1 Pharmacology 1 Pharmacological Basisof Therapeutics 2015

IPBP IA Exam Study Guide:
Pharmacology 1: Pharmacological Basis of Therapeutics
International Post-Baccalaureate
PharmD (IPBP) Program
Internal Assessment (IA) Exam
STUDY GUIDE
PHARMACOLOGY 1:
PHARMACOLOGICAL BASIS
OF THERAPEUTICS
2015
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TABLE OF CONTENTS
1. Principles of Pharmacology
2. Drug Formulations
3. Routes of Drug Administration
4. Fundamentals of Pharmacokinetics
5. Introduction to Pharmacodynamics
6. Receptors And Signal Transduction
7. Dose-Response Curves: Agonists and Antagonists
8. Biological Variability
9. Adverse Drug Reactions
10. Drug-Drug Interactions
11. Parasympathetic (Cholinergic) System
12. Sympathetic (Adrenergic) System
13. COPD and Asthma
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Principles of Pharmacology
Learning Outcomes
Provide a definition/description of: pharmacology, drug product/substance, pharmacokinetics,
bioavailability, pharmacodynamics (receptor, agonist, antagonist), compliance, plasma protein
binding, pharmacogenetics, toxicology and drug toxicity.
Know the classification of Pharmacology.
Describe what is meant by ADME = Absorption, Distribution, Metabolism and Excretion).
Explain the concepts of drug-target (receptor) interactions, drug response, and be able to give
examples of molecular mechanisms of action due to a drug interacting with a receptor.
List the various drug targets.
Define onset of action and duration of action.
Know the clinical significance of some of the common drug-receptor interactions.
Know the principles of drug classification and nomenclature.
Know how to study pharmacology!
Pharmacology: The study of the effects of chemical substances on living systems, from individual cells to
complex body organs. These effects are a result of the interaction of that chemical with a (regulatory)
molecule (aka receptor), resulting in the activation or inhibition of a normal body process.
pharmakon = drug or medicine
logos = study
Relevance of Pharmacology
Integrated Science links introductory disciplines and clinical medicine
Basis of Therapeutics
Therapeutics is cornerstone of clinical practice
Emphasis in all clinical licensure exams
Drug Substance: Substances that bring about a change in a biological function through their chemical
action(s). This change serves one of the following purposes: diagnose, mitigate, treat or prevent a certain
disease-state.
Drug Product: The finished dosage form (e.g., capsule or ointment) that contains the drug substance in
association with other non-drug/inert substances (excipients).
Aspirin as an example
Ancient Drugs from the nature
Extracts, natural chemical compounds
Rational drug discovery
Synthetic chemistry
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Classification of Pharmacology
Common Divisions
Autonomic
Central Nervous System (CNS)
Cardiovascular
Neuropharmacology
Biochemical Pharmacology
Immunopharmacology
Molecular Pharmacology
Pharmacokinetics: How the body handles a drug (ADME; Absorption, Distribution, Metabolism,
Excretion).
The journey that a drug travels, and the changes that it undergoes the moment it enters the human
body.
Every step of this journey involves crossing a membrane.
A= Absorption: The process by which a drug moves from its sites of administration and reaches blood
circulation, which will then result in its
D= Distribution: to the site of action (target organ) by one of the following systems, i.e., blood circulation or
the lymphatic system. The drugs ability to reach its target is impacted by two processes, one known as
M= Metabolism: in which the body inactivates the drug through enzymatic degradation (primarily in the
liver); the other process is known as
E= Excretion: in which the drug is eliminated from the body (primarily in the kidneys and liver, and in the
feces).
Drug Bioavailability: The measure of the rate and extent (amount) to which the active ingredient/moiety
becomes available at the site of action. Or, defined as the fraction of unchanged drug reaching the systemic
circulation following administration.
Pharmacodynamics: The term used to describe how the drug affects the body (includes biochemical and
physiological effects, as well as the drugs mechanism of action)
Drug (Agonist or Antagonist)
Receptor
Receptor: Structure on the surface of a cell (or
inside a cell) that selectively receives and binds a
specific substance causing a change or
modulating cell function.
Agonist: A molecule that binds to a receptor,
producing a physiological or pharmacological
response.
Antagonist (blocker): A molecule that binds to a
receptor and prevents the binding of an agonist. An ideal antagonist does not produce any
response by itself.
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Drug-Receptor Interaction
Outside Cell
Drug
MEMBRANE R E MEMBRANE
Inside Cell
G-Protein
C D
G-Protein 5
Drug Targets
Receptors
Enzymes
Carrier molecules
Ion channels
Drug Response: - The biochemical or physiological event/change that results after a drug binds to its target
receptor. Can be either quantitative or qualitative.
Onset of action: The time from the drug administration to the beginning of the therapeutic effect or
pharmacological activity.
Duration of action: The time for which a therapeutic effect can still observed.
Summary
Plasma-Protein Binding
- Albumin is the most abundant plasma protein, and is the one responsible for drug binding.
- Many drugs bind with low affinity to albumin.
- This reduces the availability of a drug for diffusion or transport into the drugs target organ.
- Two or more drugs can compete for binding to albumin.
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Compliance: Taking the drug according to the prescribed dosage regimen. Drugs do not work if you do not
take them. Compliance is essential for the successful treatment of disease.
Drug Classification an example

Anatomical
- Central Nervous System (CNS)
Therapeutic use
- Antidepressant
Pharmacological mechanism
- SSRI (selective serotonin reuptake inhibitor)
Chemical group
- Cyclic, propylamine derivative
Generic name/ Chemical substance
- Fluoxetine (N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-1-amine)
Drug Nomenclature
Chemical name
2-[4-(2-methylpropyl)phenyl] propanoic acid (IUPAC)
Generic name
Ibuprofen
Proprietary/ Brand name
Motrin
Chemical Nature of Drugs
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Medicinal Chemistry
Why Chemistry is Important?
Drugs are chemicals
Drug-target interaction
SAR (Structure-Activity Relationship)
Drug Discovery
Pharmacogenetics: Study how people's genetic make-up/variations correlate with their responses to a
specific medication (inter-patient variability in drug response). The ultimate goal of pharmacogenetics is to
tailor medical treatments specifically to the individual, increasing effectiveness while reducing adverse side
effects.
Toxicology: Toxicology is the study of deleterious effects of chemical, physical or biological agents on
living systems.
Toxicity of Drugs
Side effects
Adverse (untoward) effects
Desirable side effects
Generally results from the interaction of the drug with side-targets, and as a result of
using higher-than-necessary dose (overdose). May also be related to a drug-drug
interaction.
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Drug Formulations
Learning Outcomes
1. Describe the difference between drug substance, drug product and excipients.
2. List the various types of dosage forms, and provide representative examples of each.
3. Describe the properties, advantages and use of some of the common solid, liquid and semi-solid
dosage forms.
4. Define controlled release dosage forms, provide representative examples and describe their
advantages.
5. Understand the relationship between the dosage form and the route of its administration.
Drug Substance: Is the drug product component that produces the pharmacological activity. Also known
as the active pharmaceutical ingredient (API). May be produced by chemical synthesis, recovery from a
natural product, recombinant DNA technology (rDNA), or a combination of these processes.
Drug Product: The finished dosage form (e.g., capsule or ointment) that contains the drug substance in
association with other non-drug/inert substances (excipients).
Excipients: The non-drug or inert substance component(s) of a dosage form. Include vehicle, diluents,
disintegrant, lubricant, binder, antioxidant, coloring & flavoring agents, etc.
Dosage Forms
Solid dosage forms: e.g., Tablets, Capsules
Liquid dosage forms: e.g., Injectables, Oral solutions/ suspensions
Semi-solid dosage forms: e.g., Ointments, Creams
Solid Dosage Forms

Tablets: A mixture of active substances and excipients pressed or compacted into a solid.
- The most commonly used solid dosage form.
- Advantages: Low manufacturing cost, simple to identify, most stable of all oral dosage forms, easy
and convenient to use.
- Shapes: usually disc or capsule-like (called caplets), although can be made in any shape.
Tablet Types
A. Tablets for oral ingestion. (e.g., enteric coated tablets which offer delayed drug release)
B. Tablets for use in the oral cavity (e.g., sublingual).
C. Tablets for preparing solutions (dissolved in water before administration such as effervescent
tablets).
Capsules: A small gelatin shell containing powder, beads, etc. Most are intended to be
swallowed as a whole, but, occasionally the contents are removed from the shell and used as
a premeasured dose.
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- Supplied in two forms, hard or soft. Hard gelatin capsules are normally used for powdered
ingredients, whereas soft gelatin capsules are used for active ingredients dissolved in oils.
Suppositories
- A solid (or semi-solid) dosage form intended to be inserted into a body orifice (e.g., rectum or
vagina)
- Mostly used for local effects, but can also be used for systemic effects.
- The drug is released after the suppository melts at body temperature or dissolves in body
secretions.
Liquid dosage forms

Suspensions:
- Suspension of finely divided material in water.
- Available in suspension form or as powder which is dissolved in water at time of dispensing.
- Also available for injection
Drops:
- Solution (saline) containing; used as a vehicle to administer a drug in the eye or to the ear.
- Some are used for the oral administration of drugs to children.
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Syrups:
- Solutions that contain high concentrations of sucrose or other sugars, i.e., any liquid dosage formed
prepared in a sweet, viscous vehicle.

- Dilute sucrose solutions are an excellent source for microbial growth.
Semi-solid dosage forms

Ointments:
- are intended for external use.
- used as 1. emollients to make the skin more paliable, or 2. protective barriers to prevents harmful
substances from coming in contact with the skin, or 3. vehicles in which to incorporate medication.
Aerosol Products
- Are pressurized dosage forms designed to deliver drugs systemically or topically with the aid of a
liquefied or propelled gas (propellant).
- Systemic or pulmonary drug delivery is provided by metered dose inhalers (MDI), which are
devices that allow a drug to be inhaled as a fine mist of drug or drug-containing particles.
- MDIs use special metering valves to regulate the amount of formulation or drug that is dispensed
with each dose (i.e., each actuation of the container).
- Uses 1. compressed gases such as carbon dioxide or nitrogen, or 2. liquefiable gases such as
chlorofluorocarbons.
Controlled-Release Dosage Forms

- Also known as delayed-release, sustained-release, sustained- action, or timed-release dosage
forms.
- They are mainly designed to release drug substance slowly to provide prolonged action in the
body.
Advantages:
- Fewer problems with patient compliance
- Improved treatment efficiency.
- Less fluctuation in drug level.
- Improved ability to provide special effects (e.g., morning relief of arthritis by bedtime dosing)
- Reduced cost.
Notes:
-The route of drug administration is dependent on the dosage form of a given drug.
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- Different disease states may warrant different routes of administration, and thus, the same drug
may exist in different dosage forms.
Tablet injection ointment transdermal patch
- Specific dosage forms may be required for certain drugs (e.g., insulin is not given orally because it
is digested in the stomach.
Routes of Drug Administration

Learning Outcomes
List and describe the common routes of drug administration.
Know why and how do we select a proper route of drug administration.
Explain the advantages, disadvantages and special uses of these routes.
Define hepatic first pass metabolism, and list which routes of drug administration do not expose
the drug to the first pass effect.
Describe some of the common wrong route errors.
Introduction:
Each new drug is designed and tested in a dosage form that is administered by a specific route.
Routes of administration are chosen to enable the drug to penetrate barriers presented by the
body.
Routes of Administration
Why is the route of drug admin important?
Absorption
Bioavailability
Reduce toxicity
How do you select the optimal route?
Target
Nature of drug
Patients age
Patients condition
Dosage Forms
n Solid dosage forms
E.g. Tablets, Capsules
n Liquid dosage forms
E.g. Injectables, Oral solutions/ suspensions
n Semi-solid dosage forms
E.g. Ointments, Creams
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Routes of Administration
Enteral Routes
1. Oral (per os = PO) (by mouth)
2. Nasogastric
stomach pH (1-3)
intestinal pH (6-8)
enteric coated tablet
Dosage forms: tablet, capsule, liquid
Drug: e.g. aspirin, penicillin V
- The PO route exploits existing weaknesses in human barrier defenses.
- The efficiency of this route/process is determined by the drug size and hydrophobicity, and
sometimes by the presence of carriers through which the drug may enter the cell.
- In general, hydrophobic and neutral drugs cross membranes more efficiently than hydrophilic or
charged drugs, unless the membrane contains a carrier molecule that facilitates the passage of
hydrophilic substance.
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Membrane Overview:
Advantages
Convenient, easy self administration
Safer, less likely to introduce a systemic infection as a complication of treatment.
Less expensive
Disadvantages
Slow onset of action
Inactivation by stomach acid/ enzyme
Chemical interaction (food)
Irritation of gastrointestinal tract (GIT)
First-pass metabolism (liver)
Hepatic First-Pass Metabolism: Removal and metabolism of a substantial portion of a drug by the
hepatocytes in its first pass through the liver. Occurs with enteral (esp. oral, nasogastric) route. E.g.
lidocaine, propranolol
- In addition, the liver can excrete the drug into the bile a process called biliary excretion.
- All oral drugs are subject to first-pass metabolism.
- Also, there is evidence that significant first pass metabolism can occur in gastrointestinal (GI)
epithelial cells
Parenteral Routes
- The drug is introduced directly across the bodys barrier defenses into the systemic circulation
or some other tissue space, immediately overcomes barriers that can limit the
effectiveness of orally administered drugs.
- The onset of drug action differs among the sub-routes depending on the rate of blood flow to the
tissue or site of drug administration.
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Sites of Intramuscular Injection (2)

Gluteus medius/ maximus
Not ideal in obese
Vastus lateralis
Ideal for children under 1 year
Drugs that are soluble only in oil-based solutions are often given IM
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Sites of Subcutaneous Injection
Intraperitoneal
# Provides large absorbing surface
# Primarily used on lab animals
# First pass effect
# Risks: infection, injury
Parenteral Routes (Summary)

Advantages
Fast onset (IV>IM>SC)
Valuable in emergency
Bypass first pass in liver (not lung)
Increased bioavailability, and better control of delivered dose.
Useful when GIT malfunctions, or unconscious patients.
Disadvantages
Maintenance of sterility >> high cost
Inconvenient, often painful (SC)
No retreat, hence more caution (IV)
Anaphylactic reactions more dangerous
Absorption erratic in obese & during exercise (IM, SC)
Difficult to perform (IV, obese), requires a health care professional (e.g., nurse)
Increased risk of infection.
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Topical
- Skin (cutaneous) - Ocular (eye) - Otic (ear)
- Nasal - Rectal - Vaginal
Skin:
Transdermal
Dosage form: patches
Local (capsaicin)
Systemic (estrogen, nicotine)
Simple and convenient
Ideal for a drug that must be slowly and continuously administered over extended periods.
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Other Common Routes

Inhalation:
Target: Lung tissue or systemic circulation
Dosage form: Aerosol, gas
Drugs: anti-asthmatics (direct into target organ), gaseous anesthetics, Antibiotics (tobramycin; e.g., for
Cystic Fibrosis)
Advantages Disadvantages
- Immediate effect - Erratic dosing better now
- Bypass first pass - Difficult in children
Sublingual:
- Target: systemic - Dosage form: tablet - Drug: nitroglycerine (angina)
- Advantage
Bypass first pass
Rapid onset
- Disadvantage
Bad taste
Many drugs do not penetrate oral mucosa
Not used for irritating substances
Subligual
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Spinal Routes
Wrong-route Error
Administration of drugs via non-recommended routes
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Fundamentals to Pharmacokinetics
Learning Outcomes
1. To be able to define the goal of drug therapy.
2. Know the concept of individual variability in drug response
3. To be able to define and differentiate pharmacokinetics and pharmacodynamics and their
relationship with dose-response curves.
4. To be able to understand the fundamental hypothesis in pharmacology regarding the effect of a
drug and its concentration
5. To be able to describe the four main pharmacokinetic processes (ADME) and factors affecting
each process.
6. Describe the four methods of drug transport.
7. Understand the use of the HendersonHasselbalch equation to calculate the unionized
and ionized forms of a drug.
8. Describe the difference between gastric and intestinal absorption.
9. Know the general anatomy of the gastrointestinal tract.
10. To be able to define pharmacokinetic terms such as bioavailability, oral bioavailability.
11. Understand the impact of different formulations on drug bioavailability.
The Goal of Drug Therapy

- Achieve a desired beneficial effect (cure a disease) with minimal adverse effects.
- To achieve our goal, we should employ a rational approach that combines the principles of
pharmacodynamics and pharmacokinetics to clarify the dose-effect (response) relationship
Selection of an appropriate drug
Selection of the right dose/dosing interval
- A relationship exists between the beneficial or toxic effect of a drug and its plasma
concentration
An Example
Regimen A is better than Regimen B (dose too high, causing toxicity).
- A drug needs to reach its target organ/tissue within our body before it is able to combat disease.
- For a drug to reach its target organ, a drug must be able to cross the physiologic barriers (that
exist to limit the access of foreign substances to the body).
- Therefore, an appreciation of the factors that affect the ability of the drug to act within our body
is important for clinical practice.
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Dose-Response Relationship
Pharmacokinetics
The study of the time course of drug absorption (except for the IV route), distribution, metabolism and
excretion (ADME). All of these processes require the passage of the drug across the cell membrane.
v Drug Disposition refers to the fate of a drug after its absorption
- Distribution - Metabolism - Excretion
v The combined process of drug metabolism and excretion is also called drug elimination.
Absorption: Movement of a drug from its site of administration to the systemic circulation.
Principles on Absorption
Absorption of a drug is a complex process that depends on

the physicochemical nature of the drug
the formulation of the drug (drug vehicle)
the route of administration
the state of the patient
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Oral Administration
A summary of the processes involved in drug absorption, distribution, metabolism and excretion.
The Anatomy of the Gastrointestinal Tract
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Absorption of Drugs by the Gastrointestinal Tract (GIT)
Bioavailability (F)
Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation
following administration by any route.
The area under the concentrationtime curve (AUC) is used to measure the extent of
bioavailability for a drug given by a particular route.
AUC DoseIV
F=
AUC IV Dose
The AUC obtained following IV administration is used as the reference value.
For IV route, F = 1, since the drug is directly introduced into the blood stream and there is no
absorption process involved.
When drugs are given by any route other than the IV route, the extent of absorption and
bioavailability must be defined in order for one to prescribe it rationally and be able to make
appropriate quantitative adjustments, or route of delivery changes.
Notes
The above information is for small molecule drugs in general.

The bioavailability of large molecule drugs (e.g., peptides and proteins such as insulin)
administered by non-parenteral routes is much lower (e.g., < 0.1% when dosed by the oral route).
Therefore, peptide- and protein-based drugs are usually administered using parenteral routes (IV,
IM and SC).
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Oral Absorption
Oral Bioavailability (F)

Also known as bioavailable fraction (F)
Calculation
AUC PO DoseIV
F=
AUC IV DosePO
Factors determining oral bioavailability
Extent of absorption
First-pass elimination
Factors Affecting Extent of Oral Absorption (Oral Bioavailability)
The physicochemical nature of the drug
A balance of hydrophilicity/lipophilicity is needed for a drug to be highly absorbed in the
GI tract. Incomplete absorption could be due to
v Too high hydrophilicity of the drug (atenolol) because it cannot pass through the
lipid cell membrane.
v Too high lipophilicity of the drug because it cannot dissolve in water.
Incomplete absorption may also result from activating the P-glycoprotein efflux pump in
epithelial cells.
Formulation has a major impact on bioavailability.
Formulation Vs. Bioavailability
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Conclusions
Rate of Absorption
The rate of absorption is determined by
the physicochemical nature of the drug
the drug formulation
the route of administration
The rate of absorption should not be confused with the extent of absorption (bioavailability,
measured by AUC values).
The rate of absorption determines the onset of action of the drug. The fast the drug is absorbed,
the fast the drug acts.
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The Time Course of Drug Effect
Distribution
Learning Outcomes
1. Describe the process of drug distribution.
2. Know the various fluid compartments in the human body.
3. Understand the influence of plasma protein binding on drug distribution.
4. Understand the relationship between protein & tissue binding with drug distribution.
5. Define the process of drug elimination.
6. Be able to read the pharmacokinetic parameters of a drug package insert.
7. To be able to understand and use pharmacokinetic parameters such as volume of distribution, clearance
and half-life.
8. Understand the concepts of drug accumulation and steady state.
9. Understand the concept of dosing regimens and know how to individualize a dosage in renal or hepatic
disease.
10. Understand the relationship between drug distribution and Enterohepatic Recycling, Biliary & Fecal
Excretion.
Once a drug begins to be absorbed, it undergoes various transport processes which deliver it to various
body areas (liver, kidney, skeletal muscle, bone, brain, etc.) away from the absorption site.
These transport processes are referred to as drug distribution and are evidenced by the changing
concentrations of drug in various body tissues and fluids.
Distribution of Fluid Compartments
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Principle on Drug Distribution

Only the unionized and unbound (free) form of the drug can permeate across biological
membranes.
Protein Binding
Effects the distribution of drug.
Many drugs are bound to plasma proteins
To albumin for acidic drugs (e.g., salicylates)
To a1-acid glycoprotein for basic drugs (e.g., propranolol)
Binding to other plasma proteins generally occurs to a much smaller extent.
Characteristics of Protein Binding
Protein binding is reversible.
Protein binding is saturable (capacity-limited) at high drug concentrations. However, for most
drugs, the therapeutic range of plasma concentrations is limited. Therefore, percent bound is
constant.
Tissue Binding
Many drugs accumulate in tissues at higher concentrations than those in the extracellular fluids
and blood.
The concentration of quinacrine (an antimalarial agent) in the liver may be several
thousand-fold higher than that in the blood.
Tissue binding usually occurs with cellular constituents such as proteins, phospholipids,
or nuclear proteins.
Tissue binding generally is reversible.
Tissue-bound drug may serve as a reservoir.
Principles on Distribution
A drug with high plasma protein binding usually has a small volume of distribution.
A drug with high tissue binding tends to have a large volume of distribution.
Elimination
The process of drug (xenobiotics) removal from the body
Two major processes and responsible organs
Metabolism the liver
Excretion the kidney (major), the bile, etc.
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Package Insert: Ambien
Volume of Distribution (Vd)

The volume of distribution (Vd) relates the amount of drug in the body to the concentration of
drug in blood or plasma C:
Vd is an apparent or imaginary term. It does not relate to real physiological volume of an organ.
Vd can vastly exceed any physical volume in the body because it is the volume apparently
necessary to contain the amount of the drug homogeneously at the concentration found in the
blood or plasma.
Physical volumes for a 70 kg person
Total body water: 42 L
Extracellular water: 17.5 L or 14 L
Blood: 5.6 L
Plasma: 2.8 L
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Examples
Vd of digoxin : 500 L
Vd of chloroquine: 13000 L
Vd of gentamicin: 18 L
Drugs with high Vd values are not homogeneously distributed in the body.
Clearance (CL)
Clearance is a measure of the bodys efficiency in eliminating drug.
Clearance is the single most important factor determining drug concentrations.
Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug
concentration: CLTotal = CLR enal + CLHepatic + CLOther CL = Rate of eli mi nation
Clearance is additive: C
There are four major factors that may affect clearance:

The dose
v Some drugs (e.g., ethanol) exhibit capacity-limited elimination.
The organ blood flow
v Some drugs (high-extraction drugs, e.g., lidocaine) are rapidly cleared by the organ of
elimination.
The intrinsic function of the liver or kidneys
The unbound fraction of drug
Half-life (t1/2 or T1/2)
Half-life is the time required to change the amount of drug in the body by one-half during
elimination or during a constant IV infusion.
In the simplest and most useful case, the body may be considered as a single compartment of a
size equal to Vd and drug decay follows first order kinetics. The time course of drug in the body
will depend on both Vd and CL:
0.693 Vd
T1/ 2 =
CL
Or
Half-life is useful because it indicates the time needed to decay 50% from any concentration
following drug administration by any route.
Half-life is also useful in IV infusion because it indicates the time required to attain 50% of
steady state concentration or to decay 50% from steady-state conditions after a change in the
dosing rate.
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Individualizing Dosage in Renal or Hepatic Disease
Biliary and Fecal Excretion

Active transport systems analogous to those in the kidney also are present in the canalicular
membrane of the hepatocyte.
These systems secrete drugs and metabolites into the bile.
Ultimately, drugs and metabolites are released into the intestinal tract during the digestive
process.
Direct active secretion of drugs and metabolites may also occur from the systemic circulation
into the intestinal lumen.
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Enterohepatic Recycling
Subsequently, drugs and metabolites can be reabsorbed back into the body from the intestine - a
process termed enterohepatic recycling.
Enterohepatic recycling, if extensive, may prolong significantly the presence of a drug and its
effects within the body prior to elimination by other pathways.
Introduction to Pharmacodynamics
Learning Outcomes
Be able to:
1. Define pharmacodynamics, receptor, and drug (i.e., agonist or antagonist).
2. List some drug actions not meditated by a receptor.
3. Provide examples of proteins as receptors.
4. Define, in general terms, the function of a receptor.
5. Describe the concept of a key & a lock and its relationship with a drug & a receptor.
6. Describe what is meant by a reversible or irreversible drug-receptor interaction.
7. Differentiate between binding affinity and intrinsic activity.
8. Understand drug selectivity and its relationship with the site of drug action.
9. Understand the concepts of receptor up-or down-regulation.
10. Define receptor desensitization and describe its mechanisms.
11. Understand the concept of structure-activity relationship and how it relates to drugs efficacy
or activity.
12. Define what a Pharmacophore is.
Pharmacodynamics
The terms used to describe effects of a drug on the body.This includes the drugs
biochemical and physiological effects, and is related to its mechanism(s) of action.
Such effects are typically described in quantitative terms in order to determine
appropriate dose ranges for patients.
Relationship between the drug concentration (or dose) and effect.
For a drug to elicit/result in a specific effect (i.e., pharmacological response), the drug has
to bind to its target/receptor (i.e., Drug-Receptor interaction/binding).
What is a Receptor?
- A macromolecule or component of a cell or organism that interacts with a drug/ligand* and
initiates the chain of events leading to the drugs observed effects.
- Proteins form the most important class of receptors.
* in latin-- ligare = to bind
What is a Drug
- A chemical substance that interacts with a biological system/receptor to produce a physiologic effect
- All drugs are chemicals but not all chemicals are drugs
- In general divided into:
Agonists: drugs mimicking physiological activity

Antagonists: no stimulatory action, but block an agonist
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Receptor
The body, cell or organism contains RECEPTORS FOR:
Neurotransmitters, hormones, and growth factors
Transporters, structural proteins, and enzymes
Other cellular constituents can serve as therapeutic targets as well (e.g., nucleic acids as
receptors for anticancer agents).
i) Regulatory proteins (mediate action of endogenous chemical signals such as hormones &
neurotransmitters
ii) Enzymes (may be inhibited or activated by drug binding)
iii) Transport proteins (eg Na+, K+ATPase)
iv) Structural proteins (eg tubulin)
Actions of Drugs not Mediated by Recpetors

- Some drugs act by simple mechanisms related to their chemical or physical properties
Neutralization of gastric acid by a base
Increasing osmolarity of fluids (mannitol)
Cholesterol binding resins
EDTA, a chelating agent, used for the treatment of lead (Pb2+) intoxication
Receptor Function
Receptors are specialized on transmission of information:
They recognize and bind their Ligand (ligand- binding domain)
Binding propagates its regulatory signal into the target cell (Message propagation; effector
domain)
The activation of a receptor (R) by its ligand (e.g., neurotransmitter, hormone, etc.) propagates
the signal or information from the extracellular to the intracellular domain.
Drug-Receptor Interaction
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The binding of a drug to a receptor is determined by the following forces:

Hydrogen bonds
Ionic bonds
Van der Waals forces
Covalent bonds
Receptor-Drug Interaction
Reversible: Most interactions between a drug and a target (receptor or an enzyme) are reversible: After a
while, the drug disengages, and the receptor or enzyme resumes normal function.
Irreversible: Following the binding step, the ligand then reacts with the functional groups of
the receptor. Ligand becomes covalently bound to the receptor. The synthesis of new receptor protein
may be required to generate a receptor free of an irreversible blocker.
Receptor Properties
- Binding affinity & Intrinsic activity - Selectivity
- Up- and down-regulation - Desensitization
Binding Affinity
A measure of the attraction force between the receptor and the drug.
The affinity of a drug for a receptor determines the concentration required to form a significant
number of drug-receptor complexes, and ultimately the magnitude of the observed response.
Intrinsic Activity: A measure of the ability of a drug to generate an effect

A drug's action is affected by the degree of attraction (affinity) with the receptor and by its
ability to produce an effect.
Drugs vary in their affinity and intrinsic activity
Drugs that activate receptors (agonists) must have both great affinity and intrinsic activity: They
must bind effectively to their receptors, and the drug bound to its receptor (drug-receptor
complex) must be capable of producing an effect in the targeted area (i.e., receptor activation). In
contrast, drugs that block receptors (antagonists) must bind effectively, but they have little or no
intrinsic activity.
Agonists Intrinsic Activity = 1
Antagonists Intrinsic Activity = 0
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Selectivity
h A measure of the ability of the drug to solely interact with its intended target.
h The molecular features of a drug (e.g., size, shape, hydrophobicity, flexibility, electrical charge,
etc.) determine whether it will bind to a particular receptor among a variety of binding sites that
exist in a cell, tissue, or whole animal.
Some drugs attach to only one type of receptor; others, like a master key, can attach to several
types of receptors throughout the body. A drug's selectivity can often be explained by how
selectively it attaches to receptors.
Selectivity Vs. Site of Drug Action

The site of drug action is determined by location and functional capacity of its receptors and does not
necessarily depend on drug distribution
widespread receptor widespread effect
localized receptor localized effect
- Digoxin - Na+, K+ - ATPase inhibitor (Congestive heart failure)
- Sildenafil citrate - selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5;
erectile dysfunction disorder)
- Morphine - opioid receptor agonist (pain)
Receptor Up- and Down-Regulation

Receptor density (number of receptors per area) can be modified by the ligand/drug-induced
cellular mechanisms of up- or down-regulation.
Up-regulation: increase the number of receptors.
Down-regulation: decrease the number of receptors.
Desensitization
- Desensitization is an intrinsic pharmacological property of the receptor. In the prolonged
presence of an agonist, the receptor becomes desensitized/inactivated (i.e., loss or
decrease in response).
- This is a reversible mechanism. After removal of the drug (washing) for some time, the receptor
can be again activated by an agonist.
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Tachyphylaxis: Rapid desensitization

Tolerance: Reduction in response after repeated administration
Strcuture-Activity Relationship (SAR)

- Both the affinity of the drug for the receptor and its intrinsic activity depend on its chemical structure
- The actual conformation and shape/structure of the drug determines its specificity
Pharmacophore:A set of structural features (the chemistry) in a molecule that is recognized at a

receptor site (i.e., ligand-binding domain) and is responsible for that molecule's pharmacological or
biological activity.
Receptors And Signal Transduction

LEARNING OBJECTIVES
1. Understand the concept of drug-receptor interaction and the resulting altered function.
2. Describe how receptors are classified and give representative examples of each group.
3. List some of the important properties of the signal transducing receptors.
4. Describe and give examples of the various types of receptors, and be able to differentiate between
ionotropic and metabotropic receptors, as well as differentiate between voltage-
and ligand gated channels.
5. Understand the role of G-proteins, list their main families, and describe their regulatory cycle.
6. Understand Enzyme-linked receptors and their signal transduction cascades.
7. Understand intracellular receptors and their signal transduction cascades.
8. Understand the concept of receptors as catalysts.
9. Understand the integrative role of receptors.
10. List the various ways of how receptors were identified and characterized.
11. Understand the process of receptor desensitization and its impact on signal transduction.
12. Give examples of some of the receptor-based disease states.
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Introduction
Receptor Classification
Important General Properties of Signal Transducing Receptors
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Receptor Types
Receptors
Ionotropic Receptors
Metabotropic Receptors
Ionotropic Receptors
Voltage-gated ion channel
Ligand-gated ion channel
Voltage-Gated Ion Channel

The voltage-gated calcium channels that play a role in neurotransmitter release in pre-synaptic
nerve ending
Intrinsically-associated ion channels (transducer)
Very fast response m-second to second. (e.g., ion flux)
Ligand-gated ion channel
Nicotinic cholinergic
(Gamma-AminoButyric Acid (GABAA)
Glutamate
Metabotropic Receptors
Associated to G-proteins (transducer) (i.e., are G-Protein Coupled Receptors)
No intrinsically-associated ion channel
Slower response (mediated by effectors and second messengers)
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G- proteins are signal transducers

They convey information (agonist binding) to effector proteins
Effectors adenylyl cyclase, phospholipases, plasma ion channel (Ca 2+, K+)
Enzyme-Linked Receptors
- Include Receptor Tyrosine Kinases (RTKs). (e.g., growth factor receptors like EGF, or hormone
receptors like insulin). Also include receptor tyrosine phosphatases
- Slow acting over hours to days.
- A transmembrane receptor (R) whose intrinsic enzymatic activity (located on its cytoplasmic
domain) is allosterically regulated by a ligand that binds to its extracellular domain, leading to
R dimerization and thus R activation.
Intracellular Receptors
- A lipid-soluble (hydrophobic) ligand/drug can cross the membrane to act on an intracellular receptor
(e.g., an enzyme or a regulator of gene transcription).
- Receptor may contain ligand binding domain, DNA binding domain and a regulatory domain- e.g.,
thyroid hormone receptor, steroid receptor
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Dose-Response Curves: Agonists and Antagonists

Learning Objectives
1. Understand the concept of ligand affinity, Ka and Kd, and its relation with pharmacophores.
2. Understand EC50 or ED50, IC50, TD50, and the therapeutic index (TI).
3. Understand the ligand binding isotherms, both the hyperbolic and the sigmoidal and how they
are used to derive the Kd.
4. Know the relationship between the Kd/Ka and the affinity.
5. Understand and define full agonist, antagonist (competitive, noncompetitive/irreversible and
allosteric), and partial agonist.
6. Understand the outcome of the competition between an agonist and a partial agonist
7. Define chemical and physiological antagonism
8. Define synergism and additivity
9. Differentiate between and define gradal and quantal dose response curve
10. Understand potency and efficacy
Understanding Ligand/Drug Affinity
Pharmacophore Interaction with the Ligand Binding Site (amino acid)
Pharmacophore is a structural feature (or the chemistry) of the drug that interacts with the ligand binding
pocket of a specific receptor
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Ligand-Binding Isotherm Receptor-Ligand Interaction
Units for Affinity Measurement

Kd = concentration units:
-1 M (molar) -1 mM (millimolar) = 103 M - 1 M (micromolar) = 106 M
- 1 nM (nanomolar) = 109 M - 1 pM (picomolar) = 1012 M
Ka = 1/concentration units: e.g., M1 (1/M); mM1 (1/mM); M1 (1/M); nM1 (1/nM); pM1 (1/pM)
Drug Affinity
Kd = 1/Ka (association constant).
Lower Kd (or higher Ka) values Higher affinity, difficult to dissociate (within hours), nM to pM.
Higher Kd (or lower Ka) values Lower affinity, dissociate quickly (within seconds), mM.
Ligand/Drug Classification
1. Full Agonist (full and partial); 2. Antagonist (competitive and allosteric); 3. Inverse agonist
Agonists: drugs that bind to physiological receptors and mimic the effects of the endogenous compound
(e.g., neurotransmitters, hormones, etc.).
- For instance, nicotine mimics the effect of the endogenous neurotransmitter cetylcholine
(i.e., is able to activate the nicotinic acetylcholine receptor.
Full Agonists: compounds that are able to elicit a maximal response following receptor
occupation and activation
Partial Agonist: compounds that can activate receptor, but are unable to elicit a maximal
response of the receptor system
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Full Vs. Partial Agonist
Partial Agonist
Competition Between Agonist and Partial Agonist
Competitive Antagonist
i Drugs that bind to the same site as the agonists, inhibiting its binding and effect. An antagonist
shows no pharmacological effect on the receptor by itself (i.e., lacks intrinsic activity).
i This inhibition is mediated by a steric mechanism.
Their effect can be surmounted (or reversed) by increasing the concentration of the agonist (i.e., a
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competitive antagonist increases the agonist concentration required for a given response)
Drug Binding Inhibition
i When drug I is present at increasing concentrations, it is necessary to apply higher concentrations of

drug A to obtain the same maximal effect (shift to the right).
i The EC50 of drug A increases linearly with the concentration of drug I.
Key features of a competitive antagonist:

Reversible binding to the receptor.
The blockade can be overcome by increasing the agonist concentration.
The maximal response of the agonist is not decreased.
The agonist dose-response curve in the presence of a competitive antagonist is shifted parallel to the
right with no change in the maximal response
Noncompetitive Antagonist
i Drugs that bind irreversibly to sites different from the agonist binding site(s) but inhibit the receptor function.
i They are called non-competitive antagonists because they do not compete for the same binding site as the
agonists.
i This inhibition is mediated by an allosteric mechanism. Allostery = comes from the Greek allos ("other) and
stereos ("space)
i Noncompetitive antagonists decrease agonist maximal effect without decreasing agonist affinity (EC50). Their
effect is the equivalent of removing receptors from the system.
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At higher concentrations of drug B, there is a decrease in the maximal response of drug A.
Noncompetitive Agonist
i Drugs that bind to site(s) different from the agonist site(s) but enhance the agonist-activated receptor.
i This functional enhancement is mediated by an allosteric mechanism
i In the presence of increasing concentrations of drug B (co-agonist), the maximal effect of drug A (agonist) is
reached at lower concentrations (left-shifted or potentiation).
Irreversible Antagonist
- Chemically reactive compound, therefore covalently binds with the receptor.
-The receptor is irreversibly inactivated and the blockade cant be overcome with increasing agonist
concentration. Shifts the agonist dose-response curve to the right and depresses maximal responsiveness.
- Irreversible & Non-surmountable.
- The antagonist inactivates the receptors. The effect of irreversible antagonists cannot be overcome by
more drug (agonist).
Other Antagonistic Mechanisms

Chemical Antagonist
- It does not involve a receptor (i.e., a chemical antagonist does not depend on interaction with the
agonists receptor, although such interaction may occur).
- A drug inactivates the effect of another drug by directly binding to the second drug (e.g., a
chelator/sequester that interacts directly with the drug being antagonized to remove it or prevent it
from binding its receptor).
- Heparin, an acidic anticoagulant. If there is too much bleeding and haemorrhaging.
- Protamine sulfate is a base. It forms a stable inactive complex with heparin and inactivates it.
Physiological Antagonist
The use of a drug that activates a regulatory pathway or receptor (with an intrinsic activity = 1), and that
is opposed to the pharmacological action of the drug of interest. For example, while Insulin use in
diabetes will blood sugar, the Glucocorticoid Hormones will blood sugar.
Synergism Vs. Additivity

- Synergism: The combined effect of two drugs is higher than the sum of their individual effects.
(e.g., Valium + alcohol; and Codeine + acetaminophen )
- Additivity: The combined effect of two drugs is equal to the sum of their individual effects.
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Effective Concentration/Dose 50
- ED50 / EC50: The dose/concentration required to produce 50% of the maximum response/effect of the
drug
- A Pharmacological response is a function of the dose or concentration of a drug.
Dose Response Curve

- Graphical representation of the relationship between dose and response; two shapes, rectangular or
sigmoidal. Usually, it is convenient to have log scale on axis of drug concentration.
The intensity and duration of a drugs effects are a function of the drug dose and drug concentration at
the site of action.
Types of Dose Reponses

1.Graded
-Continuous scale -Measured in a single biologic unit -Relates dose to intensity of effect
2.Quantal
-All-or-none pharmacologic effect - Population studies - Relates dose to frequency of effect,
E.g., Analgesia, sleep or lethal dose of anesthetics.
Graded Dose-Response Curve Lidocaine Quantal Dose-Response
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Quantal Dose-Response Distribution Cumulative Dose-Response Curve
Potency Vs. Efficacy
Rank Order of Potency: A > B > C > D Rank Order of Potency: A > B > C > D
Rank Order of Efficacy: A = C > B > D
Therapeutic Index (TI):
A measure of the relative safety of the drug (i.e., the ratio between the dose required to produce a toxic effect to
that required to produce a therapeutic effect). The larger the value of TI, the safer the drug is.
Pharmacogenetics & Biological Variability

Learning Outcomes
Be able to:
1. Differentiate between and define pharmacogenetics, pharmacogenomics.
2. Know the sources and types (genetic and environmental) of individual variability, and give
representative examples of each.
3. Define and understand unusual/idiosyncratic responses to drug (hyporeactivity, hyperreactivity, and
hypersensitivity)
4. Differentiate between tolerance and Tachyphylaxis.
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5. Understand Differentiate between pharmacokinetic and pharmacodynamic variability.

6. Understand the role of age in biological variability.
7. Understand genetic and racial variability (e.g., metabolism), and give representative examples of
genes or enzymes linked to biological variability.
8. Understand the role of receptor polymorphism in biological variability and give representative
examples.
9. Understand ED50, TD50, LD50, LD99, and Therapeutic Index (TI).
Pharmacogenetics
- Study how people's genetic variations/make up correlate with their responses to a specific medication.
- The ultimate goal of pharmacogenetics is to tailor medical treatments specifically to the individual,
increasing effectiveness while reducing adverse side effects.
Pharmacogenomics
Pharmacogenomics = Pharmacogenetics + Genomics
Pharmacogenomics: systemic genomic analysis in populations of treated subjects to identify gene
variants that predict drug response, including the occurrence of adverse reactions
Individual Variability in Drug Response

Types of individual variability:1. Inter-individual 2. Intra-individual
Sources of individual variability in drug response
1. Genetic factors (genetic make-up; pharmacogenetics) 2. Environment
(Nurture or Nature)
1. Pharmacogenetics/ Genetic factors
a. Receptors (e.g., change in their number or function)
b. Disposition factors, primarily metabolism
2. Environmental:
a. Disease (e.g., a concurrent disease may affect how patient X responds to drug Y
b. Other drugs or chemicals
- Inhibition at a receptor (drug-drug interaction)
- Inhibition of drug metabolism and clearance (drug- drug interaction)
- Induction of drug metabolism (drug-drug interaction)
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- Up-regulation of receptors
Biological Variability
Idiosyncratic Drug Response: Unusual (infrequently observed in most patients)
Unusual responses to drug administration:
- Hyporeactivity: intensity of effect is decreased
- Hyperreactivity: intensity of effect is increased
The intensity of an effect for a given dose is lower (hyporeactive) or higher (hyperreactive), in
comparison to that seen in most individuals.
- Hypersensitivity allergic or other immunologic response to drugs resulting from previous

sensitizing exposure.
Tolerance: responsiveness usually decreases as a consequence of continued drug administration.

(Need greater doses of a drug to produce original degree of effect as time progresses. Or need to
substitute with a different drug.)
Tachyphylaxis: responsiveness diminishes rapidly after administration of a drug (the first few doses),
(i.e., very rapid tolerance)
Sources of Individual Variability

Pharmacokinetic variability: Differing concentration at the site of action
Pharmacodynamic variability: Differing response to the same concentration at the site of action
1. Patients may differ in: a. rate of absorption of a drug; b. distribution in body compartments; c.
clearance rate
Depend on: Age, weight, sex, disease state, liver & kidney function, and genetic differences
2. Patients may differ in:
a. Concentration of endogenous receptor ligand (variability in the response to a
pharmacologic antagonist) e.g., Propranolol (-blocker) slows heart rate in patients with
pheochromocytoma (disease/tumor where endogenous catecholamines are elevated), without
changing the heart rate of a well-trained marathon runner
a. Concentration of receptor-sites and their function
- Antagonist may elevate density of receptors
- Agonist may decrease number of receptor [[Clonidine (2 agonist) is used to
treat hypertension (decreases blood pressure). When withdrawn, can produce hypertensive crisis
because it down regulates the 2-adrenergic receptors]]
a. Integrity of biochemical and physiological processes [[General health of patient,
pathophysiologic mechanism of the disease]]
Effect of age
Renal glomerular filtration (per body area) in newborns is about 20% of adults (until 1 week of
age). Renal function declines with age: - 25% at age 50 - 75% at age 75
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Effect of Genetic factors: metabolism (1)

Patients maybe Slow or fast acetylators. Slow acetylators have a defect in their enzyme. -
Single recessive gene.
Prevalence of slow acetylator phenotype in various gene pools

- Ethiopian--- 90% - European Caucasian--- 50% - East/Central Asian--- 10%-20%
- Canadian Eskimo----- 5%
Isoniazid (INH): used to treat tuberculosis (TB)Causes peripheral Neuropathy as a side effect,
which varies among individuals
Effect of Genetic factors: metabolism (2)
- Some patients have prolonged apnea following succinylcholine administration.

- This is attributed to a deficiency in Butyrylcholinesterase, which may result from a genetic
polymorphism.
Biological Variability
Is related to: 1. Genetic factors 2. Racial differences
Racial differences: e.g., Ethanol Metabolism: Asians may have higher incidence of differences in
ethanol metabolism due to a missense polymorphism in the enzyme acetaldehyde dehydrogenase
normally responsible for breaking down acetaldehyde, which is a metabolite of alcohol that causes
adverse effects like flushing and palpitations
Racial differences:
Cytochrome P450 2D6 (CYP2D6
activity of CYP2D6 polymorphically distributed in the population
8-10% Caucasians deficient in CYP2D6 (i.e., therefore, are poor metabolizers)
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extensive metabolizers (gene duplication of CYP2D6 )

different reactions to trycyclic antidepresants and codeine
different therapeutic and adverse responses
Receptor Polymorphisms: Some pharmacogenetic variations are known for specific drug receptors. The
number of therapeutically significant receptor polymorphisms appear to be much more limited than
the number of therapeutically significant drug metabolism polymorphisms
Individual effective concentration: The concentration of a drug that produces a specified effect in a
single patient.
Effective Dose (ED50): The dose of a drug required to produce a specified effect in 50% population
Toxic Dose (TD50): The dose of a drug required to produce a specified toxic effect in 50% population
Lethal Dose (LD50): The dose of a drug resulting in mortality of 50% animal population
Adverse Drug Reactions (ADRs)

Learning Outcomes
Understand the significance of adverse drug effects (ADRs) and their impact on patients lives,
and the economy, etc.
Know the terms that are used to refer to drug-adverse effects (i.e., ADRs).
Know the definition of ADRs according to WHO and the FDA.
Be able to describe the two types of ADRs.
Understand how one can recognize an ADR.
Know the ADR surveillance programs, and the role of the pharmacist in such programs.
Understand post marketing surveillance, its goals and the agency that is responsible for it.
Be able to define pharmacovigilance, and safety pharmacology.
Know that some ADRs might be beneficial, life threatening, and that they impact patient
compliance.
Be able to define carcinogenesis, and teratogenesis.
Understand and list the mechanisms of ADRs, and be able to give representative examples of
each (e.g., PK related, PD related, etc.)
Understand how certain disease states may enhance/influence ADRs, and be able to give
representative examples.
Know the definition of drug-drug interaction, and its relationship with adverse drug reactions
(ADRs).
Know and understand the mechanisms underlying drug-drug interactions (including plasma
protein binding), and be able to give representative examples of each.
Know that a drug-drug interaction can be considered desirable, and be able to give examples of
such cases.
Introduction:
ADRs are a cause of significant morbidity and mortality in patients in all arenas of health care today.
It has been estimated that from 1/3 to as high as1/2 of ADRs are believed to be preventable.
The Institute of Medicine reported in 2000 that an estimated 7000 deaths occur each year due to adverse
drug events.
The cost of morbidity and mortality due to drug-related events was recently estimated to be $136 billion
annually.
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The suffering that patients experience because of adverse drug reactions cant be Quantified.
The terms adverse drug reaction, adverse drug event, untoward drug reaction, drug misadventure,
side effects, or drug related problem are often used interchangeably.
Definitions:
A. according to the Food and Drug Administration (FDA)--any adverse event associated with
the use of a drug in humans, whether or not considered drug related, including the following: 1.
an adverse event (AE) occurring in the coarse of the use of a drug in professional practice; 2. AE
occurring from a drug overdose, whether accidental or intentional; 3. AE occurring from
drug abuse; 4. AE occurring from drug withdrawal; and 5. any significant failure of
expected pharmacological action.
Types of Adverse Drug Reactions
- Two types, Type A and Type B
Type A:
1. are extensions of the drugs known pharmacology.
2. are responsible for the majority of adverse effects.
3. usually dose dependant and predictable, but can be due to concomitant disease-states, drug-drug
interactions, or drug-food-interaction.
4. can be minimized by understanding the pharmacology of the drug being prescribed, monitoring drugs
with a narrow therapeutic window, and avoiding polypharmacy when possible.
Type B
1. include idiosyncratic reactions, immunological or allergic reactions, and arcinogenic/teratogenic
reactions.
2. usually are not due to an known pharmacology of the drug, but seem to be a function of patient
susceptibility.
3. rarely predictable, are usually not dose-dependent, and seem to concentrate in certain body system,
such as the liver, blood, skin, kidney, nervous system, and other body systems.
4. are uncommon, but are generally very serious and can be life threatening.
5. Except for the immediate hypersensitivity reactions, usually take 5 days before the patient
demonstrates hypersensitivity to a drug. There is no maximum time for the occurrence of a reaction, but
most occur within 12 weeks of initiation of therapy.
Recognition of ADRs
- Drugs must always be considered as a possible cause of disease or symptoms that are among a
patients list of complaints. Complete drug histories, including nonprescription drugs, must also be
carried out.
- Recognition is often subjective, and it is not always possible to demonstrate strong causality
between the drug and the occurrence.
Surveillance Programs
- Pharmacists, as well as all health-care professionals, should take an active role in monitoring,
reporting and trending ADR information. Some of the activities involved in a concurrent and
ongoing ADR surveillance program at an institutional level include some of the following
components:
1. Pharmacy departments should take the lead in the collection of information and should submit
all reviews and reports to the pharmacy and therapeutics committees for review and evaluation.
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a. encourage all health-care professionals to be involved in reporting.

b. monitor patients using high-risk agents.
c. notify prescribers of suspected ADRs.
d. Report appropriately identified ADRs to the FDA (MedWatch) using the
Adverse Events Reporting System (AERS); Also, Vaccine AERS (VAERS).
2. Evaluation of the causes of ADRs should be done. ADR report
information should be used for educational purposes and prevention
of further occurrences of ADRs.
Post Marketing Surveillance (PMS)

- Mandated by the regulatory authorities (FDA) and is necessary to confirm the existence of a
(rare) adverse event occurring after the approval of drug for human use.
- The goal of Post-Marketing Surveillance (PMS) system is to monitor the ongoing safety of
marketed drugs. This is accomplished by reassessing drug risks based on new data learned after
the drug is marketed, and recommending ways of trying to most appropriately manage that risk.
- This work is accomplished primarily through the Division of Pharmacovigilance (FDA; CDER).
Pharmacovigilance: all scientific and data gathering activities relating to the detection, assessment, and
understanding of adverse events. Principally involves the identification and evaluation of safety signals
(i.e., a concern about an excess of adverse events compared to what would be expected to be associated
with a product's use.)
Terminology
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- Carcinogenesis: occurs when a normal cell transforms to a neoplastic (cancer) cell and the neoplastic
cell undergoes clonal expansion (is able to reproduce)
- Teratogenesis: is the induction of defects in the fetus, when a drug is given to a pregnant woman
Mechanisms of ADRs
1. on target adverse effects: the result of the drug binding to its intended receptor/target, but at an
inappropriate concentration, or in the incorrect tissue. (e.g., an NSAID inhibiting the
cyclooxygenase (COX) activity both in joints and the stomach.
2. off target adverse effects: the result of the drug binding to a target/receptor for which it was
not intended. (e.g., a b2-receptor agonist activating b1-receptors).
3. Production of toxic metabolite.
4. Production of harmful immune responses.
5. Idiosyncratic responses: rare adverse effects for which in obvious mechanism is NOT apparent.
Examples of ADRs
- PKs related:
1. A geriatric (older) patient may experience an adverse effect, due to elevated plasma
levels of a drug, as a result of reduced elimination of the drug, or its active metabolite.
2. Drug x may compete with drug y for plasma protein binding, and displaces it from binding.
Therefore, elevating its (free) plasma level, which in turn results in adverse effects.
- PDs related:
- As a result of the co-administration of two or more drugs which share the same receptor/target
or signaling pathway. For example, sildenafil (used to treat erectile dysfunction) and
nitroglycerine (for angina pectoris). Sildenafil inhibits phosphodiesterase type 5 (PDE 5), and
thus prevents the degradation of cGMP, thereby prolonging its action, and nitrogylecrine
stimulates guanylyl cyclase to increase cGMP levels in vascular smooth muscle cells. Co-
exposure to the two drugs increases cGMP to an even greater degree, increasing the risk of
severe hypotension. cGMP = cyclic GMP
-Drug-Herb Interaction related:
- Grapefruit juice is an inhibitor of the CYP450 enzymes (i.e., CYP3A4) mainly in the
gastrointestinal tract. For certain drugs which are known to be CYP 3A4 metabolized (e.g.,
antihypertensive Plendil), less drug is metabolized prior to absorption, and greater amounts of
these drugs reach the systemic circulation, leading to higher blood levels, and potentially to
increases in therapeutic and/or toxic effects.
-Disease-Enhanced ADRs:
- Thyroid hormone regulates the basal metabolic rate of the body. Hence, hyperthyrodism can
increase the rate of metabolism of some drugs, whereas hypothyrodism can do the opposite.
Drug-Drug Interactions
Drug-drug interaction: simply defined as one drug affecting the pharmacological/therapeutic effect of
another, when co-administered.
- As the population has aged and increasing numbers of patients have been prescribed multiple
medications, the potential for drug-drug interactions has grown.
- May result in an undesirable adverse drug reaction (ADR), or interference with the
pharmacological activity of one of the drugs in concern.
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- The mechanisms often involve pharmacokinetic or pharmacodynamic effects, which can be

disease or age related. Drug-herb interactions are also an important subset of drug-drug
interaction.
Pharmacokinetic Drug-Drug Interactions:

- Arise if one drug changes the absorption, distribution, metabolism, or excretion of another drug,
thereby altering the concentration of active drug in the body.
Certain drugs, or foods, may alter the gastric pH, or that of the intestine, and therefore affect the
absorption of a second drug. For example, antacids will raise the gastric pH and therefore, may interfere
with the disintegration, dissolution and absorption of the dosage form/drug. Antacids such as sodium
bicarbonate may raise (basify) the pH of the urine and interfere with the elimination of drugs (i.e.,
enhance the elimination of an acidic drug). Also, agents that lower (acidify) the pH of the urine (e.g.,
ammonium chloride), may interfere with the elimination of drugs (i.e., enhance the elimination of basic
drugs.)
Pharmacokinetic Drug-Drug Interactions
- Plasma protein binding: A drug that binds to plasma proteins, such as albumin, may displace a
second drug from the same protein to increase its free plasma concentration and thereby increase its
bioavailability to target and nontarget tissues. This effect can be enhanced in a situation where
circulating albumin levels are low, such as liver failure, or malnutrition (decreased albumin synthesis) or
nephrotic syndrome (increased albumin excretion).
- Can sometimes be desirable
e.g., because penicillin is cleared via tubular secretion in the kidney, the elimination half-life of this drug
can be increased if the drug is given concomitantly with probenecid, an inhibitor of renal tubular
transport.
e.g., the combination of imipenem, a broad spectrum antibiotic, and cilastatin, a selective inhibitor of a
renal dipeptidase (dehydropeptidase I). Because imipenem is rapidly inactivated by dehydropeptidase I,
coadministration of imipenem with cilastatin is required to achieve therapeutic concentrations of the
antibiotic.
Pharmacodynamic Drug-Drug Interactions
- Arise when one drug changes the response of target or nontarget tissues to another drug. Toxic
pharmacodynamic interactions can occur when two drugs activate complementary pathways, leading to
an exaggerated biological effect. For example, the coadministration of antithrombotic drugs after hip
replacement surgery. Because warfarin plasma concentrations may not reach a therapeutic level for
several days, patients are sometimes coadministered low-molecular-weight heparin and warfarin during
this time. Significant bleeding may result if the effects of the two drugs synergize to produce
supratherapeutic levels of anticoagulation.
Drug-Herb Interactions
The safety and efficacy of a drug may be altered by co-exposure with various non-pharmaceuticals, such
as foods, beverages, and herbal and dietary supplements. One should inquire about patient use of such
products before instituting pharmacological management.
Drugs affecting the Autonomic Nervous System

The ANS is primarily concerned with visceral functions necessary for life, such as heart beat, smooth
Page 52 of 66
muscle contraction/relaxation of blood vessels and GI and respiratory tracts, exocrine & certain
endocrine secretion as well as food digestion. Activities of the ANS are not under conscious control. The
ANS is made of two fibers (one pre- and one post-ganglionic fiber) except adrenal medulla, where only
one preganglionic fiber innervates the adrenal medulla. The sympathetic and parasympathetic divisions
of the ANS originate within the nuclei in the CNS, i.e., the cell bodies of these neurons originate in the
spinal cord (Sympathetic) or the medulla and the spinal cord (parasympathetic). Thus, the terms
thoracolumbar and craniosacral, denote the sympathetic and parasympathetic division of the ANS,
respectively.
Parasympathetic system
Intro to basic Neurobiology:
It is important for you to understand the Nernst equation so that you understand what direction ions
flow and why they stop flowing at certain voltages.
It is also important to know what SNAREs are, as a SNARE protein is the target of Botox.
Introduction to the ANS:

The nervous system is divided into two general categories. What are they and how are they further
subdivided?
The ANS can be defined through both anatomical and chemical/pharmacological classification.
o What is the anatomical definition?
o What is the pharmacological definition (ligands and receptors)?
What are the exceptions to the traditional classification?
You need to know what the ANS controls this will explain much of the side effects of drugs that
target the ANS as most side effects are on-target effects. Use the figure below as a study guide.
system system
Page 53 of 66
What are the two chemical types of AChE inhibitors and are both used clinically?
Nicotinic Agonists and Antagonists
(note: these drugs do veer out of the ANS):
It is important to understand where the nAChR resides and what it is doing in each case.
o What junctions contain the nAChR?
o What happens when these receptors are activated?
Where does Ach bind to the nAChR?
Continued stimulation does what to the receptor?
o What does this mean pharmacologically?
What are the two broad categories of use for nAChR drugs?
o Why are there only two categories?
How does a partial agonist work as an antagonist?
Does Chantix only have effects through the 42 receptors?
How does Botox work and what specifically is Botox?
o What can Botox be used for?
How is Ach involved in muscle contraction?

Non-Depolarizing Blockers (aka antagonists) are listed below

General
Type Drug Elimination
Duration*
Pancuronium Long Hepatic metabolism and renal elimination
Hepatic metabolism and elimination with ~30%

Steroid Vecuronium Medium
renal elimination as unchanged drug
Derivatives
Pipecuronium Long Primarily Renal elimination as unchanged drug
Rocuronium Medium Hepatic metabolism and elimination

Primarily hepatic elimination with some renal
Tubocurarine Long
elimination as well.
Doxacurium Long Primarily Renal elimination as unchanged drug

Isoquinoline
Derivatives Hofmann reaction & plasma esterase elimination
Atracurium Medium
with renal elimination
Mivacurium Short Hydrolysis by plasma Cholinesterase
Page 54 of 66
* Short = less than 20 min, Medium = 30 min to ~90 min, Long = 80 min and beyond (ranges are due to
differences in patients)
Understanding the general duration and elimination is key to clinical practice. Duration is important as
you want to minimize the dosing so choosing the correct drug for the procedure is important. Likewise
elimination of a drug in the hospital is always important as disease can effect elimination so you want to
take advantage of the elimination pathways that are not diseased in a patient.
What is the Hoffman rxn?

o What is Laudanosine and is it a concern under standard dosing?
Succinylcholine is a ______________ but acts as a _____________.
o Why is this true?
What is a phase I and phase II block?
o Can you explain or draw this?
Muscarinic Agonists and Antagonists:
The above chart shows agonists and antagonists that are used clinically to treat various conditions, and it
shows the target of these drugs.
Just like for the nAChR, it is important to understand where the muscarinic receptors reside and what it
is doing in each case.
Where are predominately M odd receptors and where are predominately M even receptors?
What do M even receptors do on the molecular level?
What do M odd receptors do on the molecular level?
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o What is an autoreceptor this is key to understand for PBT3 (neuro pharm)

What is the generic name of the drugs that activate muscarinic receptors and what are they used to
treat?
You should understand the side effects of Muscarinic agonists that can be defined by DUMBBELLS
o Defecation (diarrhea)
o Urination (uncontrolled bladder)
o Miosis (constriction of the pupil)
o Bradycardia
o Bronchospasm
o Emesis (vomiting)
o Lacrimation (tearing)
o Lethargy
o Salivation (drooling)
There are a number of antagonists that are used, but there are some simple groupings. You should know
the following drugs, what they are used for, and if they cross the BBB.
Atropine
Scopolamine
The drugs used to target the bladder as a group why do we use these drugs?
o Why are M3 receptor antagonists used to treat over active bladder?
o What side effects would you predict for the drugs and why would you predict those side effects?
Acetylcholinesterases:
What is the difference between butylcholinesterase and acetylcholinesterases (AChE)?
o Does this have any effect clinically?
What is the physiological purpose of AChE?
What is the chemistry behind how AChE work?
If you block AChE function what happens to ACh?
o How about the nAChR and muscarinic receptors?
o What would this do?
What are the two chemical types of AChE inhibitors and are both used clinically?
There are a number of antagonists that are used, but there are some simple groupings. You should know
the following drugs, what they are used for, and if they cross the BBB.
Edrophonium
Neostigmine
Physostigmine
The Alzheimers drugs as a group
Isofluorphate
Echothiophate
It is also important to understand the use of AChE inhibitors in agriculture and biowarfare as you may
have to treat these poisons, but I hope you never see this!
o Which AChE inhibitors are used as insecticides?
o Why is Malathion considered safe?
How would you treat AChE inhibitor toxicity?
Page 56 of 66
o Does time matter?

o What is the MOA and chemical mechanism of the chemistry of the antidotes?
Adrenergic and Cholinergic fibers
Depending on the neurotransmitter released at the synaptic terminal, the fibers can be adrenergic or
cholinergic. Thus, if the neurotransmitter is nor-adrenaline, the fiber is adrenergic; whereas, if the
neurotransmitter is acetylcholine (ACh), then the fiber is cholinergic. All preganglionic fibers are
cholinergic because ACh is the neurotransmitter. All postganglionic fibers for the parasympathetic system
are cholinergic because ACh is the neurotransmitter. Most of the postganglionic sympathetic fibers are
adrenergic because the neurotransmitter is nor-adrenaline (NE); but, few postganglionic sympathetic fibers
could be cholinergic as well (e.g., sweat gland).
Adrenergic neurotransmission
For the synthesis of the neurotransmitter (NE or Epi) at the sympathetic neurons, tyrosine is transported by
Na+-linked carriers into cytoplasm and then becomes hydroxylated to dihydroxyphenylalanine (DOPA) by
the enzyme tyrosine hydroxylase (TH), which is the rate limiting enzyme. DOPA is then converted to
dopamine by the enzyme DOPA decarboxylase and carried into vesicles to be stored. The vesicular
monoamine transporter is responsible for this process. Inside the vesicle, dopamine will be converted to NE
by the enzyme dopamine-beta-hydroxylase. Upon nerve stimulation, the voltage gated calcium channels
located on nerve terminals will become opened and entry of calcium leads to fusion of vesicles to the
membrane and exocytosis of NE to the synaptic cleft.
Why study neurotransmission?
It is the target for the action of different drugs. For example, methyl-tyrosine (metyrosine) reduces the
synthesis of dopamine, NE and Epi by inhibiting the rate-limiting enzyme (TH). This drug is used for the
treatment of hypertension associated with pheochromocytoma (tumor of the chromaffin cells of the adrenal
gland). Alpha-Methyldopa (aldomet) deceives the dopa-decarboxylase and being converted to alpha-
methyl-dopamine and then being converted to alpha-methyl-NE by the action of dopamine-beta-hydroxylase
and stored into the vesicle as a false neurotransmitter; therefore, the drug reduces adrenergic
neurotransmission since the false neurotransmitter, released into the synaptic cleft instead of NE, cannot
activate the receptors. This drug is thought to activate alpha-2 receptors and decrease sympathetic outflow
from the CNS. Reserpine blocks the vesicular transporter, therefore blocking the storage of DA and NE,
which leads to depletion of NE stores. This drug can be used for the treatment of hypertension.
NE is recaptured by reuptake mechanism back into the presynaptic neuron (also known as NE transporter
or uptake-1). NE transporter involves a Na -K+-linkedATPase which can be inhibited by TC
antidepressants such as imipramine, or by cocaine. NE may diffuse out of the synaptic space and enter the
general circulation (uptake 2) but this is not the major pathway for the removal of NE from the synaptic
cleft. NE is oxidatively deaminated by the enzyme monoamine oxidase (MAO) which leads to excretion of
NE at the presynaptic site, where the neurotransmitter is synthesized. MAO also exists at the postsynaptic
site and oxidizes the released NE that reaches the postsynaptic site. At the postsynaptic site, NE can also be
metabolized the enzyme catechol-O-methyl-transferase (COMT). These enzymes are target for some drugs
administration of which could increase the level of NE at the presynaptic, synaptic cleft or postsynaptic
terminals.
Adrenergic Receptors
There are two types (alpha and beta) of adrenergic receptors. Recently, subtypes of each receptor have
been cloned. Activation of each subtype of the receptor will lead to different physiological responses.
Page 57 of 66
For example, activation of alpha-1 receptors will lead to vasoconstriction, leading to increased
peripheral vascular resistance and then increase in blood pressure (BP). On the other hand, activation of
alpha-2 receptor will lead to a decrease in sympathetic outflow from the CNS, thus leading to decreased
sympathetic tone and decrease in BP. Activation of beta-1 receptor increases heart rate, and its force of
contractility. Beta-2 receptors activation will lead to bronchodilation as well as vasodilation of blood
vessels in skeletal muscles. For details of physiological responses and receptor mediating such response,
please refer to Table 8-1 in Goodman & Gillman which is attached. Each of these receptors is coupled
to a signaling mechanism that mediates the effect of Epi and NE. For example, NE binding to beta-1
receptor stimulates adenylyl cyclase which causes conversion of ATP to cAMP and leading to increase
in heart rate and force of contractility of the heart muscle.
Adrenergic receptor agonists
These drugs are divided into (1) direct acting (bind to the receptor and produce their actions such as
epinephrine, norepinephrine, albuterol, phenylephrine, et., (2) indirect acting (these drugs do not bind to
the adrenergic receptors but cause release of NE or epinephrine or block the uptake of NE, such as
cocaine, amphetamine, tyramine, MAO inhibitors, etc., and (3) mixed-acting (direct & indirect acting)
work via both mechanisms. These drugs include ephedrine, metarminol and related drugs.
Epinephrine (Epi) and NE are examples of non-selective directly acting agonists. Basically, they
activate both alpha and beta receptors. Selective direct acting agonists act only on one receptor.
Examples are phenylephrine, clonidine, albuterol, etc.
Indirect-Acting Adrenergic Agonists: These drugs do not activate the receptor but may cause the
release of endogenous, prevent their metabolism or uptake. For example, tyramine which is found in
fermented foods such as ripe cheese and Chianti wine, enhances the release of norepinephrine from the
vesicular pool (possibly an acute increase in blood pressure) but after repeated administration causes a
drop in blood pressure due to depletion of NE stores, a phenomenon referred to tachphylaxis. Normally,
endogenous tyramine is oxidized by MAO and removed but if the patient is taking MAO inhibitors
(psychiatry) then the effect of tyramine could be significant, leading to hypertensive crises in some
patients who are on MAO inhibitors and taking food containing tyramine.
Mixed-Action Adrenergic Agonists: These drugs act by both mechanisms. Ephedrine is an example
and can enhance release of NE from nerve terminals but can also have stimulatory actions on and
receptors similar to epinephrine. It is not a substrate for COMT or MAO so it has a long duration of
action but only used clinically in combination with other agents to treat bronchospasm and cough.
Metaraminol is also a mixed-acting adrenergic agonist but is not used clinically.
Adrenergic receptor antagonists

The adrenergic antagonists typically have a preferential affinity for one type of adrenergic receptor
allowing for the inhibition of effects mediated by activation of specific adrenergic receptors. However,
there are some drugs that block both alpha and beta receptors. An example, will be labetalol, which
blocks both alpha and beta receptors. These drugs bind to the receptors and block the action of
endogenous adrenergic neurotransmitters. They block the receptors via competitive (reversible) and
irreversible (non-competitive) mechanisms. Some of these drugs also include partial agonist that weakly
stimulate the receptors in the absence of an agonist and block the receptor in the presence of
overstimulation of the receptor. Alpha blockers are useful to treat hypertension and beta blockers are
used to treat hypertension, glaucoma, migraine headache prophylaxis, some forms of angina and
arrhythmias. Some alpha-1 selective antagonists are used for the urinary issues associated with Benign
Page 58 of 66
Prostatic Hyperplasia.
Page 59 of 66
Asthma & COPD
Introduction to Pulmonary Biology:

One part of understanding the disease state and pharmacology of asthma & COPD is to understand how
you breathe at the anatomical level. Please look over the following web page to help study for the exam
if you are not familiar with basic pulmonary biology: http://people.eku.edu/ritchisong/301notes6.htm
What are the anatomical divisions of the respiratory system, and what is the primary purpose of
these divisions?
Do we actually have vocal cords?
What are the cell types that are found in the respiratory system?
How is gas exchanged you do not need to know this in great detail?
What muscles are used to control breathing?
o Where are these muscles located?
It is important to understand and be able to explain how to measure breathing.

On the right is a representation of the modern spirometry
that can easily be run in a pharmacy. The FEV1/FVC F ic t i o n a l C O P D m e as u rem e n t
ratio can be used to identify COPD and Asthma as well 6
as other pulmonary defects. However it cannot be used to FEV1

specific diagnose these issues without other information
V o lu m e ( L )
4
(described below).
FVC
Know how to read the spirometry chart on the left, 2
specifically understand the listed terms in both charts.
What is FEV1 and why is it important? 0

0 1 3 6
T im e ( s e c )
Demographics and Biology of Asthma & COPD:

COPD
COPD Severity chart
COPD is generally the combination of FEV1 % predicted* Stage
what two diseases?
What is the etiology and presentation of 80% Stage 1 (mild)
these two diseases?
What is the main cause of COPD in the 5079% Stage 2 (moderate)
US?
3049% Stage 3 (severe)
< 30% Stage 4 (very severe)**
* http://www.dynamicmt.com/dataform3.html
** Or FEV1 <50% with respiratory failure
Page 60 of 66
Asthma
Asthma is the combination of what two interlinked events?
o What does hyperresponsiveness mean?
What controls the bronchiolar smooth muscle contraction and dilation?
What happens in the airway of an asthmatic that is exposed to an allergen and how is this
different than normal? Some of this information should be found in your studies of Immunology.
Asthma Severity chart

Severity Clinical Characteristics
Symptoms 2 times/week, nocturnal awakenings 2 times/month, brief breathing
Mild intermittent
difficulty (exacerbations) with normal function between exacerbations and limited
(Step 1)
peak flow variability
Symptoms 2 times/week, nocturnal awakenings 2 times/month, brief
Mild persistent
exacerbations, may affect activity, with normal function between exacerbations
(Step 2)
and Peak flow decreased only 20-30%
Daily Symptoms, nocturnal awakenings > 1 time/week, frequent exacerbations
Moderate persistent
lasting days, affects activity, lung function 60-80% of predicted and peak flow
(Step 3)
variability > 30%
Continual Symptoms, frequent nocturnal awakenings, frequent, severe
Severe persistent
exacerbations, limited activity, lung function < 60% of predicted and peak flow
(Step 4)
variability > 30%
How would you identify a COPD patient, and how is this different from asthma?
How can you differentiate between asthma and COPD?
Differentiating COPD from Asthma

Clinical features COPD Asthma
Smoker or ex-smoker Nearly all Possibly
Symptoms under age 35 Rare Often
Chronic productive cough Common Uncommon
Persistent and
Breathlessness Variable
progressive
Night time waking with
Uncommon Common
breathlessness and or wheeze
Significant diurnal or day to day
Uncommon Common
variability of symptoms
Page 61 of 66
Pharmacology of Asthma & COPD:

The goal of this section is for you to understand the drugs used to treat asthma and COPD. You must
know the generic and brand names of the top 200 drugs. As of the writing of these notes we are using
2011 numbers. For Asthma and COPD these drugs are:
Generic name Brand Name
.
Albuterol Proair HFA, Ventolin HFA, & Proventil

Montelukast Singulair
Fluticasone/Salmeterol Advair
Fluticasone Propionate Flonase, Flovent HFA
Methylprednisolone Medrol
Budesonide/Formoterol Symbicort
As these are the most prescribed these will be the ones you are expected to know the most about.
You should write down what each of these are so that you know which mechanisms to focus on in your
studies; however, all presented mechanisms may appear on the exam.
What are the primary ways that smooth muscle contract and dilate?
M3 blockers are used to treat asthma and COPD.
o Which disease are the M3 blockers most effective in and why is this true?
o Are M3 blockers still used for the other disease currently?
-agonists (which -AR?) are used to treat asthma.
o What makes them good drugs for asthma, and what makes a good asthma drug?
You want to know the effects of Albuterol, but also the general SABA characteristics!
What makes a LABA different than a SABA?
o What is the structural determent of this difference?
o What is the pharmacological difference?
What does a phosphodiesterase (PDE) do?
Why is inhibiting PDE good for lung diseases?
How is roflumilast metabolized, and what does that make roflumilast?
How are methylxanthines different from roflumilast, what do they do, and what are the side
effects?
What is a primary mechanism via which Mg2+ works and why is that effective in asthma?
Would this be effective in any other diseases?
Page 62 of 66
It is critical that you understand how to use steroidal medicines! This basic biology is directly
applicable to patient care, and thus it is imperative that you understand the use of steroids.
Why do you never just remove a steroid drug from a patient?

What is the chemical difference between the 1st generation and 2nd generation corticosteroids?
o What does this difference mean pharmacologically?
o How do you administer 1st and 2nd generation drugs?
1st Generation 2nd Generation
Prednisone Beclomethasone
Prednisolone Triamcinolone
Methylprednisolone (top 200) Flunisolide
Dexamethasone Budesonide (top 200)
Fluticasone (top 200)
Ciclesonide
Why do we use steroids to control asthma?
The following diagram explains the effects of corticosteroids
What are the side effects of corticosteroids?

Are the side effects the same for the 1st and 2nd generation corticosteroids and why?
Page 63 of 66
Page 64 of 66
What drugs are considered leukotriene

pathway-modifying agents?
What is the leukotriene pathway and

why would modulating it be a good
therapy?
Why can Aspirin induce asthma?
What is the best drug to treat aspirin

induced asthma?
Page 65 of 66
Why would you use an Anti-IgE antibody?

o What does it do?
o Is this commonly used, and why?
Page 66 of 66

1 Pharmacology 1 Pharmacological Basisof Therapeutics 2015

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1 Pharmacology 1 Pharmacological Basisof Therapeutics 2015

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IPBP IA Exam Study Guide:

Pharmacology 1: Pharmacological Basis of Therapeutics

Internal Assessment (IA) Exam

Drug Classification an example

Chemical Nature of Drugs

Solid Dosage Forms

Liquid dosage forms

- Also available for injection

prepared in a sweet, viscous vehicle.

Semi-solid dosage forms

Controlled-Release Dosage Forms

Tablet injection ointment transdermal patch

Routes of Drug Administration

Sites of Intramuscular Injection (2)

Sites of Subcutaneous Injection

Parenteral Routes (Summary)

Other Common Routes

The Goal of Drug Therapy

Regimen A is better than Regimen B (dose too high, causing toxicity).

Absorption of a drug is a complex process that depends on

The Anatomy of the Gastrointestinal Tract

Absorption of Drugs by the Gastrointestinal Tract (GIT)

The above information is for small molecule drugs in general.

Oral Bioavailability (F)

The Time Course of Drug Effect

Principle on Drug Distribution

Tissue-bound drug may serve as a reservoir.

Package Insert: Ambien

Volume of Distribution (Vd)

There are four major factors that may affect clearance:

Individualizing Dosage in Renal or Hepatic Disease

Biliary and Fecal Excretion

Agonists: drugs mimicking physiological activity

Actions of Drugs not Mediated by Recpetors

The binding of a drug to a receptor is determined by the following forces:

Intrinsic Activity: A measure of the ability of a drug to generate an effect

Selectivity Vs. Site of Drug Action

Receptor Up- and Down-Regulation

Tachyphylaxis: Rapid desensitization

Strcuture-Activity Relationship (SAR)

Pharmacophore:A set of structural features (the chemistry) in a molecule that is recognized at a

Receptors And Signal Transduction

Important General Properties of Signal Transducing Receptors

Voltage-Gated Ion Channel

G- proteins are signal transducers

Dose-Response Curves: Agonists and Antagonists

Understanding Ligand/Drug Affinity

Pharmacophore Interaction with the Ligand Binding Site (amino acid)

Ligand-Binding Isotherm Receptor-Ligand Interaction

Units for Affinity Measurement

Full Vs. Partial Agonist

Competition Between Agonist and Partial Agonist

Drug Binding Inhibition

i When drug I is present at increasing concentrations, it is necessary to apply higher concentrations of

Key features of a competitive antagonist:

At higher concentrations of drug B, there is a decrease in the maximal response of drug A.

Other Antagonistic Mechanisms

Synergism Vs. Additivity

Dose Response Curve

Types of Dose Reponses

Graded Dose-Response Curve Lidocaine Quantal Dose-Response

Quantal Dose-Response Distribution Cumulative Dose-Response Curve

Potency Vs. Efficacy