1. Advanced Pharmacology-I (PHR5001) Introduction to Pharmacology
Dr. M G Azam
Asstt. Professor
Dept. of Pharmacy, NSU

2. Pharmacology The word pharmacology comes from the
Greek word for drug, pharmakon (means “an active principle”). Pharmacology is “knowledge about drugs”.
It is the study of what biologically active compounds do in the body, and how the body reacts to them.
It is the study of how drugs modify biochemical, physiological and psychological processes in the body. Pharmacology is both a basic and clinically applied science.
Ancient civilization used a mixture of magic, religion, and drugs to treat diseases, and drugs were often thought to be magical.
Most drugs in antiquity came from plants and animal parts or fluids.

3. Drug & Body
A drug is anything that affects the way an organism works. For now we only consider drugs which are used to cure a disease.
A disease is anything which affects the proper functioning of the body. It can be an infection, a genetic disorder, or the result of environmental conditions such as malnourishment, poisoning, or stress.
Engineers often find it easy to see the body as a factory.
Most of the work in our body is done by proteins. The body contains thousands of different kinds of proteins. The construction of each is determined by the DNA in the nucleus of each cell. DNA may be thought of as long strings of instructions which code for how each protein is too be built. .

4. Pharmacology
Pharmacology is the science of drugs, which deals with the detailed study of source,
chemical nature,
route of administration,
absorption,
distribution,
metabolism,
excretion,
pharmacological effects and
side effects of the drugs.
In broad aspect, “It is the subject that embraces the knowledge of history, source, physical and chemical properties, compounding, biochemical and physiological effects, mechanism of action, absorption, distribution, biotransformation, excretion and therapeutic and other uses of drugs”.

5. Pharmacology: Its Scope
Three important and interrelated areas:
Pharmacokinetics
Pharmacodynamics
Pharmacogenetics
Protein Binding: Drugs are transported in the blood stream partly in solution (as free drug) and partly bound to various blood components (e.g., plasma protein) .
Removal of active drugs from the body depends on metabolism and excretion.

6. Pharmacokinetics Pharmacokinetics is what the body does to the drug.
The magnitude of the pharmacological effect of a drug depends on its concentration at the site of action :
•Absorption
•Distribution
•Metabolism
•Elimination
e.g. Pharmacokinetics of Paracetamol :
rapidly & almost completely absorbed, orally attaining peak blood levels at min;
- 25%bound to plasma proteins, widely & uniformly distributed in the body;
- extensively metabolized in the liver, primarily by glucuronide & sulfate conjugation into inactive metabolites which are excreted in urine;
- has a plasma half life 2-3 hours .
It mainly deals with movement & fate of the drug in the body. Greek: “pharmakon” means drug, “kinein” means to move
Pharmacokinetics is the study of the time course of a drug and its metabolites in the body following drug administration.

7. Mode of action, Dosage & administration, Side-effects
Pharmacodynamics
Pharmacodynamics is what the drug does to the body.
It is the interaction of drugs with cellular proteins such as receptors or enzymes to control changes in physiological function of particular organs. It covers :
•Drug-Receptor Interactions
•Dose-Response study
•Signal Transduction : Mechanism of action, Pathways
Mode of action, Dosage & administration, Side-effects
e.g. Pharmacodynamics of Paracetamol :
Paracetamol inhibits prostaglandin synthesis in the CNS.
It has less effect on COX in peripheral tissues which accounts for its weak anti-inflammatory activity.

8. Pharmacodynamics
Pharmacodynamics includes interaction between the drug and target cells or tissues and the body’s response to that interaction. :
A) Effects of the drug: both beneficial & harmful effects
What does a drug do in the body?
B) Mechanism of actions of the drug
How does a drug act in the body?

9. Pharmacogenetics
Area of pharmacology concerned with unusual responses to drugs caused by genetic differences between individuals.
Responses that are not found in the general population but
due to an inherited trait that produces a diminished or enhanced response to a drug.
An individual's response to a drug depends on the complex interplay between environmental factors and genetic factors. Variation in drug response therefore may be explained by variation in environmental and genetic factors, alone or in combination.
Pharmacogenetics is the study of the genetic basis for variation in drug response. It can provide the basis for a rational approach to prescribe drugs which are both more safer and more effective.
CYP 3A aberration
Differences in Enzyme Activity – Most common drug metabolizing enzyme family Cytochrome P450 (CYP) includes >30 isoforms

10. Therapeutics Therapeutics deals with -
Use of drugs in living body for therapeutic purpose
Therapeutics is the extension of the knowledge gained from medical pharmacology to the rational use of drugs (RUD) in the treatment of disease
The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects

11. Pharmacotherapeutics
It deals with the practical application of drugs in the treatment and prevention of disease.
The way we use drugs to prevent and treat diseases
Vaccines prevent disease
Are the most cost-effective, most important medical development of the 20th century
Other drugs treat disease
Basic principles of drug therapy provide a conceptual framework for deploying drugs with maximal efficacy while minimizing the risk of adverse effects.

12. Drug Actions – Drug Interactions
Desired effect: Effect of drug in the body that was intended
Side effect: Additional effect on the body by the drug that was not part of the goal for that medication
Adverse reaction: One in which the body reacts to a drug in an unexpected way that may endanger a patient’s health and safety
Contraindication: Any special symptom or circumstance that indicates that the use of a particular drug or procedure is dangerous, not advised, or has not been proven safe for administration
Local effect: Response to a medication that is confined to a specific part of the body
Systemic effect: Generalized or widespread response to a drug by the body because it is absorbed into the bloodstream
S/E are unwanted, predictable pharmacological effects that occur within therapeutic dose ranges. These effects may be wanted under certain circumstances.
Contra-indications: A sign or symptom suggesting that a certain line of treatment should be discontinued or avoided (e.g., Allergies)”

13. Some other definitions
Effects (therapeutic effects)
“The desired results of administration of a medication”
"Therapeutic Window" /"Therapeutic Concentration Range" is the range of concentration over which the probability for therapeutic success is very high at only limited toxicity.
Indications
“The reasons for administering a medication or performing a treatment”
Pharmacologic Profile: A description of all of the pharmacologic effects of a drug (e.g., effects on blood pressure, respiration, renal function, endocrine function, the central nervous system, etc.).
Bioavailability: The amount of drug or other substance that is active in the tissues.
Teratogen: Compound that results in adverse effects to developing fetus.
Mutagen: Compound that results in production of a mutation that causes an effect on an inheritable characteristic (alteration in cellular DNA).
Carcinogen: Cancer causing agents
Receptor:
“A specific protein in either the plasma membrane or interior of a target cell with which the drug combines”

14. Concept of Drug-Receptor Interactions
Therapeutic and toxic effects of drugs result from their interactions with molecules in the patient. Most drugs act by associating with specific macromolecules in ways that alter the macromolecules' biochemical or biophysical activities

15. The receptor concept has important practical consequences for the development of drugs and for arriving at therapeutic decisions in clinical practice.
Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects.
Receptors are responsible for selectivity of drug action. 
Receptors mediate the actions of both pharmacologic agonists and antagonists
Agonists: Drugs that interact with a receptor to produce a biologic response are termed AGONISTS. An agonist has affinity for the receptor and efficacy.
An ANTAGONIST is a drug that binds to a specific receptor, but the drug-receptor interaction does not lead to a biologic response. An antagonist has affinity for the receptor but
low or zero efficacy
An agonist has affinity for the receptor and efficacy. A full agonist produces a ceiling effect that is not
exceeded by other drugs.
Those drugs whose maximal effects are less -regardless of the dose - are called partial agonists
An ANTAGONIST is a drug that binds to a specific
receptor, but the drug-receptor interaction does not lead to a biologic response.
An antagonist has affinity for the receptor but low or zero efficacy.

16. For Example,

17. Half -Life (T ½)
Half-life of a drug means the time in which the concentration or effects of the drug decline by one
The time needed for a drug's level in the blood stream to go down to one half its beginning level.
In the simplest case, the body may be considered as a single compartment of a size equal to the volume of distribution (Vd). The time course of drug in the body will depend on both the volume of distribution and the clearance
A change in half-life will not necessarily reflect a change in drug elimination. For example, patients with chronic renal failure have decreased renal clearance of digoxin but also a decreased volume of distribution; the increase in digoxin half-life is not as great as might be expected based on the change in renal function. The decrease in volume of distribution is due to the decreased renal and skeletal muscle mass and consequent decreased tissue binding of digoxin to Na+/K+ ATPase

18. Half-life ½ peak Drug serum Concentration (mcg) Time of Maximum
Drug concentration
Time
Drug serum
Concentration (mcg)
Peak serum concentration
½ peak

19. Dose-Response Curve Sub-effective dose
Ceiling effect, or maximal effect
Threshold effect and threshold dose
The plot shows a graded response - dose-dependent effect

20. Potency & Efficacy
Potency is related to the size of the dose necessary to produce a certain effect. It is determined in part by the affinity of the receptor for the drug. Efficacy (or intrinsic activity) is related to the maximal effect obtained by the drug (i.e., when all receptors are bound to drug)

21. ED50 is the dose required to cause a therapeutic effect (positive response) in 50% of a population

22. TD50 or LD50 is the dose required to produce a toxic effect (or death in animal studies) in 50% of the studied population.

23. Therapeutic Index is an indication of safety.
For every drug there is a dose-response curve for effectiveness and a dose-response curve for toxicity
The concept of therapeutic index refers to the relationship between toxic and therapeutic dose. This pharmacodynamic parameter is relevant to clinical practice because it determines how safe (or toxic) a drug is
Therapeutic Index is an indication of safety.
The larger the ratio the safer the drug.

24. Narrow therapeutic index drugs
Warfarin
Lithium
Digoxin
Phenytoin
Gentamycin
Amphotericin B
5-fluorouracil
AZT (zidovudine)
In clinical studies, the dose, or preferably the concentration, of a drug required to produce toxic effects can be compared with the concentration required for the therapeutic effects in the population to evaluate the clinical therapeutic index.

25. Key Pharmacokinetic Parameters
(unit)
Description
Measure of:
Influenced by: F*
(%)
Bioavailability
Fraction of dose available in systemic circulation
Absorption and elimination (gut and liver during first pass)
AUCp
(uM.hr)
Area under the plasma concentration vs. time curve
Systemic exposure; Important determinant for efficacy and safety
Both F and CLp
AUCoral = F x Dose
CLp
CL*p
(L/hr/kg)
Plasma clearance
Rate of drug elimination
Metabolic/excretion rate, plasma protein binding, blood flow
T1/2
(hr)
Elimination half-life
Time to reduce plasma concentration by 50%;
Important determinant of dosing frequency
Both CL and Vd
T1/2  Vd/CLp
Vd*
(L/kg)
Volume of distribution
Drug distribution to tissues
Plasma and tissue binding
* Need Intravenous dosing

27. Drug Development Process
Discovery and formulation: Synthesis of a potential new drug molecule and an understanding of its interaction (mechanism) with the appropriate biologic targets. Repeated application of this approach leads to compounds with increased potency and selectivity
Preclinical evaluation: Relevant biologic effects, drug metabolism, and pharmacokinetic profiles and particularly an assessment of the relative safety of the drug must be characterized in animals before human drug trials can be started.
Clinical evaluation -Phases I-IV: With regulatory approval, human testing can then go forward in three phases before the drug can be considered for approval for general use.
Post-marketing surveillance: A fourth phase of data gathering and safety monitoring is becoming increasingly important.
The processes of new drug discovery and development are long, complicated and dependent upon the expertise of a wide variety of scientific, technical and managerial groups.

28. The development and testing process required to bring a drug to market
Pre-clinical drug development is a complex, regulatory-driven process designed primarily to assess the safety and viability of new molecular entities.