Dr.

Nurhidayati
Departmen of Pharmacology
School of Medicine
Mataram University
2004-2005
Drug Receptors and Pharmacodynamics
(how drugs work on the body)
The action of a drug on the body,
including receptor interactions,
dose-response phenomena, and
mechanisms of therapeutic and toxic
action.
Pharmacodynamics
The biochemical and physiologic mechanisms of drug
action
What the drug
does when it gets there.
Drug Mechanisms
Receptor interactions
Non-receptor mechanisms


Drug Actions
Most drugs bind to cellular receptors
Initiate biochemical reactions
Pharmacological effect is due to the alteration of an
intrinsic physiologic process and not the creation of a
new process

2004-2005
Drug Receptor
A macromolecular component of a
cell with which a drug interacts to
produce a response
Usually a protein

Major Classes of Receptors
Ligand-Gated Ion Channels
Tyrosine Kinase-Linked Receptors
G-Protein Coupled Receptors
Ligand-Activated Transcription Factors

Location of Receptors
Membran cell
Intracellular receptor
Cytosolic
Nuclear
The Lock and Key Model of Ligand-
Receptor Interaction
a ligand such as a hormone or neurotransmitter
(the "key") bind to specific receptors (the "lock)
this binding "unlocks" the cell's response.

many drugs work by mimicking a naturally
occurring hormone or neurotransmitter
if the drug causes the receptor to respond in the
same way as the naturally occurring substance, then
the drug is referred to as an agonist
these are drugs that can pick the lock.

other drugs work in the opposite way as
antagonists.
these drugs bind to the receptor, but do not
produce a response.
because the drug prevents the receptor from
binding to the normal hormone or
neurotransmitter, it has an inhibitory effect on the
naturally occurring substance.



Cholinergic Neurons
Na
+
Choline
Ca
++

Receptor
Acetylcholinesterase
Acetylation

TERMS
AGONIST
FULL AGONIST
PARTIAL AGONIST
ANTAGONIS
COMPETITIVE REVERSIBLE
NON-COMPETITIVE IRREVERSIBLE
PHYSIOLOGICAL
CHEMICAL
SELECTIVE AND NON-SELECTIVE
DIRECT AND INDIRECT (???)
Receptor Interactions
Agonist Receptor
Agonist-Receptor
Interaction
Lock and key mechanism
Receptor Interactions
Receptor
Perfect Fit!
Induced Fit
Receptor Interactions
Antagonist Receptor
Antagonist-Receptor
Complex
DENIED!
Competitive
Inhibition
Agonist Receptor
Antagonist
Inhibited-Receptor
DENIED!
Receptor Interactions
Non-competitive
Inhibition


Chemistry of Drug-Receptor Interactions

Most drug-receptor
interactions
Reversible
weak chemical bonds
Irreversible drug-receptor
interactions
not common
strong chemical bonds
(covalent)
e.g. aspirin, anti-tumour
drugs
usually undesirable
reversal of effects/toxicity
mutagenicity/carcinogenicity

2004-2005
Agonists and antagonists

agonist has affinity plus intrinsic activity
antagonist has affinity but no intrinsic activity
partial agonist has affinity and less intrinsic activity
competitive antagonists can be overcome
2004-2005
Agonist Drugs
drugs that interact with and activate
receptors; they possess both affinity and
efficacy
two types
Full an agonist with maximal
efficacy
Partial an agonist with less then
maximal efficacy


Pharmacological Antagonists

Competitive Antagonists
Non-Competitive Antagonists

2004-2005
Antagonist Drug
Antagonists interact with the
receptor but do NOT change the
receptor
they have affinity but NO efficacy
two types
Competitive
Noncompetitive
2004-2005
Competitive Antagonist
competes with agonist for receptor
surmountable with increasing
agonist concentration
displaces agonist dose response
curve to the right (dextral shift)
reduces the apparent affinity of the
agonist i.e., increases 1/Ke
2004-2005
Noncompetitive Antagonist
drug binds to receptor and stays bound
irreversible does not let go of receptor
produces slight dextral shift in the agonist DR curve
in the low concentration range
this looks like competitive antagonist
but, as more and more receptors are bound (and
essentially destroyed), the agonist drug becomes
incapable of eliciting a maximal effect

Chemical antagonism

interaction of two drugs in solution such that the
effect of active drug is lost

e.g.
metal chelators plus toxic metals
Protamin against heparin effect
Dimercaprol against efect of toxic metals



Physiological Antagonism
interaction of two drugs with opposing physiological
actions
e.g.
histamine: lowers arterial pressure through
vasodilation (H1 receptors); and epinephrine raises
arterial pressure through vasoconstriction (-adrenergic
receptors)


Relationship of Drug Concentration and
Receptor Binding

2004-2005
Response
Dose
Full agonist
Partial agonist
Agonist Dose Response Curves

Agonist Types: Its All Relative

A: full agonist
maximum potency,
maximum efficacy
B: partial agonist
maximum potency,
reduced efficacy
C: full agonist
reduced potency,
maximum efficacy
D: partial agonist
reduced potency, reduced
efficacy

Competitive Antagonists - Effect on Dose
Response Curves

A
agonist + no antagonist
agonist has maximum
potency, maximum
efficacy
B
agonist + competitive
antagonist
agonist has reduced
potency, but maximum
efficacy

Non-Competitive Antagonists - Effect on
Dose Response Curves

A
agonist + no antagonist
agonist has maximum
potency, maximum
efficacy
B
agonist + non-
competitive antagonist
agonist has maximum
potency, but reduced
efficacy

Non-receptor Mechanisms
Actions on Enzymes
Enzymes = Biological catalysts
Speed chemical reactions
Are not changed themselves
Drugs altering enzyme activity alter processes
catalyzed by the enzymes
Examples
Cholinesterase inhibitors
Monoamine oxidase inhibitors
Non-receptor Mechanisms
Changing Physical Properties
Mannitol
Changes osmotic balance across membranes
Causes urine production (osmotic diuresis)
Non-receptor Mechanisms
Changing Cell Membrane Permeability
Lidocaine
Blocks sodium channels
Verapamil, nefedipine
Block calcium channels
Bretylium
Blocks potassium channels
Adenosine
Opens potassium channels
Non-receptor Mechanisms
Combining With Other Chemicals
Antacids
Antiseptic effects of alcohol, phenol
Chelation of heavy metals

Non-receptor Mechanisms
Anti-metabolites
Enter biochemical reactions in place of normal substrate
competitors
Result in biologically inactive product
Examples
Some anti-neoplastics
Some anti-infectives

Drug Response Relationships
Time Response
Dose Response
Latency
Duration of Response
Maximal (Peak) Effect
Effect/
Response
Time
Time Response Relationships
Effect/
Response
Time
IV
SC
IM
Time Response Relationships
Dose Response Relationships
Potency
Absolute amount of drug required to produce an effect
More potent drug is the one that requires lower dose to
cause same effect
Potency
Effect
Dose
A B
Which drug is more potent?
A!
Why?
Therapeutic
Effect
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Efficacy
Degree to which a drug is able to produce the desired
response

Max effect of Drug A
effect Max effect of Drug B



A B Dose
A = Furosemid
B = Thiazid

Max effect of Drug A
Max effect of Drug B
effect


A B Dose



Dose Response Relationships
Threshold (minimal) dose
Least amount needed to produce desired effects
Maximum effect
Greatest response produced regardless of dose used
Dose Response Relationships
Which drug has the lower threshold dose?
Effect
Dose
A
B
Which has the greater maximum effect?
A
B
Therapeutic
Effect
Dose Response Relationships
Loading dose
Bolus of drug given initially to rapidly reach therapeutic
levels
Maintenance dose
Lower dose of drug given continuously or at regular
intervals to maintain therapeutic levels

Effective Concentration 50% (ED
50
)
Concentration of the drug which induces a specified
clinical effect in 50% of subjects

Lethal Dose 50% (LD
50
)
Concentration of the drug which induces death in 50%
of subjects

Therapeutic Index

A measure of drug safety
Considers dose required for a toxic effect versus that
required for the desired beneficial effect

In general, a larger T.I.
indicates a clinically safer
drug
The therapeutic index
Therapeutic dose
Toxic dose
Therapeutic index =
Toxic dose
Therapeutic dose
Therapeutic Index
Why dont we use a
drug with a TI <1?
ED50 < LD50 = Very Bad!
Some drugs with a low therapeutic index


Lithium

Digoxin

Carbamazepine

Cyclosporin

Phenytoin

Phenobarbitone

Theophylline
(Aminophylline)

Warfarin



Beneficial versus Toxic Drug Effects

No drug causes only a single, specific effect
Selectivity in clinical actions is limited to a specific
dose range (T.I.)

1. Effects mediated by identical receptors in the
same tissue.
2. Effects mediated by identical receptors in
different tissues.
3. Effects mediated by different receptors.


Drug Desensitization

effect of a drug often diminishes
when given continuously or
repeatedly
desensitization,
tachyphylaxis, refractoriness,
resistance, tolerance
receptor-mediated and non-
receptor-mediated mechanisms
Receptor Mediated
loss of receptor function
reduction of receptor number
Non-Receptor Mediated
reduction of receptor-coupled
signaling components
reduction of drug concentration
physiological adaptation

Receptor Mediated Desensitization
1. Loss of Receptor Function
rapid desensitization due to change
in receptor conformation
usually due to feedback of cellular
effects of agonist
Example: phosphorylation of specific
amino acids in G-protein coupled
receptors blocks coupling to G-
proteins
2. Reduction of Receptor Number
slower, long-term desensitization
due to change in receptor number
usually due to feedback of cellular
effects of agonist
Example: phosphorylation of specific
amino acids in G-protein coupled
receptors causes removal from cell
surface

Non-Receptor Mediated Desensitization

1. Reduction of Receptor-Coupled Signaling Components
depletion of signaling molecules required for biological response
Example: prolonged stimulation of G-protein coupled receptors can
lead to depletion of intracellular secondary messengers
2. Increased Metabolic Degradation
increase in the rate of metabolism and/or elimination of drug
lowers plasma drug concentrations
Example: barbiturates induce the expression of metabolic enzymes
(cytochrome P450s) that degrade this drug
3. Physiological Adaptation
reduction or amelioration of drug effects due to opposing
homeostatic response
very few well characterized mechanisms

**all of these receptor and non-receptor dependent factors can also
contribute to interindividual differences in drug response**

Factors Altering Drug Responses
Age
Pediatric or geriatric
Immature or decreased hepatic, renal function
Weight
Big patients spread drug over larger volume
Gender
Difference in sizes
Difference in fat/water distribution
Factors Altering Drug Responses
Environment
Heat or cold
Presence or real or perceived threats
Fever
Shock
Factors Altering Drug Responses
Pathology
Drug may aggravate underlying pathology
Hepatic disease may slow drug metabolism
Renal disease may slow drug elimination
Acid/base abnormalities may change drug absorption or
elimination

Influencing factors
Genetic effects
Lack of specific enzymes
Lower metabolic rate
Immunity
Body rhythms(cortisol levels, active immunity is
cyclic)
Diet and Nutrition
Psychological factors
Placebo effect
Pediatric Patients
Higher proportion of water
Lower plasma protein levels
More available drug
Immature liver/kidneys
Liver often metabolizes more slowly
Kidneys may excrete more slowly
Geriatric Patients
Chronic disease states
Decreased plasma
protein binding
Slower metabolism
Slower excretion
Dietary deficiencies
Use of multiple
medications
Lack of compliance


59
Drug interactions
Drug interactions
occurs whenever the diagnostic, preventive therapeutic or
toxic action of a drug is modified in or on the body by
another pharnmacologically acting chemical substance,
whether that be a prescription drug, an over the counter
drug, or something in the diet or the environment.
Impact of Drugs interaction
Adventage
Disadventage
Mechanism Drug interactions
Pharmaceutical interaction (invitro )
Pharmacokinetic interactions
Pharmacodynamic Interactions
Pharmaceutical interaction (invitro )

Drug incompatibilities
chemical or physical reactions that occur among two
or more drugs and can occur during mixing outside
the body or inside the body
62
Chemical
incompatibilities-
between two drugs and
change the molecular
structure of the drugs or
solutions, altering
pharmacologic properties.
A precipitate may form, or a
color change may occur
Physical
incompatibilities-
occur when two drugs are
loosely bound to each
other, but still retain their
original pharmacologic
properties.
The end result of a
physical incompatiblity is
usually a precipitate

63
Pharmacokinetic interactions
Major mechanisms of pharmacokinetic interactions
include interactions in which:
GI absorption of a drug is affected absorption
Plasma Protein binding is m odified distribution
Drug metabolism is stimulated or inhibited
biotrasformation/metabolism
Drugs Elimination elimination

ADME
Altered Absorption (Availability)
Change in gastrointestinal pH
Ketoconazole needs acidic conditions in gut
H-2 blockers + ketoconazole dissolution of ketoconazole is
decreased, resulting in reduced absorption
Drug binding in GI tract
E.g. tetracycline and calcium
Change in gastrointestinal flora
Antibiotics with OCs
Change in gastrointestinal motility
Metoclopramide and digoxin
Malabsorption caused by other drugs
Orlistat (Xenical) and fat soluble vitamins
Enzyme Inhibition
Often rapid, reversible and relatively short acting.
E.g. erythromycin and cyclosporin
erythromycin is a substrate and an inhibitor
of CYP 3A4

May be prolonged due to long half- life of drug.
E.g. amiodarone and S-Warfarin
amiodarone is an inhibitor of CYP2C9 but
not a substrate for this CYP



Enzyme Activation

Phenobarbital + warfarin phenobarbital
increases the metabolism of warfarin,
resulting in reduced anticoagulation

Protein Binding
Drug Displacement
Plasma Tissue
Drug A
protein bound
Drug A
free
Drug A
free
Drug B
Drugs A and B both bind to the same plasma protein

phenytoin + valproic acid protein binding of valproic acid is reduced
and total Css decreased
Excretion
Drug A increases or reduces the excretion (usually
renal) of Drug B.
Blood levels of B fall below or rise above normal
therapeutic range.
Becomes either ineffective or toxic.

Hydralazine + digoxin hydralazine increases the renal
clearance of digoxin via Increase in Renal Blood Flow
antacids + aspirin antacids reduce the tubular
reabsorption of salicylate via an increase in urine pH
probenecid + penicillin probenecid prolongs the half-life
of penicillin, allowing single dose therapy via Inhibition of
Active Tubular Secretion


69
Pharmacodynamic Interactions
Additive effect
occurs when two or or more drugs having the same effect are
combined and the result is the sum of the individual effects
relative to the doses used.
This additive effect may be beneficial or harmful to the client.

Synergistic effect
occurs when two or more drugs, with or without the same overt
effect, are used together to yield a combined effect that has an
outcome greater than the sum of the single-drugs active
components alone
Response
Hi
Lo
Time
Cumulative Effects
Drug A
Drug B
Response
Hi
Lo
Time
A B
Additive Effects
A + B
Response
Hi
Lo
Time
A B
A + B
Synergistic Effects
Pharmacodynamic Interactions 2
Potentiation
describes a particular type of synergistic effect-a drug
interaction in which only one of two drugs exerts the
action that is made greater by the presence of the
second drug.
Antagonistic
reactions have the opposite effect of synergism and result
in a combined effect that is less than either active
component alone.
eg. Protamine administered as an antidote to
anticoagulant action of heparin

74
Drug-Food Interactions
Food is known to induce physiologic changes in the GI
system that may decrease, increase, or delay the
absorption of drugs; or the drug may take longer to
reach peak blood levels after a dose
Foods decreasing drug effectiveness
Foods increasing drug effectiveness
75
Patient-related factors that affect
drug interactions
Factors that may
influence the response to
drug interactions are:

Chronic disease states
Dietary excess or
insufficiencies
Various drugs
Alcohol intake
Environmental factors
Genetic make up?
Age
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Adverse Drug Reactions
Adverse Drug Reactions (Adverse effect, side effect)
Describes the potential unwanted effects that a patient
may experience as a result of a drug
Adverse drug reactions are divided into two
categories :
Type A reactions
produce 70-80% of all reactions, are dose dependent,
and are often predictable and preventable
Type B reactions
immunologic in nature or idiosyncratic, are not dose
dependent, usually not preventable or avoidable
77
Type A reactions
Primary Reactions
Expected extensions of a
drugs known
pharmacologic
properties
eg. Drowsiness and
lethargy from sedatives
and hypnotics
Secondary Reactions
undesirable secondary
reactions including
severe drowsiness and
sleepiness from
antihistamines,
excessive tiredness and
impotence from
antihypertensives
78
Type B reactions
and Idosyncratic reactions
Allergic Reactions (Drug allergies or hypersensitivity
reactions) range from very mild to very severe uticaria to
true anaphylaxis type reactions
types of allergic reactions
Type I-anaphylactic or atopic reaction
Type II- Cytotoxic reaction
Type III-Autoimmune reaction
Type IV-Cell-mediated hypersensitivity
Idosyncratic reactions
an unexpected, abnormal, or peculiar reaction to a drug
occurring in a small portion of the population