Pharmacodynamics
Study Questions
• What is Pharmacodynamics?
• How do drugs act?
• What are receptors? What are their various types?
• How are receptors discovered?
• What are Drug-Receptor interactions?
• Which factors are involved in D-R interactions?
• What is a ligand? What are its types?
• What are the types of agonist and antagonist?
• What is antagonism ? What are its types?
• What is potency and efficacy of a drug?
• What are the characteristics of receptors?
PHARMACOLOGY
PHARMACON + LOGOS
PHARMACODYNAMICS
PHARMACON + DYNAMICS
Pharmacodynamics
Greek word 'dynamics' means action/effect
Study of effects & mechanisms of action of
drugs
Relationship of the plasma concentration of
the drug with
magnitude of response
duration of action
What the drug do to the body?
HOW DO DRUG ACT?
• RECEPTORS
• WITHOUT RECEPTORS
1. Chemically
2. Water molecules
What is the chemical nature of receptors ?
RECEPTORS ARE PROTEINS
Enzyme
Transport
Regulatory
Non-regulatory
Structural
Nucleic acids
Sterols
TYPES OF RECEPTORS
•Cholinoceptors Active
•Adrenoceptors Inactive
•Cholinergic Open
•Adrenergic Close
•Dopamine Productive
•Histamine Non-productive
•Serotonin Orphan
•GABA Spare
Nicotinic Acetylcholine Receptors
HOW ARE RECEPTORS DISCOVERED
• Sequence Homology to known receptors
• Molecular genetic strategies
• Studies in cultured cells
• Studies in bacteria & yeast
• Cloning Technique
• X-ray crystallography
• Nuclear resonance spectroscopy
How do drug-receptor
interactions occur ?
D-R
1. Ligand
2. Receptor
3. Forces
AGONIST : A IA
ANTAGONIST : A
•AGONIST :
1. Full
2. Partial
3. Inverse
•ANTAGONIST :
1. Reversible
2. Irreversible
a) True
b) Pseudo
c) Allostearic
Agonist
Antagonist
Inverse agonist
• Binds to the same receptor as an agonist
but induces a pharmacological response
opposite to that of an agonist
R* R
Full agonist : 100%
Partial agonist : Less than 100%
Antagonist : 0%
Inverse Agonist : Less than 0%
ANTAGONISM : Phenomenon
1. Pharmacological---- same receptor
2. Physiological------ different receptors
3. Chemical----------- no receptor
Potency
Efficacy
CHARACTERISTICS OF RECEPTORS
1. Show selectivity
2. Target for drugs
mediates the effect of:
(a) agonist & (b) antagonist
3. Determine dose of drug
4. Determine the therapeutic & toxic
effects of drug
PHARMACODYNAMICS II
•Transduction
•Transmembrane Signaling
•Signal Transduction
•Receptor Domains
1. Ligand binding domain
2. Message propagation
1+2=Functional Domains
RECEPTOR EFFECTOR COUPLING
Receptor Effector System
1. Receptor
2. Enzymes
3. G-Proteins
4. Second messengers
RECEPTORS FOR TRANSMEMBRANE
SIGNALING
• Receptors for nitric oxide
• Nuclear receptors
• Tyrosine kinase receptors
Cytokine receptors
• Ligand gated channels
• Receptors associated with G-proteins
LIGAND GATED ION CHANNEL
G- PROTEIN COUPLED RECEPTOR
TYROSINE KINASE RECEPTOR
NUCLEAR RECEPTOR
G-PROTEINS
Enzymes II-Messengers
• Adenylyl cyclase ATP--------cAMP
• Guanylyl cyclase GTP--------cGMP
• Phospholipase C PIP2--------DAG,IP3
& Calcium ions
SECOND MESSENGER PATHWAYS
SIGNAL TRANSDUCTION MECHANISMS
• AMPLIFY
• CO-ORDINATE
• TERMINATE POST-RECEPTOR SIGNALING
DESENSITIZATION OF RECEPTORS
• Fast process
• Reversible
• No decrease in actual # of receptors
• Phosphorylation of receptors occur
• New receptors are not synthesized
DOWN REGULATION OF RECEPTORS
• Slow process
• Reversible sometimes/ irreversible
• Decrease in actual # of receptors
• Degradation of receptors occur
• New receptor synthesis is needed
RECEPTOR REGULATION
NORMAL
DOWN-
REGULATION
UP-
REGULATION
Individual factors that alter response to
drug therapy
• Age
• Body mass
• Gender
• Environmental milieu
• Timing of administration
• Pathological states
• Genetic factors
• Psychological factors
Two drugs at one time
drug interaction
changing the effect of one drug by the
administration of another drug(s)
» can either increase or decrease the
effect of each drug
» can either be beneficial or detrimental
Type of drug interactions
Summative
Drug interaction in which the combined
effects of two drugs is equal to the sum of
each drug
» Acting individually
• 1+1=2
• Codeine + aspirin = better pain
control
Synergistic
drug interaction in which the combined
effects of two drugs is greater than the
sum of each drug acting individually
• 1 + 1 = 3 or more
• propranolol + hydralazine +
hydrochlorothiazide = better B/P
control
Potentiation
Drug interaction in which the concurrent
administration of one drug increases
the effect of the other drug
• 1+1>2
• probenecid + penicillin = higher blood
levels of penicillin
Antagonistic
Drug interaction in which the combined
effect of two drugs is less than the sum
of the individual effects of each agent
• 1 + 1 = less than 1
• morphine sulfate + naloxone
hydrochloride = reversal of respiratory
depression in morphine sulfate
overdose
PHARMACODYNAMICS III
Drug responsiveness
Drug responsiveness may be
affected:
• At the level of ligand
• At the level of receptor
• At post-receptor level
• At the level of individual
I. At the level of ligand
• Concentration of drug in plasma
• Affected by ADME processes
• Specially absorption & metabolism
II. At the level of receptor
Altered receptor functions
• Receptor diseases
• Receptor desensitization
• Down & up-regulation
• Receptor autoimmune diseases
• Inherited mutations of genes
DESENSITIZATION OF RECEPTORS
• Fast process
• Reversible
• No decrease in actual # of receptors
• Phosphorylation of receptors occur
• New receptors are not synthesized
DOWN REGULATION OF RECEPTORS
• Slow process
• Reversible sometimes/ irreversible
• Decrease in actual # of receptors
• Degradation of receptors occur
• New receptor synthesis is needed
• Mutated receptors for vasopressin
INHERITED MUTATIONS OF GENES
• Receptor for thyrotropin
• Precocious puberty
• Mutations in beta-2 adrenoceptors
• Mutation in α-2c & α-1 adrenoceptors
• Mutations in G-proteins
• Mutations of genes encoding growth factor
receptors
III. At post-receptor level
• Compensatory mechanisms
• Diuretics e.g thiazide ----depletion of
volume ----compensation---- Renin
angiotensin aldosterone mechanism ----
Conservation of fluid----increase BP
IV. At the level of individual
• Age
• Body mass
• Gender
• Environmental milieu
• Timing of administration
• Pathological states
• Genetic factors
• Psychological factors
1. Age
• children have immature hepatic and renal
systems
• aged have declining hepatic and renal systems
• in both age groups
metabolism and excretion are affected
which result in accumulation of drugs and
the need to adjust dosages of drugs
2. Body mass
• Dose & body mass are directly proportional to
each other
• average adult drug dose
–based on the drug quantity that will
produce a particular effect in 50% of
persons who weigh about 150lbs(70kg)
3. Gender
• body size differences
–women typically smaller (need less drug)
• proportion of fat and water
–women typically have more fat, less H2O
4. Environmental milieu
• mood and behavior
–modified by the drug itself or
personality of the user
• physical environment
–unusually cold or hot
–unusually deprived of oxygen (high
altitude)
[Link] of administration
• food
–a drug is absorbed more rapidly if food is
not present in GIT
• biologic rhythms
– sleep-wake cycle
–drug-metabolizing enzyme rhythms
– corticosteroids secretion rhythm
6. Pathologic state
• pain
• anxiety
• circulatory, hepatic, or renal dysfunction
7. Genetic factors
• genetically determined abnormal
susceptibility to a chemical
8. Psychologic factors
• Symbolic investment in drugs
and faith in their efficacy or
health personnel
• Placebo effect
