PHARMACODYNAMICS

Qualitative Aspects of Drug effects

(What Drugs Do To a Living Organism)

 Drugs does following two things –

1. Produce desirable or beneficial effects

2. Cause undesirable adverse effects due to drug factors or by

some non-drug factors

 Aim of Pharmacotherapy – to provide maximum benefits

with minimal risk due to adverse effects
 Quantitative Aspects of Drug Effects (Measurement of Drug
Effects)
 Qualitative + Quantitative aspects – provide basis for evaluation
and comparison of drug effectiveness and safety
 One of the Basic Principles of Pharmacology – the degree of
effect produced by a drug depends on the quantity of the drug
administered i.e. the dose
Dose
- It is the required amount of drug in weight, volume, moles or
International Units, that is necessary to provide a desired effect
(OR) the appropriate amount of a drug needed to produce a
certain degree of response in a given patient
- Also called therapeutic dose (clinical practice) or Effective Dose
(experimentation in animals)
- Dose – prophylactic dose, therapeutic dose & toxic dose
- Varies from person to person and one clinical situation to other –
hence indicated by a Range
- Ex: dose of Aspirin – 300 mg to 1 mg (minimum to maximum)

 Drugs can be administered as:

Single Dose
- Ex: Single oral dose of Albendazole (400 mg) – eradicate
roundworms
Daily Dose
- Quantity of a drug to be administered in 24 hr, either all at once or
in equally divided doses
- Dose interval decided on plasma half-life, aVd
Total Dose
- The maximum quantity of the drug that is needed during the
complete course of the therapy
- Ex: Total Dose of procaine penicillin-G for treatment of early
Syphilis – 6 million units – given as 0.6 million units/ day for 10
days
Loading Dose (Priming Dose)
- The large dose of the drug to be given initially to provide the
effective plasma concentration rapidly
Maintenance Dose
- The loading dose is normally followed by a maintenance dose,
usually half of the loading dose
- Needed to maintain the steady state plasma concentration attained
after giving the loading dose
 After giving a dose, the drug effects can be measured for
quantitative assessment of its safety and efficacy
 Measured by plotting curves

 Dose-response relationship has 2 components

1. Dose-plasma concentration relationship

2. Plasma concentration – response relationship
 To plot a curve
- X-axis – independent variable
- Y-axis – dependent variable
Ex: Dose – Plasma concentration curve, time – Plasma conc. curve
 2 types of curves are possible
1. Graded Dose – Response Curve (DRC)
2. Quantal Dose – Response Curve
 Graded Dose – Response Curves
 Relationship between different doses (graded doses) and their
relative response
 These curves obtained by administering increasing doses of the
drug to a single subject or an isolated tissue
 Doses plotted on X-axis and % response on Y-axis
 Dose is increased – magnitude of response also increases until no
further increase in response with further increase in dose
 Response called Maximal Response and the Dose called Maximal
Dose/ Ceiling Dose
 Graph – Hyperbola
 When the effect reached maximum, large increments in dose –
changes in response too small – extremely difficult to display
dose range – hence logrithmic scale
Log Dose-Response Curves
- Log of dose Vs % response

- Curve – sigmoid/ S-shaped – middle portion almost a straight line

Information from the curve

- Middle portion of curve – ED50/ Effective Dose – dose that
provides 50% of the maximal response
- Smaller the ED50, more potent is the drug

- Two drugs – same effect by same mechanism – two parallel

curves – curve of less potent drug would be located on the right
side
- Location of LDR curve on X-axis – affinity of drug with receptor;
curve close to Y-axis – greater affinity
- Drug Potency/ Potency – the dose of a drug required to produce a
standard effect/ response
- The closer the LDR curve towards Y-axis – smaller is the dose
required to produce the given effect and hence greater the potency
- Drug efficacy/ Efficacy – maximal response that can be elicited by
the drug
- Efficacy reflected by the height of the LDR curve on the Y-axis –
more height more efficacy
- Depending on the type of drug, both higher efficacy or lower
efficacy could be clinically advantageous
- The slope of the DRC is also important
- A steep slope indicates – moderate increase in dose will
markedly increase the response (dose needs individualization)
- A flat slope – little increase in response will occur over a wide
dose range (standard doses can be given to most patients)
 Quantal Dose – Response Curve
 All or None basis

 Barbiturates – anaesthesia or No anaesthesia

 Such predetermined responses on “all or none” basis are called

as Quantal Responses
 Evaluation of Drug Safety
Therapeutic Index (Margin of safety)
- Therapeutic Ratio/ Therapeutic Index is calculated as follows –
Therapeutic Index = LD50/ ED50
Where,
LD50 = median lethal dose – dose which kills 50% of the recipients
ED50 = median effective dose – dose that produces specified effect
in 50% individuals
- TI – more than 1 – drug is safe
- Drugs having larger value of LD50 but smaller value of ED50 –
more safe
Therapeutic Range/ Therapeutic Window

- Bounded by the dose which produces minimal therapeutic effect

and the dose which produces maximal acceptable adverse effect

- This optimal therapeutic range of plasma concentration of the

drug is called its Therapeutic Window

- Plasma concentration of some drugs that fall within the

therapeutic window are –

1. Theophylline – 5-10 µg/ ml

2. Digoxin – 0.5-1.4 ng/ ml

3. Phenytoin – 10-20 µg/ ml

Drug Specificity
- Specificity of a drug refers to the range of actions produced by it

- Drugs – one or a limited number of actions, some have

widespread effects on many organs
- Depends on whether a drug acts on a single receptor/ target or on
many targets, how widely the target is distributed in the body
Ex:
Omeprazole – Highly specific drug
- Single action – inhibition of gastric acid secretion by inhibiting
proton pump (H+ K+ ATPase)
Chlopromazine – multiple targets
- Antagonist on D2, α-adrenergic, muscarnic cholinergic, H1, some
5HT receptors
- Thus, wide range of actions
 FACTORS MODIFYING DRUG ACTION
 Dosage – the method of dosing

 Variation in response to the same dose of a drug between

different patients and even in the same patient on different
occasions
 Reasons for variations in drug response

1. Individual difference in pharmacokinetic handling of drugs

2. Variations in number or state of receptors, coupling proteins etc

3. Variations in neurogenic/ hormonal tone or concentration of

specific constituents
 A multitude of host and external factors influence drug
response
1. Genetic factors

2. Nongenetic factors
 Factors modify drug action either
a. Quantitatively – plasma concentration and/ or the action of drug
is increased or decreased. Seen by most factors and need
adjustment of drug dosage
b. Qualitatively – the type of response is altered (allergy or
idiosyncracy)
 Various factors include –

1. Age, Body size/ weight and Body Surface Area

- An average adult dose – quantity that will produce desired effect
in 50% population b/w 18-65 yrs of age weighing about 70 Kg
- For exceptionally obese or lean individuals, children – dose
calculated on body weight (BW) basis

Individual dose = BW (Kg) x average adult dose

70
Individual/ Child Dose = BSA (m2) x Adult Dose
1.8
Young’s Formula
- Applicable for children up to 12 yr of age; assumption that a 12
yr old should receive ½ of the adult dose
- Child’s Dose = Age in yrs x Adult Dose

Age + 12
Dilling’s Formula
- Assumption that a 20-yr old should receive an adult dose

- Child’s Dose = Age in yrs x Adult Dose

20
Clark’s Formula
- Child’s Dose = Wt. of Child(lb) x Adult Dose

150
- Infants and children are not small adults – physiological
difference from adults
- New born has low GFR, immature tubular transport, inadequate
hepatic metabolism, more permeable BBB, faster transdermal
absorption
- Therefore, infant doses must be learned as such and not derived
from any formula
- Solid dosage forms and metered dose inhalers – difficult to
administer to young children
- In elderly, renal function declines progressively – drug doses have
to be reduced; also reduction in hepatic metabolism
- In general, the incidence of adverse drug reactions is much higher
in the elderly
2. Sex
- Drug responses in men and women are not always the same

- Morphine and barbiturates may produce excitation prior to

sedation in women
- Ephedrine may produce more excitation and tremors in women
than in men
- Clonidine, α-methyldopa, β-blockers, diuretics and ketoconazole
– cause loss of libido only in men but not in women
- In women consideration must also be given to menstruation,
pregnancy and lactation
3. Environmental factors and time of drug administration
- Environmental factors – exposure to insecticides, carcinogens,
tobacco smoke and consumption of charcoal broiled meat –
induce drug metabolism
- Subjective effects of a drug – markedly affected by setup in
which drug has been taken
Ex:
- Slightly higher doses of sedatives-hypnotics needed to induce
sleep in day light than at night
- Glucocorticoids taken as single morning dose – minimise the risk
of pituitary-adrenal suppression
- Food interferes with absorption of ampicillin
- Fatty meal enhances absorption of griseofulvin and lumefantrine
- Statins – greater inhibition of cholesterol synthesis when taken in
the late evening
4. Psychological and Emotional factors
- Efficacy of a drug can be affected by the patient’s beliefs,
attitudes and expectations
- Particularly applicable to centrally acting drugs
- Some patients even respond to placebo
(Nocebo – harms by creating a panic or fear for nothing; Nocebo
reactors – pessimists whose symptoms do not respond to
medications)
5. Genetic factors and Idiosyncracies
- A small cross-section of population respond to drugs in unusual
and highly unpredictable manner
- Genetic variability in drug response – due to single gene mutation
or polygenic
- Some responses are due to pharmacogenetic reasons and others
are idiosyncracies (reason unknown)
6. Metabolic disturbances and pathological state
- Not only drugs modify disease processes, a disease-induced
abnormality may also modify a drug effect i.e., drug disposition
and drug action – GI, liver, kidney and thyroid diseases etc.
Ex:
▪ Low acidity – decreases iron absorption – decreased response to
iron therapy
▪ Liver disease – bioavailability of drugs having first-pass
metabolism is increased
▪ Impaired renal function – streptomycin, gentamicin, kanamycin
accumulate to toxic levels – nephrotoxicity and ototoxicity
▪ Hyperthyroidism – very sensitive to sympathomimetics; relatively
resistant to digitalis or morphine
▪ Hypothyroidim – drugs respond in opposite manner

▪ Diarrhoea and vomiting – oral drugs prove to be ineffective

7. Route and frequency of drug administration

- Route of administration governs the speed and intensity of drug
response
- Parenteral route – more rapid, more pronounced and more
predictable drug action
- Drugs are usually administered according to half-lives, but not
always – Ex: streptomycin in the treatment of TB (t ½ 2-4 hrs)
- Sometimes a drug may exhibit an entirely different response
when administered by different routes
Ex: Magnesium sulfate
▪ Oral – purgative action

▪ Local on sprained joints – decreases swelling

▪ IV – CNS depression and hypotension

- Sometimes, different mode of administration of the same drug is

preferred for different therapeutic purposes
Ex: Oxytocin
▪ Slow IV infusion – induction of labor

▪ IM injection – check postpartum haemorrhage

▪ Intranasal spray – let-down of milk from engorged breasts

8. Species and Race

- There exists differences in responsiveness to drugs among
different species
- Important while extrapolating results from experimental animals

Ex: Rabbits are resistant to atropine, rats & mice to digitalis

- Racial differences exist among humans
Ex: Blacks require higher and Mongols require lower
concentrations of atropine and ephedrine to dilate the pupil
9. Other Drugs
- Drugs can modify the response to each other by pharmacokinetic
or pharmacodynamic interaction between them
10. Cumulation
- Any drug will cumulate in the body if rate of administration is
more than the rate of elimination
- Lead to dangerous overdosage and toxicity

- More likely with drugs having long t ½ and lipid soluble drugs
with shorter t ½
- Avoided – Loading Dose & Maintenance Dose

Ex: Prolonged use of chloroquine causes retinal damage

- A course of emetine should not be repeated within 6 weeks
11. Tolerance Drug Tolerance
- Refers to the requirement of increase in dose in order to produce
the pharmacological response of equal magnitude and duration
- It is a widely occurring adaptive biological phenomenon

- Loss of therapeutic efficacy after prolonged/ intensive use of a

drug – generally called Refractoriness
- Ex: Sulfonyl ureas in type 2 diabetes, β2-agonists in bronchial
asthma
 MODIFIED DRUG EFFECTS AFTER REPEATED
ADMINISTRATION OF A SINGLE DRUG
Drug Tolerance
- It is an inability of the subsequent administration of the same
dose, of the same drug, to be as effective as its initial dose
- A common phenomenon seen with CNS active drugs –
morphine, alcohol, barbiturates, LSD and amphetamine
- Not necessary that tolerance to be developed to all
pharmacological effects of a drug
- Reverse Tolerance/ Sensitisation – for a given dose there is a
greater response than seen after the initial dose
- Types of tolerance

1. Innate/ Natural/ Congenital Tolerance

2. Acquired Tolerance

3. Cross Tolerance
Innate Tolerance
- The species/ individuals inherently less sensitive to the drug i.e.
genetically determined lack of sensitivity to a drug
- Ex: Rabbits are tolerant to large doses of atropine as they possess
atropine esterase enzyme in liver – destroys atropine faster
Acquired Tolerance
- Occurs by repeated use of a drug in an individual who was
initially responsive
- Due to either pharmacokinetic or pharmacodynamic reasons

- Tolerance due to PK – called as Drug Disposition or Metabolic

Tolerance
- Due to PDs – Cellular Adaptive/ Target Tissue/ Pharmacodynamic
Tolerance
Drug Disposition
- May occur when a drug reduces its own absorption or increases
its own metabolism through microsomal enzyme induction
- Net result – decrease in the effective concentration of the drug at
the site of action
Ex:
PK tolerance due to poor absorption
- Chronic alcoholics can tolerate large amounts of alcohol due to
thickened gastric mucosa – reduces the extent of alcohol
absorption
PK tolerance due to increase in rate of biotransformation
- Barbiturates

PK tolerance due to faster excretion

- Amphetamine
Cellular Adaptive Tolerance
- Occur due to some kind of adaptive changes that have taken place
within the system after repeated drug administration
- May be due to either

Drug-induced changes in the receptor density or

Impairment in receptor coupling to signal transduction pathways
- Ex: drugs like morphine and its congeners, caffeine, nicotine,
LSD
Acute Tolerance (Tachyphylaxis)
- Acute development of tolerance after a rapid and repeated
administration of a drug at shorter intervals
- Rarely seen in clinical practice
Cross Tolerance
- Development of tolerance to pharmacologically related drugs i.e
drugs belonging to same category
- Ex: Individuals tolerant to morphine are also tolerant to heroin
and other narcotic analgesics
Drug Resistance
- Refers to unresponsiveness of microorganisms to an antimicrobial
agent after its repeated use and similar to tolerance
- 3 types

1. Natural Resistance

2. Acquired Resistance

3. Cross Resistance

Natural Resistance
- Some microorganisms have always been resistant to certain
antibiotics
- No significant clinical problem
- Ex: Gram-negative bacilli – unaffected by Penicillin-G;
Mycobacterium tuberculosis – insensitive to Tetracyclines or
Cephalosporins
Acquired Resistance
- Subsequently developed resistance by a microorganism (initially
sensitive) due to the use of an antimicrobial agent over a period of
time
- Ex: Staphylococci, Coliform or Tubercle bacilli – commonly
develop resistance to antimicrobial agents
Cross Resistance
- If a microorganism resistant to one antimicrobial agent exhibits
resistance to another antimicrobial drug belonging to the same
category (to which organism was not exposed earlier) – called as
cross resistance
- Ex: a microorganism becoming resistant to one sulfa drug
exhibits resistance to all sulfonamides
Drug Allergy
- An adverse, unexpected response to the usual therapeutic doses
of a drug resulting from a previous exposure to the same
substance
- Alternative drug given in the therapy

Cumulation
 MODIFIED DRUG EFFECTS AFTER CONCURRENT
ADMINISTRATION OF TWO DIFFERENT DRUGS

Summation

- When two drugs elicit the same response, but with different
mechanism and their combined effect is equal to algebraic sum of
their individual effects – drugs are said to exhibit summation of
effects

Ex:

Aspirin + Codeine – Analgesic effect by Summation

Aspirin – inhibition of Prostaglandin synthesis

Codeine – Agonist at opioid Receptors

Additive Effects
- When the combined effect of two drugs, acting by same
mechanism, is equal to that expected by simple addition – called
additive effects
Ex:
Ibuprofen and Paracetamol – same mechanism – Combined
Analgesic Effect
Synergism
- When the combined effect of two drugs is greater than the
algebraic sum of their individual effects, the phenomenon is
called as Synergism
- Outcome is either the Potentiation (Supraadditive) or
Prolongation of effects
- Result when two drugs act at different sites or when one drug
alters the pharmacokinetics of the other drug
Ex:

➢ Two drugs acting at different sites – synergism

• Sulfamethoxazole + Trimethoprim – Cotrimoxazole

Both are Bacteriostatic – Combination is Bacteriocidal

• Antihypertensives (β-blockers) + Diuretics (Frusemide) –

Synergism

➢ One drug alters the Pharmacokinetics of the other – Synergism

• Levodopa + Carbidopa – Treatment of Parkinsonism

Carbidopa prevents theperipheral metabolic degradation of

levodopa – thus greater amounts of levodopa reach the brain
Drug Antagonism
- When one drug decreases or abolishes the action of another, they
are said to be Antagonist (OR)
- When the combined effect of two drugs is less than the sum of
the effects of the individual drugs – the phenomenon is called
Drug Antagonism
- Four mechanisms by which one drug may oppose the action of
another –
1. Physical Antagonism

2. Chemical Antagonism

3. Physiological/ Functional Antagonism

4. Pharmacological/ Pharmacodynamic/ Receptor Antagonism

a. Competitive Antagonism
b. non-competitive Antagonism
Physical Antagonism
- Based on the Physical properties of the drugs

Ex: Charcoal adsorbs alkaloids and can prevent their absorption –

used in alkaloidal poisoning
Drug Combinations
- Multiple drug therapy involves either

a. Concurrent administration of more than one drug (leads to

Drug-Drug Interactions) OR
b. Simultaneous administration of two drugs mixed in a single
dosage form (FDCs)