This document provides an overview of pharmacology concepts including:
- Pharmacokinetics describes what the body does to drugs through absorption, distribution, metabolism and excretion.
- Pharmacodynamics describes what drugs do to the body through receptor interactions and clinical effects.
- Key pharmacokinetic processes like absorption, distribution, metabolism and elimination are influenced by drug and body factors and determine drug availability at target sites.
2. Pharmacology?
Pharmacology studies the effects of drugs and how
they exert their effects:
Acetylsalicylic acid (ASA) can reduce inflammation, pain
and fever inhibit the action of a human cell membrane
enzyme known as cyclooxygenase (COX) , which is
responsible for the synthesis of a number of inflammatory
mediators
Penicillin cures certain bacterial infections by disrupting
the synthesis of cell walls in susceptible bacterial strains
3. Pharmacology?
Pharmacokinetics
It is what the body does to the drug
How the body absorbs, distributes, metabolizes, and
excretes drugs
Pharmacodynamics
Is what the drug does to the body
Study the mechanisms by which drugs work
Clinical interactions of drugs
4. PHARMACOKINETICS
Process for a drug to reach the target organ at a
concentration sufficient to have a therapeutic effect
A successful drug should have an ability to cross
physiologic barriers that other foreign substances do not
have
This is possible through:
Drug absorption
Use of distribution systems with the body to reach the
target organ at a sufficient concentration
The drug’s ability to reach the target is limited also by:
Metabolism: enzymatic degradation
Excretion: drug eliminated from the body
9. Factors affecting absorption of
drugs
Factors related to drugs:
1. Lipid water solubility:
LWS coefficient is the ratio of dissolution of drug in lipid as
compared to water. Greater the LWS coefficient, more is the lipid
solubility of drug and greater is the absorption.
2. Molecular weight
Smaller the molecular size of drug, rapid is the absorption
3. Degree of Ionization
Different drugs are either Acid or basic and are present in ionized
or unionized form. Acid drugs are better absorbed from acid area.
4. Physical form
Drugs may exist as solids, gases and liquids.
Gases are rapidly absorbed than the liquids while liquids are
rapidly absorbed than solids
5. Formulation, particle size etc
10. Factors affecting absorption of
drugs
Factors related to the Body:
1.Area of absorptive surface:
Most of the drugs are given orally bcz of largearea of
absorptive surface,so that the greater absorption
occurs. Intestinal resection decreases the surfaces area
leading to a decreased absorption.
2.Vascularity:
More the vascularity, more is the rate of absorption.
3. pH:
Acidic pH favors acidic drugs absorption while basic pH
is better for basic drugs.
4. Presence of other substances:
Eg: Vit C enhances the absorption of Iron
11. Factors affecting absorption of
drugs
5. GI mobility
6. Functional integrity of absorptive surface: edema
7.Diseases: Diarrhea, malabsorptive sd etc
12. Absorption
Biological membranes:
All human cells are limited by a lipid bilayer
membrane→ passive diffusion +++ for non polar
small molecules
Facilitated diffusion: Transmembrane carrier proteins
for bigger molecules
Active transport: needs energy
Endocytosis: some drugs bind to specific cells and form
vesicles form which drugs are released into the cell
13. Absorption
Central Nervous System:
Well insulated from foreign substances
Blood-brain barrier: tight junctions prevent passive
diffusion
Drugs acting into in the CNS:
Sufficiently small and hydrophobic to cross the mbne
or use existing transport proteins in the BBB
BBB bypassed using intrathecal drug infusion
14. Absorption
BIOAVAILABILITY
The fraction of administered drug that reaches
the systemic circulation
Depends on:
Route of administration
Chemical form of drug
Patient’s specific factors (eg: GI and hepatic
transporters and enzymes)
15. ABSORPTION
Bioavailability
The fraction of the dose of a drug (F) that enters
the general circulatory system,
F= Amount of drug that enters systemic circulation
Dose administered
F = AUC/Dose
18. ABSORPTION
Different routes of administration of drugs
Enteral: weak barriers, but acid (gastric) and basic
(duodenal) can ↓bioavailability, easy, no risk of
bloodsteram infection
First pass hepatic metabolism: ↓bioavailability
Parenteral (IV, IM, SC, IT): rapid delivery, pain, infection,
irreversible
For IV drugs: bioavailability = 1.0
Mucous membrane: rapid delivery, no first pass, low
infection, direct delivery to affected tissue
Transdermal: simple, painless, excellent for continuous
administration. Requires highly lipophilic drug, may be
irritating
19. ABSORPTION
Clinical example of FIRST PASS Metabolism :
Morphine
Undergoes extensive first pass metabolism
Oral bioavailability is 30 – 50 %
Oral dose not comparable with IV dose
20. Distribution
1. Definition:
Distribution is the process of delivering a drug from the
bloodstream to the tissues of the body
It is a reversible transfer of drug between one
compartment (blood) to another (extra vascular tissue)
Plasma concentration: poor measure of tissue
concentration
Distribution affects the duration of action of the drug
21. Distribution
2. Significance:
Pharmacological action of drug depends upon its
concentration at the site of action
Thus distribution plays important role in:
Onset of Action
Intensity of Action
Duration of Action
24. FACTORS AFFECTING DISTRIBUTION OF
DRUGS
1. Tissue Permeability of Drugs
Physicochemical Properties of drug like:
• Mol.size, pKa, o/w Partition Coefficient
Physiological barriers to diffusion of drugs
• Simple Capillary Endothelial Barrier
• Simple Cell Membrane Barrier
• Blood Brain Barrier
• Blood-CSF Barrier
• Blood Placental Barrier
• Blood Testis Barrier
2. Organ/tissue size and perfusion rate
3. Binding of drugs to tissue components.
binding of drug to blood components
binding of drug to extra cellular components
25. FACTORS AFFECTING DISTRIBUTION OF
DRUGS
4. Miscellaneous:
Age:
Total body water
Fat content
Skeletal muscles
Organ composition
Plasma protein content
Pregnancy
Obesity
Diet
Disease states
26. METABOLISM
Definition
Chemical alteration of drug in the body.
Non polar lipid soluble compounds are made polar lipid
insoluble, so that they are easily excreted.
SITES
Primary site – Liver
Others – Kidney, Intestine, Lungs, Plasma
27. METABOLISM
Drug Biotransformation : convert lipophilic /
hydrophobic drug (to enter cells) to hydrophilic
metabolites.
Advantages
Termination of drug action - (↓ toxicity)
Reduced lipophilicity.
Renal / biliary excretion ↑ - (↓renal reabs)
29. METABOLISM
CONSEQUENCES
A) Drug inactivation - inactive or less active
Propranolol,Pentobarbitone,Morphine,Chloramphenicol,Parac
etamol,Ibuprofen,lignocaine
B) Active drug to Active metabolite- Active metabolite
Effect is due to parent drug and its active metabolite
C) Inactive drug (Prodrug) - Active drug
Prodrugs are inactive drugs which need BT in the body to form
active metabolites.
ADV
More stable
Better BA
Less toxicity
Eg: Levodopa - Dopamine
Enalapril - Enalaprilat
30. METABOLISM
TYPES
Biotransformation reactions - 2 types
Phase I / Non synthetic / Functionalization
A functional group is generated
Metabolite – active or inactive
Phase II / Synthetic / Conjugation
An endogenous radical is conjugated
Metabolite is usually inactive
32. INHIBITION OF DRUG
METABOLISM
One drug can inhibit the metabolism of another drug
↑ in circulating levels of slowly metabolized drug
Prolongation or potentiation of its effects
Consequences
Precipitate toxicity of the object drug.
can be therapeutically beneficial. Eg: aversion of
alcohol with disulfiram, Reversal of SKM paralysis
of d-tc by neostigmine
e.g:Valproate,Ketoconazole,Cimetidine,Ciprofloxacin,Er
ythromycin,INH
Code – Vitamin K cannot cause enzyme inhibition.
33. MICROSOMAL ENZYME
INDUCTION
Inducers of enzymes that mediate the phase I
reaction enzymes (eg: Barbiturates)
Drugs, insecticides, carcinogens will induce the
synthesis of microsomal enzyme proteins
Accelerated metabolism and reduced
pharmacological response
Consequences
Drug- drug interactions
Can lead to toxicity. Eg: Alcoholics more prone to
hepatotoxicity of paracetamol due to↑ production of
NABQI
Decreased duration of action.
EG:Griseofulvin,Phenytoin,Rifampicin,Smoking,Carbam
34. First Pass Metabolism
Presystemic metabolism/ First pass effect
Metabolism of a drug during its passage from the site
of absorption into the systemic circulation.
↓BA
↓therapeutic response
SITES
Gut wall
Gut lumen
Liver (major site)
Lungs
Skin
35. Attributes of drugs with FPM
Oral dose is higher than sublingual or parenteral.
Oral BA is increased in patents with severe liver
disease.
Drugs with FPM usually have short plasma t1/2.
Oral BA is increased if another drug competing
with it in first pass metabolism is given
concurrently. Eg: CPZ & Propranolol
36. ELIMINATION
Clearance
Factor that predicts the rate of elimination in
relation to the drug concentration
Rate of elimination = CL x C
CLsystemic = CLliver + CLkidney + CLother
Rate of elimination
Plasma concentration (C)
Clearance (CL) =
37.
38. ELIMINATION
Effect of disease processes
Disease processes can alter the elimination of a
drug:
Hepatic failure
Renal failure
40. RENAL EXCRETION:
• Most important organ for Elimination.
• Free drugs (eg. Furosemide,gentamicin)
• Drug Metabolites
PROCESSES THAT DETERMINE RENAL
– Glomerular filtration.
– Active tubular Secretion.
– Passive tubular reabsorption.
FACTORS OF GLOMERULAR FILTRATION:
• Molecular size.
• Plasma protein binding
• Renal Blood Flow
41. BILIARY EXCRETION & ENTEROHEPATIC
CIRCULATION:
• Drugs excreted in Bile:-Quinine,
Colchicines, Corticosteroids.
• Some drugs secreted through bile but after
being delivered to intestine, are
reabsorbed back and the cycle is
repeated. Eg: Digitoxin.
• Other drugs with enterohepatic circulation:
• Morphine, Chloramphenicol, Tetracycline
etc.
42. ALVEOLAR EXCRETION:
• Gases & Volatile liquids eg: General
Anaesthetics, Ether, Alcohol
• Depends on partial pressure in the blood.
• Eucalyptus oil and garlic oil eliminated
through expectoration.
43. ELIMINATION THROUGH BREAST
MILK:
• May cause unwanted effect in Nursing
infant.
• Drugs transferred to breast milk according
to pH partition principle.
• Basic drugs not ionised at plasma alkaline
pH, get accumulated in Milk. Eg:
Chloramphenicol, Tetracycline, Morphine
etc.
44. Half-Life
It is defined as the time required for drug blood levels
to be reduced by 50%.
Factors affecting half-life
Decreased:
Ageing (decreased muscle and off course Vd)
P450 induction
Increased:
Obesity ( adipose tissue and Vd)
P450 inhibition
Cardiac failure
Hepatic failure
Renal failure
45. PHARMACODYNAMICS
Pharmacodynamics is the study of drug effects.
Wanted effects of drugs
Side effects
Clinical Interactions with other drugs:
Synergy
Antagonism
Addition
46. Pharmacodynamics
Drug-receptor interactions
2 properties determine the nature of a drugs
pharmacological effect:
Affinity
Refers to how well a drug binds to its receptor
Intrinsic activity or efficacy
refers to the magnitude of effect the drug has once bound to the
receptor
47. PHARMACODYNAMICS
Definitions
Agonist: Mimic actions of neurotransmitter at same
site
Affinity for receptor
Intrinsic activity
Antagonist: Block actions of neurotransmitter at
same site
Affinity for receptor
NO intrinsic activity
48. PHARMACODYNAMICS
Agonists
Full agonist
Drug that generates a maximal response from a
receptor (Emax)
Demonstrates high affinity & high intrinsic activity
Partial agonist
Fails to achieve maximal effect even in high dose
Demonstrates reduced intrinsic activity
50. PHARMACODYNAMICS
Antagonists
Reversible
Competitive
The effect of the antagonist can be overcome by increasing the
concentration of the agonist
The 2 molecules are competing for the same receptor
Non-competitive
Do not bind to the same site on the receptor as the agonist
Effect results from preventing receptor activation through
conformational distortion
Effect cannot be overcome by increasing the concentration of
agonist
Irreversible
Irreversibly bind to the receptor
Increasing agonist concentration will not overcome the blockade
53. Drug potency and efficacy
Drug potency which refers to the amount of
drug needed to produce a certain response.
Drug efficacy refers to the maximal response
that can be elicited by the drug.
54. Drug potency and efficacy
Drug B is less potent but
equally efficacious as drug A.
Drug C is less potent and
less efficacious than drug A.
Drug D is more potent than
drugs A, B, & C, but less
efficacious than drugs
A & B, and equally
efficacious as drug C.
56. Combined effect of Drugs
Synergism:
When the action of one drug is facilitated or increased by
the other, they are said to be synergistic.
Additive Synergism
The effect of the two drugs is in the same direction and
simply adds up:
Effect of drugs A + B = effect of drug A + effect of drug
B.
Absorption: refers to movement of a drug from site of administration to bloodstream
Ionisation: pKa = pH at which 50% of drug molecules are ionized (charged)
Only uncharged molecules are lipid soluble.
The pKa of a molecule influences its rate of absorption through tissues into the bloodstream.
pH varies among tissue sites
e.g., stomach: 3-4, intestines: 8-9
Acid drugs are unionized in acidic medium
Passive diffusion: movement of sbtce from an erea of higher concentration to an erea of lower concentration.
Facilitated diffusion: movement from higher to lower concentration using a carrier protein in the cell
The CNS presents special challenges to the pharmacologic therapy
This diagram shows the evolution of the concentration of the drug in the blood/body after its absorption from the site (route) of administration.
first pass metabolism: it is the fraction of drug lost during the processs of absorption which is generally related to the liver and gut
.
Bulk flow : it refers to the transport of fluids or electrolytes between cells through openings, or pores between cells
Age: Difference in distribution pattern is mainly due to Total body water -(both ICF &ECF) greater in infants, Fat content - higher in infants & elderly, Skeletal muscle - lesser in infants & elderly.
PREGNANCY:
During Pregnancy, due to growth of UTERUS,PLECENTA,FETUS…Increases the volume available for distribution drug
OBECITY :
In obese persons, high adipose (fatty acid) tissue so high distribution of lipophilic drugs
Tachyphylaxis: it is a rapid diminishing response to successive doses of a drug,rendering it less effective.