Drug Receptors and Pharmacodynamics

(how drugs work on the body)

Dr. Nurhidayati
Departmen of Pharmacology
School of Medicine
Mataram University
 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.

2004-2005
Pharmacodynamics
The biochemical and physiologic mechanisms of drug
action

What
Whatthe
thedrug
drug
does
doeswhen
whenititgets
getsthere.
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
Drug Receptor
A macromolecular component of a
cell with which a drug interacts to
produce a response
Usually a protein

2004-2005
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

Acetylation

Ca++


Acetylcholinesterase

Receptor
TERMS
AGONIST
FULL AGONIST
PARTIAL AGONIST
ANTAGONIS
COMPETITIVE  REVERSIBLE
NON-COMPETITIVE  IRREVERSIBLE
PHYSIOLOGICAL
CHEMICAL
SELECTIVE AND NON-SELECTIVE
DIRECT AND INDIRECT (???)
Receptor Interactions
Lock and key mechanism

Agonist Receptor

Agonist-Receptor
Interaction
Receptor Interactions
Induced Fit

Receptor

Perfect Fit!
Receptor Interactions
Competitive
Inhibition

Antagonist Receptor

Antagonist-Receptor
DENIED!
Complex
Receptor Interactions
Non-competitive Antagonist
Inhibition

Agonist Receptor

DENIED!
‘Inhibited’-Receptor
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
 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
2004-2005
Pharmacological Antagonists

Competitive Antagonists
Non-Competitive Antagonists
 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

2004-2005
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 (α-adrenergic
receptors)
Relationship of Drug Concentration and
Receptor Binding
 Agonist Dose Response Curves

Full agonist
Partial agonist
Response

Dose
2004-2005
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
Time Response Relationships
Maximal (Peak) Effect

Effect/
Response

Latency Duration of Response

Time
Time Response Relationships

IV
IM
SC
Effect/
Response

Time
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
A B
Therapeutic
Effect
Effect
A!
Why?
A!
Why?

Dose
Which drug is more potent?
 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

12/17/2020 A B Dose 40
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
B

A
Therapeutic
Effect
Effect

Dose
Which drug has the lower threshold dose? AA

Which has the greater maximum effect? BB

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% (ED50)
Concentration of the drug which induces a specified
clinical effect in 50% of subjects

Lethal Dose 50% (LD50)

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’
Toxic dose

Therapeutic dose

Toxic dose
Therapeutic index =
Therapeutic dose
Therapeutic Index

Why
Whydon’t
don’twe
weuse
useaa
drug
drugwith
withaaTI
TI<1?
<1?

ED50
ED50<<LD50
LD50 ==Very
VeryBad!
Bad!
 Some drugs with a low therapeutic index
 

Lithium Digoxin

Carbamazepine Cyclosporin

Phenytoin Phenobarbitone

Theophylline Warfarin
(Aminophylline)
 
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 Dietary deficiencies
Decreased plasma Use of multiple
protein binding medications
Slower metabolism Lack of compliance
Slower excretion
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
Disaventage

59
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
 Physical
Chemical
incompatibilities-
incompatibilities- occur when two drugs are
between two drugs and
loosely bound to each
change the molecular other, but still retain their
structure of the drugs or original pharmacologic
solutions, altering properties.
pharmacologic properties. The end result of a
A precipitate may form, or a
physical incompatiblity is
color change may occur usually a precipitate

62
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
63
 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
Drug B Plasma Tissue
Drug A
protein bound

Drug A Drug A
free free

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
 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

69
Cumulative Effects

Hi

Drug B

Response

Drug A
Lo
Time
Additive Effects

Hi

A+B

Response
A B

Lo
Time
Synergistic Effects
Hi A+B

Response
A B

Lo
Time
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
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

74
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
75
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

76
Type A reactions
Primary Reactions Secondary Reactions
Expected extensions of a undesirable secondary
drug’s known reactions including
pharmacologic severe drowsiness and
properties sleepiness from
eg. Drowsiness and antihistamines,
lethargy from sedatives excessive tiredness and
and hypnotics impotence from
antihypertensives

77
 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

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