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Drug Properties
1. Name (Generic vs. brand name) & class
a. Ex: Propranolol (Inderal) -Adrenergic β-blocker
2. Indication: why would you put someone on this drug
a. FDA established & “off label indications”
b. Ex: Propranolol for hypertension
3. Mechanism of Action: Site @ which drug acts &
mechanism of how desired effect produced
a. Ex: Propranol blocks β-adrenergic receptors in ♥
myocardium  reducing sympathetic-mediated
contractile force (antihypertensive agent) (NE or
epinephrine bind site; β-blocker sits on β receptor
so sympathetic stim blocked)
4. Side effects: undesired effects of the drug
a. Ex: β lockers
i. ♥  too much antihypertensive effect
ii. Lungs broncho-constriction can be fatal in asthma or other
obstructive lung disorders
5. Contraindications
a. Conditions that make taking the drug unsafe
i. Ex. Propranol’s is asthmatics
b. Co-administration w/ other drugs that could produce undesirable or altered effects
 Pharmacodynamics: The effects of the drugs on the body. The biochemical and physiological effects of the
drug and the underlying mechanisms
 Pharmacokinetics: The effects of the body on the drug including relationship between administration, timecourse of its distribution, & magnitude of [ ] attained in different parts of body
 Free drug in plasma is what get to tissues, bound drug is carried in blood but can’t get to action site. Free drug
can get to locus of action and reservoirs
(Any alteration of any of the following can affect therapeutics)
Absorption: how much gets into the blood stream (blood level is more important than the dose)
Distribution: to site of action and across barriers and to everywhere else
Metabolism: degradation (activation of pro-drugs)
Excretion: removal
Absorption
 In the bloodstream, the drug can remain in its free form or bind to
plasma proteins
o Drug binding is a reversible equilibrium ( free drug ↔
bound drug)
o Free drug is metabolized ([ ] ↓) bound form becomes free
o Binding to plasma proteins varies from drug to drug
 Some don’t bind at all, some > 95% bind
 Drug movement in & out of the tissue is reversible
o Equilibrium is driven by [free drug]
 ( ↑ [free drug] in the plasma ↑ tissue penetration)
o As [free drug] in plasma ↓ (i.e. via elimination) the drug returns from tissue into bloodstream and
therefore terminates the drug action
 The importance of blood level of drug can be seen with this curve
o Shape of curve depends on rates of absorption, distribution, metabolism & excretion
o Ascending part  absorption more rapid
o Descending part metabolism & excretion more rapid than absorption
o But all are occurring together

MEC (Minimal effective concentration)- Enough drug is present to enter tissues to interact w/ receptors
and produce effect
o Desired effect usually seen at lvl ABOVE MEC
o Goal is to achieve desired therapeutic range
Distribution
4 primary mechanisms of drug permeation
1. Aqueous diffusion: across epithelial tight junction,
aqueous pores (something charged isn’t going to get thru
lipids, but can squeeze thru tight junction)
a. Driving force is the concentration gradient (K+,
Cl-)
2. Lipid diffusion: since compartments are separated by lipid
barriers, lipid diffusion it is the most important limiting
factor (b/c any drug needs to pass thru the lipid barrier)
a. Driving force is concentration gradient
3. Carrier Molecules: exist for certain substances (i.e. peptides, amino acids, glucose) that are important for
cell fxn but are too large or lipid insoluble to passively diffuse thru the membrane
a. Drugs that resemble these substances use the carriers
b. Active transport or facilitated diffusion
4. Endocytosis & Exocytosis
a. Endocytosis (pinocytosis):
polar substance too large to
enter the cell otherwise
i. Iron, Vitamin B12
b. Exocytosis is a mechanism of
secretion for many
substances
Fick’s Law of Diffusion
• Tell’s us how readily a molecule will cross
the membrane
• Rate of diffusion= Surface area x conc/
resistance of membrane x thickness
o
pH & Drug movement
 Most drugs are either weak acids or weak bases
 Both acids & bases have protonated and unprotonated species
 Acids readily donate protons in aqueous solution, thus becoming deprotonated, but ionized
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o
HA ⇌ A– + H+
o
C8H7O2COOH ⇌ C8H7O2COO– + H+
Neutral Aspirin ⇌ Aspirin Anion + Proton
Bases in aqueous solution accept protons (becoming ionized when protonated)
o
BH+ ⇌ B + H+
o
C12H11CIN3NH3+ ⇌ C12H11CIN3NH2 + H+
Pyrimethamine cation ⇌ Neutral pyrimethamine + Proton
Law of Mass Action
o
HA ⇌ A– + H+ (acid)
BH+ ⇌ B + H+
(base)
 Both rxns move to left in acid (low pH) & to right in alkaline (high
pH)
 So move to left will give either a neutral acid or a charged base
 Uncharged (neutral) species is more lipid-soluble
 weak acid: more will be neutral, lipid-soluble form at acid
pH
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Drug partitions from one comp. to another (acid ♥’s acids & bases ♥’s bases)
 weak base: more will be neutral, lipid-soluble form at alkaline pH
How much of one species (charged vs. uncharged) of an acid or base that predominates in a body
compartment depends on the pKa of the drug & pH of the environment
o pKa= pH @ which acid or base is equally protonated (ionized, charged) & unprotonated (unionized, uncharged) (50:50)
 pKa specific for each drug
The lipid-soluble forms of acids (HA) and bases (B) will readily pass thru lipid membranes separating the
compartments of the body
o Drugs “partitions”/distributes btwn compartments to the extent that it is lipid soluble
o Drug remains “trapped” w/in a compartment where pH doesn’t favor the lipid-soluble form
Henderson–Hasselbalch equation: used to determine how much of a weak acid or base is in the
protonated vs. non-protonated species at a given pH
o
pH - pKa = log [non-protonated species]/[protonated species]
 For acids: pH - pKa = log [A– ]/[HA]
 For bases: pH - pKa = log [B]/[BH+]
 NEED to know drugs pKa and whether it’s an acid or base
o Ex. Aspirin pKa = 3.5 Stomach pH  2.5
o How much aspirin is in the protonated species in the stomach?
 2.5 - 3.5 = log [A– ]/[HA]
 –1 =
log [A– ] / [HA]
Log of 10= 1
exponent used with 10 to get 10
 Inv log of –1= 0.1
Log of 100=2
 So 1/10 = [A– ] / [HA]
Log of 1000=3
 A– = 1 AH = 10 Total = 11
Log of 1,000,000=6
 % protonated = 1 0/ 11 ≈ 91%
Antilog of 1=10
Antilog of 3=1000
The lipid-soluble component (aspirin) will readily
pass through the mostly-lipid cell walls and into the
surrounding capillary beds (absorption).
Calculate what proportion (%) will be ionized in the blood compartment (pH = 7.5).
• 7.5 - 3.5 = log [A– ]/[HA] Log [A– ]/ [HA] = 4;
• inv log of 4 = 104  [A– ] / [HA] = 10,000/ 1= 99.99%
pH - pKa
-2
-1
0
+1
+2
Weak acid:
% nonionized
99
90
50
10
1
Weak base:
% nonionized
1
10
50
90
99
Acid or Base
• If pH< pKa  protonated
• If pH > pKa  unprotonated
Protonated acid is neutral, unprotonated acid is charged
Protonated base is charged, unprotonated base is neutral
HA ⇌ A– + H+
BH+ ⇌ B + H+
Direct Application: excretion of drug by kidney
• Drugs remaining in lipid-soluble form during passage down renal tubule will be
reabsorbed into surrounding capillary bed via simple passive diffusion.
I.e. if drug is at a toxic dose & want to accelerate excretion of drug, (ie, ↓ reabsorption)
• Adjust urine pH to maintain drug in ionized form  Ion trapping
• Weak acids excreted faster in alkaline urine
• Weak bases excreted faster in acidic urine
↑ pH : Sodium bicarbonate (NaHCO3)
• ↑ excretion of weak acids (eg salicylates & some barbiturates)
↓ pH: Ammonium chloride (NH4Cl), cranberry juice
•
↑ excretion of weak bases (morphine)
Ex of test question:
• In the intestine (pH 8.0), which will be better absorbed, a weak acid (pKa 6.8) or a weak base (pKa 7.1)?
Answer:
• If we alkalinize the urine to a pH of 7.8, will a lower or higher percentage of a weak acid (pKa 6.8) be ionized,
compared to normal urine pH (7.2)?
• Aspirin is a weak organic acid with a pka of 3.5. What percentage of a given dose will be in the lipid soluble
form at a stomach pH of 1.5?
• For which of the following drugs is excretion most significantly accelerated by acidification of the urine?
a. Weak acid w/ pka=5.5
b. Weak acid w/ pka =3 c. Weak base w/ pka= 7.5 d. Weak base w/ pka = 7.1
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Absorption
• Goals:
 Administered drug delivered to systemic circulation
o [drug] can be measured in plasma
 Plasma [drug] attains therapeutic level
o CT= target drug concentration in plasma
 Bioavailability (F)
 F= Fraction (or %) of drug that reaches the systemic
circulation via a given route of administration
 =Amt absorbed/ Amt administered
 For IV dose, it is equal to unity (100%) F=1
 Drugs taken orally (PO) go thru liver before reaching systemic
circulation and may be metabolized ↓ the amount of drug in
systemic circulation
o Morphine well-absorbed PO, but 90% metabolized on its 1st pass thru liver)
 Hence dosage will depend on whether the drug is administered orally or via IV
o Ex: 40mg orally or 2mg IV
• Intramuscular is high b/c lots of blood vessels
• Subcut is not commonly used
• Oral- major range of variability
• Rectal- somewhat better b/c 50% goes to liver & is metabolized while 50%
right into systemic
• KNOW: IV, intramuscular, transdermal (high F) vs. oral/rectal (low F)
Converting from one dosage form to another
• Dose of new form = [Dose x F (current form) ]/ F(new form)
• Ex: Patient is stable on digoxin .175mg IV a.d. How much to give patient
orally q.d.? F (P.o) =.7 So .175 x 1/ .7 = .25mg
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Generic vs. Brand Name:
 Bioequivalnce- same active ingredients, identical strength/ [], dosage form
& administration route
Distribution
 Blood flow to tissue: well-perfused tissues/organs get lots of drug quickly
o Liver, kidney, brain, lungs, muscle,etc.
o Sites of action, toxicity, and metabolism
 Organs with flow perfusion (ex. Fat, bone) receive drug slowly
 Mass of tissue- bigger tissue  more drug (i.e. skeletal m.)
 Passage thru capillary walls
o Many capillaries have loose jxn allowing passage of drugs
 ionized drugs given IM may be absorbed into tissue
 MW is most important factor: 200-500
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o Lipid solubility is most important for passage thru the cell wall
Presence of specialized barriers
o Blood-brain barrier (BBB)- consists of capillaries w/ tight junctions
 Highly impermeable
 Pervents passage of large or ionized molecules
 Low MW (200-300) & lipid soluble drugs may cross
o Placental barrier Much less selective then BBB and hence must drugs pass thru it & may affect fetus
 Subject to usual physicochemical properties (MW<1000 Da, lipid solubility, plasma protein
binding, etc)
Binding to plasma proteins
o Albumin(most important plasma protein)
 In general it favors acidic drugs (i.e. phenytoin and other antiepileptics, salicylates)
 May also bind neutral compounds
 Free drug crosses membrane
o α1-acid glycoprotein- (AAG)
 Binds more basic drugs (i.e. lidocaine,quinidine, propranolol)
o Bound drugs can’t distribute to tissues why plasma-protein binding is clinically important
 ↑ [unbounded drug]  ↑’s rate of drug elimination
 [Albumin] low in many disease states (i.e. cirrhosis)  ↓ total plasma [drug]
 Less drug can be carried
 ↑ in serum [albumin] are uncommon
 Competition for binding between drugs- very significant source of drug interactions
“Sites of loss”- areas where drug is not used or has no effect
o Fat (can stay in adipose tissue for prolonged time (i.e. marijuana) and nothing happens b/c not receptors
in fat)
o GI tract (i.e. stomach sink)
o Others (any site lacking receptors to cause effect)
Apparent Volume of Distribution (Vd )
Vd = dose (mg)/ [drug]plasma (mg/ml)
 Doesn’t refer to any physiological compartment in the body
 The volume necessary to account for total amount of drug
administered if it were present throughout the body at the same []
found in the plasma
 Extent to which a drug is taken up by the body as a whole is
greater when drug is highly distributed among body tissues
 Vd is relatively low for drugs that are retain primarily w/in
vascular compartment & relatively high for drugs that are highly
distributed
 For very highly distributed drugs, the Vd is often greater than the
volume of total body water
o Which reflects the low [drug] in the vascular
compartment
 This demonstrates that Vd is an extrapolate volume based on [drug]plasma rather than physical volume
Squares on right are for a specific volume of plasma (1mL)
(B) If 12mg is given & only 1mg in blood, other 11mg are in tissue
Vd -Volume that we’d find if all 12 mg are equal in portion that’d be in plasma
(a) Volume needed is 6 ml
As more is in plasma, volume of distribution decreases
Calculating Vd
 Ex: 400 mg is administered and drug measured in plasma is .01 mg/mL. What is the Vd ?
o Vd = 400mg/ .01 mg/mL = 40,000 mL= 40 L
o Indicates that much of the drug is distributed to tissues outside the plasma
o
o
Suggest that if we administer this drug, attempting to achieve a target plasma [], must account
for this distribution
So if we have a small amount in plasma, big Vd b/c most
of it “distributed” to tissue
Metabolism & Excretion
 Most effective & common way of terminating drug action
98% of drugs :
Active drug  Metabolism (biotransformed)  inactive drug
(non-polar, lipid-soluble; absorbed)
(polar, water—soluble, excreted)
Metabolism rxns fall in 2 categories
 Phase I Reactions
o Convert parent drug into more polar metabolite by introducing or unmasking a function group
(i.e. –OH, -NH2, -SH)
o Metabolites usually inactive but sometimes just modified
o If sufficiently polar, phase I metabolites are excreted
 Phase II reactions
o Endogenous substrate added to phase I metabolite form highly polar conjugate ↑ excretion
o Substrates: glucuronic acid, sulfuri acid, acetic acid, amino acids
o Some parent drugs form conjugate directly
 Liver is the principal organ of drug metabolism
o Drug taken orally Liver (First Pass Effect)
o Other tissues that are considerably active: GI tract, Lungs, Skin, Kidneys
 Many drug metabolizing enzymes are located in the lipophilic membranes of sER of hepatocytes and
intestinal epithelia
 Liver pathology (hepatitis, cirrhosis) will impair drug metabolism  ↑ drug bioavailability
Cytochrome P-450 Enzymes (wavelength at which absorbed is 450- identifier)
 Series of enzymes & cytochromes that can oxidize a variety of drugs
 Mixed function oxidases functionally coupled to each other (microsomal enzymes)
o Require O2 & NADPH
o Isozymes (CYP1A, CYP2C9, CYP3A4)
 Location: sER
 Main role for p450 system is metabolism and detoxification of substances
 P450 system can be altered (metabolic rate depends on whats being metabolized (induction vs. inhibition)
 Can vary from person to person (There are >30 human p450 isozyme systems)
CYP-450 Isozymes to know: 1A2
 Inducing agent (will metabolize)- carbamazepine & phenobarbitol
 Also: theophylline, warfarin
 Inhibiting agents:Cimetidine, (anti-histamine agent for ulcers), grapefruit juice, erythromycin (antibiotic)
o Also: Theophyline, warfarin
 Induction: Chronic drug exposure (e.g. barbs) induces enzymes, so initial dose given later is quickly
metabolized (↓ bioavailability) and less effective
 Inhibition: results in reduced metabolism of all drugs metabolized by this
enzyme more unchanged drug reaching systemic circulation (↑
bioavailability)
Rate of Elimination
=Amount eliminated (wt)/ time (mg/min or mg/hr)
Clearance
 Theortical volume of blood completely cleared of drug per unit time
 Relates elimination rate to [ ]
 CL= Rate of elimination/[drug] (volume/time, ml/min or ml/hr)
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Ex: 1 L contains 1,000mg of drug, [] = 1 mg/mL
In 1 hr, 900 mg of drug remains
o Loss of 100 mg 100mL have been cleared
=-100ml/hr
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Rate of elimination is dependent on rate of biotransformation & on rate of excretion by 1+ routes
o Net rate of all processes involved in terminating presence of drug in the body can be ascertained
by following the rate of decline of [drug] in the blood
o When [drug] is high  rate of elimination is rapid
o When [drug] is low  rate of elimination is slow
 (First-Order) amount of drug metabolized or excreted in a given unit of time is
directly proprotional to [drug] in the systemic circulation at the time
 If elimination of drug follow 1st-order-elimination can be described by biologic ½ life
(T ½ )
 T ½ = time required to eliminate ½ of the quantity of drug present in the system since
time when measurement is taken
o Useful in (1) comparing rates of elimination of several drugs and (2) for
calculating for a particular drug and (3) relates to duration of
therapeutic/other effects
The time it takes for [ ] to ↓ by ½ is indicated at 2 places on the curve
 The ½ life is constant for 1st order
 Not the same, but related to clearance (and Vd)
 T ½=(0.7 x Vd)/CL
 Without a loading dose steady state reached after 4-5 T ½’s
Ex: 1st Order Kinetics for a drug like morphine
Time Period Blood Level
Blood Level
Amount Drug
Initial
Final
Eliminated
0-2 hr
8
4
4
% of Drug
Eliminated
50
2-4 hr
4
2
2
50
4-6 hr
2
1
1
50
In 1st order actual amt of drug eliminated in a given time depends on amount of drug that is present
However, the % of total drug that is eliminated in a given time is constant.
Zero Order Kinetics
• Some drugs have Zero-Order Kinetics (ETOH, aspirin (ASA at large doses (>3
tabs)), phenytoin—anti-seizure)
• These drugs over saturate the enzymes
• A constant amount of drug is lost per unit time.
• % amount of drug cleared, (T ½), varies.
Ex: Zero- Order Kinetics for a drug like ETOH
Time Period Blood Level Initial Blood Level Final Amount Drug
% of Drug
Eliminated
Eliminated
0-2 hr
8
6
2
25
2-4 hr
6
4
2
33
4-6 hr
4
2
2
50
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Zero order: actual amount of drug eliminated in a given time is constant and independent of the amount of
drug present
o Metabolism is based on enzyme availability
o Enzyme saturation, so can’t ↑ metabolism
o So if ↑ blood levels can produce toxicity (drunk)
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First order
vs.
98% of all drugs are first order
Half contant half-life (fixed, constant)
50% metabolized per t1/2
o I.e. if 10 mcg/ml at 2 hr & 5mcg/ml at 8hr
o What will be the half life?
Zero order
- Enzymes are saturable
- meaning there is way more than enzyme
enzyme saturation  NOT rate limiting
-Can become first order
Elimination
 Renal excretion of drugs via kidneys
o Factors effecting excretion:
 age, pre-existing renal disease (↓ GFR), enzyme deficiencies, etc
o Filtration of drugs at glomerulus
o Tubular secretion at proximal tubule
o Reabsorption of drugs (into renal capillaries
 Biliary & Fecal excretion
o Secretion of conjugates in bile
o Bile salt residue both reabsorbed and excreted in feces
o Enterohepatic circulation  return to liver
o Extremely lipohphilic drugs (organophosphates)  may secret into bile but may be re-absorbed and
therefore “re-dosed”
 Pulmonary excretion
o Gases & Volatile alcohols (Breathalyzer test)
 Sweat & Salvia less significant
 Milk- nursing mother/newborn
Steady-state Concentration
 With multiple dosing or continuous infusion, drug will accumulate until the
amount administered per unit time is = to the amount cleared per unit time
 Plasma concentration at this point is the Css (Steady-state Concentration)
o This is our target, what we want to achieve
o Css = Infusion rate (mg/min) = mg/ml
Clearance (ml/min)
o Many need to re-administer to stay at steady
Steady State
 Rate of drug administrate RA = Rate of drug elimination RE
 [Drug] remains constant
 Example:
o Man on left is able to shovel “drug” into container of sand at rate of
2/min
o Man on right is able to remove 1 unit of sand containing “drug” and return the sand to container each
min
o Amount of ”drug” removed per unit of
time (RE ) will be determined by [drug] per
unit of sand as well as clearance (volume
of sand cleared of “drug”
o Eliminated rate constant KD is a faction of
total volume cleared per unit of time (1/6
in example)
How long it takes us to reach plateau is directly related
to half-life
It takes about 4 ½ lives to get to plateau (steady admin)
if you do dosing (i.e. very 4 hrs) you’ll have peaks
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Time it takes to reach steady-state depends only the ½ life of the drug.
About 94% of steady-state is reached in 4 half-lives 
Regardless of [] you are aiming for, it is fxn of ½ life to reach target []
Loading Dose
Loading
 Single large dose used to achieve therapeutic level
more quickly than repeated smaller doses
 ½ life of a drug is relatively long (6.7 days for digitoxin), it will take quite a while to reach steady state (4
½ lives or over 3 weeks)
 Sometimes patient can’t wait that long
 If steadily infuse after giving a loading dose then you
get the sum (graph C)
 Loading dose = Vd x CT/ F
o CT = Css  goal we are trying to achieve in
blood (must include Vd so we know what is not
staying in the blood)
o F is bioavailability
o I.e. 40 L x 4mg/L / 1.0 = 160 mg
 Example of Theophylline
o Target [theophylline] = 7.5 mg/L
o What would be the loading dose and
maintenance dose in patient who weighs 60 kg?
o Vd = .5 I/kg Cl= .04 L/Kg/hr T1/2 = 8.3 hr
 LD= Vd x CT
 .5 L/Kg x 50 kg x 7.5 mg/L = 225 mg “bolus”
 Maintenance dose at SS = CL x CT = .04 L/Kg/Hr x 60 kg x 7.5 mg/L
 = 18mg/Hr maintenance dose”
Pharmacodynamics: (Drugs affect the body) Receptor Theory &
Dose Response
Targets for Drug Actions
 Receptors: macromolecular components of cell that
when stimulated (by agonist)  cellular response
o Ex: NE binds to α-adrenergic receptors
embedded in surface membrane of vascular
smooth m. cells
o Drug-receptor complex initiates a series of
intracellular events that result in muscle cell
contraction & collectively at level of blood
vessel, vasoconstriction
Receptor Binding Forces (From least  most strength)
1. Van der Waals: weak attractive force between
molecules
a. Electrons shift w/in molecules creating
transient shifting charges
2. Hydrogen: H+ on one molecule- electronegative region
on another
3. Ionic: between atoms of opposite charge
4. Covalent: Electrons shared between atoms
 Don’t see a lot of drugs covalently binding w/ drug site- if they do bind they lock receptor up rendering it
inoperable, cells must replace these receptors
Receptor Binding Forces
 VdW’s
forces are most
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common
o usually w/ several of them occurring between the drug &receptor
Then H+ then ionic  overall weak and brief
Multiple bonds between different regions of the receptor allow for specificity of fit of drug (lock & key)
Covalent interactions are irreversible and once bound, the
receptor is useless
Receptor turnover: replacement of old receptors w/ new ones
is required to restore receptor-mediated activity in the affected
cells
o These interactions are rare
Dose-Response Relationship
 Graded dose-response curve
o At low dose, response ↑ rapidly
o As dose is increased, the response increment
diminishes
o High doses  response ceiling or plateau
(So as drugs max out @ higher [] )
 Similarly, in a lab setting, a drug-receptor binding curve
can be constructed
 Info Drug-Receptor Binding Curve (D-R) tell about drug
o Efficacy (Emax) : max response that can be
o
o
o
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produced by the drug
Potency (EC50): [] @ which drug elicits 50%
of max response
Bmax: The number of receptor sites available
to the drug for binding
KD: Equilibrium dissociation constant, the [free
drug] @ which ½-maximal binding is observed
 If KD is low, binding affinity is high 
if KD is high, binding affinity is low
Data from D-R curve is then transformed to semilog scale for more ready comparison
o Linear vs. semi-log (good for looking across huge dosage scales)
Potency & Efficacy
 More efficacy (Emax) mean greater response elicited
 A, C & D are more efficacious than B (higher Emax)
 A is more potent than C which is more potent than D
 Drug w/ lowest EC50 is most potent
Affinity: propensity of drug to bind to receptor
 property of drug-receptor interaction
 High affinity  strong binding to receptor (low Kd)
 Low affinity  little or no binding to receptor (high
Kd)
Intrinsic Activity: drug’s ability to elicit response
 Response produced by effectors
o Can be direct result of receptor activation
o Can be mediated by intracellular molecules
coupled to receptor
o Partial agonist may have similar affinity as full
agonist but lower intrinsic activity
Antagonists: Block or reverse effect of agonist but have no effect of their own
1. Competitive antagonists: compete for the same site on receptor. If large
enough [agonists] are used, they can overcome the antagonist blockade
revealing the agonist response
2. Noncompetitive antagonists: binds to the receptor at a site other than the
agonist binding site and either prevents agonist binding or prevents the
agonist effect
a. Reduces the max response the agonist can produce
b. May also bind irreversibly to the binding site (but more rare)
Other types of antagonism:
 Chemical- direct antagonist/agonist interaction
o One drug binds to & inactivates the actions of a 2nd drug
 I.e. Protamine (+ charged protein) binds to & inactivates heparin (- charged)
 Physiological: working thru an opposing regulatory pathway
o Hyperglycemic effects of glucocorticoid are opposed by insulin
Quantal Dose-Effect Curve
Determined in population, not individuals like D-R curves
 Specificied quantal effect is chosen
o
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I.e. relief of headache, HR lowered by 20 BPM, seizure terminated
Determine dose required to achieve desired effect in large # of patients
or experimental animals
For most drugs, a frequency distribution of the response plotted against
the log of the dose produces a normal distribution curve of variation
The summated responses produce a quantal dose-effect curve
representing the % of individuals who exhibit the desired effect plotted
as a function of log dose
Median effective dose (ED50): dose at which 50% of individuals exhibit the specified quantal response
Similar curves can be established for other important pharmacologic end points such as median toxic dose
(TD50) and median lethal dose (LD50)
ED50 is similar (but distinct) to EC50 in the dose-response curve- both allow for comparison of potency
among drugs for a given effect
o Multiple quantal effects for a drug (i.e. selectivity of action) can be established
 Cough suppression vs. sedation for opiate drug
 Anti-inflammatory effects vs. Na+ retention for corticosteroids
Therapeutic Index (TI)
= TD50/ED50
Determined from quantal dose-response curves
o Example: Compare drugs for lowering heart rate
 ED50 for drug A is 2 mg, TD50 = 40 mg T.I. =20
 ED50 for drug B is 2 mg, TD= 10mg, T.I.=5
 SO DRUG A is 4x SAFER than Drug B
TI is a relative indicator of the margin of safety of a drug
Its value is that it stresses the relationship between the effective and toxic doses of a drug