerated endocytosis of receptors (internalization) from the cell surface, which is faster than de novo synthesis of receptors. It is responsible for ‘tolerance’ or ‘tachyphylaxis’.

b. Up-regulation: On continuous exposure of tissues to an antagonist, the formation of new receptors increases (up regulation) and is responsible for increased tissue sensitivity. This may be responsible for rebound hypertension/angina pectoris following withdrawal of beta-adrenoceptor blocker. Sometimes hormones may also cause up-regulation of receptors,- e.g. increased cardiac sensitivity to catecholamines in thyrotoxicosis.

Degree and character of response of a drug varies from one individual to another individual. Hence to achieve desired therapeutic effect the optimum dose of a drug differs from person to person. This is why the doses of official preparations of drugs are always expressed in the form of range which gives therapeutic effect in the majority of subjects. However, these doses may not be applicable under all circumstances. So the important factors, which modify the effect of a drug, are:

1. Body weight and age: Determination of a proper dose of a drug is most important in therapeutics. The best way to calculate dosage is in terms of milligrams per kilogram body weight. However, doses calculated in this way may not be applicable to excessively obese patients or those suffering from oedema, dehydration, emaciation, cachetia and malnutrition.

Factors modifying the effect of a drug in Pharmacodynamics

Body weight and age, Sex, Genetic factors, Diet and environment, Metabolic disturbances, Route of administration, Emotional factors, Cummulation, Presence of disease, Additive effect, Synergism, Antagonism, Tolerance

Drug dependence in Pharmacodynamics

The body surface area is calculated from the height and weight of the child. Infants are sensitive to many drugs because many drug metabolizing enzymes are either absent or deficient. So these drugs may show prolonged action in infants. Same is true in old individuals where metabolism of a drug may depend on the functional state of the liver, disease or previous exposure of the patient to the drug.

2. Sex: Sometimes excitement may be evoked in the females by central nervous system depressants like morphine or barbiturates. One has to be careful while prescribing a drug to a female patient during menstruation, pregnancy and lactation.

3. Genetic factors in Pharmacodynamics: To produce the same therapeutic effect, the dose of a drug may vary by 4 to 6-fold among different individuals. This is due to different rates of drug metabolism which is controlled by the amount of microsomal enzymes. The amount of microsomal enzymes are genetically determined. So there are now some specific genetic defects which are responsible for variation in drug responses, e.g.

  • Glucose-6-phosphate dehydrogenase deficiency leads to haemolysis with primaquin and other oxidizing drugs.
  • Inability to hydroxylate phenytoin leads to toxicity at usual doses.
  • Atypical pseudocholinesterase causes succinylcholine apnoea.
  • Malignant hyperthermia occurs after halothane.
  • Acetylator polymorphism causes isoniazid neuropathy, procainamide and hydralazine induced lupus.
  • Acute intermittent porphyria is precipitated by barbiturates.
  • Resistance to cournarine anticoagulants is due to an abnormal receptor for them.
  • Mongolism-fatality is seen with therapeutic dose of atropine.
  • Erythrocyte diaphorase methemoglobinemia is seen after administering certain drugs such as acetanilide, sulfonamide and nitrites.

4. Diet and environment in Pharmacodynamics: Although food interferes/decreases the rate and extent of drug absorption, most drugs are taken after meal to avoid the risk of gastric – irritation and associated nausea and vomiting. However, under special circumstances, drugs are given empty stomach, e.g.

  • Antimotion sickness drugs for quick action
  • Anthelmintics to avoid mixing with food
  • Penicillin V to prevent inactivation in gut

Dose of a hypnotic drug is more to produce sleep during day time than what is needed at bedtime in the night. DDT, polyhydrocarbons, and alcohol enhance biotransformation of drugs such as theophylline by inducing microsomal enzymes.

5. Metabolic disturbances in Pharmacodynamics: Alteration in physiological parameters of the body may modify the effect/dose of a drug, e.g.

  • Metabolic acidosis reduces vasoconstriction effect of noradrenaline.
  • Salicylates decrease body temperature only in the presence of pyrexia (fever).
  • Maximum amount of iron is absorbed from gut in patients suffering from iron deficiency anemia.

6. Route of administration in Pharmacodynamics: Smaller doses are required for i.v. administration of a drug than oral doses. This is particularly so for drugs which are incompletely absorbed, e.g. morphine and digoxin. On i.v. administration, onset of action of a drug is quick but chances of drug toxicity is also more.

7. Emotional factors: The personality of a physician/patient may influence the drug effect, e.g.

  • Placebos (inert dosage form) given by physician to patients of angina pectoris and bronchial asthma may produce beneficial therapeutic effect.
  • The dose of chlorpromazine will be ten times more than usual dose to produce quietening effect in some schizophrenic patients.

8. Cummulation: Some drugs are excreted slowly. So their continuous administration may lead to a sufficiently high concentration of the drug in the body to produce toxicity. Examples of such drugs are emetine, heavy metals, and digitalis. Most often cummulation is undesirable. Rarely may it be desirable such as use of phenobarbitone in the treatment of epilepsy.

9. Presence of disease:

  • Cirrhosis of liver prolongs the effect of barbiturates and chlorpromazine.
  • Impairment of kidney function may lead to toxicity of aminoglycoside antibiotics.
  • Myxoedema prolongs the action of morphine delaying its rate of oxidation.

10. Summation effect: On simultaneous administration, if two drugs produce same pharmacological effect by different mechanism of action and the total pharmacological effect is equal to the sum of their individual effect, it is called summation effect e.g.

  • Paracetamol (inhibition of prostaglandin synthesis) + codeine (opioid receptor agonist) as analgesic
  • Ephedrine (adrenoèeptor agonist) + theophylline (inhibition of phosphodiesterase enzyme) as bronchodilator

11. Additive effect: On simultaneous administration, if two drugs produce same pharmacological effect by same mechanism of action and the total pharmacological action of two drugs is equal to the sum of their individual effect, it is called additive effect, e.g.

  • Aspirin + paracetamol as analgesic! antipyretic (inhibition of prostaglandin synthesis)
  • Nitrous oxide + ether as general anaesthetic (inhibition of neuronal activity by a membrane effect).

12. Synergisms In this case, there occurs facilitation of pharmacological response by concomitant use of two drugs and their total effect will be more than the sum of their individual effect. Examples are:

  • Acetylcholine + physostigmine
  • Levodopa + carbidopa!benserazide
  • Sulfonamide + trimethoprim
  • Tyramine + MAO inhibitor
  • Adrenalin + cocaine/desipramine
  • Methyl alcohol + thiazide diuretic.

13. Antagonism: When two drugs, administered simultaneously, oppose the action of each other on the same physiological system, the phenomenon is called antagonism. It can be of following types:

i. Chemical antagonism: It involves reduction or abolition of the biological activity of a drug by a chemical reaction with another agent, e.g. between acids and alkalies; BAL and arsenic.

ii. Functional antagonism: In this case, two agonists oppose the action of each other acting independently of each other, e.g. acetylcholine and adrenaline on dogs blood pressure.

iii. Coin petitive or reversible antagonism (equilibrium type): In this type of antagonism, the agonist and antogonist compete with each other for the same receptors. The extent of antagonism will depend by the relative number of receptors occupied by the two compounds. Other features are:

  • Antagonist has chemical resemblance with agonist.
  • Antagonism can be overcome by increasing the concentration of the agonist at receptor site. It means the maximal response to agonist is not impaired (surmountable).
  • Antagonist shifts the dose response curve to right.
  • Emay of agonist is obtained with high concentration of agonist.
  • Duration of action is short. It depends on drug clearance.

Examples:

  • Acetyichotine and atropine
  • Morphine and naloxan

iv. Non-competitive antagonism: Here an antagonist inactivates the receptor (R) in such a way so that the effective complex with agonist cannot be formed irrespective of the concentration of the agonist. This can happen by various ways:

  • The antagonist might combine with R at the same site in such a way that even higher concentration of the agonist cannbt displace it.
  • The antagonist might combine at a different site of R in such a way that agonist is unable to initiate characteristic biological response.
  • The antagonist might itself induce a certain change in R so that the reactivity of the receptor site where agonist should interact is abolished.

Other features of this antagonism are:

  • Antagonist has no chemical resemblance with agonist.
  • Maximum response is suppressed (insurmountable).
  • Although antagonist shifts the dose response curve to right, the slope of the curve is reduced.
  • The extent of antagonism depends on the characteristics of antagonist itself and agonist has no influence upon the degree of antagonism or its reversibility.
  • E max of agonist is decreased even with high concentration of agonist.
  • Duration of action is long which depends upon new receptor synthesis. Examples are methysergide, phenoxybenzamine, and verapamil.

v. Physiological antagonism: In this interaction of two drugs, both are agonists. So they act at different receptor sites. They antagonize the action of each other because they produce opposite actions. Classical example of physiological antagonism is adrenalin and histamine. The former causes brorichodilatation while the latter causes bronchoconstriction. So adrenalin is a life saving drug in anaphylaxis.

Clinical significance of drug antagonism in Pharmacodynamics

  • It helps to correct adverse effects of a drug, e.g. ephedrine antagonizes sedative effect of phenobarbitone.
  • It is useful to treat drug poisoning, e.g. naloxone is used to treat acute morphine poisoning.
  • It guides to avoid drug combination with reduced drug efficacy such as penicillin and tetracycline combination.

14. Drug tolerance: It means requirement of a higher dose of a drug to produce a given therapeutic response. Drugtolerance may be:

a. Natural: In this case, the species/ individual is inherently less sensitive to the drug, e.g. rabbits are tolerant to belladona; black races are tolerant to mydriatics.

b. Acquired: It occurs on repeated administration of a drug in an individual who was initially responsive. Body is capable of developing tolerance to most drugs. However, this phenomenon is very easily recognized in case of central nervous system depressants. Tolerance need not develop equally to all the actions of a drug, e.g.

  • Tolerance develops to sedative action of chiorpromazine but not to its antipsychotic action.
  • Tolerance develops to sedative action of phenobarbitone but not to its anti-epileptic effect.
  • Tolerance develops to analgesic and euphoric effects of morphine but not to its constipating and miotic actions.

c. Cross-tolerance: It means development of tolerance among pharmacologically related compounds, e.g. alcoholics are tolerant to barbiturates and general anesthetics.

Mechanisms of development of tolerance:

i. Pharmacodynamics/drug disposition tolerance: In this case, there is decreased availability of drug at receptor site due to Pharmacodynamics reasons, e.g.

a. Due to enzyme induction as in case of repeated use of barbiturates, rifampicin, ethanol.

b. Due to decreased rate of absorption.

c. Due to rapid elimination of a drug such as phenylbutazone which is rapidly excreted in rodents, dogs and cats than in human beings. So these animals are relatively tolerant to phenylbutazone.

ii. Pharmacodynamics cellular tolerance: In this type, cells of the target organs become less responsive. It may be of two types:

a. Physiological adaptation occurs due to activation of homeostatic (compensatory) mechanisms, e.g. with carbonic anhydrase inhibitor diuretics, vasodilator hypotensives.

b. Tissue tolerance is seen with many drugs. e.g. morphine, alcohol, barbiturates, psychotropic drugs. It may be due to down regulation of receptors.

Ta chyphyl axis: It is a rapid development of tolerance. In this case, the effect diminishes rapidly when a drug is given continuously or repeatedly. It is a reversible phenomenon. The tissue regains its normal sensitivity following a drug free period of some minutes or hours. It may be due to:

a. Tight binding of agonist molecule leading to desensitization in ionic channel-coupled receptor, e.g. N-ACh receptors at the neuromuscular junction.

b. Down regulation of receptors.

c. Depletion of neuronal mediators as seen in case of indirectly acting sympathomimetics, e.g. tyrarnine, ephedrine, amphetamine.

15. Drug dependence: It is a condition in which an individual is dependent on a drug. It is seen with drugs which are capable of altering mood and feelings of an individual. These drugs are liable to be used repeatedly to derive euphoria, pleasure, and withdrawal from reality. Drug dependence is a biological phenomenon, which consists of: (a) psychic dependence and (b) physical dependence.

a. Psychic dependence is a condition in which drug produces a feeling of satisfaction and a psychic derive to take the drug periodically or continuously to have a feeling of pleasure or to avoid discomfort of hfe, e.g. heavy cigarette smoking.

b. Physical dependence is an altered physiological state which is produced by repeated administration of a drug. In this case, the body achieves an adaptive state. Hence intense physical disturbances (withdrawal syndrome) occur when drug is withdrawn, e.g. alcohol drinking.

When a drug is used for a “non-medical” purpose, it is supposed to be misused or abused, The drugs of abuse can be classified as under:

I. Drugs used or present in commonly used beverages:

a. Caffeine in tea, coffee and cold drinks.

b. Tobacco (nicotine) for smoking, chewing or intranasal administration.

c. Ethyl alcohol.

II. Prescribed drugs, e.g. morphine, mepridine, barbiturates, tranquilizers, amphetamines.

III. Banned drugs such as heroin, cocaine, ganja, charas, LSD and other hallucinogens.

Principles of treatment of drug dependence in Pharmacodynamics

1. Gradual or sudden withdrawal of the drug.

2. Substitution therapy.

3. Specific-drug therapy, e.g. antabuse in alcohol drug dependence.

4. Correction of nutritional deficiencies.

5. Psychotherapy and occupational therapy.

6. Community treatment and rehabilitation.

Points for Dental Students

It is essential for the dental students to have a basic knowledge of Pharmacodynamics of each drug. This helps:

1. To select a suitable drug to be used in a particular situation with safety and maximum benefit to the patient.

2. To understand rational basis of use of a drug in a particular disease.

3. To know the various factors which modify the dose and effect of a drug so that necessary adjustments may be carried out for proper use of a drug.

4. To have knowledge of Pharmacodynamics interactions in order to prescribe drugs rationally. For example, bronchial relaxation depends upon the formation of cyclic 3’, 5’-AMP (cAMP). Catecholamines increase the formation of this ‘second messenger’ by stimulating adenylcyclase while aminophylline inhibits the breakdown of cAMP. So when two drugs are combined will be useful in the treatment of bronchial asthma. On the other hand, severe ototoxicity develops due to simultaneous use of aminoglycoside antibiotics and ethacrinic acid.

TO REMEMBER

1. Pharmacodynamics deals with the actions, interactions and the mode of action of drugs.

2. The terms ‘action and effect’ are not synonymous. The action deals with the initial consequences of drug molecules- cell interaction and effect includes the remaining events.

3. Drugs produce only a quantitative and not a qualitative change in the functions of the target organ, i.e. stimulation, depression, and irritation. They may modify immune status or used as anti- infective agents.

4. Drugs produce their overt effects by a variety of fundamental actions, viz.

a. Acting outside the cell by their physical and chemical properties;

b. Acting on intracellular constituents;

c. Acting on cell membrane;

d. By their antimicrobial action.

5. Drug receptor interaction in Pharmacodynamics is a lock (receptor) and key (drug) system. Pharmacological receptors are macro- molecular proteins on which drugs (ligand) interact and produce a biological response either by transduction or the signaling mechanisms.

6. Agonist is a drug which binds to the receptor (has affinity) and activate it (has intrinsic efficacy) while antagonist has affinity but no intrinsic efficacy. Inverse agonists are drugs which produce responses that are paradoxical in nature.

7. Mixed agonist-antagonist is a drug that acts simultaneously on a mixed group of receptors with agonistic action on one set and an antagonistic action on another set.

8. Drugs can produce a graded response (measurable and varies with dose) or quantal response (all or none response – not measurable).

9. A drug with high intrinsic activity at low unit weight doses is said to be potent while efficacy refers to the maximum or peak response produced by a drug.

10. Pharmacogenetics deals with genetically mediated variations in drug responses.

11. Additive/summation effect means the total pharmacological action of two drugs will be equal to the sum of their individual effect on simultaneous administration, while in case of synergism the total effect will be more than the sum of their individual effect.

12. Antagonism in Pharmacodynamics means two drugs oppose the action of each other on the same physiological system on simultaneous administration. It may be chemical, competitive, and non-competitive, functional or physiological.

13. Drug tolerance in Pharmacodynamics means requirement of a higher dose of a drug to produce a given therapeutic response. It may be natural or acquired.

14. Drug dependence in Pharmacodynamics is a condition in which an individual is dependent on a drug. It may be psychic dependence (psychic derive to take drug to have a feeling of pleasure) or physical dependence (altered physiological state due to repeated administration of a drug).

[Source: Principles of Pharmacology for Dental Students]

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