Pharmacodynamics Flashcards
Pharmodynamics
The action of a drug on a living organism
When a drug binds to a receptor, one of the following actions usually occurs:
An ion channel opens or closes Biochemical messenger (second messengers) Normal cellular function is inhibited A cellular function is turned on (DNA transcription)
Law of mass action
The amount of drug-receptor complex formed determines the magnitude of the response. as drug concentration increases, the drug-receptor complexes increase and drug effect increases.
Relationship between drug-receptor complex formation and concentration of drug
Proportional, but the relationship is not linear. Use semilogarithmic graph.
Drug-target interactions are regulated by which two properties
Affinity- How strong is the binding
Efficacy- how well does the drug work to alter the activity of the receptor?
Affinity is influenced by what?
Size and shape of drug molecule
Types, number and spatial arrangement of receptor
Intermolecular forces
is affinity influenced by concentration?
No
Bonds from weakest to strongest
Weakest Van der Waal Hydrophobic Hydrogen Ionic Covalent Strongest
KD
Dissociation constant. Describes the drug concentration at which 50% of the receptors are occupied. Measure of drug’s affinity.
Does not always indicate half maximal response.
relationship between KD and affinity
inverse. High KD means that it takes a high drug concentration to bind 50% of the receptors. Poor affinity.
Low KD means it takes a low concentration to bind 505 of the receptors. Good affinity.
KD is found on which graph?
Drug receptor occupancy curve. Semi-log. Found at 50% mark on Y.
Beta 1 selective blockers. As concentration increases, the drug will bind
to receptors for which it has a lower affinity.
Two types of drug-target relationships
Graded: How much the drug works. Continual.
Quantal: All or none. yes or no.
Graded Dose-Response curves
Measures continual effect.
Emax: Maximum drug activity. Measure of efficacy. Any increase in conc will not increase effectivity of drug. Found at top of graph.
EC50: Concentration that has 50% of max effect. Measure of potency/strength. Found in center of each curve.
Quantal Dose-Response Curves
Measures responses that are all or none. Gives relationship between drug dose and frequency at which a biologic effect occurs.
Emax: Response in 100% of population
ED50: Response in 50% of population
TD50: Toxic response in 50% of population
LD50: Lethal response in 50% of population
Therapeutic Index
A measure of the safety of a drug (larger is better)
Found by dividing TD50 or LD50 by ED50.
Agonist
Binds to receptor and elicits a response
Antagonist
Binds to a receptor but does not elicit a response. Blocks receptor- prevents something from binding to it.
Full agonist vs partial agonist
Full (strong) produces max activation of receptor and elicits max response from tissue.
Partial (weak) produces a weaker response compared to the full agonist. Takes more drug molecules bound to more receptors to produce the same effect as full agonist.
Inverse Agonist
Drug that binds to a cell, which in its natural state, is on. Drug turns it off.
Ex: Drug has ion channel always open. Ions always flowing. Drug binds and closes channel.
Technically an agonist bc it caused a response. An antagonist would have prevented it from closing.
What does it mean that antagonist have zero intrinsic activity?
They do not cause a reaction- they simply present the receptor from being occupied by another molecule.
Competitive reversible antagonist (?? i think)
Antagonist competes directly with the agonist molecule. Increased concentration of agonist will overcome the antagonism.
Emax will be the same, but the curve will shift to the right. Will produce same max response, but will require more molecules to do it.
Competitive irreversible antagonist
Compete directly with agonist for receptor binding site. Very strong bond-irreversible. Will reduce the maximal agonist effect since it permanently reduces the number of receptors available to an agonist.
Emax of agonist will decline due to decreased receptors available to bind.
Noncompetitive antagonist
Does not compete with agonist for same binding site. Both antagonist and agonist can be bound at the same time (but antagonist is more powerful). Increasing concentration of the agonist will not reverse the inhibitory action!
Similar curve to irreversible antagonist. Emax of agonist will decline due to antagonists bound. EC50 stays the same.
4 families of receptor types
Ligand gated ion channel
G protein coupled receptor
Enzyme linked
Intracellular
Quickest to slowest response time based on receptor type
Quickest: Ligand gated ion channel G protein Enzyme linked Intracellular Slowest
Flow of ions through a ligand gated channel is depend on
The binding of a ligand to the receptor on the channel. The ligand can include a NT or drug.
Two examples of ligand gated ion channels
- Cholinergic receptors: Binding of agonist opens sodium channel and causes action potential. Excitatory.
- GABA receptors: binding of agonist opens chloride channels- causes hyperpolarization. Inhibitory.
Voltage gated ion channels
Change confirmation in response to changes in membrane voltage
Binding of drug causes the channel to open or close.
Ex: local anesthetics
GPCR activation
Ligand binds. GTP replaces GDP on the alpha subunit of the G protein.
The alpha + GTP dissociates and interacts with adenylyl cyclase –> camp production –> second messengers produce further actions
Response time difference between ligand gated ion channels and GCPR
GCPR have a slower response, but last longer.
Examples of second messengers in GPCR
cAMP regulates protein phosphorylation
Phospholipase C
Guanylyl cyclase to form cGMP. Relaxes smooth muscle cells.
How do enzyme-linked receptors work?
Have systolic enzyme activity as part of their structure and function. Binding of ligand activates or inhibits the activity of the enzyme.
2 examples of enzyme linked receptors
Insulin receptor
VEGF
Intracellular receptors
Receptors are located inside cell. Ligand must be lipid soluble (steroid hormone) and travel to the receptor inside the cell. Complex will migrate to nucleus and regulate gene expression
Response time: 30 mins
Can last hours to days
Spare receptors
In some cases, maximal response can be achieved when only a fraction of receptors are occupied.
EC50 will be lower than KD due to amplification of secondary messengers. Common with GPCR or single ligand interacts with many G proteins.
What causes spare receptors?
Common with GPCR or single ligand interacts with many G proteins.
Receptor Desensitization
If receptors are continually bound, it may lead to changes in the responsiveness of the receptor- usually causes decreased response. Evolved to prevent cell damage.
Two mechanisms of receptor desensitization
Tachphylaxis: Receptor is still present but is unresponsive to the ligands. Light switch unplugged from the wall.
Endocytosis: Cell engulfs receptor and is sequestered from further activation.
Can be recovered- needs a break.
Tolerance
Decreased response to a drug due to desensitization (changes at receptor level), metabolism, or behavioral (ex drinking coffee). Dose must be increased to achieve the same effect.
Tolerance can lead to ___ and then ____
Dependence –> withdrawal
Dependence
Pt feels abnormal in absence of drug. Ex: dependent on drug. Need coffee. If not, will get headaches or be shaky.
Withdrawal
Drug is no longer given to dependent patient. Symptoms are often opposite of the effect of the drug.
