pharmacodynamics.pptx

following presentation covers the topic pharmacodynamics, factors affecting drug response and mechanism of drug action in detail.

1. Pharmacodynamics, mechanism of drug action and factors modifying drug response Presented by: Aishwarya sinha

2. CONTENTS Pharmacodynamics Principles of drug action Mechanism of drug action Receptor subtypes Action effect sequence Transducer mechanism Dose response relationship Factors affecting drug response Conclusion References

3. PHARMACODYNAMICS Pharmacodynamics is the study of drug effects it elucidates the complete action-effect sequence and the dose-effect relationship . Modification of the action of one drug by another drug is also an aspect of pharmacodynamics.

4. PRICIPLES OF DRUG ACTION Drugs ( except those gene based) do not impart new functions to any system, organ or cell; they only alter the pace of ongoing activity . The basic type of drug action can be classified as: STIMULATION DEPRESSION IRRITATION REPLACEMENT CYTOTOXIC ACTION

5. STIMULATION It refers to selective enhancement of the level of activity of specialized cells , e,g . adrenaline stimulates heart However, excessive stimulation depression of that function. Eg - high dose of picrotoxin (CNS stimulant) produces convulsions followed by coma and respiratory depression.

6. DEPRESSION It means selective diminution of activity of specialized cells, eg - barbiturates depresses CNS Certain drugs stimulate one type of cells but depress the other, e.g. acetylcholine stimulates intestinal smooth muscle but depresses SA node in heart.

7. IRRITATION This connotes a nonselective, often noxious effect and is particularly applied to less specialized cells (epithelium, connective tissue ). May result in loss of function.

8. REPLACEMENT This refers to the use of natural metabolites, hormones or their congeners in deficiency states . levodopa in parkinsonism , insulin in diabetes mellitus , iron in anaemia .

9. CYTOTOXIC ACTION Selective cytotoxic action on invading parasites or cancer cells, attenuating them without significantly affecting the host cells is utilized for cure/ palliation of infections and neoplasms , e.g . penicillin, chloroquine, zidovudine , cyclophosphamide, etc .

10. MECHANISM OF DRUG ACTION Majority of drugs produce their effects by interacting with discrete target biomolecules which are usually proteins , which can be grouped into:-

11. ENZYMES Almost all biological reactions are carried out under catalytic influence of enzymes; hence, enzymes are a very important target of drug action. Drugs can either increase or decrease the rate of enzymatically mediated reactions. in physiological systems enzyme activities are often optimally set . Drugs foreign substance, hence; stimulation of enzymes by drugs is unusual.

12. Several enzymes are stimulated through receptors and second messengers , e.g . adrenaline stimulates hepatic glycogen phosphorylase through β receptors and cyclic AMP . Stimulation of an enzyme Increases affinity for substrate Rate of reaction ( kM )

13. ENZYME INDUCTION (synthesis of more enzyme protein) causes apparent increase in enzyme activity. Enzyme induction is different from stimulation as kM does not change . ENZYME INHIBITION is a common mode of drug action.

14. NON SPECIFIC INHIBITION Heavy metals, strong acids, alkalies , alcohol, formaldehyde inhibit enzyme non specifically. These inhibitors are too damaging to be used systemically. Chemical or drugs Alter tertiary structure of enzyme Inhibition of enzyme

15. SPECIFIC INHIBITION Many drugs inhibit a particular enzyme without affecting others, it is called as specific inhibition.

16. COMEPTITIVE (EQUILIBRIUM TYPE) The drug being structurally similar competes with the normal substrate for the catalytic binding site of the enzyme so that the product is not formed or a nonfunctional product is formed, and a new equilibrium is achieved in the presence of the drug.

17. It binds only to enzyme and not to enzyme-substrate complex (ES ). This type of inhibition is mostly surmountable, i.e. inhibition can be overcome by increasing the dose of the substrate. It results in increase in Km( Michaelis menton’s constant) but does not affect the Vmax . Km: amount of substrate required to produce half of the maximal velocity Vmax : maximum reaction velocity.

18. If the drug binds very strongly to the active site, so that it cannot be displaced even by large concentration of substrate, it can result in irreversible competitive inhibition . In this type of inhibition, Km rises and Vmax decreases . Organophosphates are irreversible competitive inhibitors .

19. COMPETITIVE (NON EQUILIBRIUM TYPE) drugs which react with the same catalytic site of the enzyme but either form strong covalent bonds or have such high affinity for the enzyme that the normal substrate is not able to displace the inhibitor. Eg :- Organophosphates react covalently with the esteretic site of the enzyme cholinesterase . kM is increased and Vmax is reduced in these type of inhibition

20. NON COMPETITIVE INHIBITION The inhibitor reacts with an adjacent site and not with the catalytic site, but alters the enzyme in such a way that it loses its catalytic property. Thus , kM is unchanged but Vmax is reduced . It binds to both enzyme as well as ES with equal affinity This type of inhibition is insurmountable , i.e. inhibition cannot be overcome by increasing the dose of the substrate.

21. Mostly non-competitive inhibitors are irreversible but carbonic anhydrase inhibitors are reversible non-competitive inhibitors.

22. ION CHANNELS Proteins which act as ion selective channels participate in transmembrane signaling and regulate intracellular ionic composition. This makes them a common target of drug action.

23. TRANSPORTERS substrates Translocated across membrane Using specific transporter (carrier) Diffusion against concentration gradient Diffusion in direction of concentration gradient

24. Many drugs produce their action by directly interacting with the solute carrier (SLC) class of transporter proteins to inhibit the ongoing physiological transport of the metabolite/ion. Eg :- Desipramine and cocaine block neuronal reuptake of noradrenaline by interacting with norepinephrine transporter (NET) Amphetamines selectively block dopamine reuptake in brain neurons by dopamine transporter (DAT).

25. RECEPTORS The largest number of drugs do not bind directly to the effectors, but act through specific regulatory macromolecules called as receptors. Receptor : It is defined as a macromolecule or binding site located on the surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function. Two important terms related to the receptors are affinity and intrinsic activity (IA) .

26. If a drug has no affinity, it will not bind to the receptor. So, all type of drugs acting via receptors (agonist, antagonist, inverse agonist and partial agonist) possess some affinity for the receptors . Drugs may be divided into four types based on their intrinsic activities . AFFINITY: the ability of a drug to combine with the receptor. INTRINSIC ACTIVITY: the ability to activate the receptor. It varies from –1 through zero to +1.

27. BASED ON INTRINSIC ACTIVITY:-

28. AGONIST : It will bind to the receptor and activate it maximally. i.e. IA is + 1. ANTAGONIST : Binds to the receptor but produces no effect (IA is 0). But now agonist is not able to bind to the receptor because these are already occupied by the antagonist. Thus, it decreases the action of the agonist but itself has no effect.

29. TYPES OF ANTAGONISM

30. PARTIAL AGONIST : It activates the receptor submaximally (IA between 0 and +1). It will produce the similar effect in the absence of agonist but it will decrease the effect of a pure agonist . INVERSE AGONIST : These type of drugs bind to the receptor and produce opposite effect (IA is negative ).

31. RECEPTOR SUBTYPES The delineation of multiple types and subtypes of receptors for signal molecules has played an important role in the development of a number of targeted and more selective drugs. The following criteria have been utilized in classifying receptors: Pharmacological criteria Tissue distribution 3. Ligand binding 4. Transducer pathway 5. Molecular cloning

32. Pharmacological criteria Classification is based on relative potencies of selective agonists and antagonists. This is the classical and oldest approach with direct clinical bearing. It was used in:- Cholinergic receptors M type N type Adrenergic receptor α β

33. TISSUE DISTRIBUTION The relative organ/tissue distribution is the basis for designating the subtype e.g. the cardiac β adrenergic receptors as β1 , while bronchial as β2 . This division was confirmed by selective agonists and antagonists as well as by molecular cloning.

34. LIGAND BINDING Measurement of specific binding of high affinity radio-labelled ligand to cellular fragments ( usually membranes) in vitro, and its displacement by various selective agonists/antagonists is used to delineate receptor subtypes. Multiple 5-HT receptors were distinguished by this approach.

35. TRANSDUCER PATHWAY Receptor subtypes may be distinguished by the mechanism through which their activation is linked to the response,. e.g . M cholinergic receptor acts through G-proteins , while N cholinergic receptor gates influx of Na+ ions.

36. MOLECULAR CLONING The receptor protein is cloned and its detailed amino acid sequence as well as three dimensional structure is worked out. Subtypes are designated on the basis of sequence homology.

37. ACTION-EFFECT SEQUENCE ‘ Drug action ’ and ‘ drug effect ’ are often loosely used interchangeably, but are not synonymous . Drug action is the initial combination of the drug with its receptor resulting in a conformational change in the latter (in case of agonists), or prevention of conformational change through exclusion of the agonist (in case of antagonists). Drug effect is the ultimate change in biological function brought about as a consequence of drug action, through a series of intermediate steps (transducer).

38. RECEPTOR RECOGNITION OF SPECIFIC LIGAND MOLECULE TRANSDUCTION OF SIGNAL INTO A RESPONSE

39. TRANSDUCER MECHANISMS A handful of transducer pathways are shared by a large number of receptors, the cell is able to generate an integrated response reflecting the sum total of diverse signal inputs. The transducer mechanisms can be grouped into 5 major categories

40. G-PROTEIN COUPLED RECEPTOR (GPCRs) These are a large family of cell membrane receptors which are linked to the effector (enzyme/channel/transporter) through one or more GTP-activated proteins (G-proteins) for response effectuation. STRUCTURE OF GPCRs : The molecule has 7 α- helical membrane spanning hydrophobic amino acid (AA) segments which run into 3 extracellular and 3 intracellular loops . Agonist binding site between helices on extracellular face.

41. A number of G proteins distinguished by their α subunits have been described. The important ones with their action on the effector are:

42. A limited number of G-proteins are shared between different receptors and one receptor can utilize more than one G-protein ( agonist pleotropy ), e.g. the following couplers have been associated with different receptors

43. The rate of GTP hydrolysis by the α subunit and thus the period for which it remains activated is regulated by another protein called ‘ regulator of G protein signaling ’ (RGS). The onset time of response through GPCRs is in seconds . There are three major effector pathways through which GPCRs function. cAMP Pathway Phospholipase IP3/DAG Pathway Channel regulation

44. A. ADENYLYL CYCLASE: cAMP PATHWAY

45. Cyclic GMP (cGMP) as a second messenger the cGMP serves as an intracellular second messenger only in a limited number of tissues Vascular smooth muscle Intestinal mucosal cell kidney Mediates relaxation Inhibition of salt and water absorption Anion secretion and natriuresis

46. B. Phospholipase C: IP3-DAG pathway Activation of phospholipase Cβ (PLcβ) by the activated GTP carrying α subunit of Gq hydrolyses the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate (PIP2 ) generates the second messengers inositol 1,4,5-trisphosphate (IP3 ) and diacylglycerol (DAG). IP3 being water soluble diffuses to the cytosol and mobilizes Ca2+ from endoplasmic reticular depots The lipophilic DAG remains within the membrane, but recruits protein kinase C ( PKc ) and activates it with the help of Ca2+.

47. C. CHANNEL REGULATION The activated Gproteins ( Gs , Gi , Go) can also open or inhibit ionic channels specific for Ca2+ and K+ , without the intervention of any second messenger like cAMP or IP3, and bring about hyperpolarization/depolarization/changes in intracellular Ca2+ concentration . Gs Opens Ca2+ channels in heart and skeletal muscle Gi /Go Opens K+ channels in heart and skeletal muscle

48. ION CHANNEL RECEPTORS Also called as ligand gated ion channels . AGONIST binding channel opens depolarization/ hyperpolarization/ changes in cytosolic ionic composition These are the fastest acting receptors . It includes GABAA and 5-HT3 receptors.

49. The receptor is usually a pentameric protein . The subunits are mostly arranged round the channel like a rosette and the α subunits agonist binding sites. The onset and offset of responses through this class of receptors is the fastest (in milliseconds).

50. TRANSMEMBRANE ENZYME LINKED RECEPTOR This class of receptors are utilized primarily by peptide hormones , [( insulin, epidermal growth factor (EGF), nerve growth factor (NGF) and many other growth factor receptors.] The commonest protein kinases are the ones which phosphorylate tyrosine residues on the substrate proteins and are called ‘receptor tyrosine kinases’ (RTKs) These are made up of a large extracellular ligand binding domain connected through a single transmembrane helical peptide chain to an intracellular subunit having enzymatic property.

51. unliganded monomeric state Kinase remains inactive Binding of hormones Dimerization of receptor Conformational changes activate the kinase to autophosphorylate tyrosine residues on each other increases their affinity for binding substrate proteins. response

52. TRANSMEMBRANE JAK-STAT BINDING RECEPTOR This type of receptor has two sites Extracellular site Drug binds Intracellular site Enzymatic activity

53. Agonist induced dimerization alters the intracellular domain configuration increase its affinity for a cytosolic tyrosine protein kinase JAK (Janus Kinase). JAK gets activated and phosphorylates tyrosine residues of the receptor Binds to STAT (signal transducer and activator of transcription). phosphorylated STAT dimerize and translocate to the nucleus regulates gene transcription resulting in a biological response

54. RECEPTORS REGULATING GENE EXPRESSION Synonyms: transcription factors, nuclear receptors these are intracellular (cytoplasmic or nuclear) soluble proteins which respond to lipid soluble chemical messengers that penetrate the cell. These may be present in the cytoplasm (glucocorticoids, mineralocorticoids, and vitamin D) or in the nucleus (T3 , T4 , Retinoic acid, PPAR, estrogen, progesterone and testosterone).

55. Both type of receptors finally act by nuclear mechanisms (i.e. by affecting transcription ). All the intracellular receptors are considered a part of ‘Nuclear Receptor Superfamily.

56. Hormone binds to receptor Restricting proteins are released Receptor dimerizes DNA binding regulatory segment folds in active configuration The liganded receptor dimer moves to the nucleus The whole complex attaches to specific DNA sequences of the target genes and facilitates their expression so that specific mRNA is synthesized on the template of the gene. This mRNA moves to the ribosomes and directs synthesis of specific proteins which regulate activity of the target cells.

57. REGULATION OF RECEPTORS Receptors exist in a dynamic state; their density and efficacy to elicit the response is subject to regulation by the level of on-going activity , feedback from their own signal output and other physiopathological influences. This has clinical relevance in clonidine/CNS depressant/ opioid withdrawal syndromes, sudden discontinuation of propranolol in angina pectoris . Prolonged deprivation of agonist supersensitivity of the receptor and effector system

58. Mechanism unmasking of receptors or their proliferation (up regulation ) or accentuation of signal amplification by the transducer . Continued receptor stimulation desensitization or refractoriness

59. The changes may be brought by: Masking or internalization of the receptor (it becomes inaccessible to the agonist) or impaired coupling of the transducer to the receptor. In this case refractoriness develops as well as fades quickly. Decreased synthesis/increased destruction of the receptor (down regulation): refractoriness develops over weeks or months and recedes slowly.

60. FUNCTIONS OF RECEPTORS To propagate regulatory signals from outside to inside the effector cell when the molecular species carrying the signal cannot itself penetrate the cell membrane. To amplify the signal . To integrate various extracellular and intracellular regulatory signals. To adapt to short term and long term changes in the regulatory mechanism and maintain homeostasis

61. NON RECEPTOR MEDIATED DRUG ACTION This refers to drugs which do not act by binding to specific regulatory macromolecules. Drug action Physical/chemical means Small molecules/ions enzymes

62. DOSE RESPONSE RELATIONSHIP When a drug is administered systemically, the dose-response relationship has two components : the intensity of response increases with increase in dose (or more precisely concentration at the receptor), but at higher doses, the increase in response progressively becomes less marked. dose-plasma concentration relationship plasma concentration-response relationship.

63. DOSE RESPONSE CURVE It is a graph between the dose of a drug administered (on X-axis) and the effect produced by the drug (on Y-axis ). As plasma concentration is more closely related to response , the graph between plasma concentration and response is usually called DRC . Two types Dose plasma concentration curve plasma concentration-response curve. Quantal G raded

64. QUANTAL DRUG RESPONSE CURVE Variation in sensitivity of response to increasing doses of the drug in different individuals can be obtained from quantal DRC. When the response is an ‘all or none’ phenomenon (e.g. antiemetic drug stopping the vomiting or not), the y-axis (response axis) shows the number of person responding and X-axis shows the plasma concentration. It is used to calculate ED50 and LD50 .

65. MEDIAN EFFECTIVE DOSE : It is the dose that will produce the desired response in half of the (50%) recipients. MEDIAN LETHAL DOSE: : It is the dose that will result in death of 50% of the animals receiving the drug . ED50 potency LD50 safer the drug

66. THERAPEUTIC INDEX (T.I .): It is a measure of the safety of a drug. It is calculated as a ratio of LD50 to ED50 . Drugs having high T.I. are safer whereas those having low T.I. are more likely to be toxic. T.I = LD50 / ED50

67. When the response can be graded (e.g. reduction in BP), the y-axis shows the magnitude of response . DRC is usually hyperbola in shape . As curved lines cannot give good mathematical comparisons, so usually the dose is converted to log dose to form log DRC , which gives a sigmoid shaped curve . Three important parameters ( potency, efficacy and slope of curve ) can be determined from DRC.

68. POTENCY It is the measure of the amount of a drug needed to produce the response. Drugs producing the same response at lower dose are more potent whereas those requiring large dose are less potent. In DRC, more a drug is on left side of the graph, higher is its potency and vice a versa.

69. EFFICACY It is the maximum ef f ect produced by a drug . More the peak of the curve greater is the efficacy. It is clinically more important than potency.

70. SLOPE If the DRC is steeper, that means the response will increase dramatically with slight increase in dose . drugs having steeper DRC have narrow therapeutic index (like barbiturates) than those having less steep curves (e.g. benzodiazepines ). DRC can also be utilized to know whether a drug is competitive or non competitive inhibitor.

71. Competitive inhibitor Non competitive inhibitor Curve will shift to right Flattening of DRC efficacy decreases same agonist will have less potency in the presence of antagonist.

72. PHARMACOGENETIC CONDITION Due to different genetic make up, some drugs have different effects in different individuals, so these drugs may show either toxicity or lack of effect in certain individuals, if used in conventional dosage. ACETYLATOR POLYMORPHISM : Some individuals are slow acetylators and some are fast acetylators . The drugs metabolized by this route may be ineffective in fast acetylators and may show toxicity in slow acetylators . Drugs are: Sulfonamide, Hydralazine, Isoniazid, Procainamide.

73. Glucose-6-phosphate Dehydrogenase (G-6-PD) Deficiency : Oxidant drugs may produce hemolysis in the patient with deficiency of this enzyme . Atypical Pseudocholinesterase and Succinylcholine : Succinylcholine is a very short acting drug due to metabolism by pseudocholinesterase . In such individuals this drug may produce prolonged apnea.

74. Inability to Hydroxylate Phenytoin. Resistance to Coumarin Anticoagulants. Malignant Hyperthermia by Halothane.

75. FACTORS MODIFYING DRUG RESPONSE The same dose of a drug can produce different degrees of response in different patients and even in the same patient under different situations. Various factors modify the response to a drug.

76. BODY WEIGHT The recommended dose is calculated for medium built persons. For the obese and underweight persons, the dose has to be calculated individually. Body surface area is a better parameter for more accurate calculation of the dose, it is inconvenient and hence not generally used.

77. AGE The pharmacokinetics of many drugs change with age resulting in altered response in extremes of age . In newborn due to lack of fully mature organs, various drugs can have different effect than adults . The blood-brain barrier is not well-formed and drugs can easily reach the brain. The gastric acidity is low, intestinal motility is slow, skin is delicate and permeable to drugs applied topically. CHLORAMPHENICOL GREY BABY SYNDROME

78. Hence calculation of the appropriate dose based on the body weight is important to avoid toxicity . Also pharmacodynamic differences could exist, BARBITURATES EXCITATION SEDATION ADULTS CHILD

79. In the elderly, the capacity of the liver and kidney to handle the drug is reduced and they are more susceptible to adverse effects. Hence lower doses are recommended , e.g. elderly are at a higher risk of ototoxicity and nephrotoxicity by streptomycin.

80. 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.

81. SPECIES AND RACE Response to drugs may vary with species and race. For example, rabbits are resistant to atropine. Such variation makes it difficult to extrapolate the results of animal experiments. Blacks need higher doses of atropine to produce mydriasis .

82. DIET AND ENVIRONMENT Food interferes with the absorption of many drugs. For example, tetracycline 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 enhanced metabolism of some drug.

83. ROUTE OF ADMINISTRATION Occasionally route of administration may modify the pharmacodynamic response, E.g.:- MAGNESIUM SULPHATE PURGATIVE INTRACRANIAL TENSION LOCAL EDEMA ANTICONVULSANT ORAL IV TOPICAL ENEMA

84. 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 metabolizing enzymes since the production of these enzymes is genetically controlled. EXAMPLES-

85. A. ACETYLATION OF DRUGS The rate of drug acetylation differs among individuals who may be fast or slow acetylators , e.g. INH, sulfonamides and hydralazine are acetylated. Slow acetylators treated with hydralazine are more likely to develop lupus erythematosus

86. B. ATYPICAL PSEUDOCHOLINESTERASE Succinylcholine is metabolised by the enzyme pseudocholinesterase . Some people inherit an atypical pseudocholinesterase which cannot quickly metabolise succinylcholine . When succinylcholine is given to such people they develop a prolonged apnea due to persistent action of succinylcholine .

87. DOSE 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 increase in doses may with some drugs produce effects opposite to their lower-dose effect, e.g . MYASTHENIA GRAVIS NEOSTIGMINE MUSCLE POWER MUSCLE PARALYSIS THERAPEUTIC DOSE HIGH DOSE

88. DISEASES Presence of certain diseases can influence drug responses, e.g . Malabsorption Drugs are poorly absorbed . Liver diseases Rate of drug metabolism is reduced due to dysfunction of hepatocytes. Also protein binding is reduced due to low serum albumin . Cardiac diseases In CCF, there is edema of the gut mucosa and decreased perfusion of liver and kidneys. These may result in accumulation and toxicity of drugs like propranolol and lignocaine.

89. REPEATED DOSING Repeated dosing can result in - CUMULATION : Drugs like digoxin which are slowly eliminated may cumulate resulting in toxicity . TOLERANCE: Tolerance is the requirement of higher doses of a drug to produce a given response. TOLERANCE ACQUIRED NATURAL

90. Natural tolerance The species/race shows less sensitivity to the drug, e.g. rabbits show tolerance to atropine; Black race are tolerant to mydriatics . Acquired tolerance develops on repeated administration of a drug. The patient who was initially responsive becomes tolerant, e.g. barbiturates, opioids and nitrites produce tolerance. Tolerance may develop to some actions of the drug and not to others, e.g. morphine— tolerance develops to analgesic and euphoric effects of morphine but not to its constipating and miotic effects.

91. MECHANISM OF TOLERANCE DEVELOPMENT Pharmacokinetic Changes in absorption, distribution, metabolism and excretion of drugs may result in reduced concentration of the drug at the site of action and is also known as dispositional tolerance , e.g. barbiturates induce microsomal enzymes and enhance their own metabolism . Pharmacodynamic Changes in the target tissue, may make it less responsive to the drug. It is also called functional tolerance . It could be due to down regulation of receptors as in opioids or due to compensatory mechanisms of the body, e.g. blunting of response to some antihypertensives due to salt and water retension .

92. Cross tolerance is the development of tolerance to pharmacologically related drugs, i.e. to drugs belonging to a particular group. Thus chronic alcoholics also show tolerance to barbiturates and general anesthetics. Tachyphylaxis is the rapid development of tolerance. When some drugs are administered repeatedly at short intervals, tolerance develops rapidly and is known as tachyphylaxis or acute tolerance, e.g. ephedrine, amphetamine, tyramine.

93. PSYCOLOGICAL FACTORS The doctor-patient relationship influences the response to a drug often to a large extent by acting on the patient’s psychology . The patients confidence in the doctor may itself be sufficient to relieve a suffering, particularly the psychosomatic disorders. This can be substantiated by the fact that large number of patients respond to placebo . Placebo is the inert dosage form with no specific biological activity but only resembles the actual preparation in appearance (dummy medication).

94. Placebo medicines are used in – 1 . clinical trials as a control to compare and assess whether the new compound is significantly better than the placebo. 2 . to benefit or please a patient psychologically when he does not actually require an active drug as in mild psychosomatic disorders and in chronic incurable diseases . Substances used as placebo include lactose, some vitamins, minerals and distilled water injections.

95. PRESENCE OF OTHER DRUGS The concurrent use of two or more drugs can influence the response of each other. The two drugs that interact does not necessarily mean that their concurrent use is contraindicated, many can be used together with dose adjustments. Eg - Additive prolongation of prothrombin time and bleeding by administration of ceftriaxone or cefoperazone to a patient on oral anticoagulant.

96. CONCLUSION Pharmacokinetics and pharmacodynamics models help in understanding the various parameters involved with controlled release systems. They also help in designing specific requirements required for drug molecules to be formulated as controlled release system, there by enhancing better opportunities for the development of controlled release systems in future.

97. REFERENCES Essentials of medical pharmacology 8 th edition : Dr. K D Tripathi Review of pharmacology 14 th edition : Sparsh Gupta Basic and clinical pharmacology : Bertram G. Katzung Textbook of pharmacology for dental and allied health sciences- Padmaja Udaykumar