Mechanisms of Drug-Receptor Interactions (Pharmacodynamics) Flashcards
Receptors location:
membrane, cytoplasm or nucleus
Receptors structure:
protein
Receptor function:
activates or inhibits
What is signal transduction?
is the process by which molecular signals are transmitted from OUTSIDE a cell to INSIDE a cell, ultimately resulting in a cellular response
What are the 4 receptor families?
- G-protein-coupled receptors
- Ligand-gated ion channels
- Enzyme-linked receptors
- Intracellular receptors
G-protein coupled receptors (GPCRs):
most common site of drug action - most targeted by drugs
G-protein coupled receptors (GPCRs) mechanism:
- Receptor
- G-protein
- Second messengers (cAMP, IP3, DAG & Ca2+)
- Protein kinases
- Biological responses
GPCR activation can either…
INCREASE or DECREASE production of second messengers
What are examples of GPCRs?
ex: muscarinic receptors, adrenergic receptors, dopamine receptors
What are the 3 G-protein isoforms?
Gαs → stimulates adenylate cyclase (AC↑) → cAMP↑
Gαi → inhibits adenylate cyclase (AC↓) → cAMP↓
Gαq → stimulates phospholipase C (PLC ↑) →IP3, DAG, Ca2+
What is the Ligand-gated ion channels concept?
- Ion channels are pore-forming membrane proteins that control ions across membrane.
- Abundant on excitable cells, e.g. neurons, muscle cells
Ligand-gated ion channels classification:
LGICs and Voltage gated ion channels (VGICs)
LGICs vs. Voltage gated ion channels (VGICs)
LGICs: ligand binding
VGICs: Changes in electrical membrane potential
Describe the LGICs mechanism:
- binds to ligands (conformational change in receptor) & opens channel
- SELECTIVE permeability
- DIRECTION of movement is determined by electrochemical gradient (influx or efflux)
What are examples of Ligand-gated ion channels (LGICs)?
ex: nicotinic receptor (Na+), GABA receptor (Cl-), glutamate NMDA (Ca2+)
What is the Enzyme-linked receptors mechanism?
induce tyrosine phosphorylation
What are examples of Enzyme-linked receptors?
ex: growth factor receptors, insulin receptor, cytokine receptor
Where are Intracellular (nuclear) receptors located?
in intracellular (cytosol or nucleus), NOT IN MEMBRANE
What are the receptor ligands in Intracellular (nuclear) receptors?
are lipid soluble
What is the mechanism of Intracellular (nuclear) receptors?
ligand binds to receptor –> bound receptor translocates to nucleus –> binds to DNA –> REGULATE GENE EXPRESSION
What are examples of Intracellular (nuclear) receptors?
ex: steroid receptors (estrogen receptor), glucocorticoid receptor
What is the duration of effect of activated receptors?
Intracellular (nuclear) receptors (LONGEST - hours to days) > Enzyme-linked receptors > GPCR > LGIC (SHORTEST - ms’s)
What are the relationships b/t drug dose & the pharmacologic response?
- Relationship of drug concentration to receptor binding
- Relationship of drug concentration to pharmacologic
effect
Describe the relationship of drug concentration to receptor binding
Bmax: the maximal specific binding of a ligand (drug) to receptor
Kd: represents the concentration of drug at which half-maximal binding is observed
Affinity: strength of binding b/t a ligand & its receptor
- Kd –> affinity; Kd lower indicates affinity higher
Selectivity - preference for one receptor over another
- Kd R1 < R2 –> affinity R1 > affinity R2 –> selectivity R1 > selectivity R2
Describe the relationship of drug binding to pharmacologic effect
Emax : the maximal effect induced by a drug (agonist)
EC50 : the concentration of drug producing an effect that is
50 percent of the maximum
Potency: detect drug amount required to produce a given percentage of its maximal effect
- EC50 –> potency; Lower EC50 indicates higher potency
Efficacy: the ability of a drug (agonist) to elicit a biological response
- Emax –> efficacy; Higher Emax indicates higher efficacy
- In selecting a drug, efficacy is usually more important than potency
What are agonists?
bind to a receptor & elicit a biological response: have affinity & efficacy
can be blocked by antagonist
Full agonists:
good efficacy
Partial agonists:
low efficacy
What happens when partial agonists are used alone?
When administered alone, partial agonist
activates the receptor
What happens when partial agonists are used with full agonist?
When administered in the presence of a full
agonist, the partial agonist reduces the
effects of the full agonist
What are antagonists?
bind to a receptor, no biological response: have affinity, but no efficacy (if an agonist is not present)
- can decrease the actions of another agonist drug or endogenous ligand
Antagonist vs Partial agonist
Use alone: biological response?
Antagonists: produce no biological response
Partial agonists: produce biological response
Antagonist vs Partial agonist
Use with full agonist: biological response?
Antagonists: reduce a full agonist-produced biological
response
Partial agonists: reduce a full agonist-produced
biological response
Antagonist vs Partial agonist
Use antagonist with partial agonist together:
biological response?
Antagonists reduce a partial agonist-produced
biological response
What is the Competitive antagonists mechanism? What is the effect on agonist?
bind to the same site with agonists; increasing agonist - overcome the inhibition;
- effect on agonist: shift dose-receptor curve to right; EC50 higher, potency lower; less effect on Emax & efficacy
What are irreversible antagonists? What is the effect on agonist?
bind to same site (very high affinity) or allosteric site; increasing agonist - cannot overcome the inhibition
effect on agonist: no shift of dose-receptor curve; less effect on EC50 & potency; Emax and efficacy lower
Describe the Variation in drug responsiveness: Hyporeactive, Hyperreactive, & Idiosyncratic
Hyporeactive: a lower response to a drug than
is usual among the population.
Hyperreactive: a higher response to a drug than
is usual among the population.
Idiosyncratic: individuals exhibit an unusual
drug response
- genetic differences, immunologic reaction
Describe the Variation in drug responsiveness: Tachyphylaxis, Tolerance
Tachyphylaxis: an acute rapid loss of response to a drug
Tolerance: a chronic gradually loss of response to a drug
receptor desensitization –> tachyphylaxis & tolerance
- reduced receptor response to an agonist
What are adverse effects of drugs?
an undesired harmful effect from a medication
Therapeutic index (TI)
What is TI?
comparison of the drug amount that causes the therapeutic effect to the amount that causes toxicity.
TI = TD50/ED50
Used for safety measurement
What is therapeutic window?
the range between the minimum toxic dose and the minimum therapeutic dose
TI is high - therapeutic window is wide - safety is high
High affinity - high selectivity - high TI - high safety
