General Pharmacodynamic Principles

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PHARMACOLOGY & TOXICOLOGY - Emax for agonist remains the same for any

CHAPTER 2:
DRUG RECEPTORS &PHARMACODYNAMICS fixed conc. of antagonist.
GENERAL PHARMACODYNAMIC PRINCIPLES -the presence of competitive antagonist
increases the agonist conc. required for a given
Receptors degree of response & so, the agonist concentration-
• Receptors largely determine the quantitative relations effect curve is shifted to the right.
between dose or conc. of drug and - Competitive inhibition can be reversed by
pharmacologic effects. increasing the conc. Of the agonist
-receptor’s affinity for binding a drug determines the - Schild equation: (dose ratio) related to
conc. of drug dissociation constant (Ki) of the antagonist.
• are responsible for the selectivity of drug action
• mediate the actions of pharmacologic agonists &
antagonists 1. degree of inhibition produced by a competitive
antagonist depends on the conc, of antagonist
MACROMOLECULAR NATURE OF DRUG RECEPTORS 2. Clinical response to a competitive agonist
Characteristics of Receptors (RETS) depends on the conc. of agonist
1. Regulatory proteins
-best-characterized drug receptors • Noncompetitive antagonist
-mediate the actions of endogenous chemical signals -irreversible, covalent bond w/ receptor
- neurotransmitters, autacoids, & hormones -ex. Phenoxybenzamine
-mediates effects of therapeutic agents
• Negative allosteric modulators
2. Enzymes --Separate from agonist binding site: drug
-may be inhibited by binding a drug can modify receptor activity .
-dihydrofolate reductase - reversible
- act through binding to a diff. site on the
3. Transport protein receptor relative to the classical site bound by the
-can be useful drug targets agonist and reduce activity of the receptor
-NA/K-ATPase • Positive allosteric modulators
-norepinephrine & serotonin: anti-depressant drugs -(ex. Benzodiazepines)
-dopamine tranporters: cocaine
D. Partial Agonist
4. Structural proteins - resemble full agonists in the presence of an
-drug targets antagonist that irreversibly blocks some of the
- tubulin receptor sites.

RELATIONSHIP BETWEEN DRUG CONC. & RESPONSE E. Other Mechanisms of Drug Antagonism
- Antagonism that do not need a receptor (ex. Protamine,
A. Concentration-Effect Curves & Receptor Binding heparin)
of Agonists 1. Chemical Antagonist
-as dose increase, response increment diminishes - ionic bonding
- described by hyperbolic curve - makes other drugs unavailable for interactions
B. Receptor-Effector Coupling and Spare Receptors with proteins involved in blood clotting
• Coupling: the overall transduction process that links 2. Physiologic Antagonist
drug occupancy of receptors and pharmacologic -bet. Endogenous regulatory pathwasys (ex.
response. Glucocortocoid hormones, insulin)
• Spare receptors/receptor reserve: -produces less specific & less easy to control
-The ability of a ligand/agonist to elicit a maximal
response even if most of the receptors are not occupied. SIGNALING MECHANISMS & DRUG ACTION
-may be demonstrated using irreversible How come some of the effects of drugs persist even if the
antagonists drug has already been cleared by the body?
- temporal
• Sensitivity of a cell/tissue to a conc. of agonist FIVE (5) BASIC MECHANISMS
depends on:
-affinity of receptor for binding the agonist 1. Lipid soluble ligand that crosses the membrane and
-degree of spareness: total no. of receptors acts on an intracellular receptor.
present compare w/ the no. actually needed 2. A transmembrane receptor protein whose
to elicit maximal biologic response. 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 and stimulates
an intracellular protein tyrosine kinase.
4. A ligand-gated ion channel that can be induced to
C. Competitive and Irreversible Antagonists open.
• Competitive Antagonist: a ligand that competes 5. Receptors that stimulate GTP binding signal
for receptor binding sites therefore reducing the transduction which modulates production of second
effect in a gradual fashion messenger.
4. Ion Channels
1. Intracellular Receptors for Lipid-Soluble Agents - most useful drugs
-ligand-gated ion channels: drugs mimic/ block actions of
-ligands that are lipid-soluble to cross plasma natural agonists. (ex. Nicotic acetylcholine (Ach) receptor )
membrane & act on intracellular receptors. -synaptic transmitters.
-Ligands: steroids (corticosteroids, - receptors transmits its signal across the plasma
mineralocorticoids, sex steroids, Vit. D), & thyroid membrane by increasing transmembrane conductance of the
hormone ( receptors stimulate the transcription of relevant ion & thereby latering the the electrical potential
genes by binding to DNA seq. “response elements”) across the membrane.
- “gene-active” receptors
- ex. Glucocorticoid hormone -Volatage-gated ion channels: do not bind
release of hsp90 permits conversion to active neurotransmitters directly but are controlled by membrane
configuration. potential.
-w/o mimicking or antagonizing
a. All of these hormones produce their effects after
lag period of 30 mins to several hrs. . -CFTR
b. Effects can persist for hours/ days after agonist
conc. reduced to zero. (slow turnover of 5. G-Proteins & Second Messenger
enzymes) -extracellular ligands act by increasing the intracellular con-
centrations of second messengers such as cyclic
2. Ligand-Regulated Transmembrane Enzymes adenosine-3′,5′- monophosphate (cAMP), calcium ion, or
Including Receptor Tyrosine Kinases the phosphoinositides
- use transmembrane signaling system w/ 3 separate
-mediates the first steps in signaling by: components:
insulin, epidermal growth factor (EGF), platelet- a. Extracellular ligand: is selectively detected by a
derived growth factor (PDGF), atrial natriuretic cell-surface receptor
peptide (ANP), transforming growth factor-β (TGF-β), -receptor triggers activation of GTP-binding protein
trophic hormones (G protein)
- These receptors are polypeptides consisting of an - G protein changes the activity of an effector
extracellular hormone-binding domain and a element.
cytoplasmic enzyme domain, which may be a -element then changes the concentration of the
protein tyrosine kinase, serine kinase, or intracellular 2nd messenger.
guanylyl cyclase -ex. cAMP: adenylyl cyclase (effector enzyme)
- 2 domains connected by hydrophobic segment
-Gs and other G proteins activate their downstream effectors
-tyrosine kinase signaling function: when bound by GTP.
a. binding of a ligand (polypeptide hormone or -G proteins produces the phenomenon of spare receptors.
growth factor) to receptor’s extracellular domain. -G-protein-coupled receptors (GPCRs): receptors that
b. change in receptor conformation signal via G proteins. They make up the largest receptor
c. 2 receptor molecules bind to one another family.
(dimerize) -also called “seven-transmembrane” (7TM) or
d. this activates tyrosine kinase enzyme activity in “serpentine” receptors.
cytoplasmic domain of the dimer.
e. Leads to phosphorylation of receptor &
downstream signaling protein. RECEPTOR REGULATION
f. Activated receptors catalyze phosphorylation of -Desensitization phenomenon: after reaching initial
tyrosine residues on diff. target signaling proteins. high level, response diminishes. Rapidly reversible.
Mechanisms that contribute: phosphorylation of the
- down regulation: limits intensity & duration of EGF and receptor
PDGF -Continued stimulation of the receptor reduces the
-Ligand binding induces accelerated endocytosis of signaling response which triggers endocytosis of
receptors from cell surface followed by degradation of the receptors.
receptors. - Once stimulation is reduced, the amount of the
receptors go back to normal once the receptor is
3. Cytokine Receptors stimulated again.
-respond to heterogenous group of peptide - Functional selectivity or agonist bias
ligands. phenomenon
- Includes: growth hormone, erythropoietin,
several kinds of interferon, and other regulators WELL ESTABLISHED SECOND MESSENGERS
of growth and differentiation. A. Cyclic Adenosine Monophosphate (cAMP)
-mechanism similar to tyrosine kinase but protein
tyrosine kinase is NOT INTRINSIC B. Phospoinositides and Calcium
- Separate molecule: Janus-kinase (JAK) family
binds NONCOVALENTLY to the receptor. C. Cyclic Guanosine Monophosphate (cGMP)
- activation of transcription STAT molecules. STAT
dimers then travel to nucleus and regulate INTERPLAY AMONG SIGNALING MECHANISMS
transcription.
cAMP and calcium-phosphoinositides may oppose VARIATIONS IN DRUG RESPONSIVENESS
one another. - idiosyncratic: infrequently observed in most patients.
Caused by genetic differences
-hyporeactive/ hyperreactive: intensity of a given dose is
ISOLATION OF SIGNALING MECHANISMS diminished/ increased
-tolerance: responsiveness decreases
PHOSPHORYLATION: A COMMON THEME -tachphylaxis: responsiveness diminishes rapidly
Reversible phosphorylation of 2nd messenger
signaling performs 2 principal functions in signaling: 4 Mechanisms Contributing to Variation:
A. Alterations in drug concentrations
• Amplification -patients differ in rate of absorption
- Multidrug resistance (MDR) genes
• Flexible regulation
B. Variation in the concentration of an endogenous
RECEPTOR CLASSES &DRUG DEVELOPMENT receptor ligand
-contributes greatly to variability in responses to
RELATION BETWEEN DRUG DOSE & CLINICAL pharmacologic antagonists.
RESPONSE
C. Alterations in receptor number & function
DOSE & RESPONSE IN PATIENTS -change in number:
-caused by hormones (thyroid hormones)
A. Graded Dose-Response Relations - agonist ligand itself induces decrease in
-to choose among drugs & to determine the number (down-regulation) or coupling efficiency
appropriate doses of a drug.. (desensitization)
1. Potency: conc. EC50 or dose ED50 Of the drug that - may cause 2 phenomena:
will produce 50% of the maximal effect -tachphylaxis or tolerance
-depends in part on the affinity (Kd) of receptors for - Overshoot : follow withdrawal of certain
binding the drug & in part on the efficiency w/ w/c drugs.
drug-receptor interaction is coupled to response. - Antagonist may increase no. of receptors in critical
level by preventing down-regulation.
2. Maximal efficacy : 100% efficacy -Pharmacogenetics: genetic factors determining drug
-determined by drug’s mode of interaction s w/ response
receptors ( as with partial agonists) or by the -Personalized or precision medicine: gene
characteristics of receptor-effector system sequencing or expression profile data.
involved.
- practical efficacy: may be limited by the drug’s D. Changes in components of response distal to the
propensity to cause a toxic effect even if the drug coud receptor
produce greater therapeutic effect. -functional integrity of biochemical processes in the
responding cell & physiologic regulation by
B. Shape of Dose-Response Curves interacting organ systems.
- Michaelis Menten relation, some do not -largest & most important class of mechanisms that
-steep dose-response curve: result from cooperative cause variation
interactions of several diff. actions of a drug. -patient’s characteristics that may limit response:
age, general health . severity & patho-physiologic
C. Quantal Dose-Effect curves mechanism
- determining dose of drug required to produce a specified -cause of failure: wrong diagnosis or physiologically
magnitude of effect in a large number of individual patients. incomplete.
- Gaussian normal curve of variation (freq. distrib. of -successful: accurately directed
responses to log of dose) -correct diagnosis, appropriate drug, unsatisfactory
-median effective dose (ED50) response.
-ED50: Effective Dose
-TD50: Toxic Dose CLINICAL SELECTIVITY: BENEFICIAL VS. TOXIC
-LD50- Lethal Dose EFFECTS OF DRUGS
- therapeutic index: related dose of drug required to produce
a desired effect to that w/c produces an undesired effect. -classify drugs acc. to principal actions.
: ratio of TD50 to ED50 - Drugs are only selective rather than specific
- Therapeutic window: rage bet. The minimum toxic dose & -Selectivity:
minimum therapeutic dose. a. beneficial/ therapeutic effects
: greater practical value in choosing b. toxic/adverse effect
the dose for a patient. -side effect: occurs via a pathway that is to one side of the
principal ection
-both curves: sigmoid in shape
: provide potency & selectivity A. Beneficial and Toxic Effects Mediated by the Same
:Grade dose:response: Maximal efficacy Receptor-Effector Mechanism
: quantal: variability of responsiveness among
individuals
B. Beneficial and Toxic Effects Mediated by Identical
receptors but in different tissues or by different
effector pathways

C. Beneficial and Toxic Effects Mediated by different
types of receptors.




















































CHAPTER 3: - First-order elimination: can be estimated by calculating
PHARMACOKINETICS & PHARMACODYNAMICS:
the area under the curve (AUC) of the time-concentration
RATIONAL DOSING & TIME COURSE OF DRUG ACTION
profile after a dose.
- Clearance can be calculated from the dose divided by the
PHARMACOKINETICS
AUC.
-“ Standard” dose of a drug: based on trials in healthy
volunteers & patients w/ average ability to absorb, distribute, &
1) Capacity-Limited Elimination
eliminate the drug.
- elimination/clearance vary depending on the
concentration of the drug achieved
A. VOLUME DISTRIBUTION (V)
- ex. Phenytoin, ethanol, aspirin
- Measure of the apparent space in the body available to
- also known as mixed-order, saturable, dose- or
contain the drug.
concentration-dependent, nonlinear, and Michaelis-
- Relates the amount of drug in the body to the
Menten elimination.
concentration of drug (C) in blood or plasma .
- When blood flow to an organ does not limit elimination,
the relation between elimination rate and concentration
(C):

- may be defined with respect to blood, plasma, or water


(unbound drug), depending on the con- centration used in
equation (1) (C = Cb, Cp, or Cu).
-That the V calculated from equation (1) is an apparent
volume -“pseudo-zero order elimination”
- can vastly exceed any physical volume in the body - Clearance has no real meaning.
because it is the volume apparently necessary to contain - AUC not used.
the amount of drug homogeneously at the concentration
found in the blood, plasma, or water. 2) Flow-Dependent Elimination
- Drugs with very high volumes of distribution: much - Some drugs are cleared very readily
- drug in the blood perfusing the organ is eliminated on
higher conc. in extravascular tissue than in the vascular
compartment, thus not homogeneously distributed. the first pass of the drug through it.
- Minimum possible volume of distribution : Drugs that - elimination depends on the rate of drug delivery to the
are completely retained within the vascular compartment. organ of elimination.
-Would have an equal to the blood component - “high-extraction” drugs
in which they are distributed, eg, 0.04 L/kg body weight or - almost completely extracted from the blood by the
2.8 L/70 kg for a drug that is restricted to the plasma organ.
compartment. - Blood flow to the organ is the main determinant of
drug delivery,
B. CLEARANCE
C. HALF-LIFE
- Factor that predicts the rate of elimination in relation to the - Time required to change the amount of drug in the
drug concentration (C) body by ½ during elimination.
- Time course of drug in the body depend on: volume of
distribution & clearance:

- May be defined with respect to blood (CLb), plasma (CLp),


or unbound in water (CLu), depending on where and
how the concentration is measured. - indicates the time required to attain 50% of steady
- It is important to note the additive character of state—or to decay 50% from steady-state conditions—
clearance. after a change in the rate of drug administration.
- Elimination of drug from the body may involve processes - change in half-life will not necessarily reflect a change
occurring in the kidney, the lung, the liver, and other in drug elimination.
organs.
- Added together separate clearances equal total systemic D. DRUG ACCUMULATION
clearance. -if the dosing interval is shorter than four half-lives,
- Two major sites of drug elimination:kidneys & liver.
accumulation will be detectable.
- Renal clearance: clearance of unchanged drug in the
urine. - Accumulation is inversely proportional to the fraction of
- Liver: the dose lost in each dosing interval.
biotransformation of parent drug - fraction lost: 1 minus the fraction remaining before
excretion of unchanged drug into bile the next dose. T
- fraction remaining: can be predicted from the dosing
- Clearance is constant over the concentration range interval and the half-life.
(elimination is not saturable, and the rate of drug elimination - index of accumulation; accumulation factor:
is directly proportional to concentration (rear- ranging
equation):
- The systemic bioavailability of the drug (F) can be predicted
from the extent of absorption (f) and the extraction ratio (ER):

F= f x (1-ER)

F. RATE OF ABSORPTION
-determined by the site of administration & drug
formulation.
-Dosage B- require 2x the dose to attain blood conc.
equivalent to A.
-In multiple dosing regimen: dosage A & C would yield
-drug given once every half-life; accumulation factor is the same average blood level conc.
1/0.5, or 2 . -Zero- order: mechanism of drug absorption when the
rate is independent of the amount of drug remaining in
E. BIOAVAILABILITY the gut.
- Fraction of unchanged drug reaching the systemic -First-order: when dose is dissolved in gastrointestinal
circulation following administration by any route. fluids, rate of absorption is usually proportional to the
- if first-order elimination: area under the blood gastrointestinal fluid conc.
concentration-time curve (AUC) is proportional to the
dose and the extent of bioavailability for a drug. G. EXTRACTION RATIO & THE FIRST PASS EFFECT
- intra- venous dose: bioavailability= equal to unity - Systemic clearance is not affected by bioavailability.
- orally: less than 100% (lack of absorption from the gut - Clearance can affect the extent of availability because
& first-pass elimination by the liver. it determines the “extraction ratio”
-drugs w/ high extraction ratios will show marked
variations in bioavailability between subjects because of
differences in hepatic function & blood flow.
- drugs highly extracted by the liver, bypassing hepatic
sites of elimination: increases in drug availability
-poorly extracted by the liver, little change in availability:
shunting of blood past the liver.

H. ALTERNATIVE ROUTES OF ADMINISTRATION


-Oral: convenience
-Topical: maximize conc. at the site of action and
minimize it elsewhere
-Transdermal: to prolong duration of drug absorption
-sublingual/ rectal: avoid first-pass effect

-To avoid hepatic first-pass effect:


to a great extent: sublingual tablets & transdermal
preparations
(sublingual & transdermal provides direct access to
systemic veins)
to a lesser extent: rectal suppositories
(50% of rectal dose assumed to bypass liver)

TIME COURSE OF DRUG EFFECT

1. Immediate Effects
-drug effects are directly related to plasma conc. but
1. Extent of Absorption doesn’t necessarily mean that effects simply parallel the
- Too hydrophilic: drug cannot cross the lipid cell time course of coc.
- Enalapril (angiotensin-converting enzyme ACE
membrane (atenolol)
inhibito) on ACE
- Too lipophilic: drug is not soluble enough to cross the - it is only when the conc. is low in relation to the C50
water layer adjacent to the cell. (acyclovir). that the concept of “half-life of drug effect” has meaning.

-Reverse transporter assoc. w/ P-glycoprotein. 2. Delayed Effects


- delayed in relation to changes in plasma conc.
2. First-Pass Elimination - may reflect the time required for the drug to distribute
-liver: metabolism from plasma to site of action.
can excrete drug into the bile - some drugs bind tightly to receptors, & it is the half-life
-The effect of first-pass hepatic elimination on bioavailability of dissociation that determines delay in effect (digoxin)
is expressed as the extraction ratio (ER): -Dissociation process: controls the time to receptor
equilibrium
-Elimination process: controlling the time to
accumulate to steady state with a constant rate infusion.
-Reason for delayed drug effects: Slow turnover of
physiologic substance
3. Cumulative Effects - When intermittent doses are given, the loading dose calcu-
-renal toxicity due to constant infusion lated from equation (12) will only reach the average steady-
-constant infusion state concentration and will not match the peak steady-state
- intermittent dosing: produces higher peak concentration
concentrations. - To match the peak steady-state concentration, the loading dose
* both produces the same average steady-state conc. can be calculated from equation:
-eg. Effects of drugs to cancer
Tumor growth (consequence of cumulative
exposure to drug).

RATIONAL DOSAGE REGIMEN Target concentration intervention: application of


Based on the assumption that there is a target concentration to pharmacokinetics & pharmacodynamics to dose
achieve the desired effect. individualization
PHARMACOKINETIC VARIABLES
A. Maintainance Dose A. Input
- Dose of the drug given to “maintain” steady state - Amt. of drug that enters the body depends on the
concentrations patients adherence to the prescribed regimen & on the
- Dependent on the clearance of the drug. rate & extent of transfer from the site of administration
- Clearance: most important in defining a rational steady- to the blood.
state drug dosage regimen. -Failure of adherence: Overdosage & uunderdosage
- Steady-state: dosing rate (“rate in”) must equal the rate of -Variations in bioavailability: due to metabolism
elimination (“rate out”) during absorption.
- Substitution of the target concentration (TC) for
concentration (C) in equation (4) predicts the maintenance B. Clearance
dosing rate: -Abnormal Clearance: Impairment of kidney, liver or
heart
- Creatinine clearance: indicator of renal function

C. Volume of Distribution
- If desired target concentration is known, clearance will
determine the dosing rate. -Apparent volume of distribution reflects a balance
-If the drug is given by a route that has a bioavailability less between binding to tissues: decreases plasma
than 100%, then the dosing rate predicted by equation (9)
must be modified. For oral dosing: concentration and makes the apparent volume larger;
and binding to plasma proteins: increases plasma
concentration and makes the apparent volume smaller.

D. Half-life
- If intermittent doses are given, the maintenance dose is
calculated from: PHARMACODYNAMIC VARIABLES
A. Maximum Effect
- stead-state concentration by continuous infusion depends - helpful in avoiding ineffectual increases of dose with
only on clearance. the risk of toxicity.
- V distribution and half-life need not to be known B. Sensitivity
- Estimates of dosing rate and average steady-state
concentrations, which may be calculated using clearance, are INTERPRETATION OF DRUG CONCENTRATION
independent of any specific pharmacokinetic model. In contrast, MEASUREMENT
the determination of maximum and minimum steady-state
concentrations requires further assumptions about the Clearance
pharmacokinetic model. - single, most important factor in determining drug
- accumulation factor: assumes that the drug follows a one- concentrations
compartment model -Interpretation of measurements of drug concentrations
- peak concentration prediction: assumes that the absorption depends on the 3 factors that influence clearance:
rate is much faster than the elimination rate. - dose -organ blood flow -intrinsic function of the
liver or kidneys.
B. Loading Dose - Factors affecting protein binding:
- Done for drugs with multicompartment pharmacokinetics -Albumin Concentration
- Done to achieve steady state concentrations quickly - Alpha 1-acid glycoprotein Concentration
- drugs with long half-lives -Capacity Limited Protein Binding
- Raises the conc. of drug in plasma to the target conc. - Binding To Red Blood Cells
- Only the amount of the loading dose need be computed—not
the rate of its administration Dosing History
- if a loading dose is to achieve the target concentration, then Timing of Samples for Concentration Measurement
from equation -Absorption: first 2 hours

Initial Predictions of Volume of Distribution & Clearance


A. Volume of distribution
-Calculated for a particular patient using body weight
-If obese: calculated form fat-free mass (FFM)
B. Clearance

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