this ppt includes 1.factors modifying drug effect 2.bioavilability and bioequivalence 3.drug interactions 4.adverse drug reaction

1. 1.FACTORS MODIFYING DRUG EFFECT
2.BIOAVAILABILITY & BIOEQUIVALENCE
3.DRUG INTERACTIONS
4.ADVERSE DRUG REACTION
PRESENTED BY
DR SAIMEERA P
PG SCHOLAR
DEPT OF RSBK
MVRAMC

2. 1.FACTORS MODIFYING DRUG EFFECT
• Variation in response to the same dose of a drug between different patients and even the same patient on different
occasions is a rule rather than exception.
• One or more of the following categories of differences among individuals are responsible for the variation in drug
response.
1. Individuals differ in pharmacokinetic handling of drugs: attain varying plasma/target site / concentration of drug.
This is more marked for drugs disposed by metabolism.
2. Variation in neurogenic/hormonal tone or concentrations of specific constituents .
• Various factors modify actions of the drugs they are discussed as follows,

3. 1) Age:
•The four important stages of life Infant, Child, Adult and older age shows a great physiological difference.
•The infants don't have well developed metabolic machinery and have lower glomerular filtration rate, hence drugs
administrated gets very slowly metabolised and excreted slowly resulting in toxic effects of the drug.
•The metabolic machinery is still not well developed in childhood, moreover, the children are more susceptible to CNS
depressants.
•In older days of life due to wear and tear of body tissues, the metabolism and excretion of drugs get affected.
•Hence the dose required for children and elderly patients should be calibrated to avoid toxic effects.
•The doses of the drugs can be calculated by using following formulae.

4. 2) Body Weight:
•Normal doses of the drugs are decided for considering 70kg body wt. as the normal body weight of an adult.
•However, such doses fail miserably for excessively obese patients and children.
•Hence for obese patients and children the dose is calculated by using Hamburger's formula.

5. 3)Sex:
•Females are delicate in the physical as well as physiological way as compared to males.
•Due to smaller body size, they require lesser dose as compared to the males.
•As females have to pass through delicate conditions of life like, Menstruation, Pregnancy, lactation, Menopause, the drugs
should be very carefully administered as responses may vary in these situations.
4)Route of drug administration:
•Drugs given by oral route gets absorbed slowly and incompletely as compared to those given by the parenteral routes.
•Faster and complete the drug absorption quicker will be the therapeutic response of the drug.
5)Time of drug administration:
•Our body follows a typical circadian rhythm, hence the hypnotic drugs require lesser dose to induce sleep during the night
as compared to during day time.
•Oral hypoglycemics are more effective when given in morning time.

6. 6)Emotional Factors:
•Placebos (Duplicate dosage forms which copy the external appearance of original one but lack active drug) are found
useful in controlling certain psychological aggravation of disorders like angina, asthma, insomnia etc.
7)Genetics of the patient:
•Drug metabolism is carried out by the enzyme machinery of the patient, lacking certain enzymes due to genetics the
patient may suffer from complications.
8)Previous drug therapy:
•Certain drugs like Phenobarbitone are very powerful enzyme inducers which increase metabolism of other drugs
administered.
9) Diseased condition:-
• Absorption of iron gets increased during anaemia.
• In case of the kidney failure drugs which gets primarily through kidney like penicillin may cause toxicity.
• Liver cirrhosis is characterized by decreased metabolic activity of the liver,inability to metabolise the drugs like
barbiturates may produce their toxicity.

7. 2.(a)BIOAVAILABILITY
• Also known as physiological availability or Biological availability.
• Definition:- study of the rate and extent to which active ingredient is absorbed from a dosage form and
becomes available at the site of action.
• It refers to the rate and extent of the drug absorbed in the systemic circulation after administration.
• Drug is administered in the body in the form of dosage through various routes.
• Then the administered drug reaches the blood and other body fluids.
• BA of a drug can be determined by testing the drug in biological fluids drawn at different intervals.

8. • According to the definition when a medication is administered through intravenous route , its BA is 100%
• But when a medication is administered via other routes such as oral , its BA decreases due to incomplete
absorption or first pass metabolism.
• BA is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic
circulation.
• Eg: if 100 mg of a drug is administered orally & 60 mg of this drug is absorbed unchanged the BA will be
60%.
• Determination of the amount of the drug in the plasma at periodic time intervals indirectly presents the rate
and extent at which the active pharmaceutical ingredient is absorbed from the drug product becomes
available at the site of the action.
• BA concept can be applied to drugs which are in active forms .

9. APPLICATION OF BA
• BA is one of the important aspect of pharmacokinetics ; it must be considered when calculating dosages for intravenous
routes of administration.
• To produce products comparable to the competitioner’s products ,BA studies are useful.
• Results of BA studies of the original product (first developed product) are referred as a benchmark for subsequent
batches.
• After deciding and developing the formulation of a drug ,manufacturer can use BA studies to obtain batch to batch
uniformity in the manufacture.
• BA studies are helpful in bioequivalence studies which are required by regulations.

10. BENEFITS OF BA STUDIES
Helps to find :-
• Speed at which the drug is absorbed.
• Proportion of the drug absorbed from the dosage form .
• Duration of drug’s presence in the biological fluid or tissue ,which is related to drug action.
• Relationship between drug blood levels and therapeutic effectiveness(or toxic effects).
• Effect of nutrients on absorption of the drug etc.

11. 2.(b)BIOEQUIVALENCE STUDIES (BE)
• Defined as the absence of a significant difference in the rate and extent to which the active ingredient or
pharmaceutical equivalent or pharmaceutical alternative becomes available at the site of drug action when
administered at the same molar dose under similar condition in an appropriately designed study.
• If two drugs are bioequivalent there should not be any significant difference in bioavailability between two drugs.
• In general BE is evaluated by comparing the BA of test and reference products.
• BE study focuses on the release of the drug substance from a drug product and subsequent absorption into the
systematic circulation. For this reason approaches for BA &BE remains the same .
• BE studies aim at determining whether chemically equivalent products manufactured by different companies are
therapeutic equivalent.

12. • BE test in requirement usually arises when a patent of innovator’s drug product expires. Other manufacturers may
then wish to market the same formulation of the drug.
• Formulations that are bioequivalent with that of the innovated drug is called generic products.
 BE is also done during
 The course of development of the new drug.
 When a formulation is changed.
 When site or method of manufacture is altered.
• Health authorities have made BE studies mandatory for all drug products before approval for marketing.
• It provides an assurance by the manufacturer to the patient that their product gives the best therapeutic effect and
safety.

13. BENEFITS OF BE STUDY
• It allows interchangeability /substitution of one produtct by another equally effective product.
• Minimize the variations of efficiency and safety of a product from batch to batch produced by same company.
• Helps in introducing generic drugs of innovator drugs at lower cost.
• Helps in improving the formulation by reducing the formulation variables.

14. CONCLUSION
• BA & BE studies play an important role during drug development process for both innovative and generic drugs.
• They are critical for ensuring consistency in standards of quality ,efficacy & safety of pharmaceutical dosage forms.

15. 3.DRUG INTERACTIONS
• Drug interactions are said to occur when the pharmacological activity of a drug is altered by the concomitant use of another drug
or by the presence of some other substance.
• The drug whose activity is affected by such an interaction is called as the object drug.
• The agent which precipitates such an interaction is referred to as the precipitant.
• Drug interactions include –
1. Drug-drug interactions.
2. Food-drug interactions, eg:- inhibition of metabolism of several drugs by grapefruit juice.
3. Chemical-drug interactions, eg:- interaction of a drug with alcohol, tobacco or environmental chemicals.
4. Drug-laboratory test interaction, eg:- alteration of diagnostic laboratory test results by the presence of drug.
5. Drug-disease interactions, eg:- worsening of disease condition by the drug.

16. • The net effect of a drug interaction is –
1. Generally quantitative i.e. increased or decreased effect.
2. Seldom qualitative i.e. rapid or slower effect.
3. Precipitation of newer or increased adverse-effects.
• Most interactions are specific types of adverse reactions with altered efficacy of the drug, for example an enhanced
pharmacological activity (e.g. haemorrhagic tendency of warfarin when phenylbutazone is given subsequently) or a decrease
in the therapeutic activity resulting in loss of efficacy like that of tetracycline when concomitantly administered with food,
antacids or mineral supplements containing heavy metal ions. Drug interactions are thus –
o Mostly undesirable.
o Rarely desirable (beneficial) – for e.g., enhancement of activity of pencillins when administered with probenecid.

17. Factors Contributing to Drug Interactions
Some of the more important risk factors that lead to drug interactions include –
1. Multiple drug therapy – is very common in most acute and chronic care settings, for e.g., therapy in patient suffering from
hypertension and congestive heart failure includes antihypertensives as well as digitalis which together may lead to abnormal
heart rhythms. Concurrent use of non-prescription drugs, for e.g. aspirin as well as herbal medications also lead to drug
interactions. Theoretically, the possibility for drug interactions to occur is over 50% when a patient is receiving five
medications, and the probability increases to 100% when seven drugs are used.
2.Multiple prescribers - Some individuals go to more than one physician, and it is common for a patient to be treated by one or
more specialists in addition to a family doctor. It is frequently difficult for one prescriber to become aware of all the
medications that have been prescribed by others for a particular patient, and many difficulties arise from such situations. For
example, one doctor may prescribe an anxiolytic for a patient while another prescribes an antihistamine having sedative
properties with the possible consequence of an excessive depressant effect.
3. Multiple pharmacological effects of drug - Most drugs used in current therapy exhibit more than one type of
pharmacological action and have the capacity to influence many physiological systems.

18. Therefore, two concomitantly administered drugs will often affect some of the same systems, for e.g. antihistamines (secondary
effect is sedation) enhance the sedative effect of tranquillizers.
4. Multiple diseases/Predisposing illness – Some patients take several drugs owing to their suffering from more than one
disease, for e.g. a patient with both diabetes and hypertension. Multiple therapies in such individuals generally result in drug
interactions, for e.g., oral hypoglycaemics and beta-blockers can result in decreased response to antidiabetic drug resulting in
elevated blood sugar levels.
5. Poor patient compliance – this results when a patient does not take medication in the manner intended by the doctor; which
may be due to inadequate instructions from the doctor or pharmacist, confusion regarding taking several medicines, etc. all of
which may lead to either underdosing or overdosing, and a consequent drug interaction.
6. Advancing age of patient – Increased tendency of drug interaction episodes in elderly is generally due to decrease in liver
function in such individuals.
7. Drug related factors - Clinically significant interactions are most likely to occur between drugs that have potent effects, a
narrow therapeutic index and a steep dose-response curve (e.g., cytotoxic, antihypertensive, and hypoglycemic drugs, digoxin,
warfarin, etc.).

19. Mechanisms of Drug Interactions
The three mechanisms by which an interaction can develop are —
1. Pharmaceutical Interaction – Also called as incompatibility, it is a physicochemical interaction that occurs when drugs
are mixed in i.v. infusions causing precipitation or inactivation of active principles, for example, ampicillin, chlorpromazine and
barbiturates interact with dextran in solutions and are broken down or form chemical complexes.
2. Pharmacokinetic Interactions – These interactions are those in which the absorption, distribution, metabolism and/or
excretion of the object drug are altered by the precipitant and hence such interactions are also called as ADME interactions. The
resultant effect is altered plasma concentration of the object drug.
Pharmacokinetic interactions can thus be classified as –
(i) Absorption interactions – are those where the absorption of the object drug is altered. The net effect of such an interaction
is
• Faster or slower drug absorption.
• More, or, less complete drug absorption.
.

20. Major mechanisms of absorption interactions are –
 Complexation and adsorption.
 Alteration in GI pH.
 Alteration in gut motility.
 Inhibition of GI enzymes.
 Alteration of GI microflora.
 Malabsorption syndrome
(ii) Distribution interactions – are those where the distribution pattern of the object drug is altered. The major mechanism for
distribution interaction is alteration in protein-drug binding.
(iii)Metabolism interactions – are those where the metabolism of the object drug is altered. Mechanisms of metabolism
interactions include –
• Enzyme induction – increased rate of metabolism
• Enzyme inhibition – decreased rate of metabolism. It is the most significant interaction in comparison to other interactions and
can be fatal.

21. (iv)Excretion interactions – are those where the excretion pattern of the object drug is altered. Major mechanisms of
excretion interactions are –
• Alteration in renal flood flow – e.g. NSAIDs (reduce renal blood flow) with lithium.
• Alteration of urine pH – e.g. antacids with amphetamine.
• Competition for active secretion – e.g. probenecid and penicillin.
• Forced diuresis.
3. Pharmacodynamic Interactions – are those in which the activity of the object drug at its site of action is altered by the
precipitant. Such interactions may be direct or indirect.
(i) Direct pharmacodynamic interaction is the one in which drugs having similar or opposing pharmacological effects are
used concurrently. The three consequences of direct interactions are –
(a) Antagonism: The interacting drugs have opposing actions, e.g. acetylcholine and noradrenaline have opposing effects on
heart rate.
(b) Addition or Summation: The interacting drugs have similar actions and the resultant effect is the sum of individual drug
responses, e.g. CNS depressants like sedatives, hypnotics, etc.

22. (c) Synergism or Potentiation: It is enhancement of action of one drug by another, e.g. alcohol enhances the analgesic activity of
aspirin.
(ii) Indirect pharmacodynamic interactions are situations in which both the object and the precipitant drugs have unrelated
effects but the latter in some way alters the effects of the former, for example, salicylates decrease the ability of the platelets to
aggregate thus impairing the haemostasis if warfarin induced bleeding occurs.
 The resultant effect of all pharmacodynamic interactions is thus altered drug action without a change in plasma concentration.
 Of the various types of interactions, the pharmacokinetic interactions are most common and often result in differences in
pharmacological effects.
 Several examples of such interactions are known but few are clinically significant.
 Clinically important effects are precipitated by drugs having low therapeutic indices, e.g. digoxin or those having poorly
defined therapeutic end-points, e.g. antipsychotics.
 The net effect of all pharmacokinetic interactions is reflected in the altered duration and intensity of pharmacological action of
the drug due to variation in the plasma concentration precipitated by altered ADME.
 All factors which influence the ADME of a drug affect its pharmacokinetics.

23. Interactions Affecting Absorption of Drugs
 Altered absorption after oral administration is very common.
 The interaction may result in a change in the rate of absorption (an increase or a decrease), a change in the amount of drug
absorbed (an increase or a decrease) or both.
 Several mechanisms may be involved in the alteration of drug absorption from the GIT.
 In general, drugs that are not absorbed completely/rapidly are more susceptible to changes in GI absorption.
 A decrease in the rate of absorption is clinically significant in acute conditions such as pain where the drug is administered in
a single dose but is of little importance for drugs used in chronic therapy.
 An alteration in parenteral drug absorption is rare but can occur when an adrenergic agent such as adrenaline or a cholinergic
drug such as methacholine is extravascularly injected concomitantly with another drug.
 These agents alter the systemic absorption of the latter due to vasoconstriction or vasodilation.

24. Interactions Affecting Distribution of Drugs
 Though several factors govern the distribution of drugs to various tissues, clinically significant interactions result due to
competition between drugs for binding to proteins/tissues and displacement of one drug by the other.
 Competitive displacement, which results when two drugs are capable of binding to the same site on the protein, causes the
most significant interactions.
 Greater risk of interactions exists when the displaced drug is highly protein bound (more than 95%), has a small volume of
distribution and has a narrow therapeutic index, and when the displacer drug has a higher degree of affinity than the drug to
be displaced.
 In such situations, displacement of even a small percent of drug results in a tremendous increase in the free form of the drug,
which precipitates increased therapeutic or toxic effects.
 Drugs may also be displaced from binding sites in tissues.
 An interesting example of this is oral hypoglycaemics such as the sulphonylureas (tolbutamide, glibenclamide , etc.).
 These agents exert their therapeutic effects by displacing insulin from protein binding sites in pancreas, plasma and other
regions resulting in its elevated levels.

25. Interactions Affecting Metabolism of Drugs
 The most important and the most common cause of pharmacokinetic interactions is alteration in the rate of biotransformation
of drugs.
 Major problems arise when one drug either induces or inhibits the metabolism of another drug.
 Even the environmental chemicals can bring about such an effect.
 The influence of enzyme inducers and inhibitors become more pronounced when drugs susceptible to first-pass hepatic
metabolism are given concurrently.
 The metabolic pathway usually affected is phase I oxidation.
 Enzyme inducers reduce the blood level and clinical efficacy of co-administered drugs but may also enhance the toxicity
of drugs having active metabolites.
 In contrast to enzyme induction, which is usually not hazardous, enzyme inhibition leads to accumulation of drug to toxic
levels and serious adverse effects may be precipitated.

26. Interactions Affecting Excretion of Drugs
 Clinically significant renal excretion interactions occur when an appreciable amount of drug or its active metabolite are
eliminated in the urine.
 Excretion pattern can be affected by alteration in GFR, renal blood flow, passive tubular reabsorption, active tubular
secretion and urine pH .
 An interesting pharmacokinetic interaction that results due to the pharmacodynamic drug effect is between thiazide diuretics
and lithium.
 Owing to the influence of former on the renal tubular transport of sodium, the lithium ions are retained in the body resulting
in its toxicity.
 Biliary excretion, the other major mechanism of drug excretion, is altered by agents that inhibit biliary transport or modify
bile flow rate.

27. Reducing the Risk of Drug Interactions – Principles of Drug Interactions Management
The consequences of drug interactions may be –
• Major – life threatening
• Moderate – deterioration of patient’s status
• Minor – bothersome or little effect.
 The risk of drug interactions is a challenge that embraces a number of considerations.
The following are guidelines to reduce and manage drug interactions.
1. Identify patient risk factors such as age, the nature of the patient's medical problem (e.g., impaired renal function), dietary
habits, smoking, and problems such as alcoholism influence the effect of certain drugs.
2. Take thorough drug history and maintain complete patient medication records.
3. Keep knowledge about actions (both primary and secondary pharmacological actions) of drugs being utilized.
4. Consider therapeutic alternatives.
5. Avoid complex therapeutic regimens where possible.

28. 6. Educate the patient to comply with instructions for administering medications. They should be encouraged to ask questions
about their therapy and to report any excessive or unexpected responses
7. Monitor therapy: Any change in patient behavior should be suspected as drug-related until that possibility is excluded.
8. Individualize therapy: priority should be assigned to the needs and clinical response of the individual patient, rather than to
the usual dosage recommendations, standard treatment, and monitoring guidelines.
9. Involve the patient as a partner in health care. If the optimal benefits of therapy are to be achieved with minimal risk, each
participant must be knowledgeable about and diligent in fulfilling his responsibilities.

29. 4.ADVERSE DRUG REACTION
• Adverse drug reactions are unwanted effects caused by normal therapeutic doses. Drugs are great mimics of disease,
and adverse drug reactions present with diverse clinical signs and symptoms.
• The classification proposed by Rawlins and Thompson (1977) divides reactions into type Aand type B.
• Type A reactions, which constitute approximately 80% of adverse drug reactions, are usually a consequence of the
drug’s primary pharmacological effect (e.g. bleeding from warfarin) or a low therapeutic index (e.g. nausea from
digoxin), and they are therefore predictable.
• They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from
warfarin).
• Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term ‘side
effects’ is often applied to minor type A reactions.

30. • Type B (‘idiosyncratic’) reactions are not predictable from the drug’s main pharmacological action, are not dose-related
and are severe, with a considerable mortality.
• The underlying pathophysiology of type B reactions is poorly if at all understood, and often has a genetic or
immunological basis. Type B reactions occur infrequently (1:1000–1:10 000 treated subjects being typical).
Three further minor categories of adverse drug reaction have been proposed:
1. type C – continuous reactions due to long-term drug use (e.g. neuroleptic-related tardive dyskinesia or analgesic
nephropathy);
2. type D – delayed reactions (e.g. alkylating agents leading to carcinogenesis, or retinoid-associated teratogenesis);
3. type E end-of-use reactions, such as adrenocortical insufficiency following withdrawal of gluco corticosteroids,
or withdrawal syndromes following discontinuation of treatment with benzodiazepines or β-adrenoceptor antagonists.

31. FACTORS INVOLVED IN ADVERSE DRUG REACTIONS.
extrinsic intrinsic
Environment – sun Xenobiotics (e.g. herbicides)
Malnutrition
Patient factors
• Age – neonatal, infant and elderly
• Sex – hormonal environment,
• Genetic abnormalities enzyme or receptor
polymorphisms)
• Previous adverse drug reactions, allergy, atopy
• Presence of organ dysfunction – disease
• Personality and habits –adherence (compliance),
alcoholic, drug addict, nicotine
Prescriber factors
• Incorrect drug or drug combination
• Incorrect route of administration
• Incorrect dose
• Incorrect duration of therapy
Drug factors
• Drug–drug interactions
• Pharmaceutical –batch problems , shelf-life, incorrect
dispensing

32. IDENTIFICATION OF THE DRUG AT FAULT
• It is often difficult to decide whether a clinical event is drug related, and even when this is probable, it may be difficult to
determine which drug is responsible, as patients are often taking multiple drugs. One or more of several possible approaches
may be appropriate.
1. A careful drug history is essential.
2. Provocation testing. This involves giving a very small amount of the suspected drug and seeing whether a reaction ensues,
e.g. skin testing, where a drug is applied as a patch, or is pricked or scratched into the skin or injected intradermally.
3. Serological testing and lymphocytes testing. Serological testing is rarely helpful, circulating antibodies to the drug do not
mean that they are necessarily the cause of the symptoms.

33. 4. The best approach in patients on multiple drug therapy is to stop all potentially causal drugs and reintroduce them one
by one until the drug at fault is discovered. This should only be done if the reaction is not serious, or if the drug is
essential and no chemically unrelated alternative is available.