General Princples of Pharmacology_Approach to Learning Pharmacology

GENERAL PRINCIPLES OF
PHARMACOLOGY
Approach to Learning
Pharmacology
Marc Imhotep Cray, M.D.

Pedagogical Approach
2
 This course sets out to provide an understanding of scientific and
clinical pharmacology within the framework of biochemistry,
physiology and pathophysiology, travelling from drug effects on
molecular targets to their effects on the whole-organism.
In other words,
 You will be learning pharmacology using an approach that
integrates the actions of medications (drugs) starting from the
level of molecular targets (biologic effects) to the level of the
clinical patient (therapeutic and adverse effects), relying on
kindred basic medical sciences as the scaffolding.

“What Is Pharmacology?”
…“Medical pharmacology is a bridge between basic medical
science and clinical medicine. It makes use of all the disciplines that
comprise the scientific foundation of clinical medicine; including
anatomy, physiology, pathophysiology, pathology and immunology
biochemistry, molecular and cell biology, epidemiology, genetics and
genomics. Hence…it is particularly useful for pre-clinical student to
view and engage the subject as a major horizontal and vertical
integrator, as it pulls together all the different strands of the basic
medical science years and simultaneously introduces one to the
cornerstone of modern clinical therapeutics, i.e. drugs”…
Cray MI. Integrated Scientific and Clinical Pharmacology: A Course Syllabus and
Digital Guidebook for Medical Students. Atlanta, Georgia: IVMS, 2015; 4.
3

4
Psychology
Clinical Medicine &
Therapeutics
Veterinary
Medicine
Pharmacy Biotechnology Pathology Chemistry
Psycho-
pharmacology
Clinical
Pharmacology
Veterinary
Pharmacology
Pharmaceutical
Science
Bio-
pharmaceutics
Toxicology
Medicinal
Chemistry
PHARMACOLOGY
Pharmacokinetics &
Pharmacodynamics
Biochemical
pharmacology
Molecular
pharmacology
Chemotherapy
Systems pharmacology
Neuropharmacology
Respiratory
pharmacology
Gastrointestinal
pharmacology
Immunopharmacology
Cardiovascular
pharmacology
Endocrine
pharmacology
Pharmacogenetics Pharmacogenomics Pharmacoepidemiology Pharmacoeconomics
Genetics Genomics Clinical Epidemiology Health Economics
The Scope of Pharmacology

Importance of the GPs of Pharmacology
5
 The general principles of pharmacology are absolutely key to
gaining an understanding of how drugs exert their therapeutic and
adverse effects
 General principles are at the core of organ-systems
pharmacology, as you will be applying these principles during the
study of drug classes/organ-systems pharmacology
 Therefore, a strong knowledge of general principles will help you most
with your study of organ-systems pharmacology, as well as the prudent
application of pharmacotherapeutics during your clinical medicine training

Learning Objectives
6
1. To understand some key terms and concepts related to the
general principles of pharmacology (pharmacokinetics and
pharmacodynamics).
2. To understand the approach to the study of disease within a
medical pharmacology and therapeutics framework.
3. To understand how one should approach the study of
pharmacology and the rational underlying. (Main Objective)
Note: The terms, concepts and mechanisms provided herein are not
intended as complete discussions. Rather, they are only introduced here as
“stair-steps” and to encapsulate Objective 3. They will be explored in more
detail further in the course of study.

Lecture Outline
7
 Approach to Learning Pharmacology
o Key Terms and Concepts
o Mechanisms of Drug Action
• 4 Levels of complexity
 Approach to Disease
 Approach to Reading & Studying Pharmacology
o “The seven key questions”
 Key Points Capsule
 Comprehension Q & A
 Further Study: IVMS Tools and Resources

1. Approach to Learning Pharmacology
8
Pharmacology is best learned by a systematic approach
 understanding physiology of body
 recognizing every medication (drug) has desirable and
undesirable effects and
 being aware biochemical and pharmacologic properties of a
drug affects its characteristics such as…
o duration of action
o volume of distribution
o passage through blood-brain barrier
o mechanism of elimination, and
o route of administration

Approach to Learning Pharmacology (2)
9
 Rather than memorizing characteristics of a medication,
one should strive to learn underlying rationale for
example
 Second-generation antihistamine agents are less lipid soluble
than first-generation antihistamines  therefore 2nd Gen.
agents do not cross blood-brain barrier (BBB) as readily thus,
2nd Gen. antihistamines are not as sedating
 b/c they both bind histamine H1 receptor, efficacy is same in
treating conditions for which they are indicated (e.g., allergic
rhinitis )

Key Terms and Concepts
10
 Pharmacology: The study of substances that interact with living
systems through biochemical processes.
 Drug (medication): A substance used in prevention, diagnosis, or
treatment of a disease or prevention of reproduction.
 Toxicology: A branch of pharmacology that studies undesirable
effects of chemicals on living organisms.
 Food and Drug Administration (FDA): Federal agency responsible
for safety & efficacy of all drugs in U.S, as well as food & cosmetics.
 Adverse effect: Also known as side effect; all unintended actions
of a drug that result from lack of specificity of drug action.
N.B. All drugs are capable of producing adverse effects>>>toxicity

Key Terms and Concepts(2)
11
Classically there are two major divisions of pharmacology:
pharmacodynamics and pharmacokinetics
 Pharmacodynamics (PD): The actions of a drug on a living
organism, including mechanisms of action and receptor interaction.
 How the drug affects the body
 Pharmacokinetics (PK): The actions of the living organism on the
drug, including absorption, distribution, and elimination.
 How the body affects the drug
Third emerging division
 Pharmacogenomics: study of how genomic makeup affects PD &PK
 affects drug selection and application to individual patients based on
interindividual variations in the handling of drugs based on genetics

Pharmacogenomics
12
“Pharmacogenomics may hold the opportunity of allowing
practitioners to integrate a molecular understanding of the
basis of disease with an individual's genomic makeup to
prescribe personalized, highly effective, and safe therapies.”
Roden DM. (2012) Ch. 5 Principles of Clinical Pharmacology. In: Longo DL, Fauci AS,
et al. Harrison's Principles of Internal Medicine,18th Ed., McGraw-Hill 2012, 33.
NB “Drug-gene testing is also called
pharmacogenomics, or pharmacogenetics.
All terms characterize the study of how your genes
affect your body's response to medications.”
Link to see animation and transcript: http://mayoresearch.mayo.edu/center-
for-individualized-medicine/drug-gene-testing.asp

Major PD and PK Components & Parameters
13
Trevor AJ, Katzung BG, Kruidering-Hall M , Masters SB. Katzung & Trevor's Pharmacology Examination
& Board Review 10th Ed. New York: McGraw-Hill, 2013.

Relationship between PK and PD
Pharmacokinetics Pharmacodynamics
Dose of drug
Drug concentration
in target organ
over time
Mechanism and
magnitude of
drug effect
Absorption
Distribution
Biotransformation
Excretion
Receptor binding
Signal transduction
Physiological effect
Redrawn after Brenner GM and Stevens CW. Pharmacology 4th ed. Sanders, 2014.
14

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 Potency of drug (x-axis on dose-response curve): Relative amount of drug
needed to produce a given response
 determined by amt. of drug that reaches site of action and by affinity of
drug for receptor
 Efficacy (y-axis on dose-response curve): Drug effect as maximum response it is
able to produce
 determined by number of drug-receptor complexes and ability of
receptor to be activated once bound (intrinsic activity)
• EC50 [also ED50 in many text] refers to drug concentration that produces 50
percent of maximal response (Graded curve); whereas
• ED50 (Quantal curve) refers to drug dose that is pharmacologically effective in 50
percent of population
NB-There are two types of dose-response curves--graded and quantal--
each provides useful information for therapeutic decisions…see next slide

Dose-Response (Concentration) Curves
16
Bardal KS, Waechter JE, Martin DS. Applied Pharmacology. St. Louis: Saunders, 2011.
Graded dose-response curve
Quantal dose-response curve:
A graph of the fraction of a population that shows a
specified response at progressively increasing doses
A graph of increasing response to increasing drug
concentration or dose

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 Agonist: A drug that activates its receptor upon binding
 Affinity and intrinsic activity; whereas, antagonists have affinity but no IA
Antagonist: A drug that attenuates effect of an agonist
 Can be competitive or non-competitive each of which can be reversible
or irreversible
 Pharmacologic antagonist: A drug that binds without activating its
receptor and thereby prevents activation by an agonist
 Competitive antagonist: A pharmacologic antagonist that can be
overcome by increasing conc. of agonist
 Non-competitive antagonist: binds to an allosteric (non-agonist)
site on receptor to prevent activation of receptor

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 Reversible antagonist: binds non-covalently to receptor
therefore can be “washed out”
 A pharmacologic antagonist that can be overcome by increasing agonist
conc.
 Irreversible antagonist: binds covalently to receptor and cannot
be displaced by either competing ligands or washing
 A pharmacologic antagonist that cannot be overcome by increasing
agonist conc.
 Physiologic antagonist: A drug that counters effects of another by
binding to a different receptor and causing opposing effects

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Potential mechanisms of drug interaction with a receptor
Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed.
New York: McGraw-Hill, 2012; Fig. 1–3.)
Possible effects resulting from these
interactions are diagrammed in dose-
response curves at right
 Ligand: A substance that forms a
complex with a biomolecule (receptor)
to serve a biological purpose
 Receptor: A molecule to which a ligand
(drug) binds to bring about a change in
function of biologic system
 Receptor site: Specific region of
receptor molecule to which drug binds
 Effector: Component of a system that
accomplishes biologic effect after
receptor is activated by an agonist
 often a channel or enzyme molecule
may be part of receptor molecule itself

Marc Imhotep Cray, M.D. 20
Routes of administration (RoA)
Path by which a drug, fluid or poison is taken into body
 Routes can also be classified based on where target of
action is
 Action may be topical (local)
 Enteral (system-wide effect, but delivered through GIT), or
 Parenteral (systemic action, but delivered by routes other
than GI tract)

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 Route of administration: Drug may be delivered
 intravenously (IV) for delivery directly into bloodstream
 intramuscularly (IM), and
 subcutaneously (SC)
 Medication may be
 depot and slow release
 inhalant for rapid absorption & delivery to bronchi & lungs
 sublingual to bypass first-pass effect
 intrathecal for agents that penetrate BBB poorly
 rectal to avoid hepatic first-pass effect and for N/V, and
 topical administration when local effect is desired such as
dermatologic or ophthalmic agents
Lippincott Illustrated Reviews: Pharmacology
Sixth Ed. Wolters Kluwer, 2015.

22
Absorption: Movement of a drug from administration site into blood
stream usually requiring crossing of one or more biologic membranes
Important parameters include
• lipid solubility
• ionization
• size of molecule and
• presence of a transport mechanism

23
 Bioavailability: The percentage of an
ingested drug that is actually absorbed
into bloodstream
 By definition, intravascular doses have
100% bioavailability, f = 1.
Lippincott Illustrated Reviews: Pharmacology
Sixth Ed. Wolters Kluwer, 2015.
 Factors that influence bioavailability:
o First-pass hepatic metabolism
o Solubility of the drug
o Chemical instability
o Nature of the drug formulation

24
 Volume of distribution (Vd): The size of “compartment” into
which a drug is distributed following absorption
 ratio of amt. of drug in body to drug conc. in plasma or
blood Units=liters
 determined by equation: Vd = Dose (mg) drug
administered/Initial plasma concentration (mg/L)

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 Elimination: Process by which a drug is removed from body,
generally by either metabolism (biotransformation) or excretion
 Elimination=biotransformation (liver…) + excretion (kidneys…)
 Elimination follows various kinetic models For example
 First-order kinetics describes most circumstances means that rate of drug
elimination depends on concentration of drug in plasma as described by
equation: Rate of elimination from body = Constant × Drug concentration
 Zero-order kinetics: It is less common (PEA) means that rate of
elimination is constant does not depend on the plasma drug
concentration
• consequence of a circumstance such as saturation of liver enzymes or
saturation of kidney transport mechanisms

26
 Clearance: Ratio of rate of elimination of a drug to
concentration of drug in plasma or blood
 Units: volume/time, eg, mL/min or L/h
 Half-life: Time required for amount of drug in body or
blood to fall by 50%
 For drugs eliminated by first-order kinetics this number is a
constant regardless of concentration
 Units: time

Mechanisms of Drug Action
Drug effects are produced by altering normal functions of cells and
tissues via one of four general mechanisms:
1. Interaction with receptors (major)
Ligand-activated ion channels
G-protein–coupled receptors
 Gαs-coupled receptors
 Gαi (Ginhibitory)-coupled receptors
 Gq (and G11)-coupled receptors
Intracellular nuclear receptors
Receptor-activated tyrosine kinases
2. Nonspecific chemical or physical
interactions (least common)
 e.g., antacids
3. Antimetabolite action
 e.g., ChemoTx agents
4. Alteration of the activity of enzymes
 increasing or decreasing
27
Important Notes:
• Drugs do not produce new function/s in body, but rather augment nml physiologic and biochemical
mechanisms
• No drug has a single action, but rather, both therapeutic & adverse actions or multiple effects
• Drug vs poison is dose related, as all drugs are poisons when introduced at a high enough dose

Marc Imhotep Cray, M.D. 28
Drugs act at four different levels:
1) Molecular: protein molecules are immediate targets
for most drugs. Action here translates into actions at
next level
2) Cellular: biochemical and other components of cells
participate in the process of transduction
3) Tissue: the function of heart, skin, lungs, etc., is then
altered
4) System: the function of the cardiovascular, nervous,
gastrointestinal system, etc., is then altered
Mechanisms of Drug Action (2)

Mechanisms of Drug Action (3)
29
 To most clearly understand pharmacologic actions of
drugs (agonist and antagonist) it is necessary to know:
 which molecular targets are affected by the drug,
 nature of this molecular interaction,
 nature of the transduction system (the cellular
response),
 types of tissue that express the molecular target and
 mechanisms by which the tissue influences the body
system
NB. It is important to consider MOA of drugs
at each of the four levels of complexity.

The four levels of MOA illustrated
30
Propranolol, a β adrenergic antagonist used to treat several
diseases including angina pectoris, a cardiac condition
resulting from localized ischemia (i.e. insufficient blood flow)
in heart:
 At the molecular level, propranolol is a competitive and
reversible antagonist to action of epinephrine (Epi) and
norepinephrine (NE) on cardiac β adrenoceptors

Four levels of MOA cont.
31
 At the cellular level, propranolol prevents β adrenergic
agonism from elevating intracellular cyclic adenosine
monophosphate (cAMP), initiating protein
phosphorylation, Ca2+ mobilization and oxidative
metabolism
 At the tissue level, propranolol prevents β adrenergic
agonism from increasing contractile force of heart and
heart rate, i.e. it has negative inotropic and negative
chronotropic effects

Four levels of MOA cont.
32
 At a system level, propranolol improves cardiovascular
function
 It reduces heart's β adrenergic responses to
sympathetic nervous system activity thereby
decreasing requirements for blood flow (O2 demand)
in heart tissue useful if blood supply is limited (e.g. in
coronary artery disease)

2. Approach to Disease
33
Physicians approach clinical situations by
 taking a history (asking questions)
 performing a physical examination
 obtaining selective laboratory and imaging tests, and
 then formulating a diagnosis
The synthesis of history, physical examination, and
imaging or laboratory tests is called the clinical database
After reaching a diagnosis a treatment plan is initiated,
and patient is followed for a clinical response

Approach to Disease (2)
34
 Rational understanding of disease (pathologic,
microbiologic, immunologic and (or) behavioral) and plans
for treatment (therapeutics) are best acquired by learning
about normal human processes on a basic science level
(physiology, biochemistry neuro and behavioral science)
 likewise, being aware of how disease alters normal
physiologic processes is also best understood on a basic
science level (pathology, pathogenesis & pathophysiology)
 Sn & Sx of disease

Approach to Disease (3)
35
 Pharmacology and therapeutics require also ability to
tailor correct medication (drug) to patient’s situation and
awareness of medication’s adverse effect profile
 Sometimes, a patient has an adverse reaction to a drug as
chief complaint one must be able to identify medication as
culprit
 Again, an understanding of underlying basic science allows
for more rational analysis and drug (medication) choices

3. Approach to Reading & Studying Pharmacology
36
 There are seven key questions that help to stimulate
application of basic science information to clinical setting
These are:
1. Which medications is most likely to achieve desired therapeutic
effect and/or is responsible for described symptoms or signs?
2. What is likely mechanism for clinical effect(s) and adverse effect(s)
of medication?
3. What is basic pharmacologic profile (e.g., absorption, elimination)
for medications in a certain class, and what are differences among the
agents within the class?

Approach to Reading and Studying Pharm (2)
37
4. Given basic pharmacologic definitions such as therapeutic index (TI)
or certain safety factor (TD1/ED99), or median lethal dose (LD50), how
do medications compare in their safety profile?
5. Given a particular clinical situation with described unique patient
characteristics, which medication is most appropriate?
6. What is best treatment toxic effect of a medication?
7. What are drug-drug interactions to be cautious about regarding a
particular medication?
In the following slides we will discuss a bit more about each of these seven
key questions, explaining how they help to stimulate application of basic
science information to the clinical setting.

1. Which drug is most likely responsible for
described symptoms or signs?
38
 One must be aware of various effects, both desirable (therapeutic)
and undesirable (ADR), produced by particular medications
 Knowledge of desirable therapeutic effects is essential in selecting
appropriate drug for particular clinical application
 Likewise, an awareness of its adverse effects (AE) is necessary, b/c
patients may present with a complaint caused by a drug effect
unaware that their symptoms are b/c of the prescribed drug
 only by being aware of common and dangerous effects can one arrive at
correct diagnosis
 Learners are encouraged not to merely memorize comparative
adverse effect profiles of drugs but rather to understand
underlying biochemical and physiological mechanisms

2. What is mechanism for clinical effect(s) and
adverse effect(s) of drug?
39
As noted one should strive to learn underlying physiologic,
biochemical, and (or) cellular explanation for drug effect
 allows for rational choice of an alternative agent or reasonable choice of
an agent to alleviate symptoms or explanatory advice to pt. regarding
behavioral changes to diminish any adverse effects
o For example, if a 60-year-old woman who takes medications for
osteoporosis complains of severe “heartburn” one may be
suspicious, knowing that bisphosphonate medication alendronate can
cause esophagitis
• Instruction to patient to take medication while sitting upright and remaining
upright for at least 30 minutes would be proper course of action, b/c gravity will
assist in keeping alendronate in stomach rather than allowing regurgitation into
distal esophagus

3. What is basic pharmacologic profile for drugs in
a certain class, and what are differences among
agents within said class?
40
 Understanding pharmacologic profile of medications allows
for rational therapeutics 
 instead of memorizing separate profiles for every medication,
grouping drugs together into classes allows for more efficient
learning and better comprehension
 Excellent starting point is to study how a prototype drug within a
drug class organized by structure or mechanism of action may be
used to treat a condition (such as hypertension) 
o Then within each category of agents, one should try to identify
important subclasses or drug differences

Pharmacologic profile of a drug and differences among
agents within class (2)
41
 For example, anti-hypertensive agents can be categorized as
 diuretic agents
 β-adrenergic-blocking agents
 calcium-channel-blocking agents, and
 renin-angiotensin system inhibitors= ACEI & ARBs
 Within subclassification of renin-angiotensin system inhibitors,
angiotensin converting enzyme inhibitors (ACEI) can cause
adverse effect of a dry cough caused by increase in bradykinin
brought about by enzyme blockade
 instead, angiotensin-1 receptor blockers (ARBs) do not affect
bradykinin levels and so do not cause cough as often

4. Given basic pharmacologic definitions such as
(TI) or (TD1/ED99), or (LD50), how do medications
compare in their safety profile?
42
 Therapeutic index (TI): Defined as TD50/ED50 (ratio of dose that
produces a toxic effect in half population to dose that produces
desired effect in half population)
 Certain safety factor (TD1/ED99): Defined as ratio of dose that
produces toxic effect in 1 percent of population to dose that
produces desired effect in 99 percent of population also known
as standard safety measure
 Median lethal dose (LD50): Defined as the median lethal dose, the
dose that will kill half the population

TI or TD1/ED99, or LD50 (2)
43
 Based on these definitions, a desirable medication would
have a high therapeutic index (toxic dose is many times
that of efficacious dose), high certain safety factor, and
high median lethal dose (much higher than therapeutic
dose)
 Likewise, medications such as digoxin that have a low
therapeutic index require careful monitoring of bld
levels and vigilance for adverse effects

5. Given a particular clinical situation with
described unique patient characteristics, which
medication is most appropriate?
44
One must weigh various advantages and disadvantages, as
well as different patient attributes
Some of those may include
 compliance with medications
 allergies to medications
 liver or renal insufficiency
 age
 coexisting medical disorders, and
 other medications

Unique patient characteristics (2)
45
One must be able to sift through medication profile and
identify most dangerous adverse effects
For example,
 if a patient is already taking a monoamine-oxidase-
inhibiting agent (Selegiline) for depression then adding
a serotonin reuptake inhibitor [Fluoxetine (Prozac)]
would be potentially fatal, b/c serotonin syndrome may
ensue (hyperthermia, muscle rigidity, death)

46
Unique patient characteristics (3)
Patient profile
Age
Weight
Sex
Race
Allergies
Smoking history
Alcohol history
Diseases
Pregnant/lactating
Current therapy
Intelligence
Drug profile
Name (generic)
Class
Action
Pharmacokinetics
Indications
Contraindications/
precautions
Interactions
Adverse effects
Dosing regimen
Monitoring
Overdose/Antidote
Patient profile
 The patient is a unique individual,
with many distinguishing features that need
to be taken into account during prescribing
Drug profile
 The drug, likewise, is unique, with its
own distinguishing features
 Good prescribing involves tailoring drug
and dosing regimen to unique patient
o Clinical pharmacology provides basis
of this pharmacotherapeutic
principle
 Clinical pharmacology is a complex interaction betw. pt. and drug

6. What is best treatment for toxic effect of a
medication?
47
 If complications of drug therapy are present one should
know proper treatment
 best learned by understanding drug MOA
For example, a pt. who has taken excessive opioids may
develop respiratory depression, caused by either a heroin
overdose or pain medication may be fatal
o Tx of an opioid overdose includes
• ABCs (airway, breathing, circulation) and
• administration of naloxone, which is a competitive
antagonist of opioids

7. What are the drug-drug interactions to be
concerned with regarding a particular medication?
48
 Patients are often prescribed multiple medications, from
same practitioner or different clinicians
 Pts may not be aware of drug-drug interactions thus, a
clinician must compile pt. to maintain a current list of all
medications (Rx, OTC, and herbal) taken by patient
 Thus, one should be aware of most common and
dangerous drug-drug interactions
 again, understanding underlying mechanism allows for lifelong
learning rather than short-term rote memorization of facts that
are easily forgotten

Drug-drug interactions (2)
49
 For example, magnesium sulfate to stop preterm labor
should not be used if patient is taking a calcium-channel
blocking agent such as nifedipine
 Magnesium sulfate acts as a competitive inhibitor of
calcium and by decreasing its intracellular availability
it slows down smooth muscle contraction such as in
uterus
 Calcium-channel blockers potentiate inhibition of
calcium influx and can lead to toxic effects such as
respiratory depression

Key Points Capsule
50
❖ Understanding the pharmacologic mechanisms of drugs
allows for rational choices for therapy, fewer medication
errors, and rapid recognition and reversal of toxic effects
❖ The therapeutic index, certain safety factor (TD1/ED99), and
median lethal dose are various methods of describing the
potential toxicity of medications
❖ There are seven key questions to stimulate the application
of basic science information to the clinical arena

Key Points Capsule (2)
51
Focus of study for each drug:
 Classification and class prototype/s (as applicable)
 Mechanism of action-biologic, therapeutic and adverse
 Indications (therapeutic use)
 Adverse effects (common vs dangerous)
 Drug-drug interactions, cautions and contraindications
 Pharmacokinetic properties, drug-disease interactions and
other patient-specific considerations
 Toxicities and antidotes (or) treatment

“What Is Pharmacology?” A Capsule
…“Medical pharmacology is a bridge between basic science and
clinical medicine. It makes use of all the disciplines that comprise the
scientific foundation of clinical medicine; including anatomy,
physiology, pathophysiology, pathology and immunology
biochemistry, molecular and cell biology, epidemiology, genetics and
genomics. Hence…it is particularly useful for pre-clinical student to
view and engage the subject as a major horizontal and vertical
integrator, as it pulls together all the different strands of the basic
medical science years and simultaneously introduces one to the
cornerstone of modern clinical therapeutics, i.e. drugs”…
Cray MI. Integrated Scientific and Clinical Pharmacology: A Course Syllabus and
Digital Guidebook for Medical Students. Atlanta: IVMS, 2015; 4.
52

Question
54
1. Bioavailability of an agent is maximal when the drug has
which of the following qualities?
A. Highly lipid soluble
B. More than 100 Daltons in molecular weight
C. Highly bound to plasma proteins
D. Highly ionized

Answer
55
1. A. Transport across biologic membranes and thus
bioavailability is maximal with high lipid solubility.

Question
56
2. An agent is noted to have a very low calculated volume
of distribution (Vd). Which of the following is the best
explanation?
A. The agent is eliminated by the kidneys, and the patient
has renal insufficiency.
B. The agent is extensively bound to plasma proteins.
C. The agent is extensively sequestered in tissue.
D. The agent is eliminated by zero-order kinetics.

Answer
57
2. B. The volume of distribution is calculated by
administering a known dose of drug (mg) IV and then
measuring an initial plasma concentration (mg/L). The ratio
of the mass of drug given (mg) divided by the initial plasma
concentration (mg/L) gives the Vd. A very low Vd may
indicate extensive protein binding (drug is sequestered in the
bloodstream), whereas a high Vd may indicate extensive
tissue binding (drug is sequestered in the tissue).

Question
58
3. Which of the following describes the first-pass effect?
A. Inactivation of a drug as a result of the gastric acids.
B. Absorption of a drug through the duodenum.
C. Drug given orally is metabolized by the liver before
entering the circulation.
D. Drug given IV accumulates quickly in the central nervous
system (CNS).

Answer
59
3. C. The first-pass effect refers to the process in which
following oral administration a drug is extensively
metabolized as it initially passes through the liver, before it
enters the general circulation. Liver enzymes may metabolize
the agent to such an extent that the drug cannot be
administered orally.

Question
60
4. A laboratory experiment is being conducted in which a mammal is
injected with a noncompetitive antagonist to the histamine receptor.
Which of the following best describes this agent?
A. The drug binds to the histamine receptor and partially activates it.
B. The drug binds to the histamine receptor but does not activate it.
C. The drug binds to the receptor, but not where histamine binds, and
prevents the receptor from being activated.
D. The drug irreversibly binds to the histamine receptor and renders it
ineffective.

Answer
61
4. C. A noncompetitive antagonist binds to the receptor at a
site other than the agonist-binding site and renders it less
effective by preventing agonist binding or preventing
activation.

Question
62
5. A 25-year-old medical student is given a prescription for asthma,
which the physician states has a very high therapeutic index. Which
of the statements best characterizes the drug as it relates to the
therapeutic index?
A. The drug’s serum levels will likely need to be carefully
monitored.
B. The drug is likely to cross the blood-brain barrier.
C. The drug is likely to have extensive drug-drug interactions.
D. The drug is unlikely to have any serious adverse effects.

Answer
63
5. D. An agent with a high therapeutic index means the toxic
dose is very much higher than the therapeutic dose, and it is
less likely to produce toxic effects at therapeutic levels.

Question
64
6. A drug M is injected IV into a laboratory subject. It is noted
to have high serum protein binding. Which of the following is
most likely to be increased as a result?
A. Drug interaction
B. Distribution of the drug to tissue sites
C. Renal excretion
D. Liver metabolism

Answer
65
6. A. High protein binding means less drug to the tissue, the
kidney, and the liver. Drug interaction may occur if the agent
binds to the same protein site as other drugs, thus displacing
drugs and increasing serum levels.

Question
66
7. A bolus of drug K is given IV. The drug is noted to follow
first-order kinetics. Which of the following describes the
elimination of drug K?
A. The rate of elimination of drug K is constant.
B. The rate of elimination of drug K is proportional to the
patient’s renal function.
C. The rate of elimination of drug K is proportional to its
concentration in the patient’s plasma.
D. The rate of elimination of drug K is dependent on a
nonlinear relationship to the plasma protein concentration.

Answer
67
7. C. First-order kinetics means the rate of elimination of a
drug is proportional to the plasma concentration.

Further study tools and resources:
68
IVMS Online Medical Pharmacology Course (5 components):
Instructor: Marc Imhotep Cray, M.D. Course Website: Link
 Integrated Scientific and Clinical Pharmacology: A MS1 & MS2 Course Syllabus and Digital
Guidebook (2015)
• Medical Pharmacology: Core Concepts and Learning Objectives
• Medical Pharmacology Case Studies
• Medical Pharmacology Unit e-Notes
• Medical Pharmacology Glossary of Terms
e-Learning resource center: IVMS Medical Pharmacology Cloud Folder

General Princples of Pharmacology_Approach to Learning Pharmacology

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