1. GENERAL PHARMACOLOGY
KING EDWARD MEDICAL UNIVERSITY LAHORE
B.Sc.(Hons.) DENTAL TECHNOLOGY
BATCH 2021-24
SUBMITED TO: DR. SHARMEEN
2. Learning objectives:
1. Definitions of terms used in pharmacology
2. Sources of drugs
3. Routes of drug administration
4. Drug absorption
5. Membrane transporters
6. Distribution of drugs
7. Biotransformation of drugs
8. Drug excretion, elimination and clearance
9. Dose-effect relationship
10. Processes of pharmacokinetics
11. Mechanisms of drug action
12. Adverse drug reactions
13. Drug-drug interactions
3. WHAT IS PHARMACOLOGY?
●Pharma = Drugs
●Logos = Knowledge
“It is the science of drugs that deals with their actions on living system.”
It includes physical and chemical properties, biochemical and physiological
effects, mechanism of action, therapeutic uses and adverse effects of drugs.
4. WHAT IS DRUG?
“Any chemical that affects the
processes of a living organism.”
or
“Any substance that is used to
prevent, diagnose, treat, or relieve
symptoms of a disease or abnormal
condition.”
6. PHARMACOLOGY Detailed study of drugs.
PHARMACOKINETICS Study of what the body does to the administered drug.
It includes:
Absorption
Distribution
Metabolism
Excretion
PHARMACODYNAMICS Study of what the administered drug does to the body.
It includes:
Mechanism of action of drugs
Pharmacological effects of the drug
Clinical uses of the drugs
Adverse effects of the drugs
7. PHARMACY Study of identification, selection preparation, compounding
and dispensing of medicines.
THERAPUTICS Art and science of treatment of disease.
Or
Study concerned with cure of disease or relief of symptoms.
TOXICOLOGY Study of undesirable effects of chemicals on living system
from individual cells to complex ecosystems and their
treatment.
8. CHEMOTHERAPY Study of effects of drugs on microorganisms and parasites,
living and multiplying in the living body without damage to
the host cells.
It includes:
Anti-microbial drugs
Anti-mycobacterial drugs
Anti-viral drugs
Anti-fungal drugs
Anti- protozoal drugs
PHARMACOGNOSY Study of identification of drugs from natural sources.
POSOLOGY Study of doses (a specified amount of drug used at a time) of
drugs.
20. “The transfer of a drug from its site of administration to
the blood stream is called drug absorption.”
21. FACTORS AFFECTING DRUG
ABSORPTION
1. Physical nature of the drugs
2. Lipid solubility
3. Drug concentration
4. Surface area
5. Blood supply
6. Presence of other substances in the GIT
7. Diseases of GIT
8. First pass effect
28. “Drug distribution is the process by which a drug reversibly leaves
the bloodstream and enters the interstitium and then the cells of
the tissues.”
29. FACTORS AFFECTING DRUG
DISTRIBUTION
The delivery of a drug depends on:
1. Blood flow
2. Lipid solubility
3. Capillary permeability
4. Volume of distribution
5. Degree of binding of the drug to plasma and tissue proteins
6. Redistribution of drug
30. 1- BLOOD FLOW
• The rate of blood flow to tissue capillaries vary widely due to the unequal
distribution of cardiac output to various organs.
• High blood flow and high lipid solubility permits drugs like thiopental and
propofol to rapidly move into CNS. A subsequent slower distribution to
skeletal muscles and adipose tissue lowers the plasma concentration
sufficiently so that the higher CNS concentrations fall and consciousness is
regained.
• Brain, liver and kidneys have higher flow rates whereas adipose tissue,
skin and viscera have lower flow rates.
31.
32. 2- CAPILLARY PERMIABILITY
• It depends on capillary structure and chemical nature of the drug.
• In liver and spleen there are large discontinuous capillaries through which
plasma proteins can pass whereas in brain the capillary structure is
continuous and there are no slit junctions.
• Ionized or polar drugs generally fail to enter the CNS because they are
unable to pass through the endothelial cells of the CNS.
33.
34. 3- BINDING OF DRUGS TO PLASMA
PROTEINS AND TISSUE PROTEINS
• Binding to plasma proteins: Reversible binding to plasma proteins
sequesters drugs and slows their transfer out of vascular compartment.
Plasma albumin is the major drug protein and act as drug reservoir
• Binding to tissue proteins: Numerous drugs accumulate In tissues as a
result of binding to lipids proteins or nucleic acids. E.g. Acrolein
(cyclophosphamide metabolite) is toxic to the kidney because of its
accumulation in renal cells.
• Hydrophobicity: The chemical nature of a drug strongly influences its
ability to cross cell membranes. Hydrophobic drugs can pass through
membranes in contrast to hydrophilic drugs which must pass through the
slit junctions.
35. 4-VOLUME OF DISTRIBUTION
“The apparent volume of body fluids into which a drug is able to distribute
according to it’s concentration in blood or plasma is called volume of
distribution.”
• It is calculated by dividing the dose that gets into systemic circulation by the
plasma concentration at zero time.
Vd = amount of drug In the body
plasma concentration of drug
37. PLASMA COMPARTMENT
• Drugs with very large molecular weight bind extensively to plasma
proteins which cannot pass through the endothelial slit junctions.
• Makes almost 6% of body weight. In a 70 kgs male about 4L of body fluid.
• Heparin shows this type of distribution.
38. EXTRACELLULAR FLUID
• Drugs with low molecular weight can reside in plasma and also move to
interstitial fluid. Together both these compartments make extracellular
fluid.
• This is about 20% of the body weight . 14 L in a 70 kg man.
Aminoglycosides show this type of distribution.
39. TOTAL BODY WATER
• Drugs with low molecular weight and hydrophobic move across cell
membranes.
• It makes almost 60% of the body weight . About 42L in a 70 kg man.
• Ethanol shows this distribution.
41. “Chemical alteration of a drug by the body.”
Biotransformation or metabolism of a drug usually produces following two
important changes in it:
1. Solubility:Drug becomes water soluble
2. Biological activity:Drug usually becomes biological inactive
SIGNIFICANCE:
• Lipid soluble drugs ------------- Water soluble drugs/Hydrophilic drugs
• Active drug ---------------------- Inactive drug
• Inactive drug -------------------- Active drug
SITES: liver , kidneys , lungs , Skin , blood
42. TYPES OF METABOLISM
1- Enzymatic Metabolism
2- Non-Enzymatic Metabolism
Drugs are metabolized or alter due to changes in pH
It can be due to:
• Microsomal reactions in smooth ER e.g. Cytochrome P450
• Non-Microsomal reactions in mitochondria or cytoplasm e.g.
Oxidases, Esterases , Amidases
43. PHASES OF METABOLIC REACTIONS
PHASE – I REACTIONS PHASE – II REACTIONS
“Reactions that convert the parent drug to
a more polar product by unmasking or
inserting a polar functional group such as –
OH, -SH, -NH2”
“Reactions that increase water solubility by
the conjugation of drug molecule functional
group with a polar substrate such as
glucoronate, acetate, or sulfate, forming
covalent bond.”
It includes oxidation, reduction, deamination
and hydrolysis.
It includes glucuronidation, acetylation,
sulfation, etc.
Phase –I enzymes are found in SER of liver. Phase –II enzymes are found in cytosol.
Enzymes are CYP3A4 , CYP2D6 Enzymes are monoamine oxidase,
xanthine oxidase, alkyl dehydrogenase.
44. FACTORS AFFECTING METABOLISM
1. Genetic factors
2. Age
3. Sex
4. Food
5. Environment
6. Diseases of liver
7. Individual factors
8. Effects of other drugs
• Enzyme induction
• Enzyme inhibition
46. As drug binds to a receptor, it alters the physical, biochemical or molecular
activities of cell through signal transduction and generate a response.
“The process which describes the relation between dose of a drug with the
degree of it’s response is called dose response relationship.”
Magnitude of drug response depends on:
• Receptor sensitivity
• Drug concentration at receptor site
47. 1- Graded Dose – Response Relationship
“It shows the response of one or more drugs in a single individual.”
The horizonal axis of the curve shows log of dose.
The vertical axis of the curve shows the response.
It can be described under following headings:
1. Potency: “The amount of drug neend to produce a biological effect.”
2. Efficacy: “The ability of a drug to produce a maximum biological effect.”
3. Slope: “It determines the change in the degree of response to a change in the dose
of the drug.”
• A steep and prolonged curve shows that a small change in the dose of drug will produce a large
response.
• A short and low sloping curve shows that a change in the dose produces a small change in its
response.
48. 2- Quantal Dose – Response Relationship
“It shows the response of a drug in a large number of
experimental animals or human beings.”
It is required int two situations:
1. For diseases or events which occurs in attacks
2. For great individual variations in the degree of response to a
drug
51. “Elimination is irreversible removal of drug from the body. It involves
biotransformation(metabolism) and excretion (intact removal of drug from
body).”
• Metabolism results in products with increased polarity which allows the
drug to be eliminated.
• Once a drug enters the body, elimination begins. Major routes of
elimination are hepatic metabolism, biliary elimination and urinary
excretion.
• These elimination processes decrease plasma concentration exponentially.
“A constant fraction of drug is eliminated per unit of time.”
53. “Volume of blood from which the drug is cleared per unit of time.”
CL= 0.693× Vd / t1/2
Where;
CL = Clearance life
0.693 = Natural log constant
Vd = Volume of distribution
t1/2 = Elimination half life
54. DRUG CLEARANCE BY KIDNEY
• Drugs must be sufficiently polar to be eliminated from body.
• Kidney cannot efficiently excrete lipophilic drugs that readily cross cell
membrane and are reabsorbed in distal convoluted tubules. Therefore lipid
soluble agents are first metabolized into hydrophilic (more polar)
substances in the liver via phase I and phase II reactions.
• Drug passes through various process in kidney before elimination.
55. 1- GLOMERULAR FILTERATION
Drugs enter the kidney through
renal arteries which divide to
form glomerular capillary
plexus. Free drug floats through
capillary slits into bowman
space as part of glomerular
filtrate. Glomerular filtration
rate is 120 mL/min/1.73m2
56. 2- PROXIMAL TUBULAR SECRETION
Secretion primarily occurs in
the proximal tubules by two
active transport systems:
• One for anions
• One for cations
57. 3- DISTAL TUBULAR REABSORPTION
• As drug moves toward DCT its concentration increases and exceeds that of
perivascular space . The drug may diffuse out of nephrotic lumen back into
the systemic circulation .
• Manipulating the urine pH to increase the fraction of ionized drug in the
lumen may be done to minimize the amount of back diffusion and
increases the clearance of an undesirable drug .
58. ION TRAPPING
• Weak acids can be eliminated by alkalization of the urine, elimination of
weak bases may be increased by acidification of urine. This process is
called ion trapping.
• For example, a patient presenting with phenobarbital(weak acid)
overdose can be given bicarbonate which alkalinizes the urine and keeps
drug ionized thereby decreasing its reabsorption.
60. • Drug excretion may also occur via intestine, bile, lungs and breast milk .
• Drugs that are secreted into the intestine or into bile are excreted into feces.
• Lungs are involved in elimination of anesthetic gases.
• Excretion of most drugs into sweat, saliva, tears, hair and skin occurs
only to a small extent.
61. TOTAL BODY CLEARANCE
“The total body clearance is the sum of all clearances from drug
metabolizing and drug-eliminating organs.”
CLtotal = CLhepatic + CLrenal + CLpulmonary + CLother
• When a patient has an abnormality that alters half life of a drug adjustment
in dosage is required.
62. • The half life of a drug may be increased by decreased hepatic blood
flow, renal disease and decreased metabolism .This may require
decrease in dosage or less frequent dosing intervals.
• The half life may be decreased by Inc. hepatic blood flow or increased
metabolism. This may require Inc. in dosage or more frequent dosing
intervals.
64. Four processes of pharmacokinetics
1. Absorption
2. Distribution
3. Metabolism
4. Elimination
65. Absorption – transfer of a drug from site of administration to the
bloodstream.
Distribution – process by which a drug leaves the bloodstream and enters
the extracellular fluid and tissues.
Metabolism- detoxification or breakdown of drug into metabolites that no
longer exert any effect.
Elimination- metabolic waste products are removed from body .e.g by
kidneys, lungs , bile , skin.
67. Pharmacodynamics – “action of drug on body”
Drugs can interact with following target sites In a cell
1. Receptors
2. Ion channels
3. Enzymes
4. Carrier molecules
68. TYPES OF MECHANISM
Based on target sites actions of drugs can be classified as following:
1. Receptor mediated mechanism
2. Non receptor mediated mechanism
69. RECEPTOR MEDIATED MECHANISM
Receptor – “membrane bound or intracellular macromolecular
protein which is capable of binding the specific functional
groups of drug or endogenous substance”
Types of receptors and signal transduction mechanism
1. Ionotropic receptors ( ligand gated ion channels)
2. Metabotropic receptors ( G-protein coupled receptors)
3. Enzyme linked receptors
4. Intracellular receptors
70. 1- IONOTROPIC MECHANISM
Also known as “ ligand gated
ion channels”
These are cell surface receptors
Agonist binding open the
channel and causes
depolarization/hyperpolarization
/ change in ionic composition
Na, K , Ca, Cl…
Examples
Nicotinic cholinergic, GABA,
etc.
71. 2- METABOTROPIC RECEPTORS
These are large family of cell
membrane receptors linked to
the effector through GTP
activated proteins.
Agonist binding site is located
on extracellular face While
another recognition site is
formed by Cytosolic segments
binds the G protein.
Examples
Muscarinic, Dopamine D2 beta
adrenergic..etc.
72. 3- ENZYME LINKED RECEPTORS
These receptors cause
conformational changes on
activation resulting in increased
intracellular enzyme activity.
These also cause a signal
cascade effect.
They posses tyrosine kinase
activity.
Examples
Insulin , growth hormone, etc.
73. 4- INTRACELLULAR RECEPTORS
These are intracellular soluble
protein which respond to lipid
soluble chemical messenger that
penetrate the cell.
Capable to binding specific
genes and facilitates their
expression so that specific
mRNA can be synthesized.
Examples
All steroid hormones, thyroxine,
vitamin D, etc.
74.
75. NON-RECEPTOR MEDIATED MECHANISMS
1. By chemical action
. Neutralization . Chelating . Ion exchange
2. By physical action
. Osmosis . Absorption
