Basic principles in pharmacology

1. BASIC PRINCIPLES OF
PHARMACOLOGY
MODERATOR –Dr. Itishri
PRESENTED BY- Dr. Richa Kumar
07/11/16

2. BASIC PRINCIPLES OF
PHARMACOLOGY
PHARMACOKINETICS
PHARMACODYNAMICS

3. PHARMACOKINETICS
• ABSORPTION
• METABOLISM
• DISTRIBUTION
• ELIMINATION
PHARMACODYNAMICS
• RECEPTOR THEORY
• DOSE RESPONSE
CURVE
• THERAPEUTIC INDEX

4. PHARMACOKINETICS
• Describes what body does to a drug
• Determines the concentration of a drug in
plasma or at the site of drug effect
• BASIC PRINCIPLES- absorption, distribution
metabolism & elimination.

5. ABSORPTION
• Drugs are weak acids or weak bases
• Present in ionized and non-ionized form
• Non-ionized form is usually lipid soluble form,
which easily crosses the cell membrane including
BBB, renal tubules, GIT epithelium, placenta and
hepatocytes.
• Non-ionized= pharmacologically active

6. DETERMINANTS OF IONIZATION
1 Dissociation constant of drug : pK
2 pH of surrounding fluid
NONIONIZED IONIZED
pH= pK 50% 50%
Acidic drug(barbiturates)
ph> pK
BASIC DRUG(opiods,LA)
pH< pK

7. ION TRAPPING
• Opioids – accumulation of ionized form in acidic
environment of stomach
• Basic drugs like Local anesthetics from mother to
fetal blood.(fetal pH lower than maternal blood
ph)

8. BIOAVAILABILITY(F)
• Its the percentage of a drug which enters blood in
unchanged form.
• MAIN FACTOR which determines it is route of
drug
• for injected i.v. drug is 100 percent
• Clinical significance :
amount of drug absorbed
Rate at which it is absorbed
Drug response in comparison to blood levels in
the body

9. HALF LIFE
• The time in which peak plasma concentration of drug
becomes half
t ½ = 0.693/k where k is the elimination rate constant
It helps in estimating
 rate of excretion of drug
 Duration of action of drug

10. • Short T ½ means rapid excretion and short
duration of action
• Long T ½ means slow excretion and long
duration of action
• Drug is completely eliminated in 6 half lives
• Clinical action lies upto 4 half life of a drug.

11. STEADY STATE
• When plasma concentration stabilizes
• Rate of administration = rate of elimination
• Depends of T ½
• Takes about five T ½ to reach a steady state
• Only important for drugs given in infusion
form

12. ROUTE OF ADMINISTRATION AND
SYSTEMIC ABSORPTION OF DRUGS.
• Choice of drug administration depends on
systemic absorption rate (SAR)
• determines drug effect and duration of action.
• Changes in SAR necessitate adjustment in dose or
time interval between repeated drug doses
• depends upon-drug’s solubility, local conditions at
site of drug administration like blood flow at that
site, area of absorbing surface.

13. ROUTES OF DRUG ADMINISTRATION
INTRAVENOUS ADMINISTRATION
INHALATIONAL
ORAL TRANSMUCOSAL / SUBLINGUAL
TRANSDERMAL
RECTAL

14. DISTRIBUTION
CENTRAL COMPARTMENT- that section of body which
dilute the drug within first minute after injection.
PERIPHERAL COMPARTMENT
• Anesthetic drugs distribute extensively into peripheral
tissues.
• Represent additional volumes that are attached to the
central volume.
• Reflects the drug's solubility in tissue relative to blood or
plasma.
• The more soluble a drug is in peripheral tissue relative to
blood or plasma, the larger the peripheral volumes of
distribution

15. VOLUME OF DISTRIBUTION-
Vd=
• Depends on lipid solubility and plasma protein
binding.
• tells about extent of tissue penetrance
dose administered
immediate plasma concentration

16. REDISTRIBUTION
• VESSEL RICH GROUP- concentration of drug rapidly
rises to equilibrate with arterial blood levels.
• But for highly fat soluble drugs the capacity of fat to
hold the drugs exceeds the capacity of highly
perfused tissues.
• Muscles play intermediate role.
REDISTRIBUTION accounts for
offset of drug eg. FENTANYL

17. PROTEIN BINDING
• Most acidic drugs – albumin
• Most basic drugs -α-acid glycoprotein
• Affects –distribution of drug
-potency of drug
• Non-selective
• Age , hepatic disease, renal failure, and pregnancy
DECREASES plasma protein concentration.
• Alteration important only for drugs which are highly
(>90%) protein bound
Free fraction

18. PHARMACOKINETIC MODELS
FIRST ORDER KINETICS
• Constant fraction of drug is
excreted in unit time
• Rate of elimination directly
proportional to plasma
concentration
• T ½ =constant
• Clearance =constant
ZERO ORDER KINETICS
• Constant amount of drug is
excreted in unit time
• Rate of elimination
=constant
• T ½ increases
• Clearance decreases
These are hypothetical structures that are used to describe the
fate of a drug in a biological system following its administration

19. First order kinetics Zero order kinetics

20. ONE COMPARTMENT MODEL
Body depicted as kinetically homogenous unit
• Drug achieves instantaneous distribution throughout the
body & equilibrates instantaneously between tissues

21. TWO COMPARTMENT MODEL
Resolves body into central & peripheral compartment
However the drug does not achieve instantaneous distribution
i.e. equilibration between the two compartments

22. Drug distributes into more than one compartment
• Influenced by physiochemical properties of the drug
• A drug may only enter and leave the model through the
central compartment.
MULTI COMPARTMENT MODEL

23. CONTEXT SENSITIVE HALF LIFE
• Time for plasma concentration to decrease by 50% from an
infusion that maintains a constant concentration
• Context being the duration of infusion
On stopping an infusion, decline in
plasma conc. by 3 possible processes
I. Distribution to 2nd compartment
II. Distribution to 3rd compartment
III. Excretion
Relative contribution of these
to their initial decline in
plasma concentration vary
according to the duration of
the infusion

24. • Context sensitive half life is more for Longer
infusion because drug accumulated in
peripheral compartment also equilibrates with
plasma levels of drug.
• It is more relevant than half life in characterizing
clinical responses.
• It is important for IV hypnotics as 50% reduction
in drug conc. is important for recovery from iv
hypnotics at termination of surgery.

25. TIME COURSE OF DRUG EFFECT
• Plasma is not the site of drug effect for
anesthetic agent
• It must diffuse from blood to target tissue to
produce its effect leading to a delay in onset
of drug effect relative to plasma conc. Of drug
• Lag time is known as HYSTERESIS

28. DOSE CALCULATIONS
• BOLUS DOSING:
=
𝐂𝐏𝐒𝐒 ×𝐕𝐝𝐬𝐬
𝐛𝐢𝐨𝐚𝐯𝐚𝐢𝐥𝐚𝐛𝐢𝐥𝐢𝐭𝐲
• Cpss is steay state plasma concentration
• Vdss is volume of distribution

29. MAINTENANCE INFUSION RATE
=
𝐂𝐏𝐒𝐒 ×𝐂𝐋
𝐁𝐈𝐎𝐀𝐕𝐀𝐈𝐋𝐀𝐁𝐈𝐋𝐈𝐓𝐘
CL= clearance of drug from plasma

30. METABOLISM
• Active drug inactive metabolite
• Active drug active metabolite
• Inactive drug active metabolite
(prodrug)
• Mostly drugs are lipohilic and converted to
hydrophilic compound so that they can be
easily excreted.

31. PHASES OF METABOLISM
• PHASE 1
• Non synthetic
• Microsomes :smooth ER
• Microsomal enzymes
(CYP450, MO,GT)
• MICROSOMAL REACTION
• Oxidation,reduction,cycliz
ation,decyclization and
hydrolysis
• PHASE 2
• Synthetic
• Cytoplasm(except
glucuronidation)
• CONJUGATION
REACTIONS
• Acetylation, methylation,
sulphation,
glucuronidation, conj.
with glutathione, glycine
conjugation

32. • PHASE 1
• Oxidation of side chain of
highly fat soluble
thiopental ,coverts it into
hydrophilic carboxylic
acid derivative
• Phenobarbital (+)
microsomal enzymes
• Grapefruit juice (-)
CYP3A4 (CYP450)
• PHASE 2
• Glucoronidation is
important for PROPOFOL,
MORPHINE,MIDAZOLAM

33. ELIMINATION / CLEARANCE
• Volume of plasma in the vascular compartment
cleared of drug per unit time by the processes of
metabolism and excretion.
• Defined in units of flow (e.g., litres/minute).
• CL= U*V/P
• CL= clearance
• U= urine concentration of drug
• P=plasma concentration of drug
• V=urine flow rate

34. HEPATIC CLEARANCE

35. HEPATIC CLEARANCE
•R=Q(Cinflow-Coutflow)
•R=Cinflow x Clearance
• R is rate of drug metabolism
• Q is blood flow in and out of liver
• C is concentration of drug

36. Cin X Clearance = Q (Cin- Cout)
Clearance= Q X (Cin−Cout)
Cin

37. EXTRACTION RATIO
Extraction ratio (ER) =
Clearance = Q x
(Cin−Cout)
Cin
Clearance = Q x ER
(Cin−Cout)
Cin

38. CL= Q X ER
1.For drugs like Propofol, ER = 1
• the clearance is simply liver blood flow.
• any reduction in liver blood flow will reduce
clearance
• Such drugs with high ER are known as "flow
dependent."
IMPORTANCE OF EXTRACTION RATIO

39. 2. For many drugs (e.g. alfentanil), the ER <<<1
• Clearance of these drugs is limited by the
capacity of the liver to take up and metabolize
the drug.
• These drugs are said to be "capacity
dependent."

40. CREATININE CLEARANCE AS A FUNCTION OF AGE AND
SERUM CREATININE(FIG.2-13)

41. RENAL CLEARANCE
• The kidneys use following mechanisms to
clear drug from the body:
Filtration at the glomerulus
 secretion into the tubules
Reabsorption into the tubules

42. • The glomerular filtration rate is typically
approximated using creatinine clearance which
can be predicted from age and weight using
COCKROFT AND GAULT EQUATION
• For men:-
• For women it is 85% of above
:
140−𝐴𝐺𝐸 𝑦𝑒𝑎𝑟𝑠 ×WEIGHT kgs
72×𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒(𝑚𝑔%)
RENAL CLEARANCE

43. PHARMACODYNAMICS

44. PHARMACODYNAMICS
• Study of intrinsic sensitivity and
responsiveness of the body to a drug.
• It is what drug does to the body
• Intrinsic sensitivity is determined by
measuring plasma concentration of a drug
required to evoke specific pharmacological
responses.
It varies from patient to patient.

45. RECEPTOR THEORY
AGONIST
ANTAGONIST

46. AGONIST
FULL
RESPONSE eg
MIDAZOLAM
on BDZ R.
INVERSE
AGONIST
Opposite
response eg
RO 19-4063
PARTIAL
AGONIST
PRODUCES PART OF
RESPONSE
eg. BRETAZENIL

47. ANTAGONIST
NO RESPONSE
FUMAZENIL –competitive antagonism on
BDZ receptor

48. INTRINSIC ACTIVITY
• It is capacity to produce a response
• +1 for agonist
• 0 to +1 for partial agonist
• 0 for antagonist
• -1 to 0 for inverse agonist

49. • Time independent relationship between
exposure of drug (x axis) and measured effect
(y axis)
• POTENCY is lowest dose at which response
begins
• EFFICACY is maximal response
CONCENTRATION vs RESPONSE
RELATIONSHIP

52. EFFECTIVE AND LETHAL DOSE
• ED 50 is dose at which there is therapeutic
effect of drug in 50% population to whom the
drug was given.
• Indicates drug potency
• LD 50 is dose at which there is toxicity in 50%
of population.
• Indicates drug safety.
Effective & Lethal Dose

53. THERAPEUTIC INDEX
• TI = LD50 / ED50
Best indicator of drug safety
>= 2 indicates Drug is safe
<2 means drug is unsafe and has narrow TI