Pharmacodynamics - Part 5 Flashcards
No drug produces a ______ effect.
single
Another word for enzyme is what?
Catalytic receptor
Enzyme dynamics:
- Binding interaction must be _____ _____ to hold the substrate sufficiently long for the reaction to occur
- Interactions must be ______ ______ to allow the product to depart
- Designing molecules with _____ binding interactions results in enzyme ________ which block the active site
strong enough
weak enough
stronger
inhibitors
Write down the basic enzyme pathway.
E + S ES EP E+P
Enzyme inhibitors will have what characteristics?
Will have structure similar to enzyme substrate
Has to bind strong enough to not be replaced easily
Enzymes follow what kind of kinetics?
Michaelis-Menten kinetics
Describe the Michaelis-Menten Plot.
X- substrate concentration
Y - reaction rate
v = Vmax{S]/Km + [S]
0.5 Vmax on line corresponds to Km concentration
Example: There are two drugs, A and B A - Km = 10 mM B - Km = 10 nm Which has higher affinity?
B - need less of the drug to produce 50% of the maximum rate
Describe the linear version of the Michaelis-Menten plot.
Lineweaver-Burk plot
1/v = Km/Vmax[S] + 1/Vmax
y = 1/v
x = 1/[S]
x-intercept = -1/km y-intercept = 1/Vmax
Reversible inhibitors:
- Inhibitor binds _____ to the active site
- _______ bonds are involved
- The inhibitor undergoes __ ______
- Inhibition depends on the _______ of inhibitor ______ and inhibitor ________
- ________ is blocked from the active site
- ________ substrate concentration reverses inhibition
- Inhibitor likely to be similar in ______ to what?
reversibly intermolecular no reaction strength, binding, concentration substrate increasing structure, substrate, product, co-factor
Irreversible inhibitors:
- binds _______ to the active site
- _______ bond formed between the drug and enzyme
- ______ blocked from the active site
- ________ substrate concentration ______ reverse inhibition
- inhibitor likely similar in _______ to the ________
irreversibly covalent substrate increasing, doesnt structure, substrate
Provide an example of an irreversible inhibitor.
Orlistat - inhibits pancreatic lipase
Why is orlistat an irreversible inhibitor?
forms a stable intermediate after conversion with pancreatic lipase
Allosteric inhibitors:
- inhibitor binds ______ to the ______ site
- ________ bonds are formed
- _______ ___ alters the ______ of the enzyme
- ______ site is _______ and no longer recognize by the substrate
- ________ substrate concentration ______ reverse inhibition
- inhibitor ______ similar in structure to the substrate
reversibly, allosteric intermolecular induced fit, shape active, distorted increasing, doesnt not
Drug target = cell membrane
Result of conformation change = ?
How would this drug work?
Cell membrane loses integrity –> breakup –> cell death
Non-polar region embedded in membrane; polar regions form channels in membrane
Drug target: cell wall
Result of conformation change?
A drug of this kind would most likely target?
Cell wall loses integrity –> breakup –> cell death
Target transglycosidase
Drug target: transport protein
Result of conformation change?
Give an example.
Inability to transport biomolecules –> altered cellular function
Cocaine
SSRI (Prozac)
Drug target: Structural proteins
Result of conformation changes?
Example?
Alter normal processes of cell cycle
Taxol
Drug target: NT receptors
Result of conformation change?
Alter synapse level activity –> restore or alter cellular function
Drug target: enzymes in cellular metabolism
Results of conformation changes?
ex?
Alter the level of metabolite(s) –> restore or alter cellular functions
Caffeine/theophylline - inhibit cAMP phosphodiesterase
Drug target: DNA
Results of conformation changes?
Alter transcription level –> restor or alter cellular function
What is pharmacological variability due to?
Variation in the composition and purity of the drug
Patient conditions
- biochemical states (fever)
- Physiological states (kidney function)
Adaptability can arise due to what?
Gene expression
Regulation in gene expression
Desensitization (tolerance)
Sensitization
Adaptability could cause an undesirable outcome under what conditions?
1 - Prolonged drug use
2 - Drug withdrawal
What is desensitization?
The drug action cannot be detected, even when the dosage is maintained or increased
What is sensitization?
The drug action is detected in a greater extent when the same dosage is used
Desensitization is often due to what?
Prolonged use
Sensitization is often due to what?
Drug withdrawal
Desensitization:
- ____-term exposure to the drug
- _______ binding of the drug could lead to change of the ________ which does not normally occur (e.g. phosphorylation)
- phosphorylated _______ changes ______ and is inactivated
- Dephosphorylation occurs once the drug is _________ from the receptor
long
prolonged, receptor
receptor, shape
released
What is another way, other than phosphorylation in which desensitization can occur?
Prolonged exposure to the drug induces receptor synthesis causing the normal dose of drug to no longer be as effective.
How could an increase in receptors lead to sensitization?
This increase in receptors means that if the person stops taking the drug, cold turkey, many receptors are available and the person will experience withdrawal symptoms.
