This slide contains all the necessary detalis regarding the aspects of pharmacotherapy along with Clinical Pharmacology and explains the important steps undertaken during Drug Development.
This slide is a work of Dr Ankit Bairwa, 2nd Year at All India Institute of Medical Sciences, Bathinda
2. Aspect of Pharmacotherapy, Clinical
Pharmacology and Drug Developement
Presented by –
Ankit Bairwa
Roll No 05
Batch 2019
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3. Pharmacotherapy
It is the safe and effective management of drug administration.
It requires the understanding of the drug, the disease, the patient and the
milieu in which it is undertakne
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4. Drug Dosage
Dose is the appropriate amount of a drug needed to produce a certain degree of
response in a given patient.
E.g. the analgesic dose of aspirin for headache is 0.3-0.6 g, its antiplatelet dose is 60-
150 mg/day, while its anti-inflammatory dose for rheumatoid arthritis is 3-5 g per day.
The dose of a drug is governed by its inherent potency, i.e. the concentration at which
it should be present at the target site, and its pharmacokinetic characteristics
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5. Types of Dose:
1. Standard dose : the same dose is appropriate for most patients-individual
variations are minor or the drug has a wide safety margin so that a large
enough dose can be given to cover them, e.g. oral contraceptives,
penicillin
2. Regulated dose : the dosage is accurately adjusted by repeated
measurement of the affected physiological parameter, e.g. anti-
hypertensives, hypoglycaemics, anticoagulants, diuretics, general
anaesthetics. In their case. measurement of plasma drug concentration is
not needed.
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6. 3. Target level dose : the response is not easily measurable but has been
demonstrated to be obtained at a certain range of drug concentration in
plasma. An empirical dose aimed at attaining the target level is given in
the beginning.
4. Titrated dose: the dose needed to pro duce maximal therapeutic effect
cannot be given because of intolerable adverse effects. Optimal dose is
arrived at by titrating it with an accept able level of adverse effect.
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8. Fixed Dose Combinations (FDCs) of drugs
A large number of pharmaceutical preparations contain two or more drugs in a fixed
dose ratio.
Advantages:
• convenience and better patient compliance.
• certain drug combinations are synergistics, e.g. levodopa + carbidopa
• therapeutic effect of two components being same may add up.
• the reduction of number of pills, improve patient compliance.
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9. Disadvantages:
• the dose of any component cannot be adjusted independently.
• some fixed dose combinations show more adverse effects.
• there will be increase in price if unnecessary drugs are included.
• contraindication to one component contraindicates the whole product.
• it becomes difficult to identify one particular drug which is causing
harmful/beneficial effects
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10. Factors modifying drugs action
Responses variation to a Drug:
1. person to person; and
2. also same person on different occasions.
Individuals differ in pharmacokinetic handling of drugs –
Varying plasma/target site conc.
Variation in number or state of receptors, coupling proteins or other components of
response effectuation.
Variations in hormonal/neurogenic tone or concentrations.
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11. Factors modify drug action either
Quantitatively: the plasma concentration and/or the action of the drug is
increased or decreased.
Qualititatively: the type of response is altered, e.g. drug allerdy or
idiosyncrasy.
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12. Factors are as follows:
1. Body Size
Influences the conc. of the drug attained at the site of action – obese/lean/children –
Body weight (BW) and Body Surface area (BSA)
Individual dose = BW(kg)/70 x average adult dose
Individual dose = BSA(m2)/1.7 x average adult dose
BSA can be calculated by Dubois Formula
BSA (m2) = BW (kg)0.425 x Height (cm)0.725 X 0.007184
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13. Age
• Young`s formula
Child dose = (Age/Age+12) x adult dose
• Dilling`s formula
Child dose = (Age/20) x adult dose
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14. Sex
• Females have smaller body size – required doses are lower
• Digoxin in Maintenance therapy of heart failure – mortality higher
• Beta blockers, methyldopa, diuretics – sexual function interference in males
• Gynaecomastia – Metoclopramide, chlorpromazine, ketoconazole etc.
• Pregnancy – particularly 3rd trimester
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15. Species and Race
Species variation in drugs responses do exist
Some strains of rabbits – resistant to atropine
Rat and mice are resistant to digitalis
Race – racial differences have been observed
Blacks require higher doses of atropine and ephedrine, while Mongols require
lower doses
Africans – beta blockers are less effective
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16. Genetics
Determinants of drug responses – transporter, enzymes, ion channels, receptors
and couplers – controlled genetically – Individual variation of responses
Pharmacogenetics: The study of genetic basis for variability in drug response is
called 'Pharmacogenetics'. It deals with genetic influences on drug action as well as
on drug handling by the body.
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17. Pharmacogenomics: Use of genetic information to guide the choice of drug and
dose on an individual basis – to identify individuals who are either more likely or less
likely respond to a drug
G-6PD deficiency – Primaquine, chloroquin, quinine, dapsone, aspirin
Malignant hypothermia with halothane etc.
Low variants of CYP2C9 – Warfarin bleeding; Isoniazid - acetylators
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18. Route of administration
Route determines the speed and intensity of drug response – Parenteral for speedy
action.
A drug may have different actions via different routes.
Ex - Magnesium Sulfate given orally causes purgation, applied on sprained joints it
decreases swelling.
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19. Environmental factors
o Drug metabolism may get induced – exposure to insecticides, carcinogens, tobacco
smoke and charcoal broiled meat etc.
o Food interferes absorption of some drugs while enhances some drugs – ampicillin
gets reduced griseofulvin gets enhanced.
o Hypnotics taken at night.
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20. Psychological factors
Efficacy of a drug can be affected by patient`s beliefs, attitudes and expectations –
particularly CNS drugs – more GA in nervous and anxious patients – alcohol impairs
performance
Nocebo: Negative psychodynamic effects of drugs.
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21. Placebo: An inert substance which is given in the garb of medicine. Works by
psychodynamic effects (not pharmacodynamics) – sometimes responses equivalent
to active drugs.
• Placebo reactors
• Induce psychological responses – release of endorphins in brain
• Uses – Control device in clinical trials and to treat a patient
• Lactose tablet/capsules or water injections etc .
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22. Pathological states
Diseases can influence drug disposition – GIT diseases, Liver diseases, Kidney
diseases, Congestive heart failure and Thyroid etc.
GIT: Achlorohydria – Reduced aspirin absorption – NSAIDs aggravate peptic ulcer
Liver diseases: Liver disease (cirrhosis) influence drug action
• Increased bioavailability of drugs with high first pass metabolism
• Serum albumin reduced – protein bound drugs like Warfarin – more free drug
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23. Kidney diseases: Pharmacokinetics of many drugs are affected
• Plasma protein, albumin reduced – binding of acidic drugs affected
• Permeability of BBB increased – Opiates etc. more CNS depression
Thyroid diseases:
• Hypothyroid states – sensitive to digoxin, morphine and CNS depressants;
• Hyperthyroid states – resistant to inotropic action – prone to cause arrhythmia
by digoxin
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24. Presence of other drugs:
Drug interactions – Pharmacokinetic and Pharmacodynamic
Cummulation:
If Rate of administration > Rate of elimination – cumulataion. Slowly eliminating drugs
are prone – Prolonged use of Chloroquine
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25. Tolerance
Requirement of higher dose of a drug to produce a given response – refractoriness
– sulfonylureas in type 2 diabetes and beta-2 agonists in bronchial asthma -
adaptive biological phenomena
Natural: Species/individual inherently less sensitive – Rabbits to atropine and Blacks
to beta – blockers.
Acquired: Repeated use of a drug in an individual who was initially responsive
become non-responsive (tolerant) – CNS depressants.
Cross tolerance: Tolerance to pharmacologically related drugs – alcoholics to
barbiturates and GA; Morphine and Pethidine
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26. Tachyphylaxis (Tachy – fast’ phylaxis – protection): Rapid development of
tolerance when a drug is repeated in quick succession – reduction of responses
Usually with indirectly acting drugs – Ephedrine, tyramine, nicotine etc. Also
down regulation of receptors
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27. Rational Use of Medicines
As per the WHO- 'rational use of medicines requires that the
patients receive medication appropriate to their clinical needs in
doses that meet their own individual requirements for an adequate
period of time, and at the lowest cost to them and to their
community
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29. Criteria to evaluate rational prescribing:
Appropriate indication
Appropriate drug
Appropriate dose, route and duration
Appropriate patient
Correct dispensing with appropriate information
Adequate monitoring
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30. Irrationalities in prescribing:
It is helpful to know the commonly encountered irrationalities in prescribing so
that a conscious effort is made to avoid them
Use of drug when none is needed; e.g. anti-biotics for viral fevers and nonspecific
diarrhoea
Incorrect route of administration: injection when the drug can be given orally.
Compulsive co-prescription of vitamins/tonics
Use of drug not related to diagnose
Selection of the wrong drug
Prescribing ineffective drug
Incorrect route of administration
Unnecessary use of drug combination.
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31. Expiry date of pharmaceutical:
It is a legal requirement that all pharmaceutical products must carry the date of
manufacture and date of expiry on their label.
The period between the two dates is called the 'life period' or 'shelf-life' of the
medicine.
Under specified storage conditions, the product is expected to remain stable (retain
>95% potency) during this period.
In India, the schedule P (Rule 96) of Drugs and Cosmetics Act (1940) specifies the
life period.
The expiry date does not mean that the medicine has actually been found to lose
potency or become toxic after it.
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32. Evidence based medicine
There is gradually transform in the practice of medicine from
'experience based' wherein clinical decisions are made based on the
experience (or rather impression) of the physician to 'evidence-
based' wherein the same are guided by scientifically credible
evidence from well designed clinical studies.
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33. Grades of strength of evidence:
Grade I Systematic reviews/Meta
analysis
Most reliable, may form the
basis of clinical decisions
Grade II Well powered randomized
controlled trial/more than one
trials
Reliable, but may be supported
or refuted by similar studies
Grade III Open label trials/pilot
studies/observational (cohort
and case-control) studies
(prospective or retrospective)
Less reliable, need more
rigorous testing, may indicate
further investigation
Grade IV Case reports/anecdotal
reports/clinical experience
Least reliable; may serve as
pointers to initiate formal
studies
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34. New Drug Development
Drug development now is a highly complex, tedious,
competitive, costly and commercially risky process
From the synthesis/identification of the molecule to
marketing, a new drug takes at least 10 years and costs
millions
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35. Approcahes to Drug Discovery
Exploration of natural sources
• Random or targeted chemical synthesis
• Rational approach
• Molecular modelling
• Combinatorial chemistry
• Biotechnology
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36. Preclinical & Non Clinical Studies
After synthesizing/identifying a prospective compound
• It is tested on animals to expose the whole pharmacological
profile
• As the evaluation progresses unfavourable compounds get
rejected at each step, so that only a few out of thousands reach
the stage when administration to man is considered
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37. The following types of tests are performed:
1. Screening tests: these are simple and rapidly performed tests to
indicate presence or absence of a particular pharmacodynamic
activity that is sought like analgesic or hypoglycaemic activity.
2. Tests on isolated organs, bacterial cultures, etc:
These also are preliminary tests to detect specific activity, such as
antihistaminic, anti-secretory, vasodilator, anti-bacterial.
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38. 3. Tests on animal models of human disease:
Such as kindled seizures in rats, spontaneously (genetically)
hypertensive rats, alloxan induced diabetes in rat or dog, etc.
4. Confirmatory tests and analogous activities:
More elaborate tests which confirm and characterize the activity.
Other related activities, e.g. antipyretic and anti-inflammatory activity
inan analgesic are tested
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39. 5. Systemic pharmacology:
Irrespective of the primary action of the drug, its effects on major
organ systems such as nervous, cardiovascular, respiratory, renal, g.i.t
are worked out.
6. Quantitative tests:
The dose-response relationship, maximal effect and comparative
potency/efficacy with existing drugs is ascertained.
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42. Clinical Trails
‘A systematic study of new drug(s) in human subject(s) to
generate data for discovering and/or verifying the clinical,
pharmacological (including pharmacodynamic and
pharmacokinetic) and/or adverse effects with the objective of
determining safety and/or efficacy of the new drug‘.
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43. Begin only when
all the preclinical studies have been completed
an approval has been received from the drug regulation authority
(DRA)
India - Central Drug Standard Control Organization (CDSCO)/Drug
Controller General of India (DCGI)
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44. prior to the conduct of a clinical trial, an IND (Investigational New
Drug) application must be filled
standards for the design, ethics, conduct, monitoring, auditing,
recording and analyzing data and reporting of clinical trials have
been laid down in the form of 'Good Clinical Practice' (GCP)
guidelines by an International Conference on Harmonization (ICH)
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45. Phase 0: Micro-dosing Studies
Very low doses, generally about 1/100th of the estimated human
dose, are administered to healthy volunteers
These sub-pharmacological doses are not expected to produce
any therapeutic or toxic effects, but yield human pharmacokinetic
information.
Costly phase 1 human trials could be avoided for candidate drugs
which would have later failed due to unsuitable human
pharmacokinetics
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46. Microdose pharmacokinetics may be quite different
from that at pharmacological doses
The phase O studies have not yet been technically fully
developed or adequately evaluated.
They are neither established nor mandatory
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47. Phase 1: Human Pharmacology and Safety
• Designed to assess the safety, tolerability, pharmacokinetics and
pharmacodynamics
• Subjects: total 20-80 subjects
• Mostly healthy volunteers
• Sometimes patients(anticancer drugs, AIDS therapy).
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48. • Starting with the lowest estimated dose (1/100 to 1/10) and
increasing stepwise to achieve the effective dose.
• Unpleasant side effects are noted,
• human pharmacokinetics parameteres are measured for 1st time.
• No blinding is done: studies open labelled.
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49. Phase 2: Therapeutic exploration and dose
ranging
This is conducted by physicians who are trained as clinical
investigators.
100-500 patients selected according to specific inclusion and exclusion criteria.
The primary aim is establishment of therapeutic efficacy, dose range
and ceiling effect in a controlled setting.
The study is mostly controlled and randomized, and may be blinded
or open label.
The candidate drug may get dropped at this stage if the desired
level of clinical efficacy is not obtained
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50. Phase 3: Therapaeutic confirmation/
comparison
These are randomized double blind comparative trials.
larger patient population (500-3000)
The aim is -- the value of the drug in relation to existing therapy.
Safety and tolerability are assessed on a wider scale.
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51. Indications are finalized and guidelines for therapeutic use are
formulated.
A new drug application' (NDA) is submitted to the licensing
authority (like FDA), who if convinced give marketing permission.
Restricted marketing permission for use only in hospitals with
specific monitoring facilities.
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52. Phase 4: Post Marketing
surveillance/Data gathering studies
o Done after drug has been marketed
o No fixed duration/patient population
o Open label(no blinding)
o It is done to detect unexpected adverse effects and drug
interactions
o Also, to explore new uses for drugs
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53. o Periodic Safety Update Reports
to be submitted every six months for the first two years after
approval of the drug
For subsequent two years need to be submitted annually and
may be extended if necessary.
o Harmful effects discovered may result in restriction or no longer
sold
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54. Stages in new drug development
Synthesis/isolation of the compound: 1-2 years
Preclinical studies: screening, evaluation, pharmacokinetic and
short-term toxicity testing in animals:
2-4 years
Scrutiny and grant of permission for clinical trials: 3-6 months
Pharmaceutical formulation, standardization of
chemical/biological/immuno-assay of the compound:
0.5-1 years
Clinical studies: phase I, phase II, phase III trials; long-term animal
toxicity testing:
3-10 years
Review and grant of marketing permission: 0.5-2 years
Postmarketing surveillance: Phase IV studies
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