PHARMACOLOGY QUIZLET

CHAPTER 1 INTRO TO PHARMACOLOGY the mechanism by which a dug interacts with and is
processed by the body
Drug
chemical that interacts with an organism to alter its Elimination
function, show biological processes and provide the mechanism by which a drug leaves the body
methods of diagnosis, treatment, and prevention of
disease Selectivity
the degree to which a drug acts at one specific site or
Pharmacology receptor
the study of the interaction of drugs with an organism
Lock and Key Receptor Theory
Pharmacodynamics a visual analogy that is used to describe interactions
the study of drugs modes of action on an organism between drugs or receptors

Pharmacy Racemic Drug

the practice of compounding and dispensing medicinal drugs that contain two isomers a part of a drug's
preparations chemical structure

Therapeutics Half-Life
the branch of medicine concerned with the application the amount of time it takes for a drug's concentration in
of remedies and the treatment of disease the body to decrease by half once administered

Hypersensitivity Loading dose

an exaggerated adverse reaction to drug
Toxicology
the study of drugs' toxic effects on an organism
Entral
absorbed through the gastrointestinal tract
administration of a higher dose than that used for
maintenance in order to rapidly increase drug
concentration
Maintenance dose
administration of a drug at dosage levels that maintain
a therapeutic drug concentration

Parenteral Potency
injected directly into the body relative drug strength

Transdermal Efficacy
absorbed through the skin using timed-release the degree to which a drug exerts its intended effect

Topical Idiosyncrasy
absorbed through the skin an unexpected reaction to a drug caused by unusual
susceptibility to the drug
Inhalation
absorbed through the respiratory tract or alveoli Agonist
drug action describing a drug that has an affinity for a
Pharmacokinetic receptor and activates a response
movement of the drug
Antagonist
Pharmacodynamic a drug action describing a drug that has an affinity for a
the drug has its effect receptor and does not activate a response

Absorption Additive
the mechanism by which a drug enters the body a drug action describing two drugs' effects as being
equal to the summation of their individual effects
Distribution
the mechanism by which the drug is transported to the Syergism
site of action drug action describing two drugs effects as being
greater than the summation of their individual effects
Metabolism with both drugs being active

1
PHARMACOLOGY QUIZLET

Potentiation Prescription
a drug action describing two drugs' effects as being includes name, strength, dosage, route of
greater than the summation of their individual effects, administration, frequency and length
with one drug being active and one drug being inactive

Cumulation Preventing Medication errors

a condition that exists when a drug's rate of elimination 5 Rights: drug, dose, pt, time, and route
or inactivation is slower than its rate of administration
QD
Tolerance Each Day
refer to the need for an ever increasing amount of a
drug to continue to produce a given effect QID
Four times daily
Tachyphylaxis
is a rapidly occurring form of tolerance Q2H
Teratogenicity Every 2 hours
a drug's potential to cause fetal damage in utero when
administered to a pregnant woman
Drugs
Lethal Dose50 Chemicals that act on livings systems at the molecular
the dose of a drug that is lethal in 50% of a test group level.
of animals
Receptors
Effective Dose50 Specific molecules in a biological system that mediate
the dose of a drug that is therapeutically effective in drug effects.
50% of a test group of animals
Pharmacology
Therapeutic Index Study of the action of drugs and effects on a living
the ratio of Lethal Dose50/Effective Dose50 system.

Chemical Name Medical Pharmacology

this is the first name a potential drug receives
Code Name
this is a name assigned to the chemical by its
manufacturer during the testing process
Generic Name
this is the name assigned to the chemical by the USAN
when it appears to have therapeutic value and the
manufacturer wants to market it
Official Name
the Generic name becomes the Official name when the
drug receives approval from the Food & Drug
Administration
Study of drugs used for the diagnosis, prevention, and
treatment of disease.
Toxicology
Branch of pharmacology that deals with the untoward
effects of drugs on living systems.
History of Pharmacology
Prehistoric methods were ineffective/toxic.
Relied on "serendipity" -- the idea that if it worked we
do it. Based only on effectiveness.
Eventually replaced by observation and experiment,
however, molecular level of knowledge was lacking.
Chemistry and Physiology lead us to know how drugs
work on the organ level.

Trade Name History of Pharmacology (Continued)

name given to a drug by its manufacturer when the In last 50 years: Advent of the controlled clinical trial.
drug is marketed -Accurate evaluation of therapeutic claims.
Research allowed us to:
Official Source of Information -Gain info of drug action and receptor
Government issued -Improve understanding of molecular basis of drug
action
Unofficial Source of Information
Non-Government issued Pharmacogenetics
The relation of a person's specific genetic makeup to
his or her response to specific drugs.

2
PHARMACOLOGY QUIZLET

Enantiomers
Therapeutic effects Dextro and Levo. D and S.
Effects of a drug that help cure or prevent the disease. E.G. Prilosec Vs. Nexium
Prilosec: Omeprazole, racemic, S has activity.
Toxic effects Nexium: Esomeprazole, S isomer, absorption/ half life
Effects of a drug that cause secondary toxic effects. +,
Extended patent life = + money for company.
ADME
Absorption, Distribution, Metabolism, Elimination Most start racemic but eventually produced as single
isomer
Drug properties
Gas, solid, liquid, gel, suspension, solution. Pharmacodynamics
Actions of drug on body:
Factors in Aqueous Solution -Determines classification
Ionization, solubility, stability. -Determines appropriate therapy

Factors for Acting on Membranes Pharmacokinetics Definition

Lipid solubility, Diffusion, Receptor binding, Partitioning, Actions of body on drug:
Blood flow. -ADME
-Choice and administration of drug to specific patient
Drug Size
Commonly between 100-1000MW. PharmacoD. Conc./Resp.
-100MW to achieve selectivity (sufficient binding). Pharmacodynamics studies the relationship between
-1000MW to allow for proper distribution. concentration and response. The concentration of the
-If greater than 1000MW, needs to be administered at drug at the site of action, and the beneficial and toxic
site. effects.
-Depends on: CONCENTRATION
Drug Receptor Interactions
Dependent on: Concentration-response curve
-Size, shape, charge, atomic makeup Plots concentration of drug versus % of maximum
-Structure + specificity effect whether therapeutic or toxic.
-3 point attachment
-Specific, mimic endogenous Drug receptors
Most are proteins.
Affinity -Selective, and change function upon binding.
Strength of the bond that a drug has to receptor. Affects -Drugs typically look like endogenous molecule.
potency. High affinity = high potency.
Agonist
Selectivity Activate receptor
Also known as specificity. Determined by type of bond.
High specificity = few effects in body. Low specificity = Antagonist
side effects all over. Prevents action at a receptor

Covalent Bonds Pharmacokinetics Imp. stuff

Covalent / Strong bond = less selectivity (but more ADME.
reactivity) Bile = feces
-commonly irreversible Kidneys = urine
Noncovalent = most common = more selectivity (less
reactivity) Absorption
-Hydrogen, Van der Waals', ionic. The measure of how quickly a drug gets into the
-Commonly reversible bloodstream

Drug Shape Common routes of absorption

Should complement receptor site. PO/PR (oral/anal)
Many exist as chiral molecules, thus have enantiomers. Inhaled, topical, transdermal,sublingual
Dextro = Right = D Intramuscular, intravenous, subcutaneous
Levo = Left = S

3
PHARMACOLOGY QUIZLET

Drug formulations FDA Modernization Act

Affect absorption. 1997: Recognized changes needed to be made for 21st
Depends on: century.
-Barriers drug is capable of passing (B/b. B/t)
-Setting in which drug will be used (Hospital vs. home) Pediatric Research Equity Act
-Urgency of situation 2003: Requires tests in pediatrics for certain drugs for
-Drug stability certain circumstances
-First pass effect
Dietary Supplement and Non-Script Drug Consumer
Distribution Protection Act
Movement of drug from site of administration to other 2006: Requires serious adverse event reporting for
parts of the body. dietary or nutrition supplements. Non regulated so far.
Depends on:
-Vascularity. Higher = higher uptake (EG Brain/kidneys) FDA
-Drug solubility in certain tissue Responsible for approval of new drugs, and oversight
-Binding of drug to macromolecules in blood IE. of marketing/sale of drugs on market.
Albumin Prescription and OTC included
-Ability to cross special barriers IE Blood brain Blood
testes DEA
Drug enforcement agency:
Elimination Classifies drug schedules on basis of abuse potential.
2 major routes.
Metabolism: Enzymatic conversion of drugs to inactive Who can write scipts?
derivatives, more polar, more water soluble, enzymes in Depends on states.
GI and liver.
Excretion: Follows metabolism or unchanged Stages of Drug Approval
Kidneys = urine 0-4 years: Preclinical: In-vitro animal testing
Liver/bile = feces 4-8 years: Human clinical trials
8-20 years: Exclusive marketing rights
Drug legislation prior to 1906 20+ years: generics form
No regulation on sale of drugs.
-Outrageous claims of benefit and safety Human Clinical Testing Phase 1
-Unregulated use of addictive substances 25-50 HEALTHY volunteers, look for toleration, check
for safe clinical dosing range. Evaluate
Federal Pure Food and Drug Act pharmacokinetics
1906: Active ingredients placed on label, purity levels
maintained. Human Clinical Testing Phase 2
-not for efficacy, just purity. 100-200 SICK volunteers are tested. Assess dose-
1912: Amended to stop false advertising claims efficacy relationship.
Dose to pharmacological/therapeutic effect.
Food Drug and Cosmetic Act
1937: Diethylene gloycol in sulfanilamide elixir kills Human Clinical Testing Phase 3
hundreds 1000s of people. Randomized controls in actual
1938: FDCA: Label with direction for safe use / conditions.
Preapproval for safety Establish safety in patients with disease, and efficacy
compared to other treatments.
Durham-Humphrey Act
1952: Prescription vs. OTC defined and federally Human Clinical Testing Phase 4
regulated (FDA) Post marketing surveillance. Safety under actual life
conditions.
Kefauver-Harris Amendment
1962: Thalidomide babies in non USA. Proprietary Drug
Required efficacy in addition to safety. Drug with trade name, protected under patent.
Patent life = 20 years. Drugs are frequently patented 5
Controlled Substances Act years before marketing. After patents expire other
1970: Scheduled drugs companies can create bioequivalent generic drugs.
More familiar to outpatient settings.

4
PHARMACOLOGY QUIZLET
Generic Drug
Drug made from a once-patented formula. Cheaper,
less "development" cost. Must have same
pharmacokinetic properties as original. Promoted in
hospitals, cheaper.
Chemical name
Not used in practice, but in lab. Long ass. Ridic.
Drug Naming Example
Nexium.
Esomeprazole magnesium
(S)-5-methoxy-2-[(4-methoxy-3,5 dimethylpyridin-2-yl)
methylsulfinyl]-3H-benzoimidazole
CHAPTER 2 DRUG RECEPTOR AND
PHARMACODYNAMICS
What are effectors?
molecules that accomplish a biological effect after
being activated by a receptor/e.g. translate drug-
receptor interaction into a change in cellular activity
What are major receptor mechanisms (4)
ligand gated channels, GPCRs, Kinase linked
receptros, hormonal receptors
What are the three main classes of receptor
molecules?
proteins, nucleic acids, membrane lipids
Broadly, what are five protein based receptor
molecules?
hormones, receptor or voltage gated ion channels,
enzymes, transport proteins, structural proteins
What is drug receptor theory (broadly)?
The size, shape, and electrical charge of a drug
determine its binding affinity to a particular receptor,
relative to other possible binding ssites
What is the name of a drug that activates a receptor?
agonist
What does an antagonist do?
block the action of an agonist (so nothing happens)
In the absence of an agonist, what happens if you give
an antagonist?
nothing. nothing happened before, so nothing will
continue to happen. much like my social life.
What is the broad use of a dose response curve?
Determine quantitative relationship between dose or
concentration and its pharmacologic effect
If drug is D and R is receptor, then what is proportional
to the response?
RD (drug receptor interaction)
What are the axis (x and y) on a dose response curve?
y = e/Emax
What is the equation that models the dose response
curve?
e/Emax=([D]/[D]+ED50)
What does the dose response curve level off at high
drug concentrations?
response saturates
What does the term potency refer to?
concentration (EC50 or ED50) required to produce 50%
of the drug's individual maximal effect
Broadly, what are the factors that impact potency?
affinity of receptors for binding the drug, and the
efficiency of the drug receptor complex to generate a
repsonse
What is the most important determinant of a drug's
clinical utility?
it's efficacy
What term is used interchangeably with efficacy?
power
What is an agonist (broadly)?
a drug that activates a receptor upon binding, bringing
about a characteristic tissue response
What is potency? (definition)
Dose or concentration (EC50, ED50) required to
produce 50% of that drug's individual maximal effect
What are the two factors that affect the relative potency
of a drug?
affinity (Kd) of the receptors for binding the drug,
efficiency of this drug-receptor complex for creating a
drug response
What is a full agonist?
drugs that occupy receptors and bring about a full or
maximal response
What is a partial agonist?
a drug that occupies the same receptor, but bring about
a less than maximal response
In clinical terms an efficacy refers to what?
the relative clinical effect of a given drug
What are the two categories of antagonists?
receptor antagonists, non receptor antagonists
5
PHARMACOLOGY QUIZLET
What are the two types nonreceptor antagonists?
chemical, physiological
What is the action of chemical antagonists?
binds the agonist directly
What is the action of physiological antagonists?
bind to a differen receptor
What are the two types of active site bind modes and
their relative classifications?
reversible (competitive), irreversible (non competitive)
How can a competitive, reversible antagonist be
overcome? What is its effect of potency, and ED50?
increase concentration of agonist, potency is reduced,
but ED50 remains the same
What is the effect of an irreversible, competitive agonist
on the dose response curve?
ED50 unchanged (e.g. potency is the same) but Emax
will be reduced (you are essentially removing
receptors)
The receptor's affinity for binding a drug determines the
concentration of drug required to form a significant # of
drug-receptor complexes, and the total # of receptors
may limit the maximal effect a drug may produce.
How do receptors largely determine the quantitative
relations b/t dose or concentration of drug &
pharmacologic effects?
The molecular size, shape, & electrical charge
determine whether, and with what affinity, it will bind to
a particular receptor among the different binding sites
available in a cell, tissue, or patient.
How are receptors responsible for selectivity of drug
action?
Agonists: Some drugs & many natural ligands
(hormones, NTs) activate the receptor to signal as a
direct result of binding to it; Antagonists: Other drugs
act by binding to receptors and interfere w/ the ability of
an agonist to activate the receptor
How do receptors mediate the actions of both
pharmacologic agonists & antagonists?
Receptors which ligands are yet still unknown
What are "Orphan" Receptors?
The best characterized drug receptors which mediate
the actions of endogenous chemical signals such as
NTs, autacoids, & hormones. These mediate the effects
of many agents.
What are Regulatory Proteins?
Enzymes (ex: Dihydrofolate reductase is the receptor
for the antineoplastic drug Methotrexate); Transport
Proteins (ex; Na+/K+ ATPase is the membrane receptor
for cardioactive Digitalis Glycosides); Structural
Proteins (Ex: Tubulin is the receptor for Colchicine, an
anti-inflammatory agent)
What are examples of how Enzymes, Transport
Proteins, & Structural Proteins serve as drug
receptors?
E = (Emax x C) / (C + EC50), where E is the effect
observed at concentration C, Emax is the maximal
response that can be produced by the drug, and EC50
is the concentration of the drug that produces 50% of
maximal effect
The relation b/t drug concentration & effect is described
by a Hyperbolic Curve according to which equation?
B = (Bmax x C) / (C + Kd), where B = total conc. of
receptor sites, Kd = equilibrium dissociation constant
which represents the conc. of free drug at which half-
maximal binding occurs, & C = conc. of free unbound
drug. The LOWER the Kd, the HIGHER the binding
affinity.
What is the equation that resembles the Mass Action
Law, which describes the association b/t 2 molecules of
a given affinity?
The transduction process that links drug occupancy of
receptors & pharmacologic response. Occurs after a
receptor is occupied by an agonist, the resulting
conformational change is only the 1st of many steps
usually required to produce a pharmacologic response.
What is Coupling?
Antagonists that reduce receptor activity below basal
levels observed in the absence of bound ligand
What are Inverse Agonists?
Higher concentrations of Agonist are required to
produce a given effect (agonist conc. is shifted to the
RIGHT, EC50 is changed); High Agonist concentrations
can OVERCOME inhibition by a Competitive Antagonist
How do Competitive Antagonists affect the Agonist
effect?
Reduces the maximal effect the Agonist can achieve by
irreversibly binding to a receptor, usually covalently,
preventing agonists from binding. (Curve does not shift,
EC50 stays the same usually)
How do Noncompetitive Antagonists affect the Agonist
effect?
Drugs that bind to a separate site on the receptor
protein & alter receptor function w/out inactivating the
receptor; Ex: Benzodiazepines bind noncompetitively to
6
PHARMACOLOGY QUIZLET
ion channels activated by the NT GABA, enhancing the
net activating effect of GABA on channel conductance
What are Allosteric Modulators? Example?
Partial Agonists produce a Lower Response, at Full
Receptor Occupancy than do Full Agonists when ALL
receptors are occupied; Partial Agonists do NOT
produce a Maximal Response b/c they competitively
inhibit the responses produced by Full Agonists
What are Partial Agonists?
One drug (positively charged Protamine) acts as a
chemical antagonist of the other (negatively charged
Heparin) simply by Ionic Binding that makes the other
drug Unavailable for interactions w/ proteins involved in
Blood Clotting
What is a Chemical Antagonist?
Glucocorticoid hormones lead to Increased Blood
Sugar, an effect opposed by Insulin. Insulin therefore is
administered to oppose the Hyperglycemic effects of a
Glucocorticoid hormone; Physiological Antagonist
produces less specific & less easy to control effects
than a receptor-specific antagonist
What is an example of Physiologic Antagonism?
1) A Lipid-Soluble Ligand that cross the membrane acts
on an Intracellular Receptor; 2) A Transmembrane
receptor protein whose intracellular enzymatic activity is
allosterically regulated by a ligand that binds to a site
on the protein's extracellular domain; 3) A
Transmembrane receptor that binds & stimulates a
Protein Tyrosine Kinase; 4) A Ligand-Gated
Transmembrane Ion Channel that can be induced to
open or close by the binding of a ligand; 5) A
Transmembrane receptor protein that stimulates a
GTP-binding signal transducer G protein, which in turn
modulates production of an intracellular 2nd messenger
What are 5 different ways that TransMEMBRANE
Signaling occurs?
Thyroid Hormones & Steroid Hormones
(Corticosteroids, Mineralocorticoids, Sex Steroids,
Vitamin D)
What are examples of Lipid-Soluble Ligands that when
binding to receptors, stimulate the transcription of
genes by binding to specific DNA sequences (response
elements) near the gene whose expression is to be
regulated?
1) The effect is produced 30 mins to several hours b/c
this is the time required for the synthesis of new
proteins; 2) Once the effects take place, they can
persist for Hours or Days after the Agonist
Concentration is at 0; This is due to the slow turnover of
most enzymes & proteins which remain active in cells
for hours to days after being synthesized
What are the 2 Therapeutically Important
Consequences of using Lipid-Soluble Agents such as
Steroid & Thyroid Hormones?
Insulin, EGF (epidermal), PDGF, ANP (atrial natriuretic
peptide), TGF-beta, & other trophic hormones
What are examples of Ligands used in Ligand-
Regulated Transmembrane Enzymes including
Receptor Tyrosine Kinases?
Begins w/ binding of ligand, typically a polypeptide
hormone or growth factor, to the receptor's extracellular
domain -> change in receptor conformation -> receptor
molecules bind to 1 another -> tyrosine kinase domains
brought together & activated -> PHOSPHORYLATE
each other & downstream signaling proteins w/ tyrosine
residues
How do Ligand-Regulated Transmembrane Enzymes
Including Receptor Tyrosine Kinases work?
When ligand binding induces accelerated Endocytosis
of receptors from the cell surface, followed by the
degradation of those receptors (& their ligands); Cell's
responsiveness to the Ligand is diminished
What is Down-regulation?
Growth Hormone, Erythropoietin, Interferons (several
types), & other regulators of Growth & Differentiation
Cytokine Receptors respond to which peptide ligands?
Unlike Tyrosine Kinase receptors, the protein tyrosine
kinase activity is not intrinsic to the receptor molecule.
Instead, a separate protein tyrosine kinase from the
JAK family binds Noncovalently to the receptor ->
receptors Dimerize -> JAKs activated to Phosphorylate
tyrosine residues on the receptor -> STATs bind ->
STATS phosphorylated by JAKs -> 2 STAT molecules
dimerize -> STAT/STAT dimer dissociates from
receptor, travels to nucleus, & REGULATES
transcription of specific genes (STAT = signal
transducer & activators of transcription)
How do Cytokine Receptors work?
ACh, Serotonin, GABA, & Glutamate (all are synaptic
transmitters)
What ligands are involved in Ligand-Gated Channels?
Each NT receptor transmits its signals across the
plasma membrane by increasing transmembrane
conductance of the relevant ion & thereby altering the
electrical potential across the membrane. Ex: ACh
binds to AChR -> Na+ flows down concentration
gradient into cells producing a Depolarization
How do Ligand-Gated Channels work? Example?
cAMP, Ca2+ ion, & the Phosphoinositides
What are 3 examples of 2nd Messengers?
7
PHARMACOLOGY QUIZLET
Extracellular Ligand is detected by receptor -> receptor
activates a G protein on cytoplasmic surface of
membrane -> activated G protein changes activity of an
effector element (an enzyme or ion channel) ->
changes conc. of intracellular 2nd messenger
(Hormone & NTs activate Gs coupled receptors which
stimulates Adenylyl Cyclase, a membrane protein that
converts ATP to CAMP)
How do G Proteins work? Example?
Receptors: Beta-adrenergic amines, Glucagon,
Histamine, & Serotonin -> Inc. Adenylyl Cyclase ->
INCREASED cAMP
What Receptors & Effect does Gs protein have?
Receptors: Alpha2-Adrenergic Amines, ACh, Opioids, &
Serotonin; Effects: Dec. Adenylyl Cyclase -> Dec.
cAMP; Open Cardiac K+ channels -> DECREASED
Heart Rate
What Receptors & Effect do Gi1, Gi2, & Gi3 proteins
have?
Receptor: Odorants (olfactory epithelium); Effects: Inc.
Adenylyl Cyclase -> INCREASED cAMP
What Receptor & Effect do Golf Protein have?
Receptors: NTs in Brain; EFFECT UNKNOWN
What Receptor & Effect do Go Proteins have?
Receptors: ACh, Bombesin, & Serotonin; Effect: Inc.
Phospholipase C -> INCREASED IP3, DAG,
Cytoplasmic Ca2+
What Receptor & Effect do Gq Proteins have?
Receptors: Photons (Rhodopsin & Opsins in retinal rod/
cone cells); Effect: Inc. cGMP Phosphodiesterase ->
DECREASED cGMP (phototransduction)
What Receptor & Effect do Gt1 & Gt2 Proteins have?
7-transmembrane (7-TM) aka "serpentine" receptors;
Agonist binds to hydrophobic transmembrane regions
of 7-TM receptor -> G Proteins interact w/ cytosolic
loop part of 5th & 6th domain -> Receptor's
Cytoplasmic Terminal Tail contains Serine & Threonine
resides whose OH groups can be phosphorylated ->
Phosphorylation -> Diminished receptor-G protein
interaction
What type of Receptors are coupled to G Proteins in
general? How do these receptors work w/ G Proteins?
After reaching an initial high level, the response (cAMP
accumulation, Na+ Influx, Contractility) diminishes over
seconds or minutes, even in the continued presence of
the agonist. This "desensitization" is rapidly reversible;
a 2nd Exposure of the agonist to the receptor when
provided a few minutes after termination of the 1st
exposure results in a response similar to the initial
response
Why does Desensitization occur w/ G Protein mediated
responses to drugs & hormonal agonists over time?
Mobilization of stored energy (the breakdown of carbs
in liver or TGs in fat cells via beta-adrenomimetic
catecholamines), Conservation of water by the kidney
(via vasopressin), Ca2+ Homeostasis (via PTH),
Increased Rate & Contractile Force of Heart Muscle
(via beta-adrenomimetic catecholamines), Production
of Adrenal/Sex Steroids (via corticotropin or FSH),
Relaxation of Smooth muscle, etc
What are the functions of cAMP?
cAMP stimulates cAMP-dependent protein kinases
(composed of 2 catalytic chains (C) & 1 cAMP-binding
regulatory dimer (R)) -> When cAMP binds to the R
dimer, active C chains are released to diffuse thru the
cytoplasm & nucleus, where they transfer phosphate
from ATP to substrate proteins (specificity of cAMPs
regulatory effects depends on the protein substrates of
the kinases) Ex: Liver is rich in Phosphorylase Kinase &
Glycogen Synthase, enzymes which are regulated
reciprocally by cAMP-dependent phosphorylation ->
Carb Storage & Release
How does cAMP exert most of its effects
biochemically?
1) cAMP-stimulated phosphorylation of Enzyme
Substrates are rapidly reversed by PHOSPHATASES;
2) cAMP itself is degraded to 5'-AMP via Cyclic
Nucleotide Phosphodiesterases (PDE); 3) Caffeine,
Theophylline, & other Methylxanthines Competitively
Inhibit & Degrade cAMP
What are the different ways cAMP & its effects are
terminated?
Receptor Activates G Protein -> PLC (Phospholipase
C) -> (1) DAG & (2) IP3 -> DAG activates PK-C
(Protein Kinase C) -> Phosphorylation -> Response; ->
IP3 (water soluble) diffuses across membrane ->
Triggers release of Ca2+ from internal vesicles -> Ca2+
binds to CaM (Calmodulin) -> CaM-E (Calmodulin-
binding enzymes) -> Response
How does Ca2+ & Phosphoinositide work as a 2nd
Messenger System?
IP3 is inactivated by Dephosphorylation; DAG is
phosphorylated to yield Phosphatidic Acid ->
Phospholipids, or it yields Arachidonic Acid; Ca2+ is
Actively removed from the cytoplasm by Ca2+ pumps
What are the different ways the IP3 & DAG pathway
are terminated?
cGMP is more rare than cAMP and is found in Intestinal
Mucosa & Vascular Smooth Muscle tissue; It's
mechanism is similar to cAMP but instead involves
stimulating Guanylyl Cyclase to produce cGMP which
activates cGMP-dependent Protein Kinase;
8
PHARMACOLOGY QUIZLET
How does the 2nd messenger cGMP work and where is
it found?
It causes RELAXATION of Vascular SM by a kinase-
mediated mechanism that results in
DEPHOSPHORYLATION of Myosin Light Chains;
cGMP synthesis is elevated in these SM cells via ANP
(Atrial natriuretic peptide) & NO (Nitric Oxide) to help in
treating Cardiac Ischemia & Acute HTN
What is the function of cGMP?
1) Amplification & 2) Flexible Regulation
All 2nd messenger signaling involves Reversible
Phosphorylation which performs which 2 functions in
Signaling?
GTP Bound to a G Protein leads to the attachment of a
Phosphoryl group to a Serine, Threonine, or Tyrosine
Residue which powerfully amplifies the initial regulatory
signal by recording molecular memory that the pathway
has been Activated
How does Amplification occur?
Different substrates of the multiple protein kinases
regulated by 2nd messengers provide signaling
pathways that can be independently regulated by
cAMP, Ca2+ or other 2nd messengers to produce
Different Effects in Different Cell Types
How does Flexible Regulation work?
The GRAPH of the Response vs. Drug Concentration/
Dose when the response of a particular receptor-
effector system is measured against increasing
concentrations of a drug; Efficacy (Emax) & Potency
(EC50 or ED50) are derived; The smaller the EC50 or
ED50, the GREATER the Potency of the drug
What is a Graded Dose-Response Curve? What
parameters are derived from this graph?
Potency
The smaller the EC50 or ED50, the GREATER the
______ of the drug
Affinity
The smaller the Kd, the GREATER the _______ of the
drug
Graded: The concentration/dose that causes 50% of
the Maximum Effect or Toxicity; Quantal: The
concentration/dose that causes a specified response in
50% of the Population under study
What is EC50, ED50, TD50, etc in GRADED Dose-
Response Curves? In QUANTAL Dose-Reponse
Curves?
EC50/ED50 is the median Effective dose; TD50 is the
median Toxic dose; LD50 is the median Lethal dose
What is EC50/ED50? TD50? LD50?
aka Maximum Efficacy or Emax; is the greatest effect
(Emax) an agonist can produce if the dose is taken to
very high levels; determined mainly by the Nature of the
Drug & its associated effector system; It can be
measured w/ a graded dose-response curve but not w/
a quantal dose-response curve
What is Efficacy? What is it determined mainly by?
Which curve can measure efficacy and which cannot?
aka as the EC50 or ED50, Potency is the amount of
drug needed to produce a given effect; Determined
mainly by the Affinity of the Receptor for the drug and
the # of Receptors available; Both Graded & Quantal
curves can determine Potency
What is Potency? What is it determined by? Which
curves measure Potency?
If the maximal drug response (Emax) is obtained at less
than maximal occupation of the receptors (Bmax); If the
EC50 < Kd; 1) The Duration of the activation of the
effector may be much greater than the duration of the
drug-receptor interaction; 2) Actual # of receptors may
exceed the # of effector molecules available
When are Spare Receptors known to exist? What are
the 2 mechanisms that lead to spare receptors?
Ratio of TD50 or LD50 to the ED50; determined from
QUANTAL response curves; Represent an estimate of
the SAFETY of a drug (b/c a very safe drug might be
expected to have a very large toxic dose & a much
smaller effective dose) The SMALLER the #, the Safer
the drug
What is Therapeutic Index (TI)? What is it determined
by? What does it represent an estimate of?
Actually more clinically relevant than TI b/c it describes
the DOSAGE RANGE b/t the minimum Effective
therapeutic concentration or dose & the minimum Toxic
concentration or dose
What is Therapeutic Window (TW)?
1) Intracellular proteins may block access of the G
protein to the activated receptor molecule (Beta-
Arrestin prevents the access of Gs coupling protein &
thus desensitizes the tissue to further beta agonist
activation); 2) Receptors are Internalized via
Endocytosis and are later either reinserted into the
membrane (morphine receptors) or degraded (beta
adrenoceptors, EGF receptors0
What are 2 Ways Receptor Response is diminished
after Frequent or Continuous Agonist Exposure?
Examples?
CHAPTER 3 PHARMACOKINETICS AND
PHARMACODYNAMICS
Define Pharmacokinetics and Pharmacodynamics
9
PHARMACOLOGY QUIZLET
Pharmacokinetics: what the body does to the drug
Pharmacodynamics: what the drug does to the body
In what ways can some drugs have direct effects
without a receptor?
- Interact directly
- Interact with water molecules (e.g. Mannitol)
Define Bioavailability
The fraction of unchanged drug reaching the systemic
circulation following administration by any route
What is the general bioavailability for drugs given via
the following routes: IV, Inhalation and Oral?
IV = 100%
Inhalation = 5 to <100%
Oral = 5 to < 100%
First-pass effect
Hepatic elimination can reduce bioavailability. Drugs
can be absorbed by the gut wall (can be metabolized in
gut wall), portal blood (can be metabolized in portal
blood) delivers drug to the liver, can be excreted into
bile, metabolized in liver, and a portion eventually
enters systemic circulation.
What are two routes that can be used to avoid the first-
pass effect?
Sublingual and transdermal, as they bypass the portal
veins
Fick's Law
Speed of diffusion = (C1-C2) x Area x k / Thickness
Barriers to aqueous diffusion (2)
- Binding to large plasma proteins
- "Charged" molecules - the electrical field may slow
diffusion
What can a lipid:aqueous partition coefficient tell us?
Indicates how well or poorly drugs move between lipid
and aqueous compartments
What is pH?
- Measure of activity of H+
- Closely related to H+ concentration
- Acidic vs. Basic
Fill in the blank: Lipophilicity __________ with each
additional carbon atom (R) added.
Increases
Protonated forms for weak bases and weak acids
Weak bases = ionic or "charged", water-soluble
Weak acids = non-ionic or "neutral", lipid-soluble
Remember: ions are water-soluble, and non-ionic/
neutrally-charged atoms are lipid-soluble.
What is the log of a number?
What are the logs of 10, 100 and 0.1?
The power that the base has to be raised to in order to
make the number.
10 = 1
100 = 2
0.1 = -1
What is the log of 0.2, then?
State the Henderson-Hasselbach Equation and define
the relationship between the parts.
Log Unprotonated/Protonated = pH - pK
As pH goes down, the amount of protonated drug
increases. As pH goes up, the amount of UNprotonated
drug increases.
SCM's
- What are they
- What do they do
- How do they work
Special Carrier Molecule
- Transports substances that are too large or too
insoluble, such as peptides, amino acids, glucose.
- Occurs via active transport or facilitated diffusion
How do S.C.M.'s work?
Give an example.
- SCM's are saturable and inhibitable
- Less selective SCM can also eliminate foreign
molecules from the cell, such as multi-drug-resistance
type 1 [MDR1] transporter.
Name four types of plasma protein
What do they have affinity for?
- Albumin = most abundant, affinity to acidic but can
bind to all drugs
- a-1 acid glycoprotein = favors basic
-B-globulin = favors basic
- Lipoproteins, transcortin = less important
Protein Binding Formula
[free drug] + k on
[unbound protein binding sites] ---> [bound drug]
<---
k off
Define volume of distribution (Vd)
The apparent volume of plasma that a given dose of
drug is dissolved in.
10
PHARMACOLOGY QUIZLET
Vd formula
Vd = amount of drug given / plasma concentration of
drug
Vd is INVERSELY proportional to plasma concentration
Plasma concentration refers to both free fraction and
protein bound.
Vd formula for the mathematically inclined
Vd = Vp + Vt (Fp/Ft)
Vp = volume of plasma
Vt = volume of tissue
Fp = fraction of unbound drug in plasma
Ft = fraction of unbound drug in tissue
Two phases of drug decline after IV injection
- Alpha or "distribution" phase
- Has rapid and slow components
- Beta or "elimination" phase
-Represents terminal elimination
Define distribution half-life and elimination half-life
Distribution half-life
- Amount of time it takes for 1/2 of drug administered to
move from central compartment to rapid equilibrating
peripheral compartment
Elimination half-life, or what we generally refer to as
"half-life"
- Amount of time it takes to eliminate 1/2 the drug from
the body
- Indicator of amount of time it takes to attain 50% of
steady state
-INdicator of amount of time it takes to decay 50% from
steady state after a change in the rate of drug
administration
Describe the processes involved in the two phases of
drug metabolism.
Phase 1 - oxidation, hydroxylation, reduction, hydrolysis
Phase 2 - conjugation
Aim of both is to create more polar, water-soluble
molecules.
What enzyme is primarily involved in Phase I
reactions?
Cytochrome P450
What happens in conjugation reactions?
Enzymes link one chemical to another to create more
water-soluble molecules to facilitate elimination from
the body.
Cytochrome P450 nomenclature
All start with CYP
First number = genetic family
First letter = genetic subfamily
Last number = specific gene
Elimination vs clearance
Elimination: all processes which result in removal of
drug from the body
- considered eliminated if changed to new form or
excreted
- units are fraction of drug eliminated / time
Clearance: measures the rate at which drug is
completely removed from the body, typically plasma
- Units are volume/time
Two orders of elimination, give an example of a process
that involves both
Zero order: constant rate
First order: constant percentage, this is the most
common
Saturable kinetics: first order until a certain point, then
zero order. Alcohol is an example. This is also known
as Michaelis-Menten elimination.
Clearance formula
Clearance = rate of elimination / C
C = concentration of drug in the blood, plasma, or
unbound drug in water
Clearance is inversely proportional to drug
concentration.
Also: rate of elimination = clearance x concentration
So elimination is DIRECTLY proportional to drug
concentration
Second clearance formula
Cl = KeVd
Ke = elimination rate constant
Vd = volume of distribution
Half life formula
Half life (T 1/2) = log of 2 / Ke = 0.693/Ke
Ke = elimination rate constant
Formula demonstrating half-life relation to clearance
t 1/2 = 0.7 x Vd/Cl. Half-life is inversely proportional to
clearance.
Rule of thumb for half-lives and full effects of drugs
11
PHARMACOLOGY QUIZLET
Four half-lives must elapse before full effects will be
seen.
Extraction Ratio fomula
ER = liver clearance (CL) / Q
Q = hepatic blood flow Approximately 90 L/hr.
Context-Sensitive Half-Time
The time required for the drug concentration in the
central compartment to decrease by 50% after
discontinuation of drug administration.
For most drugs, the half-time increases markedly as the
infusion duration lengthens. However, a drug with a
long elimination half-life CAN have a brief CSHT.
What is an inert receptor? What problem can this
potentially cause?
A receptor that does not cause a direct biologic effect.
An example is albumin, which binds with a ligand, but
causes no subsequent biological activity.
An effect would be that it may cause problems by
taking an important drug out of the plasma.
Potency
Concentration (EC50) or dose (ED50) of drug required
to produce 50% of maximum effect. A drug can have
less effect but be more potent.
Efficacy
Maximum response possible with any dose.
ED50
Median effective dose - that dose at which 50% of
subjects exhibit the specified effect
EC50
Concentration at which 50% of subject exhibit the
specified effect
TD50
Median toxic dose - dose required to produce a
particular toxic effect in 50% of subjects
LD50
Median lethal dose.
Therapeutic index
Therapeutic index is the ratio of TD50 to ED50.
TD50:ED50 (or LD50:ED50)
Larger = safer
Quantal dose-effect curves
A curve constructed if a response to a drug is not
graduated and a dose-response curve is difficult to
make. Reflects percentage of people exhibiting desired
effect, not individual responses.
Isomer
two or more different chemical compounds that have
the same molecular formula; divided into two broad
classes:
- structural isomerism
- stereoisomerism
Structural Isomers
Same molecular formula only. Linkages between atoms
can vary.
Stereoisomers, entantiomers and diastereomers
• Isomers that have the same structure (linkages
between atoms) but different spacial arrangements.
Further divided into entantiomers which are
molecules that are mirror images of each other but
are not superimposable upon one another, or
diastereomers, which are not mirror images of each
other.
Chirality
The property of handedness, of not being
superimposable on a mirror image.
Racemic
Made up of two entantiomorphic isomers as an
equimolar mixture and therefore is optically inactive (+)
Dextrorotary
Polarized light rotated to right
Levorotary
Polarized light rotated to left
2 other systems of naming isomers
D/L = relationship to glyceraldehyde molecule
R/S = for hardcore chemistry majors only
Racemic Mixtures
Most drugs are racemic mixtures
Consequence: patients are receiving doses of which
50% or more has a different or no effect
5 types of receptor mechanisms
• Ligand gated ion channels
• Metaphobores
• G protein coupled
• Intracellular receptors
• Transporters
Ligand Gated Ion Channel
Definition and examples
• Bonding of ligand results in opening of ion channel
• Examples: GABA or acetylcholine receptor
12
PHARMACOLOGY QUIZLET

• Drugs that use this mechanism: muscle relaxants (as • Phenytoin

antagonist), propofol, benzodiazepines, inhaled • Carbamazepine
agents • Other drugs:
• Rifampin
Voltage-gated Ion Channels • Glutethimide
Definition and examples • Phenylbutazone
• Spironolactone
• Some ion channels are opened by changes in • Other factors:
voltage, which can be affected by drugs. • Cigarette smoking
• E.g. verapamil effects calcium (Ca++) channels • Charcoal broiled beef
altering sensitivity of the cell to depolarization. • Dietary protein/carbohydrate ratio
• Chronic alcohol abuse
Metaphobores
Definition and examples CHAPTER 4 DRUG BIOTRANSFORMATION
• Receptor complex is trans-membranous.
• Ligand binding extracellularly results in directly Biotransformation
enzymatic conversion of intracellular substance that Chemical alteration of the drug molecule by the cells of
has further physiologic effects. the animal
• Ex: insulin, many trophic hormones such as
epidermal growth factor, atrial natriuretic peptide, One of the results of biotransformation (a)
work this way. Change in the physiochemical properties of the drug
-->The metabolite is more water soluble, polar and
G Protein coupled ionized
Definition and examples
• Like metaphobores, except the intracellular One of the results of Biotransformation (b)
substance release is not the effector Change in pharmacological activity
• Characteristic 7 transmembrane loop protein with --> Bioinactivation or detoxification (default)
intra and extra cellular components --> Bioactivation or lethal synthesis (few drugs)
• Bonding of (extracellular) ligand results in release of
(intracellular) G protein that has effect Examples of biotransformation
• Example: B adrenergic receptors Active drug to active metabolite
(aspirin --> salicylic acid)
G Protein receptor processes
• Release of G-protein complex results in activation of Inactive drug to active metabolite
adenylyl cyclase which in turn results in increased (chloral hydrate --> trichloroethanol)
cAMP.
• After binding GTP substituted for GDP. Nontoxic drug to toxic metabolite (this is lethal
• Hydrolysis of G-Protein leads to GDP and synthesis; we don't want this)
recombination with the receptor complex. (parathion --> paroxon)
-Antifreeze is an example of this
Intracellular receptors
• Ligand is lipid soluble so crosses membrane easily, Sites of Biotransformation
then acts on cellular receptor. • Liver (most important)
• E.g. steroids. • Nervous tissue
• Mechanism of action results in slow onset and • Kidney
prolonged effects. • GI tract
• Lungs
Transporters • Skin
• Some substances are too large to cross cell • Plasma
membrane after release, such as serotonin.
• Normally, transporter proteins bring these substances Characteristics of Hepatic metabolism: Enzymes lack
back into cell. _____.
• Drugs can be used to block this function, such as Specificity
fluoxetine.
Characteristics of Hepatic metabolism: Enzymatic
Inducers of drug metabolism in humans reactions are _______ reactions
• Most important to remember are: saturable
• Phenobarbital and other barbiturates

13
PHARMACOLOGY QUIZLET

Characteristics of Hepatic metabolism: Drugs can Examples of Non-microsomal hydrolases (For

compete on _______ enzyme hydrolysis in Phase I)
Same • Esterases
• Amidases
Characteristics of Hepatic metabolism: Enzymes can • Peptidases
be _______ or _______ by drugs
Induced or inhibited Examples of Esterases
• Acetylcholine
Characteristics of Hepatic metabolism: Microsomal • Succinylcholine
enzymes cause ________, _________,__________ • Procaine
and ________ to glucuronic acid
• Oxidation Example of Amidase
• Reduction Procainamide
• Hydrolysis Example of Peptidase
• Conjugation Proinsulin
Metabolites from phase I reactions that are more
Phase I reactions (non-synthetic) involve what reactive (toxic) are further handled by _______.
processes? Phase II reactions aka Conjugation
• Oxidation
• Reduction What is the most common conjugation reaction?
• Hydrolysis Conjugation to glucuronic acid
Phase II reactions (synthetic) involves what process?
Conjugation Conjugation is __________.
Combination of a drug or its metabolite (after Phase I)
Processes involved in microsomal (Smooth ER) with an endogenous substance
oxidation (Phase I)
• Hydroxylation Products of conjugation
• Deamination • Glucuronic acid
• Dealkylation • Sulfuric acid
• Desulfuration • Acetyl group
• Sulfoxide formation • Methyl group
• Glycine
Sites involved in non-microsomal oxidation (Phase I) • Methionine
Cytosol or mitochondria • Glutathione

Enzymes involved in oxidation Glucuronidation is ________.

Alcohol and aldehyde dehydrogenase Microsomal
(ethanol -->acetaldehyde)
All other conjugations are nonmicrosomal
Xanthine oxidase
(xanthine --> uric acid) Conjugation is _______ in the neonate
Deficient
Tyrosine hydroxylase
(Tyrosine --> dopa) Metabolite conjugates are usually ______ and
_______.
Monoamine oxidase Inactive and water-soluble
(Metabolism of catecholamines and serotonin)
Can conjugation reactions result in formation of
What is the most common biotransformation reaction? metabolites?
Oxidation Yes

Process involved in microsomal reduction Example of conjugation that forms metabolites

Nitro reduction of chloramphenciol Acyl glucuronidation of NSAID which is toxic to the liver

Process involved in non-microsomal reduction Factors altering biotransformation

Aldehyde reduction of chloral hydrate • Species
• Individual
• Route of Administration

14
PHARMACOLOGY QUIZLET

• Enzyme inducers How does route of administration affect

• Enzyme inhibitors biotransformation?
• Liver disease • There is a first pass effect for oral and intraperitoneal
• Hepatic blood flow routes (and drugs administered through the skin)
• Plasma protein binding
• Distribution and storage Examples of drugs that have extensive first pass effect
• Age Lidocaine
• Sex
• Diet and nutrition Propranolol
• Body Temperature
• Environmental Factors Morphine

Cats are deficient in ________. What are enzyme inducers

Glucuronyl transferases for phenols and aromatic Up regulators
amines
Drugs that stimulate the liver to produce more
(GT needed to break down aspirin) metabolic enzymes

Cats are deficient in ______ but may be able to Only _____ enzymes are inducible by drugs
conjugate endogenous substrates such as ______, Microsomal
_______ and _______. • Examples are phenobarbital, phenylbutazone,
Glucuronyl transferases griseofulvin, rifampin (and chlorinated hydrocarbon
insecticides)
Steroids, thyroxine, and bilirubin
Enzyme induction is _______.
Cats are also deficient in _______ and ________. Reversible
Hydroxylation and dealkylation
Enzyme induction may lead to ______ or _________.
Dogs lack _______ enzymes • Tolerance
acetylating • Drug-drug interactions

Ruminants have ______ plasma _______ than horses, What are enzyme inhibitors?
dogs and cats Down regulators (slow down)
Less
Pseudocholinesterase Drugs that inhibit the liver to produce metabolic
enzymes
Ruminants and horses have _____ levels of _______
enzymes Examples of enzyme inhibitors
High • Chloramphenicol
Oxidative • Cimetidine
• Ketoconazole
Pigs are deficient in ________ enzymes
Sulfate conjugating Enzyme inhibition may lead to _________.
Drug-drug interactions
Birds lack _______ enzymes
Oxidative Distribution and storage _______ biotransformation.
Decrease
Fish have _____ levels of _______ enzymes
Low Newborns and geriatric patients may have ________
Drug metabolizing biotransformation than adults
Less
How does an individual effect biotransformation?
• Certain individuals may be deficient or lack certain Examples of sex-dependent variations in drug
enzymes due to genetic differences metabolism in humans are ______, ________,
________ and _______.
Ex: 50% of dogs do not have CYP2D15 which Ethanol, propranolol, benzodiazepines, salicylates
metabolizes celecoxib
Don't recognize this factor much in animals

15
PHARMACOLOGY QUIZLET
Charcoal broiled foods are _______
Enzyme inducers (CYP1A)
Grape fruit juice is an ________.
Enzyme inhibitor (CYP3A)
Malnutrition and under-nutrition may _______
biotransformation
Decrease
Nutrition plays an important role in the regulation of
_______
drug conjugates
Liver disease may not have an effect on function liver. T
or F?
True
How does liver disease effect biotransformation?
May decrease liver enzymes
Hepatic blood flow may be _____ due to liver disease
or drugs resulting in ______ biotransformation
• Decreased
• Decreased
Plasma protein binding _______ biotransformation
Decreases
Hypothermia, shock or anesthesia may _______
biotransformation
Decrease
Animals in the tropics may have ____ biotransformation
than animals in temperate climate
• Less
• Ex: Trimethoprim in goats
Foreign chemical compounds in the air, water, & food.
What are Xenobiotics?
Lipid-Soluble; Body undergoes Drug Biotransformation
to make drugs less lipid-soluble
What important property of most drugs makes it
favorable for absorption across membranes but also
results in very slow removal of the body b/c the
molecule is readily absorbed from the urine back into
the renal tubule? What does the Body undergo to
hasten the excretion of these drugs?
Oxidation (cytochrome P450 enzymes), Reduction,
Deamination, & Hydrolysis; Reactions that convert the
parent drug to a more polar (water-soluble) or more
reactive product by unmasking or inserting a polar
functional group such as -OH, -SH, or -NH2
What are Phase I Reactions?
Synthetic reactions that involve addition (Conjugation)
of subgroups to -OH, -NH2, & -SH functions on the
drug molecule. Subgroups added are Glucuronate
(Glucuronidation), Acetate (Acetylation), Glutathione
(Glutathione Conjugation), Glycine (Glycine
Conjugation), Sulfate (Sulfation), & Methyl
(Methylation)Groups; These groups are POLAR so they
make it less lipid soluble; Reactions that increase water
solubility by conjugation of the drug molecule w/ a polar
moiety such as glucuronate, acetate, or sulfate
What are Phase II Reactions? What are the subgroup
processes involved? How do these groups make the
product less lipid soluble?
Mostly LIVER, Sometimes Kidneys, and a few drugs
are metabolized in many tissues (ex: liver, blood,
intestinal wall)
What are the Sites of Drug Metabolism?
Cytochrome P450 enzyme species (ex: CYP2D &
CYP3A4) that are responsible for much of drug
metabolism. Many isoforms of CYP have been
recognized.
What are CYP Isozymes?
Stimulation of drug-metabolizing capacity; usually
manifested in the liver by increased synthesis of
Smooth ER (contains high concentrations of Phase I
enzymes) Inducers selectively INCREASE the
subgroups of Isozymes
What is Enzyme Induction?
An ATP-dependent transport molecule found in many
epithelial & cancer cells. The transporter expels drug
molecules from the cytoplasm into the extracellular
space. In epithelial cells, expulsion is via the external or
luminal face; Expels unwanted molecules immediately
after absorption
What is P-glycoprotein?
1) Hydrolysis of Esters (Succinylcholine is metabolized
by plasma cholinesterase very SLOWLY w/ genetically
abnormal forms of the enzyme leading to an extended
neuromuscular paralysis); 2) Acetylation of Amines (Ppl
are "Slow Acetylators" if they are deficient in acetylation
capacity of Amine Drugs); 3) Oxidation (rate of
oxidation of particular drugs by certain P450 isozymes)
Which 3 Drug Metabolizing Systems have a Genetic
Factor component to it?
Carbamazepine, Phenobarbital, Phenytoin, & Rifampin
What are the most common Strong Inducers of Drug
Metabolism?
Drugs: Acetaminophen, Clozapine, Haloperidol,
Theophylline, Tricyclic Antidepressants, (R)-Warfarin;
Inducers: Smoking, Charcoal-broiled Foods,
16
PHARMACOLOGY QUIZLET
Cruciferous Vegetables, Omeprazole; Inhibitors:
Cimetidine, Fluoroquinolones, Grapefruit Juice,
Macrolides, Isoniazid, & Zileuton
What are the Inducers, Inhibitors & Drugs Metabolized
by the CYP1A2 Family?
Inducers: Barbiturates, Phenytoin, Primidone, Rifampin;
Inhibitors: Amiodarone, Chloramphenicol, Cimetidine,
Isoniazid, Metronidazole, SSRIs, & Zafirlukast; Drugs:
Barbiturates, Cholarmphenicol, Doxorubicin, Ibuprofen,
Phenytoin, Chlorpromazine, Steroids, Tolbutamide, &
(S)-Warfarin
What are the Inducers, Inhibitors & Drugs Metabolized
by the CYP2C9 Family?
Inducers: Carbamazepine, Phenobarbital, Phenytoin, &
Rifampin; Inhibitors: Fluconazole, Omeprazole, &
SSRIs; Drugs: Tricyclic Antidepressants, Phenytoin,
Topiramate, & (R)-Warfarin
What are the Inducers, Inhibitors & Drugs Metabolized
by the CYP2C19 Family?
Inducers: Ethanol & Isoniazid; Drugs: Acetaminophen,
Ethanol (minor), & Halothane
What are the Inducers & Drugs Metabolized by the
CYP2E1 Family?
Inducers: Barbiturates, Carbamazepine,
Corticosteroids, Efavirenz, Phenytoin, Rifampin, &
Troglitazone; Inhibitors: Amiodarone, Azole Antifungals,
Cyclosporine, Erythromycin, Grapefruit Juice, HIV
Protease Inhibitors, Quinine, SSRIs, Tacrolimus; Drugs:
Antiarrhymthmics, Antidepressants, Azole Antifungals,
Benzodiazepines, Calcium Channel Blockers
What are the Inducers, Inhibitors & Drugs Metabolized
by the CYP3A4 Family?
Drugs: Antidepressants, Flecainide, Lidocaine,
Mexiletine, & Opioids; Inhibitors: Amiodarone,
Cimetidine, Quinidine, SSRIs
What are the Inhibitors & Drugs Metabolized by the
CYP2D6 Family?
Drug metabolism is diminished usually by
Amiocadarone, Cimetidine, Furanocoumarins
(Grapefruit Juice), Ketoconazole, & the HIV Protease
Inhibitor Ritonavir
What is Enzyme Inhibition? What are the most common
inhibitors of drug metabolism?
Drugs that are metabolized to products that
IRREVERSIBLY Inhibit the metabolizing enzyme;
Examples: Ethinyl Estradiol, Norethindrone,
Spironolactone, Secobarbital, Allopurinol, Fluroxene, &
Propylthiouracil
What are Suicide Inhibitors?
Since, P-gp expels drugs from the intestine into the
lumen, Inhibitors inhibit P-gp and therefore INCREASE
Bioavailability & may result in toxic plasma
concentrations of drugs given at normally nontoxic
dosage; Ex: Verapamil, Mibefradil & Furanocoumarin
(Grapefruit Juice)
What is the effect of Inhibitors of P-glycoprotein (P-gp)?
Digoxin, Cyclosporine, & Saquinavir
What are examples of Drugs normally expelled by P-
gp?
Drugs being metabolized does NOT mean they are
being Inactivated. In fact, some drugs are converted to
active products which may be Toxic. Example: A large
overdose of Acetaminophen results in Reactive Toxic
Intermediates such as N-acetyl-p-benzoquinoneimine
b/c the metabolic pathways are overwhelmed
What is Toxic Metabolism? Example?
Amphetamines, Barbiturates, Phenytoin, Caffeine,
Morphine, Theophylline, Codeine, Acetaminophen,
Nicotine, Chlorpromazine, Cimetidine, Thioridazine, &
Diazepam
What are examples of Drug Substrates that undergo
P450 DEPENDENT Oxidations?
Epinephrine, Chloral Hydrate, & Ethanol
What are examples of Drug Substrates that undergo
P450 INDEPENDENT Oxidations?
Chloramphenicol, Clonazepam, Dantrolene, &
Naloxone
What are examples of Drug Substrates that are
involved in Phase I Reductions?
Aspirin, Clofibrate, Procaine, Succinylcholine,
Indomethacin, Lidocaine, & Procainamide
What are examples of Drug Substrates that are
involved in Phase I Hydrolyses?
Acetaminophen, Diazepam, Digoxin, Morphine, &
Sulfamethiazole
What are typical Drug Substrates for Phase II
Glucuronidation?
Clonazepam, Dapsone, Isoniazid, Mescaline, &
Sulfonamides
What are typical Drug Substrates for Phase II
Acetylation?
Ethacrynic Acid, Reactive Phase I metabolite of
Acetaminophen
What are typical Drug Substrates for Phase II
Glutathione Conjugation?
Deoxycholic Acid, Nicotinic Acid (Niacin), & Salicylic
Acid
17
PHARMACOLOGY QUIZLET

What are typical Drug Substrates for Phase II Glycine

Conjugation?

Acetaminophen, Estrone, & Methyldopa

What are typical Drug Substrates for Phase II
Sulfation?

Dopamine, Epinephrine, Histamine, Norepinephrine, &

Thiouracil
What are typical Drug Substrates for Phase II
Methylation?

Hydralazine & Procainamide

Which 2 Drugs are associated w/ SLOWER Metabolism
in White & African-Americans than in most Asians?

18