You are on page 1of 88

Clinical Pharmacology

for
Medical Students
A USMLE Step 1 & 2 Review
(Practice Q&A included)

Marc Imhotep Cray, M.D.


Topical Outline
Pharmacodynamics
Acronyms
Dose-Response Relationship
General Principles
Effects of Drugs on Receptors
Drug Nomenclature
Effectiveness and Safety
Phases of Clinical Drug Testing
Therapeutic Indices
Drug Administration
Therapeutic Drug Monitoring
Pharmacokinetics
Adverse Drug Reactions
Absorption
Approach to Suspected ADRs
Distribution
Variability in Drug Response
Metabolism (Biotransformation)
Drug Interactions
Elimination
Autonomic Pharmacology
Pharmacokinetic Calculation
Common Drug Endings

Marc Imhotep Cray, M.D. 2


Acronyms
ACE angiotensin converting enzyme NDC National Drug Code
ACh acetylcholine NE norepinephrine
ADR adverse drug reaction Po/w partition coefficient of a drug
ARB angiotensin receptor blocker PD pharmacodynamics
BBB blood brain barrier PDE phosphodiesterase
Cl clearance Pgp p-glycoprotein
Cr creatinine PK pharmacokinetics
CSF cerebrospinal fluid RCT randomized controlled trial
CSFa certain safety factor TBW total body water
CYP cytochrome P450 protein TDM therapeutic drug monitoring
DIN drug identification number TI therapeutic index
F bioavailability Vd volume of distribution
GFR glomerular filtration rate
HH Henderson Hasselbalch
Marc Imhotep Cray, M.D. 3
General Principles
Drug Nomenclature
Phases of Clinical Drug Testing
Drug Administration

Marc Imhotep Cray, M.D. 4


Drug Nomenclature
chemical name: describes chemical structure; consistent in all
countries (e.g. N-(4-hydroxyphenyl) acetamide is
acetaminophen)

NDC: assigned by FDA (US)

non-proprietary name: approved name (post-phase III trial),


official name (listed in pharmacopoeia), or generic name (off-
patent) such as acetaminophen

proprietary (trade) name: brand name or registered


trademark (e.g. Tylenol®)
Marc Imhotep Cray, M.D. 5
Phases of Clinical Drug Testing
 pre-clinical: testing a drug in a controlled environment (lab) on animal or
human cells before human testing to discern PK and toxicological profile

 phase I: first administration to healthy human volunteers, following


animal studies; to determine PK and PD

 phase II: first administration to patients, small sample sizes; to determine


initial safety and efficacy, dose range, PK, and PD

 phase III: large sample sizes, often double-blinded RCT; comparative (new
drug vs. placebo or standard of care) to establish safety and efficacy

 phase IV: post-marketing surveillance, wide distribution; to determine


effects of long-term use, rare ADRs, ideal dosing, and effects in real-world
practice
Marc Imhotep Cray, M.D. 6
Drug Administration
 choice of route of administration (RoA) depends on:
 drug properties
 local and systemic effects
 desired onset and/or duration of action
 patient characteristics

Marc Imhotep Cray, M.D. 7


Routes of Drug Administration
Route Advantage Disadvantage
Oral (PO) Convenient, easy to administer Incomplete absorption
Large surface area for absorption Hepatic first-pass effect
Inexpensive relative to parenteral Potential GI irritation
administration
Buccal/Sublingual (SL) Rapid onset of action Must be lipid-soluble, non-irritating
No hepatic first-pass effect Short duration of action

Rectal (PR) Almost no hepatic first-pass effect Inconvenient, irritation at site of


Use when NPO, vomiting, or application
unconscious Erratic absorption

Intravenous (IV) No hepatic first-pass effect Hard to remove once administered


Slow infusion or rapid onset of action Risk of infection, bleeding, vascular
Easy to titrate dose injury extravasation
Expensive
Intrathecal Direct into CSF Risk of infection
Bypass BBB and blood-CSF barrier
Marc Imhotep Cray, M.D. 8
Routes of Drug Administration cont’d.
Route Advantage Disadvantage
Intramuscular (IM) Depot storage if oil-based = slow release of Pain/hematoma at site of injection
drug
Aqueous solution = rapid onset of action
Subcutaneous (SC) Non-irritating drugs, small volumes Pain at site of injection
Constant, even absorption Smaller volumes than IM
Alternative to IV May have tissue damage from
multiple injections
Inhalation Immediate action in lungs Must be gas, vapor, or aerosol
Rapid delivery to blood
No hepatic first-pass effect
Topical Easy to administer Effects are mainly limited to site of
Localized (limited systemic absorption) application

Transdermal Drug absorption through intact skin Irritation at site of application


No hepatic first-pass effect Delayed onset of action
Hydrophilic drugs not easily absorbed
Marc Imhotep Cray, M.D. 9
Pharmacokinetics
Absorption
Distribution
Metabolism (Biotransformation)
Elimination
Pharmacokinetic Calculation
Marc Imhotep Cray, M.D. 10
Important PK Equations
Single-Dose Equations Abbreviations:
(1) Volume of distribution (Vd)

(2) Half-life (t1/2)

Multiple Doses or Infusion Rate Equations


(3) Infusion rate (k0)

(4) Loading dose (LD)

(5) Maintenance dose (MD)

Marc Imhotep Cray, M.D. 11


Pharmacokinetics
 study of “what the body does to a drug”

 definition: relationship betw. drug administration,


time-course/rate of absorption and distribution,
concentration changes in body compartments, and
drug’s removal from body (=ADME)

Marc Imhotep Cray, M.D. 12


Absorption
 definition: movement of drug from site of admin. into plasma

 Mechanisms of Drug Absorption


 most drugs are absorbed into systemic circulation via
passive diffusion
 other mechanisms include active transport, facilitated
diffusion, and pinocytosis/phagocytosis

Marc Imhotep Cray, M.D. 13


Factors Affecting Rate and Extent of Drug
Absorption
Po/w (oil/water) partition coefficient of a drug
local blood flow at site of admin. (e.g. sublingual vessels facilitate rapid
absorption of SL medications)
molecular size (e.g. drugs w smaller molecular weight absorb faster)
 pH and drug ionization
 drugs are usually weak acids (e.g. ASA) or weak bases (e.g. ketoconazole) and thus
exist in ionized and non-ionized forms
 non-ionized forms cross cell membranes much faster than ionized (charged) forms
 ratio of ionized to non-ionized forms is determined by body compartment pH and drug
pKa (HH equation)
total surface area for absorption
 small intestinal villi are primary site of absorption for most oral drugs

Marc Imhotep Cray, M.D. 14


Bioavailability (F)
 definition: proportion of dose that reaches systemic
circulation in an unchanged state

 decreased by limited drug absorption or first-pass effect

 IV dose has 100% bioavailability (F = 1)

Marc Imhotep Cray, M.D. 15


First-Pass Effect
 definition: drug metabolism by liver and/or gut before it
reaches systemic circulation resulting in reduced F
 occurs w PO admin. of a drug: GI tract (absorption) → portal
vein to liver (first-pass metabolism) → systemic circulation
 occurs less w PR admin. b/c drug absorbed in colon
bypasses portal system
Examples of Drugs with Examples of Drugs with
High First-Pass Effect Low First-Pass Effect
• Levodopa • Diazepam
• Morphine • Digoxin
• Propranolol • Phenytoin
• Lidocaine • Warfarin
• Organic nitrates
Marc Imhotep Cray, M.D. 16
Efflux Pump
 Pgp (P-glycoprotein 1) is a protein found in various parts of
body that acts as a multidrug efflux pump involved in
transport of drugs out of cells
 for example, opposes intestinal absorption (e.g. dabigatran
etexilate) and also enhances renal elimination of certain drugs (e.g.
digoxin, etoposide, paclitaxel, tacrolimus, cyclosporine)
 some drugs (e.g. macrolide antibiotics) inhibit Pgp function
leading to ↑serum levels of drugs transported by Pgp
o Pgp inducers (e.g. St. John’s wort) do opposite
 some tumors overexpress Pgp leading to multidrug resistance to
chemotherapeutic agents
Note: Pgp also known as multidrug resistance protein 1 (MDR1) or ATP-binding
cassette subfamily B member 1 (ABCB1) or cluster of differentiation 243 (CD243)
Marc Imhotep Cray, M.D. 17
Distribution
definition: movement of drugs betw. different Distribution of TBW
body compartments and to site of action Total Body Water
60% of body weight

major body fluid compartments include


 Plasma Extracellular Fluid Intracellular Fluid
 interstitial fluid 16-20% 40-44%
 intracellular fluid
 transcellular fluid
(e.g. CSF, peritoneal, pleural) Intravascular Interstitial
Plasma 4% Fluid 12-15%
tissue compartments include fat, brain

Marc Imhotep Cray, M.D. 18


In Netter's Atlas of Human Physiology, body water is broken
down into following compartments:
 Intracellular fluid (2/3 of body water) is fluid contained within cells
 In a body containing 40 liters of fluid (ie. about 72 kg total weight),
about 25 liters is intracellular→ amounts to 62.5% (5/8), close enough
to 2/3 rule of thumb
 Extracellular fluid (1/3 of body water) is fluid contained in areas outside
of cells
 For a 40 liter body, about 15 liters is extracellular → amounts to 37.5%
 Again, this is close to 1/3 rule of thumb cited here
o Plasma (1/5 of ECF) Of 15 liters of extracellular fluid, plasma volume averages 3
liters→ This amounts to 20%
o Interstitial fluid (4/5 of ECF)

Transcellular fluid (a.k.a. "third space," normally ignored in calculations) contained


inside organs, such as gastrointestinal, cerebrospinal, peritoneal, and ocular fluids
Marc Imhotep Cray, M.D. 19
Factors Affecting Rate and Extent of Drug
Distribution
 physiochemical properties of drug (e.g. Po/w and pKa)
 pH of fluid
 plasma protein binding
 binding within compartments (i.e. depots)
 regional blood flow

Marc Imhotep Cray, M.D. 20


Volume of Distribution (Vd)
Vd: apparent volume of fluid into which a drug distributes

maximum actual Vd (anatomic fluid volume accessible to drug)


= TBW (TBW~40 L for average adult)
 a calculated value (Vd) = amount of drug in body ÷ plasma drug conc.
 a theoretical value that does not correspond to an anatomical space
(i.e. can exceed TBW)
 small Vd corresponds to a drug that concentrates in plasma and/or
binds plasma proteins to a high degree
o Vd of plasma protein bound drugs can be altered by liver and kidney disease
 large Vd corresponds to a drug that distributes into tissues (fat,
muscle, etc.)= most is not in blood (measured) space→ therefore
“appears” to distribute in a large volume

Marc Imhotep Cray, M.D. 21


Volume of Distribution cont'd.
 example: amiodarone distributes into TBW (actual Vd
= 40 L)→ but it also concentrates in fat tissues giving
instead an apparent Vd of 400 L, therefore to
achieve a given plasma conc. of amiodarone, we dose
as though drug distributes into 400 L of body fluid

Marc Imhotep Cray, M.D. 22


Plasma Protein Binding (PPB)
 drug molecules in blood exist in an equilibrium of two forms:
1. bound to plasma protein: acidic drugs bind to albumin, basic drugs
bind to α1-acid glycoprotein
2. free or unbound: can leave circulation to distribute into tissues and
exert an effect, subject to metabolism and elimination

bound fraction is determined by drug conc., binding affinity,


and plasma protein conc. (number of binding sites)
 reduced number of binding sites (e.g. hypoalbuminemia) or
 saturation of binding sites (e.g. competition/displacement) may
result in ↑ conc. of free drug→ which is often metabolized w no
harmful effects, although→ toxicity is possible

Marc Imhotep Cray, M.D. 23


Plasma Protein Binding cont’d.
Multiple drugs and endogenous substances can compete for
same protein binding sites
For example
 ASA displaces highly protein-bound acidic drugs such as phenytoin
thus increasing risk of toxicity
 Sulfonamide displaces bilirubin which could potentially lead to
jaundice and kernicterus in neonates
NB: Special consideration must be given in dosing patients in
hypoalbuminemic states (e.g. liver failure or nephrotic syndrome)
to prevent drug toxicity
 Highly protein-bound drugs (e.g. warfarin, digoxin, diazepam, furosemide,
amitriptyline) will exert a greater effect in these pts than in healthy
individuals b/c of higher levels of free drug
Marc Imhotep Cray, M.D. 24
Question
A 23-year-old G1P0 woman who is 39 weeks’ pregnant has dysuria with
increased urinary frequency, and becomes febrile. She takes some
medication prescribed for a previous urinary tract infection (UTI), and
continues to use it through delivery. At term she gives birth to a mildly
jaundiced boy who is otherwise healthy. Five days later, however, she brings
the infant to the emergency department stating that the baby has become
fussy, refuses feeding, and wails at a high pitch. He soon becomes
extremely lethargic and stops producing urine. Which of the following
medications did the mother most likely take to treat her UTI?
A. Amoxicillin
B. Ampicillin
C. Nitrofurantoin
D. Ofloxacin
E. Trimethoprim-sulfamethoxazole
Marc Imhotep Cray, M.D. 25
Answer
The correct answer is E. Trimethoprim-sulfamethoxazole (TMP/SMX) is one
of most common treatments for simple UTIs, most of which in general
population are caused by Escherichia coli
 Sulfamethoxazole binds to, and will displace, unconjugated bilirubin from albumin
 In a newborn, this can lead to kernicterus (bilirubin encephalopathy), a disorder of
newborns caused by deposition of bilirubin in brain
 The basal ganglia are particularly affected
 Common early symptoms include lethargy, poor feeding, and absent Moro reflex
 If infants survive, they can develop seizures, mental retardation, deafness,
choreoathetoid movements, and decreased upward eye movements

Answer A is incorrect. Amoxicillin is not associated with kernicterus


Answer B is incorrect. Ampicillin is not associated with kernicterus
Answer C is incorrect. Nitrofurantoin, commonly used to Tx UTIs, is not assoc. w kernicterus.
Answer D is incorrect. Ofloxacin is not associated with kernicterus

Marc Imhotep Cray, M.D. 26


Depots
a body compartment in which drug molecules tend to
be stored and released slowly over a long period of time

fat is a depot for very lipid soluble drugs (e.g. diazepam)

some oil-based medications are injected IM for slow


release (e.g. depot medroxyprogesterone acetate q3mo;
depot risperidone q2wk)

Marc Imhotep Cray, M.D. 27


Barriers (relative)
body structures that limit or prevent diffusion of drug molecules, such
as placenta or BBB (a barrier composed of tight junctions betw.
capillary endothelial cells and astrocytes)

many of these barriers result, in part, from activity of multidrug efflux


pumps (e.g. Pgp), which serve as a natural defense mechanism against
drugs and xenobiotics

need to consider dosing route if drugs are meant to cross these barriers

Note: Main Factors Governing Penetration of BBB


• Small molecular size (<500 Da)
• High lipid solubility
• Active transport mechanisms (e.g. Pgp efflux pump)
Marc Imhotep Cray, M.D. 28
Metabolism (Biotransformation)
definition: chemical transformation of a drug in vivo to
enhance elimination
sites of biotransformation include liver (main), GI tract, lung,
plasma, kidney
as a result of process of biotransformation:
 an inactive prodrug may be activated (e.g. tamoxifen to endoxifen;
codeine to morphine)
 a drug may be changed to another active metabolite (e.g. diazepam
to oxazepam)
 a drug may be changed to a toxic metabolite (e.g. meperidine to
normeperidine)
 a drug may be inactivated (most drugs)
Marc Imhotep Cray, M.D. 29
Drug Metabolizing Pathways
phase I (P450) reactions
 minor molecular changes introduce or unmask polar
groups on a parent compound to increase water solubility
(e.g. oxidation-reduction, hydrolysis, hydroxylation)
o change in Po/w is typically minimal compared to phase II, and
o often phase I places a polar “handle” on a lipophilic drug to allow
for phase II

 mediated by CYPs found in endoplasmic reticulum

 product of reaction can be excreted or undergo further


phase II reactions
Marc Imhotep Cray, M.D. 30
Drug Metabolizing Pathways cont’d.
phase II (conjugation) reactions
 conjugation w large polar endogenous substrates (e.g.
glucuronidation, glutathione conjugation, sulfation)
 dramatically increases water solubility and renal elimination
 can result in biologically active metabolites
(e.g. glucuronides of morphine)
 can occur independently of phase I reactions

Marc Imhotep Cray, M.D. 31


Cytochrome P450 System
 CYPs are a superfamily of heme proteins that are grouped
into families and subfamilies according to their amino acid
sequence
 are responsible for metabolism of drugs, chemicals, and other
substances
Nomenclature: CYP3A4
 “CYP” = cytochrome P450 protein
o 1st number = family
o letter = subfamily
o 2nd number = isoform

 CYP1, CYP2, and CYP3 families metabolize most drugs in humans


 Most important isoforms are CYP3A4 and CYP2D6, therefore
anticipate drug interactions if prescribing drugs using these enzymes
Marc Imhotep Cray, M.D. 32
Factors Affecting Drug Biotransformation
genetic polymorphisms of metabolizing enzymes
 individual genotypes may determine rate of drug
metabolism (e.g. poor, intermediate, extensive, or
ultrarapid metabolizers)
 may lead to toxicity or ineffectiveness of a drug at nml dose
o tamoxifen and codeine are prodrugs activated by CYP2D6  nonfunctional
alleles reduce effectiveness, whereas overactive/duplicated alleles impart
“ultrarapid metabolizer” phenotype
o warfarin is metabolized by CYP2C9  nonfunctional alleles lead to greater
effect and lower dose requirements
o clopidogrel is a prodrug activated by CYP2C19, thus patients who are poor
CYP2C19 metabolizers have a higher incidence of cardiovascular events (for
example, CVA or MI) when taking clopidogrel

Marc Imhotep Cray, M.D. 33


Factors Affecting Biotransformation cont’d.
enzyme inhibition may sometimes be due to other drugs
 CYP inhibition leads to an ↑conc. and bioavailability of substrate
drug (e.g. erythromycin [CYP3A4 inhibitor] can predispose pts to
simvastatin toxicity [metabolized by CYP3A4])
enzyme induction
 certain medications enhance gene transcription leading to an ↑ in
activity of a metabolizing enzyme
 a drug may induce its own metabolism (e.g. carbamazepine) or that
of other drugs (e.g. phenobarbital can induce metabolism of OCPs)
by inducing CYP system
For examples of CYP Substrates, Inhibitors and Inducers see:
http://www.medicine.iupui.edu/CLINPHARM/ddis/main-table

Marc Imhotep Cray, M.D. 34


Factors Affecting Biotransformation cont’d.
liver dysfunction (e.g. hepatitis, alcoholic liver, biliary cirrhosis,
or hepatocellular carcinoma) may ↓ drug metabolism, but
may not be clinically significant due to liver’s reserve capacity

renal disease often results in ↓ drug clearance

extremes of age (neonates or elderly) have reduced


biotransformation capacity doses should be adjusted
accordingly

Marc Imhotep Cray, M.D. 35


Factors Affecting Biotransformation cont’d.
nutrition: insufficient protein and fatty acid intake ↓ CYP
biotransformation, and vitamin/ mineral deficiencies may also
impact other metabolizing enzymes

 alcohol: acute alcohol ingestion inhibits CYP2E1; chronic


consumption can induce CYP2E1 and ↑ risk of hepatocellular
damage from acetaminophen by ↑ generation of
acetaminophen’s toxic metabolite (NAPQI )

smoking can induce CYP1A2, thus  ↑ metabolism of some


drugs (e.g. theophylline, antipsychotic)
Marc Imhotep Cray, M.D. 36
Elimination
definition: removal of drug from body
Routes of Drug Elimination
 kidney (main organ of elimination): two mechanisms
1. glomerular filtration
 a passive process, so that only free drug fraction can be eliminated
 drug filtration rate depends on GFR, degree of protein binding of drug, and size of
drug
o Remember from physiology we can use CrCl to estimate GFR
2. tubular secretion
 an active process that is saturable allowing both protein-bound and free drug
fractions to be excreted
 distinct transport mechanisms for weak acids (e.g. penicillin, salicylic acid,
probenecid, chlorothiazide) and weak bases (e.g. quinine, quaternary ammonium
compounds such as choline)
 drugs may competitively block mutual secretion if both use same secretion system
(e.g. probenecid can reduce excretion of penicillin)
Marc Imhotep Cray, M.D. 37
Elimination cont’d.
tubular reabsorption: drugs can be passively reabsorbed back
to the systemic circulation, countering elimination mechanisms

renal function (assessed using serum Cr levels) ↓ w age and is


affected by many disease states such as diabetes

lungs: elimination of anesthetic gases and vapors by exhalation

saliva: saliva concentrations of some drugs parallel their


plasma levels (e.g. rifampin)

Marc Imhotep Cray, M.D. 38


Elimination cont’d.
stool: some drugs and metabolites are actively excreted in
bile or directly into GI tract
 enterohepatic reabsorption counteracts stool elimination, and
can prolong drug’s duration in body

 some glucuronic acid conjugates that are excreted in bile may


be hydrolyzed in intestines by bacteria back to their original
form and can be systemically reabsorbed

Marc Imhotep Cray, M.D. 39


Cockcroft-Gault Equation
 Cockcroft-Gault Equation can Estimate CrCl in Adults 20
yrs. of Age and Older
 For males
CrCl (mL/min) = [(140 – age in yrs.) x Weight (kg)] x 1.2
serum Cr (μmol/L)
 For females, multiply above equation x 0.85

NB: Only applies when renal function is at steady state

Marc Imhotep Cray, M.D. 40


Pharmacokinetic Calculation
 definition: quantitative description of rates of various steps
of drug disposition (i.e. how drugs move through body)

 pharmacokinetic principles of ADME (absorption,


distribution, metabolism, and elimination) can be graphically
represented on a concentration vs. time graph

NB: Principles of Pharmacokinetics


 Vd = amount of drug in body/ plasma drug conc.
 Cl = rate of elimination of drug/plasma drug conc.
 Half-life (t1/2) = 0.7 x Vd/ Cl

Marc Imhotep Cray, M.D. 41


Time Course of Drug Action
many kinetic parameters are measured 1. Absorption Phase
2. Peak Absorption
using IV dosing, such that absorption is 3. Post-Absorption Distribution Phase
immediate and distribution for most drugs 4. Elimination Phase (half-life based on this)
is rapid, thus elimination is main
process being measured

concentration axis is converted to a log10


conc. to allow for easier mathematical
calculations

drugs such as warfarin can exhibit


hysteresis (for a single drug conc., there
Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.
may be two different response levels)

Marc Imhotep Cray, M.D. 42


Half-Life
definition: time taken for serum drug level to fall 50%
during elimination

drugs w first order kinetics (most drugs) require five


half-lives to reach steady state w repeated dosing or for
complete drug elimination once dosing is stopped

# of Half-Lives 1 2 3 4 5
% of Steady State Conc. 50 75 75 90 96.9

Marc Imhotep Cray, M.D. 43


Steady State
drug conc. remains constant when amt. of drug entering
system is eliminated from system

drug levels in therapeutic drug monitoring are of greatest


utility when steady state has been reached

special situations
 use a loading dose for drugs w a long half-life and when there is
clinical need to rapidly achieve therapeutic levels (e.g. amiodarone,
digoxin, phenytoin)
 use continuous infusion for drugs w very short half-life and when
there is need for a long-term effect and multiple or frequently
repeated doses are too inconvenient (e.g. nitroprusside, insulin,
unfractionated heparin)
Marc Imhotep Cray, M.D. 44
Steady state of a drug displaying first-order kinetics
 Steady state of a drug w t1/2 of 3 h
 It takes about 15 h (5 x t1/2) to reach steady state .

Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Marc Imhotep Cray, M.D. 45


Clearance
a quantitative measurement of body fluid volume from which
a substance is removed per unit time

Cl = rate of elimination of drug ÷ plasma drug concentration


 b/c Cl is removal of drug from circulation, clearance is related to
elimination rate constant and apparent volume into which drug is
dissolved → Cl= 0.693 x Vd ÷ t1/2 or t1/2=0.693 x Vd ÷Cl

must consider Cl from a specific part of body and total body Cl

Marc Imhotep Cray, M.D. 46


Clearance cont'd.
 Rather than describing amount of drug eliminated,
clearance describes volume of plasma from which drug
would be totally removed per unit time

 Having an idea of how much plasma is cleared of drug over


time allows estimation of how much drug must be given to
maintain a constant plasma conc.= maintenance dose

Marc Imhotep Cray, M.D. 47


Elimination Kinetics
first-order kinetics (most common type)
 constant fraction of drug eliminated per unit time
 some drugs can follow first-order kinetics until elimination is
saturated (usually at large doses) at which point Cl decreases
becomes linear relationship when plotted on a log (conc.) vs. time
graph

zero-order kinetics (less common, assoc. w overdose, e.g.


alcohol)
 drug is eliminated at a constant rate regardless of conc. concept
of half-life does not apply
 conc. axis is converted to a log (conc.) to allow for easier
mathematical calculations
Marc Imhotep Cray, M.D. 48
First and zero order kinetics
 In first order kinetics (solid line), a
constant fraction of drug is
eliminated per unit time

 In zero order kinetics (dashed line),


a constant amount of drug is
eliminated per unit time
Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Marc Imhotep Cray, M.D. 49


Loading vs. Maintenance Dosing
A loading dose is an initial higher dose of a drug that may be
given at beginning of a course of treatment before dropping
down to a lower maintenance dose

A loading dose is most useful for drugs eliminated from


body relatively slowly, i.e. have a long systemic half-life
 Such drugs need only a low maintenance dose in order to keep
amt. of drug in body at appropriate therapeutic level, but
 Also means, without an initial higher dose, it would take a long
time for amt. of drug in body to reach that level
o Drugs which may be started w initial loading dose include
digoxin, teicoplanin, voriconazole and procainamide
Marc Imhotep Cray, M.D. 50
Calculating loading dose
Four variables are used to calculate loading dose:
 Cp = desired peak concentration of drug
 Vd = volume of distribution of drug in body
 F = bioavailability
 S = fraction of drug salt form which is active drug

Required loading dose may then be calculated as


LD=Cp Vd ÷ FS
 For an IV admin. drug, bioavailability (F) will equal 1 since drug is
directly introduced to bloodstream
 If pt. requires an PO, F will be less than 1 (depending on absorption,
first pass metabolism etc.), requiring a larger loading dose

See: Worked example of loading dose. pdf


Marc Imhotep Cray, M.D. 51
Loading vs. Maintenance Dosing cont’d.
 A maintenance dose is maintenance rate [mg/h] of drug
admin. equal to rate of elimination at steady state

 Continuing maintenance dose for about 5 half lives (t½) of


drug will approximate steady state level

 One or more doses higher than maintenance dose can be


given together at beginning of therapy with a loading dose

Marc Imhotep Cray, M.D. 52


Calculating maintenance dose
Required maintenance dose may be calculated as:
MD=Cp Cl÷ F
Where:
 MD is maintenance dose rate [mg/h]
 Cp = desired peak concentration of drug [mg/L]
 CL = clearance of drug in body [L/h]
 F = bioavailability

 For an IV admin. drug, bioavailability will equal 1, since drug is


directly introduced to bloodstream
 If pt. requires an PO, F will be less than 1 (depending on absorption,
first pass metabolism etc.), requiring a larger loading dose

Marc Imhotep Cray, M.D. 53


LD vs. MD Summary Table
Loading Dose Maintenance Dose
Use when you need an IMMEDIATE effect After a loading dose OR beginning with
maintenance doses
Often parenteral medication Steady-state levels achieved after ~5 half-lives
Rationale: give large dose of medication Can be given as either a continuous infusion
to “fill up” the volume of distribution (relatively rare, short half-life drug) OR much
more commonly as intermittent doses
Vd determines LD (LD=Cp Vd ÷ FS) Cl determines MD (MD=Cp Cl ÷ F)

Marc Imhotep Cray, M.D. 54


Pharmacodynamics
study of “what the drug does to the body”
Dose-Response Relationship
graded dose-response relationships: relates dose to intensity of effect
Efficacy
 maximum biological response produced by a drug
 measured by Emax (maximal response that a drug can elicit in a RCT or
under optimal circumstances)
Potency
 measured by EC50 (the concentration of a drug needed to produce
50% of Emax)
 a drug that reaches its EC50 at a lower dose is more potent

Marc Imhotep Cray, M.D. 55


Log(dose)-response curve illustrating efficacy
and potency

Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Efficacy vs. Potency


• Efficacy measures maximal effect of a drug (vertical axis)
• Potency measures conc. of a drug needed to produce a certain effect
(horizontal axis)
Marc Imhotep Cray, M.D. 56
Effects of Drugs on Receptors
 Agonists: drugs that mimic effects of endogenous ligand and evoke a
response when bound to receptor (has affinity and intrinsic activity)
 affinity: ability of agonist to bind to receptor, e.g. β2-agonist
salbutamol has greater affinity for β2-receptors than β1-receptors
 efficacy: ability to recapitulate endogenous response via receptor
interaction, e.g. binding of salbutamol to β2-receptors results in
smooth muscle relaxation

 full agonists: can elicit a maximal effect at a receptor

 partial agonists: can only elicit a partial effect, no matter


conc. at receptor, i.e. reduced efficacy compared to full
agonists)
Marc Imhotep Cray, M.D. 57
Effects of Drugs on Receptors cont’d.
Antagonists drugs that block action of an agonist or of an
endogenous ligand
 chemical antagonism: direct chemical interaction betw. agonist
and antagonist prevents agonist receptor binding, e.g. chelating
agents for removal of heavy metals

 functional antagonism: two agonists that act independently at


different receptors and have opposite physiological effects, e.g.
acetylcholine at muscarinic receptor compared to epinephrine at
adrenergic receptor

Marc Imhotep Cray, M.D. 58


Effects of Drugs on Receptors cont’d.
 reversible and irreversible competitive antagonism
o drugs that exert no direct effect upon binding to a given receptor
o reversible competitive antagonists reversibly bind to same receptor as
agonist, thus displacing it (e.g. naloxone is an antagonist to
morphine or heroin)
o irreversible antagonists form a covalent bond w receptor thus
irreversibly blocking substrates from binding (e.g. phenoxybenzamine
forms a covalent bond w adrenergic receptors preventing Epi and NE
from binding)

 non-competitive antagonism
o antagonist binds to an alternate site near agonist binding site,
producing allosteric effects that change ability of agonist to bind (e.g.
organophosphates irreversibly bind acetylcholinesterase)
Marc Imhotep Cray, M.D. 59
Mechanism of agonists and antagonists

Agonist Binding

© Adrian Yen 2006

Marc Imhotep Cray, M.D. 60


Mechanism of agonists and antagonists
Antagonist Binding
1) Competitive reversible binding

© Adrian Yen 2006

2) Competitive irreversible binding

© Adrian Yen 2006

Marc Imhotep Cray, M.D. 61


Mechanism of agonists and antagonists

Antagonist Binding
3) Non-competitive irreversible binding

© Adrian Yen 2006

Marc Imhotep Cray, M.D. 62


Effectiveness and Safety
Effectiveness
 ED (effective dose): dose of a drug needed to cause a
50

therapeutic effect in 50% of a test population of subjects

Safety
 LD (lethal dose): dose of a drug needed to cause death in
50

50% of a test population of subjects


 TD (toxic dose): dose needed to cause a harmful effect in
50

50% of a test population of subjects


NB: Two most clinically relevant properties
of any drug are effectiveness and safety

Marc Imhotep Cray, M.D. 63


Therapeutic Indices
Therapeutic Index: TD /ED 50 50

 reflects “margin of safety” for a drug likelihood of a therapeutic


dose to cause serious toxicity or death
 larger TI, safer a drug (e.g. warfarin has a low TI (=narrow therapeutic
window or low safety margin )requires drug monitoring
 factors that can change TI
o presence of interacting drugs
o changes in drug ADME

Certain Safety Factor: TD /ED 1 99

 >1 translates to a dose effective in at least 99% of population and toxic in


less than 1% of population

Marc Imhotep Cray, M.D. 64


ED50, TD50 and TI

Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

TI (TD50/ED50) is a measure of margin of Drug A has a much narrower TI than Drug B. Dose of
safety of a given drug Drug A required to achieve a 100% therapeutic
response will be toxic in 50% of patients
For Drug B, this is only 10%

Marc Imhotep Cray, M.D. 65


Therapeutic Drug Monitoring
Adverse Drug Reactions
Approach to Suspected ADRs
Variability in Drug Response
Drug Interactions

66
Therapeutic Drug Monitoring
definition: using serum drug concentration data to optimize
drug , e.g.→ dose adjustment, monitor compliance
 serum drug samples are usually taken when drug has reached steady
state (after approx. 5 half-lives)
TDM is often used for drugs that have:
 narrow TIs
 unpredictable dose-response relationships
 significant consequences assoc. w therapeutic failure or toxicity, and
 wide inter-patient PK variability

Examples of drugs whose levels need to be monitored include


warfarin (via INR levels), digoxin, lithium, anti-epileptics (e.g.
phenytoin, carbamazepine)

Marc Imhotep Cray, M.D. 67


Adverse Drug Reactions (ADRs)
 An ADR is an injury caused by taking a medication
 ADRs may occur following a single dose or prolonged admin. of a drug
or result from combination of two or more

 Meaning ADR differs from meaning of "side effect", as → side effect


might also imply that effects can be beneficial

 Study of ADRs is concern of field known as pharmacovigilance

 An adverse drug event (ADE) refers to any injury occurring at time a


drug is used, whether or not it is identified as a cause of injury
 An ADR is a special type of ADE in which a causative relationship can
be shown

Marc Imhotep Cray, M.D. 68


Classification ADRs
 ADRs may be classified by e.g. cause and severity
Cause
Type A: Augmented pharmacologic effects→ dose dependent and
predictable
 Type A reactions, constitute approximately 80% of ADRs→ usually a consequence of
drug’s primary pharmacological effect (e.g. bleeding when using anticoagulant warfarin)
or a low therapeutic index of drug (e.g. nausea from digoxin) = predictable
 They are dose-related and usually mild, although may be serious or even fatal (e.g.
intracranial bleeding from warfarin)
 Such reactions are usually due to inappropriate dosage, especially when drug
elimination is impaired
o term ‘side effects’ is often applied to minor type A reactions
 Type B: Idiosyncratic (Bizarre)
NB: Types A and B proposed in 1970s, other types were proposed subsequently
when found to be insufficient to classify all types of ADRs (see next slide)
Marc Imhotep Cray, M.D. 69
Characteristics of Type A-E ADRs
Classification Definition Characteristics
A (Augmented) Dose related Predictable extension of drug’s pharmacologic effect (e.g. β-
blockers causing bradycardia), >80% of all ADRs
B (Bizarre) Non-dose related Reactions unrelated to known pharmacological actions of drug
Examples include: drug hypersensitivity syndromes,
immunologic reactions (penicillin hypersensitivity), and
idiosyncratic reactions (malignant hyperthermia)
C (Chronic) Dose and time Related to cumulative doses
related Effects are well-known and can be anticipated (e.g. atypical
femoral fracture from bisphosphonates)
D (Delayed) Time related Occurs some time after use of drug (e.g. carcinogen)
May also be dose-related
E (End of use) Withdrawal Occurs after cessation of drug use (e.g. opiate withdrawal)
Redrawn after Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Marc Imhotep Cray, M.D. 70


Sample of Clinically Relevant ADRs
Classification Drug(s) ADR
A β-blockers Bradycardia
A ACEIs Cough
A NSAIDs GI bleeding
A Opiates GI upset, constipation, urinary retention,
respiratory depression
A Acetaminophen Hepatotoxicity
A Vancomycin Red Man syndrome
A Aminoglycosides Ototoxicity and nephrotoxicity
B Sulfa Drugs Stevens-Johnson syndrome Toxic epidermal
necrolysis
B Penicillins Rash
B Valproic acid, Chinese herbs Hepatotoxicity
Marc Imhotep Cray, M.D. 71
Approach to Suspected ADRs
history and physical exam: signs and symptoms of reaction
(e.g. rash, fever, hepatitis, anaphylaxis), timing, risk factors,
detailed medication history including all drugs and timing, de-
challenge (response when drug is removed), and re-challenge
(response when drug is given again)

differentiate drug therapy vs. disease pathophysiology

treatment: stop the drug, supportive care, symptomatic relief

Marc Imhotep Cray, M.D. 72


Approach to Suspected ADRs cont'd.
resources: check recent literature, FDA; contact pharmaceutical
company; call Poison Control if overdose or poisoning
suspected; check with Motherisk (www.motherisk.org ) in cases
involving pregnant or breastfeeding women

 report all suspected ADRs that are:


1) Unexpected
2) serious, or
3) reactions to recently marketed drugs (on market <5 yrs.)
regardless of nature or severity
Marc Imhotep Cray, M.D. 73
Variability in Drug Response
recommended patient dosing is based on clinical research
and represents mean values for a select population, but
each person may be unique in their dosing requirements

possible causes of individual variability in drug response


include problems with:
 intake: patient adherence
 PK
 PD

Marc Imhotep Cray, M.D. 74


Variability in Drug Response cont'd.
PK causes of individual variability in drug response:
 absorption: vomiting, diarrhea, or steatorrhea; first pass effect
increased due to enzyme induction or decreased due to liver disease
 drug interactions (e.g. calcium carbonate complexes with iron,
thyroxine, and fluoroquinolones)
 distribution: very high or low percentage body fat; intact or disrupted
BBB; patient is elderly or a neonate, or has liver dysfunction
 biotransformation and elimination: certain genetic polymorphisms
or enzyme deficiencies related to drug metabolism (e.g.
acetylcholinesterase deficiency, CYP polymorphism); kidney or liver
dysfunction
PD: genetic variability in drug response (e.g. immune-mediated reactions);
diseases that affect drug PD; drug tolerance or cross-tolerance
Marc Imhotep Cray, M.D. 75
Drug Interactions
concomitant prescriptions: one drug alters effect of
another by changing its PK and/or PD
PK interactions involve changes in drug conc.
 absorption: alterations in gastrointestinal pH, gastric emptying,
intestinal motility, gut mucosal function
 biotransformation: alterations in drug metabolizing enzymes
 excretion: alterations in renal elimination
PD interactions are due to two drugs that exert similar
effects (additive) or opposing effects (subtractive)
drug interactions can also involve herbal medications
(e.g. St. John’s wort) and food (e.g. grapefruit)

Marc Imhotep Cray, M.D. 76


Drug Interactions cont’d.
Examples of Clinically Relevant Drug Interactions
Interaction Potential Effect
Warfarin plus ciprofloxacin, clarithromycin, Increased effect of warfarin
erythromycin, metronidazole or TMP-SMX
OCPs plus rifampin, antibiotics Decreased effectiveness
of PO contraception
Sildenafil plus nitrates Hypotension
SSRI plus St. John’s wort, naratriptan, rizatriptan, Serotonin syndrome
sumatriptan, zolmitriptan
SSRI plus selegiline or nonselective MAO-I Serotonin syndrome
Some HMG-CoA reductase inhibitors plus niacin, Possible rhabdomyolysis
gemfibrozil, erythromycin or itraconazole
Redrawn after Leung P, Voruganti T. Clinical Pharmacology. Toronto Notes, 2017.

Marc Imhotep Cray, M.D. 77


Autonomic Pharmacology

Marc Imhotep Cray, M.D. 78


Subdivisions of peripheral nervous system
Peripheral Nervous System

Somatic Autonomic (ANS)

Sympathetic (SNS) Parasympathetic (PNS)


Fight or Flight Rest and Digest

Marc Imhotep Cray, M.D. 79


Autonomic Pharmacology
 most organs are innervated by both sympathetic and
parasympathetic nerves, which have opposing effects
 ACh and NE are main neurotransmitters of ANS
 ACh binds to cholinergic receptors include
nicotinic and muscarinic receptors
 NE binds to adrenergic receptors, principally include
β1, β2, α1, and α2

Marc Imhotep Cray, M.D. 80


ANS Pharm cont’d.
 ACh action is terminated by
 metabolism in synaptic cleft by acetylcholinesterase and
in plasma by pseudocholinesterase
o acetylcholinesterase inhibitors (pyridostigmine, donepezil,
galantamine, rivastigmine) can be used to ↑ ACh levels in
conditions such as myasthenia gravis or Alzheimer’s disease

 NE action is terminated by
 reuptake at presynaptic membrane
 diffusion from synaptic cleft, and
 degradation at monoamine oxidase (MAO) and catechol-O-methyl
transferase (COMT)
Marc Imhotep Cray, M.D. 81
Parasympathetic Nervous System
blood vessels, adrenals, sweat glands, spleen capsule, and
adrenal medulla do NOT have parasympathetic innervation

parasympathetic pre-ganglionic fibers originate in lower


brainstem from cranial nerves III, VII, IX, X, and in sacral spinal
cord at levels S2-S4connect w post-ganglionic fibers via
nicotinic receptors in ganglionic cells located near or within
target organ

post-ganglionic fibers connect with effector tissues via:


 M1 muscarinic receptors located in the CNS
 M2 muscarinic receptors located in smooth muscle, cardiac muscle,
and glandular epithelium
Marc Imhotep Cray, M.D. 82
Sympathetic Nervous System
sympathetic pre-ganglionic fibers originate in spinal cord at spinal
levels T1-L2/L3

pre-ganglionic fibers connect w post-ganglionic fibers via nicotinic


receptors located in one of two groups of ganglia
1. paravertebral ganglia (i.e. the sympathetic trunk) that lie in a
chain close to vertebral column
2. pre-vertebral ganglia (i.e. celiac and mesenteric ganglia) that lie
within abdomen

post-ganglionic fibers connect w effector tissues via:


 β1 receptors in cardiac tissue
 β2 receptors in smooth muscle of bronchi and GI tract
 α1 receptors in vascular smooth muscle
 α2 receptors in vascular smooth muscle
 M.D.
Marc Imhotep Cray, M3 muscarinic receptors located in sweat glands 83
ANS summary schematic

Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017.
Marc Imhotep Cray, M.D. 84
Direct Effects of Autonomic Innervation on
Cardiorespiratory System
Organ Sympathetic NS Parasympathetic NS
Receptor Action Receptor Action
Heart
1. Sinoatrial β1 ↑ HR M ↓conduction
2.Atrioventricular node β1 ↑ conduction M ↓ conduction
3. Atria β1 ↑ contractility M ↓ conduction
4. Ventricles β1 ↑ contractility M ↓ HR
Blood Vessels
1. Skin, splanchnic α1, β2 Constriction M Dilatation
2. Skeletal muscle α Constriction M Dilatation
3. Coronary β2 (lg m) Dilatation M Dilatation
α1, β2 Constriction M Dilatation
β2 Dilatation M Dilatation
Lungs
1. Bronchiolar sm. Mm. β2 Relaxation M Constriction
2. Bronchiolar glands α1, β2 ↑secretion M Stimulation

Marc Imhotep Cray, M.D. 85


Common Drug Endings
Ending Category Example
-afil 5-PDE inhibitor sildenafil
-ane Inhaled general anesthetic halothane
-azepam Benzodiazepine lorazepam
-azole Antifungal ketoconazole
-caine Local anesthetic lidocaine
-olol β-blocker propranolol
-prazole Proton pump inhibitor omeprazole
-pril ACE inhibitor captopril
-sartan ARB candesartan
-statin HMG-CoA inhibitor atorvastatin
-terol β2 agonist albuterol
-tidine H2 antagonist cimetidine
-tropin Pituitary hormone somatotropin
-vir Antiviral acyclovir
-zosin Α1 antagonist prazosin
Marc Imhotep Cray, M.D. Note: Some medications are exceptions to the rule, e.g. methimazole (antithyroid)
86
Sources and further study
Primary source of data and graphics for the generation of this PowerPoint:
Leung P, Voruganti T. Clinical Pharmacology. In: Toronto Notes: Comprehensive
Medical Reference & Review for MCCQE I and USMLE II, 2017. 33rd Ed. Kim J,
Mukovozo V, (Eds). Toronto, Ontario, Canada, 2017; 120-31.

Practice Questions (with answers and explanations sheet) for this presentation.

For more scientific background on the topics presented in this review see:
Cray M (2015). General Principles of Pharmacology (UNIT 1, pgs. 10-29). In:
Integrated Scientific and Clinical Pharmacology: A Course Syllabus and Digital
Guidebook for Medical Students (MS1 & MS2)

Reference texts in e-Book sub-folder of Dr. Cray’s Pharmacology & Therapeutics cloud
• Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Brunton LL,
Chabner BA , Knollmann BC (Eds.) ; McGraw-Hill 12th ed. 2011.
• Basic and Clinical Pharmacology, Katzung, Masters, Trevor; McGraw-Hill 12th ed. 2012
• Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition,
Sanders 2014.
Marc Imhotep Cray, M.D. 87
General References
1. Hennessy S, Flockhart DA. The need for translational research on drug-drug
interactions. Clin Pharm Ther. 2012;91:771-773.
2. Lesko LJ, Zheng S, Schmidt S. Systems approaches in risk assessment. Clin Pharm Ther.
2013;93: 413-424.
3. Kaddurah-Daouk R, Weinshilboum RM. Pharmacometabolomics: implications for
clinical pharmacology and systems pharmacology. Clin Pharmacol Ther. 2014;95:154-167.
4. White RW, Harpaz R, Shah NH, et al. Toward enhanced pharmacovigilance using
patient-generated data on the internet. Clin Pharmacol Ther. 2014;96:239-246.
5. Johnson JA, Cavallari LH. Pharmacogenetics and cardiovascular disease: implications for
personalized medicine. Pharmacol Rev. 2013;65:987-1009.
6. Wang L, McLeod HL, Weinshilboum RM. Genomics and drug response. N Engl J Med.
2011; 364:1144-1153.
7. Wheeler HE, Maitland ML, Dolan ME, et al. Cancer pharmacogenomics: strategies and
challenges. Nat Rev Genet. 2013;14:23-34.

Marc Imhotep Cray, M.D. 88

You might also like