Principles and mechanisms of drug action. Receptor theories and classification of receptors, regulation of receptors. drug receptors interactions signal transduction mechanisms, G protein–coupled receptors, ion channel receptor, transmembrane enzyme linked receptors, transmembrane receptor and receptors that regulate transcription factors, dose response relationship, therapeutic index, combined effects of drugs and factors modifying drug action.

1. Pharmacodynamics
By
Prof. Saba Shaikh

2. Topics
➢Principles and mechanisms of drug action.
➢Receptor theories and classification of receptors, regulationof receptors.
➢ Drug receptors interactions
➢signal transduction mechanisms, G-protein–coupled receptors, ion channel
receptor, transmembrane enzyme linked receptors, transmembrane JAK-
STAT binding receptor and receptors that regulatetranscriptionfactors,
➢Dose response relationship,therapeutic index, combined effects of drugs
➢Factors modifying drug action.

3. Pharmacodynamics
• Pharmacodynamics is the study of actions of the drugs on the body
and their mechanisms of action, i.e. to know what drugs do and how
they do it.

4. Drugs act by:
1. Stimulation
2. Depression
3. Irritation
4. Replacement
5. Anti-infective or cytotoxic action
6. Modification of the immune status

5. MECHANISMSOF DRUG ACTION
• Most drugs produce their effects by binding to specific target proteins like receptors, enzymes and ion
channels. Drugs may act on the cell membrane, inside or outside the cell to produce their effect. Drugs
may act by one or more complex mechanisms of action. Some of them are yet to be understood. But
the fundamental mechanisms of drug action may be:
• through receptors
• through enzymes and pumps
• through ion channels
• by physical action
• by chemical interaction
• by altering metabolic processes

6. Through Receptors
• Drugs may act by interacting with specific receptors in the body

7. Through Enzymes and Pumps
• Drugs may act by inhibition of various enzymes, thus altering the
enzyme-mediated reactions, e.g. allopurinol inhibits the enzyme
xanthine oxidase; acetazolamide inhibits carbonic anhydrase,
Enalapril inhibits angiotensin converting enzyme, aspirin inhibits
cyclo-oxygenase, neostigmine inhibits acetylcholinesterase.
• Membrane pumps like H+ K+ ATPase and Na+ K+ ATPase may be
inhibited by drugs like omeprazole and digoxin respectively

8. Through Ion Channels
• Drugs may interfere with the movement of ions across specific
channels, e.g. calcium channel blockers, sodium channel blockers,
potassium channel openers and GABA gated chloride channel
modulators.

9. Physical Action
• The action of a drug could result from its physical properties like:
Adsorption – Activated charcoal in poisoning

10. Chemical Interaction
• Drugs may act by chemical reaction. Antacids – neutralize gastric
acids

11. Altering Metabolic Processes
• Drugs like antimicrobials alter the metabolic pathway in the
microorganisms resulting in destruction of the microorganism, e.g.
sulfonamides interfere with bacterial folic acid synthesis.

12. RECEPTOR
• A receptor is a macromolecular site on the cell with which an agonist binds to bring
about a change.
• Four types or super families of receptors are identified
1. Ion channels (inotropic receptor)
2. G-protein coupled receptors (metabotropic receptor)
3. Enzymatic receptors (kinase linked receptor)
4. Transcription factors (receptors that regulate gene transcription or nuclear
receptors).

14. 1. Ion channels (inotropic receptor)
• Ion channels or receptor channels are proteins present on the cell surface. Binding of the agonist
opens the channelallowing ions to cross the membrane.
• These are called ligand-gated ion channels.

15. 2. G-proteincoupledreceptors(metabotropic receptor)
• G-protein coupled receptors are proteins spanning the plasma membrane.
• The G-proteinsare bound to the innerface of the plasma membrane.
• The G-proteinsconsist of three subunits viz., a, b and a.
• When a ligand binds to the G-protein coupled receptor,the associated G-protein gets activated.
• These G-proteins acting through second messengers,bring about a chain of intracellular changes.
• These second messengersystems are called effectorpathways.
• Thus G-proteins act as links or mediators between the receptors and the effector systems. They are called G-
proteins because of their interaction with the guanine nucleotides,GTP and GDP.
• G-proteins are of different classes like Gs Gi, Go and Gq—GS is stimulatory and Gi is inhibitory. The second
messengers include cyclic AMP (cAMP), inosital triphosphate (IP3), diacylglycerol (DAG), calcium and
cyclic GMP (cGMP). Adrenergic receptors and muscarinic cholinergic receptors are examples of G-protein
coupled receptors

16. • Effector pathways through which the G-protein coupled receptorsworkare:
• a. Adenylylcyclase/cAMPpathway
• b. Phospholipase C/IP3-DAGpathway
• c. Ion channelregulation

17. a. Adenylylcyclase pathway :
• Stimulation of adenylylcyclase results in the formation and accumulation of cAMP
within the cell. This cAMP acts through protein kinases which phosphorylate various
proteins to regulate the cell function. The response may be contraction, relaxation,
lipolysis or hormone synthesis.

18. b. Phospholipase C/IP3-DAG pathway (Fig. 4.3)
• Activation of phospholipase C results in the formation of second messengers IP3 and DAG from the
membrane phospholipids phosphoinositol pyrophosphate (PIP2). IP3 mobilises calcium from
intracellular depots and this calcium mediates responses like secretion, contraction, metabolism
and hyperpolarisation. DAG activatesprotein kinase C which regulates cell function.

19. c. Ion channel regulation :
• The activated Gproteins can directly (without the help of second messengers) convey the
signal to some ion channels causing opening or closing of the channels. The resulting
responses include depolarisation/hyperpolarisation.

20. 3. Enzymatic Receptors
• These are transmembrane proteins with an extracellular domain (site) for ligand binding and
intracellular domain to carry out the catalytic activity and the two domains are linked by a single
peptide chain.
• They are protein kinases and hence are also known as kinase linked receptors.
• Binding of the agonist to the ligand binding domain results in autophosphorylation of the
intracellular domain.
• This in turn triggers phosphorylation of various intracellular proteins resulting in the characteristic
responses, Examples receptors of insulin, leptin and growth factors including epidermal growth
factors and platelet derived growth factors.

21. 4. Receptors that Regulate Gene Transcription
• These receptors are also called transcription factors or nuclearreceptors.
• They are intracellular proteins which are in an inactive state. Binding of the agonist activates the
receptor.
• The agonist-receptor complex moves to the nucleus where it interacts with DNA, regulates gene
transcription and thereby directs the synthesis of specific proteins to regulate the activity of target
cells.
• Examples are receptorsfor steroidalhormones, thyroid hormones, vitamin D and retinoids.

22. Receptor regulation
• Up regulation:
• The number of receptors (density) and their sensitivity can be altered in many situations.
Prolonged deprivation of the agonist or constant action of the antagonist all result in an increase
in the number and sensitivity of the receptors. This phenomenon is called ‘up regulation’.
• Down regulation:
• On the other hand, continued stimulation of the receptors causes desensitization and a decrease
in the number of receptors—known as ‘down regulation’ of the receptors

23. Dose Response Relationship
• The clinical response to the increasing dose of the drug is defined by the shape of the dose
response curve (DRC). Initially the extent of response increases with increase in dose till the
maximum response is reached. The dose response curve has the shape of a rectangular hyperbola

24. • After the maximum effect has been obtained, further increase in doses does not increase
the response. If the dose is plotted on a logarithmic scale, the curve becomes sigmoid

25. • The slope of DRC has clinical significance. A steep slope indicates that a small increase in dose
produces a large increase in response, e.g. loop diuretics. Such drugs are more likely to cause
toxicity and therefore, individualization of dose is required. A relatively flat DRC indicates that
with an increase in dose, there is little increase in the response, e.g. thiazide diuretics. For such
drugs standard dosescan be given to most patients.
Dose response curves of four drugs showing different potencies and maximal efficacies.
Drug A is more potent but less efficacious than B and C. Drug D is less potent and less
efficacious than drugs B and C

26. Therapeutic index
• Definition:
• The therapeutic index is a comparison of the amount of a therapeutic
agent that causes the therapeutic effect to the amount that causes death
or toxicity. Quantitatively, it is the ratio given by the lethal or toxic dose
divided by the therapeutic dose.

27. • Median lethal dose (LD50) is the dose which is lethal to 50% of the
population.
• Median effective dose (ED50) is the dose that produces a desired effect in
50% of the test population.
• Therapeutic index (TI) is the ratio of the median lethal dose to the median
effective dose.
Therapeutic index = LD50/ED50

28. Combined effect of drugs
• When two or more drugs are given concurrently, the effect may be additive, synergistic or
antagonistic.
• Additive effect The effect of two or more drugs gets added up and the total effect is equal
to the sum of their individual actions. Examples are ephedrine with theophylline in
bronchial asthma; nitrous oxide and ether as general anaesthetics.
• Synergism When the actionof one drug is enhanced or facilitated by another drug, the
combinationis synergistic. Here, the total effect of the combinationis greater than the
sum of their independent effects. Examples of synergistic combinationare —
acetylcholine + physostigmine

29. • Antagonism One drug opposing or inhibiting the actionof another is antagonism. Based
on the mechanism, antagonism can be
• Chemical antagonism
• Physiological antagonism
• Antagonism at the receptor level
– Reversible (Competitive)
– Irreversible
• Non-competitive antagonism.

30. Chemicalantagonism
• Two substances interact chemically to result in inactivation of the effect,
e.g. chelating agents inactivate heavy metals like lead and mercury to form
inactive complexes; antacids like aluminium hydroxide neutralize gastric
acid.

31. Physiological antagonism
• Two drugs act at different sites to produce opposing effects. For example,
Insulin and glucagon have opposite effects on the blood sugar level.

32. Antagonism at the receptor level
• The antagonist inhibits the binding of the agonist to the receptor. Such antagonism may
be reversible or irreversible.
• Reversible or competitive antagonism The agonist and antagonist compete for the same
receptor. By increasing the concentration of the agonist, the antagonism can be overcome.
It is thus reversible antagonism.
• Irreversible antagonism The antagonist binds so firmly by covalent bonds to the receptor
that it dissociates very slowly or not at all. Thus it blocks the action of the agonist and the
blockade cannot be overcome by increasing the dose of the agonist and hence it is
irreversible antagonism.
• Non-competitive antagonism The antagonist blocks at the level of receptor-effector
linkage, i.e. at a different site, beyond the receptor and not on the receptor.

33. FACTORS THAT MODIFY THE EFFECTS OF DRUGS
1. Body weight
2. Age
3. Sex
4. Race and species
5. Diet and environment
6. Route of administration
7. Genetic factor
8. Dose
9. Disease
10. Repeated dosing
11. Physiological factor
12. Presence of other drugs

34. Body weight
• The recommended dose is calculated for medium built persons.For the obese and underweight
persons,the dose has to be calculated individually.
• Formula:
• Dose= bodyweight (Kg)/70 * average adult dose

35. • Age The pharmacokinetics of many drugs change with age resulting in altered response in
extremes of age. In the newborn, the liver and kidneys are not fully mature to handle the
drugs.
• Sex The hormonal effects and smaller body size may influence drug response in women.
Special care is necessary while prescribing for pregnant and lactating women and during
menstruation.
• Species and race Response to drugs may vary with species and race.
• Diet and environment Food interferes with the absorption of many drugs. For example,
tetracyclines form complexes with calcium present in the food and are poorly absorbed.
Polycyclic hydrocarbons present in the cigarette smoke may induce microsomal enzymes
resulting in enhancedmetabolism of some drugs.
• Route of administration Occasionally route of administration may modify the
pharmacodynamic response, e.g. magnesium sulfate given orally is a purgative. But given IV
it causes CNS depression and has anticonvulsant effects.

36. • Genetic factors Variations in an individual’s response to drugs could be genetically
mediated. Pharmacogenetics is concerned with the genetically mediated variations in drug
responses. The differences in response is most commonly due to variations in the amount
of drug metabolising enzymes since the production of these enzymes is genetically
controlled.
• Dose It is fascinating that the response to a drug may be modified by the dose
administered. Generally as the dose is increased, the magnitude of the response also
increases proportionately till the ‘maximum’ is reached. Further increases in doses may
with some drugs produce effects opposite to their lower-dose effect.
• Diseases Presence of certain diseases can influence drug responses.
• Repeated dosing can result in cumulation, tolerance and tachyphylaxis.

37. • Psychological factor-The doctor-patient relationship influences the response to a drug
often to a large extent by acting on the patient’s psychology.
• Presence of other drugs The concurrent use of two or more drugs can influence the
response of each other