2. Pharmacology
• It is the study of the interactions
that occur between a living organism
and chemicals that affect normal or
abnormal biochemical function.
• It is mainly concerned with safety
and efficacy of a drug.
3. Pharmacology
This field includes drug :
• Composition
• Properties
• Synthesis
• Medical Applications
• Antipathogenic capabilities
5. Importance of Pharmacokinetics and Pharmacodynamics
• Individualize patient drug therapy
• Monitor medications with a narrow therapeutic index
• Decrease the risk of adverse effects while maximizing
pharmacologic response of medications
7. Pharmacokinetics
• Study of drug movement in, through and out of the
body.
• It includes the following processes : (ADME)
Absorption Distribution Metabolism Excretion
8. Absorption
• The process by which drug proceeds from the site of
administration to the blood stream within the body.
• Orally administered solid drugs should break down into particles
of the active drug the released drug then dissolve in the aqueous
GI contents.
11. First Pass Metabolism
• A fraction of a drug is lost during the process of absorption generally
related to the liver and gut wall and its concentration is greatly
reduced before it reaches the systemic circulation.
• It leads to decreased bioavailability of a drug.
• Maximum in orally administered drugs.
12. Bioavailability
• First fundamental parameter of Pharmacokinetics.
• Rate and extent of absorption of a drug from a dosage form.
• Determined by concentration-time curve of the drug in blood or its
excretion in urine.
PLASMACONCENTRATION
TIME
C
Therapeutic success of a rapidly
and completely absorbed drug.
Therapeutic failure of a
slowly absorbed drug
Therapeutic Concentration
13. Bioavailability
• Fraction of administered dose of a drug that reaches the
systemic circulation in the unchanged form.
• IV injected drug : 100 % bioavailability
• Orally ingested drug : reduced bioavailability because :
Drug may be incompletely absorbed
The absorbed drug may undergo first pass metabolism
• SC or IM injection MAY have reduced bioavailability due to local
binding of the drug.
14. Distribution
• Process by which drug leaves the site of administration and
distributed throughout the tissues of the body.
• Factors affecting volume of drug distribution :
Lipid:water partition coefficient of the drug
pKa value of the drug
Degree of plasma protein binding
Affinity for different tissues
Fat:Lean body mass ratio
Diseases like CHF, Uraemia, Cirrhosis
15. Distribution
APPARENT VOLUME OF DISTRIBUTION ( V )
• Second fundamental parameter of Pharmacokinetics.
• Volume of distribution is the volume of plasma that would be
necessary to account for the total amount of drug in the
patient's body, if that drug were present throughout the body at
the same concentration as found in the plasma.
V = Dose administered IV
Plasma concentration
16. Metabolism (Biotransformation)
• Chemiacal alteration of the drug in the body.
• converts non-polar (lipid soluble) compounds polar so they are not
reabsorbed in the renal tubules and are excreted.
• Hydrophilic drugs eg. Gentamycin are not biotransformed and are excreted
unchanged.
• PRIMARY SITES :
Kidney Intestine Lung Plasma
19. Metabolism (Biotransformation)
NON SYNTHETIC REACTIONS
OXIDATION
• carried out by
monooxygenases in
the liver
• involve cytoP450
haemoprotein, NADPH,
cytoP450 reductase and
molecular O2
• eg. Paracetamol
REDUCTION
• converse of oxidation
• cytochrome P450
works in opposite
direction
• eg. Chloramphenicol
HYDROLYSIS
• cleavage of drug
molecule by taking up
a molecule of water
• Ester + H2O esterase
Acid + Alcohol
20. Metabolism (Biotransformation)
SYNTHETIC REACTIONS
• conjugation of the drug or its phase 1 metabolite with an
endogenous substrate to form a polar highly ionized organic acid
which is easily excreted in urine or bile.
Glucuronide
conjugation
Acetylation Methylation
Sulfate
conjugation
Glycine
conjugation
Glutathione
conjugation
21. Excretion
• Passage out of systemically absorbed drug in :
• Through the kidneyUrine
• Derived from bileFaeces
• Eliminated by lungsExhaled Air
• Important in respect to suckling infantsMilk
22. Kinetics of Elimination
• Drug Elimination = Metabolic Inactivation + Excretion
• CLEARANCE (CL) :
Third fundamental parameter of Pharmacokinetics.
Volume of plasma from which the drug is completely removed in unit
time.
CL = Rate of Elimination
Plasma Concentration
23. Kinetics of Elimination
FIRST ORDER (EXPONENTIAL) KINETICS
• Rate of elimination is directly proportional to drug concentration
• CL remains constant
• t½ is constant
ZERO ORDER (LINEAR) KINETICS
• Rate of elimination is constant irrespective of drug concentration
• CL decreases with increase in concentration
• t½ increases with dose
24. Kinetics of Elimination
PLASMA HALF-LIFE (t½)
• Time taken for the plasma concentration of a drug to be reduced to
half of its original value.
t½ = ln2 = log 2 or (0.693)
k Elimination Rate Constant
ELIMINATION RATE CONSTANT (k) :
• Fraction of the total amount of the drug in the body which is
removed per unit time.
k = CL t½ = 0.693 × V
V CL
25. Kinetics of Elimination
1 half life = 50% drug is eliminated
2 half lives = 75% (50 + 25)
3 half lives = 87.5% (50 + 25 + 12.5)
4 half lives = 93.75% (50 + 25 + 12.5 + 6.25)
So 4-5 half lives are needed for nearly complete drug elimination.
27. Kinetics of Elimination
Repeated Drug Administration
• when a drug is repeated at relatively short intervals, it accumulates in the body until
elimination and input become balanced and a steady-state plasma (Cpss) is attained.
Cpss = Dose rate
CL
• Dose rate and Cpss are in linear relation only in case of drugs that follow first order
kinetics.
Plateau Principle
• when constant dose is repeated before 4 half lives, it would achieve higher peak
concentration, because some remnants of the previous dose will be present in the body.
• After almost 4-5 half lives, increasing rate of elimination balances the amount
administered over the dose interval. Subsequently, plasma concentration plateaus and
fluctuates about an average steady-state level.
30. Pharmacodynamics
Mechanism of Drug action
1. Physical or chemical properties :
• Physical mass
• adsorptive property
• osmotic activity
• neutralization of gastric HCl
• oxidising property
31. Pharmacodynamics
2. Enzymes
• Drugs can either increase or decrease the rate of enzymatically mediated
reactions.
• Stimulation of an enzyme increases its affinity for the substrate so that
rate constant kM of the reaction is lowered.
• Induction of an enzyme ( synthesis of more protein) also increases enzyme
activity. kM does not change.
• Inhibition of enzymes.
a) Non specific inhibition
b) Specific inhibition
32. Pharmacodynamics
3. Carriers
• Drugs produce their action by interacting with the carrier protein to
inhibit the ongoing physiological transport of the metabolite.
• eg. Furosemide inhibits the Na-K-2Cl cotransporter in the ascending limb
of loop of Henle.
4. Ion channels
• Drugs affect ion channels either through specific receptors (ligand gated,
G-protein operated) or by directly binding to the channel and affecting
ion movement through it.
• Certain drugs modulate opening and closing of the channel. eg.
Sulfonylurea hypoglycaemics inhibit pancreatic ATP-sensitive k+ channels.
33. Pharmacodynamics
5. Receptors
• Drugs act through specific receptor (macromolecule or binding site that
serves to recognize and initiate the response to a signal molecule or drug)
which regulate critical functions like enzyme activity, permeability,
structural features, template function.
• Agonist activates receptor to produce effect similar to the physiological
signal molecule.
• Inverse agonist - activates receptor to produce opposite effect.
• Antagonist - prevents the action of the agonist.
• Partial Agonist - activates receptor to produce sub-maximal effect but
antagonizes the action of a full agonist.
34. Pharmacodynamics
Receptor occupation theory
• Propounded by Clark in 1937.
• Intensity of response is proportional to the fraction of receptors occupied by a
drug.
• Drug exert an all or none action on each receptor.
• A drug and its receptor have Lock and Key relationship.
• Affinity : ability of the drug to combine with the receptor.
• Intrinsic activity (Efficacy) : ability of the drug to activate the receptor.
35. Pharmacodynamics
The Two-State Receptor Model
l Equilibrium
ll Response
lll No Response
lv Partial Response
v Opposite Response
Ra Ri
RaA + Ra Ri
RaB + Ra RiB + Ri
RaC + Ra Ri +RiC
Ra Ri +RiD
36. Pharmacodynamics
Action-Effect Sequence
• Drug Action is the initial combination of the drug with its receptor resulting
in a confirmational change in the receptor (AGONIST) or prevention of
confirmational change through exclusion of the agonist (ANTAGONIST).
• Drug Effect is the ultimate change in biological function brought about as a
consequence of drug action.
Dose-Response Relationship
• Intensity of response increases with increase in dose.
• Dose-Response curve is a hyperbola because Drug-Receptor interaction
obeys Law of mass action.
E = Emax × [D]
KD + [D]
37. Pharmacodynamics
• E = observed effect at a dose [D] of the drug
• Emax = maximal response
• KD = dissociation constant of drug-receptor
complex = dose of drug at which half
maximum response is produced
• If dose is plotted on log scale, the curve
becomes sigmoid and a linear relationship is
seen between log of dose and the response
in the intermediate zone (30-70%
response)
Dose
Response
Dose
Log Dose
38. Pharmacodynamics
Drug Potency and Efficacy
• Drug potency is the amount of drug
needed to produce certain response.
• Drug efficacy is the maximum response
achievable from a drug.
• Upper limit of DRC is the index of
efficacy.
• Steep DRC means moderate increase in
dose leads to marked increase in response.
• Flat DRC means little increase in response
over a wide dose range.
• Drug B is less potent but equally
efficacious as A.
• Drug D is more potent than A, B and C
but less efficacious than A and B, and
D
C
A B
Log Dose
Response
39. Pharmacodynamics
A B
Log Dose
Response
Drug Selectivity
• Extent of separation of DRCs of a drug for different
effects is a measure of selectivity.
Therapeutic Index
• Gap between the therapeutic effect DRC and adverse
effect DRC
• Also known as Safety Margin
Therapeutic Index = Median Lethal Dose = LD 50
Median Effective Dose ED50
Therapeutic Effect
Adverse Effect
Minimal
therapeutic
effect
Maximum
acceptable
adverse
effect
Therapeutic Range
40. Pharmacodynamics
Combined effect of drugs :
• given simultaneously or in quick succession
Synergism Antagonism
Additive
Drug A + B = Drug A + Drug B
PhysiologicalPhysical Chemical
Supra-Additive
Drug A + B > Drug A + Drug B
Receptor
Non
Competitive
Competitive
41. Pharmacodynamics
Competitive (Equilibrium Type) Non-Competitive
• Antagonist binds with same receptor as agonist • Binds with different receptor
• Antagonist chemically resemble agonist • Does not resemble
• Parallel rightward shift of agonist DRC • Flattening of agonist DRC
• Surmountable antagonism • Unsurmountable antagonism
• Antagonist reduces potency of agonist • Antagonist reduces efficacy of agonist
• Response depends on both agonist and antagonist • Depends only on antagonist
• eg. ACh-Atropine • Diazepam-Bicuculline
42. Pharmacodynamics
Drug Dosage
• Dose is the amount of drug needed to produce a certain degree of response
in a patient.
• It depends on the potency and pharmacokinetics of the drug.
Types of dose
• Standard dose : Same dose is appropriate for most patients. eg OCP
• Regulated dose : Dosage is accurately adjusted by repeated measurement of
the affected physiological parameter. eg Anti-hypertensives
• Target Level dose : An emperical dose aimed at attaining the target level is
given in the beginning and adjustments are made later by actual monitoring
of plasma concentrations. eg Anti-epileptics
• Titrated dose : Optimal dose is arrived at by titrating it with an acceptable
level of adverse effect.
