Introduction to Pharmacodynamics Flashcards
Pharmacokinetics 2 vs. Pharmacodynamics 2
Pharmacokinetics (PK)
“What the body does to a drug”
Involves movement of drugs to get to the site of action ADME Absorption Distribution Metabolism Excretion
Pharmacodynamics-what the drug does to the body
Interaction at the effective site to produce pharmacologic activity
Ex: How a drug interacts with a specific receptor and triggers a change in biological regulation
What are receptors?
What are most receptors and what are they made of?
Molecular targets where drugs interact to produce an effect
Most are proteins
Made of amino acids and subunits
Where are they located?
Some imbedded in the lipid bilayer of cell membranes (transmembrane)
Others located intracellularly
Describe the types of protein strcutrures?
Primary -Amino acid sequence of protein Secondary -Microstructures due to attractions between amino acids Tertiary -Global shape due to secondary structure Quaternary -Only with multiple, distinct molecules
Why are receptors important?
- Selectivity of drug action
- Affinity depends on the properties of the drug
- Shape, charge, size - Determines the relationship between dose and the pharmacological effects of the drug
- Responsible for pharmacologic actions of agonists and antagonists
- When drugs bind to receptors, what action occurs (inhibition or excitation)
4 major types of interactions between drugs and receptors
- Transmembrane ion channels
- Transmembrane receptor-enzymes
- Transmembrane G-protein coupled receptors (GPCRs)
- Cytosolic-nuclear receptors
Examples of gated ion channels?
3
Gaba receptors-benzodiapenes-seizure medication- inhibitor
Nicotinic- ach
What do receptor-enzymes?
causes a conformational change.
What activates GPCRs?
ligand binds and activates
Then GPCR exchanges GTP for GDP
What does the activated G protein allow?
dissociation of the alpha subunit. The alpha subunit is then free to move into the cytoplasm and signal
When does signal transduction occur?
after a drug binds to a specific receptor
Changes within the cell in response to a drug
Why are receptors in the plasma membrane so important for drugs?
Most drugs are positively and negatively charged so they are unable to diffuse directly through the membrane. They need receptrs and channels
What does drug affinity depend on?
depends on the properties of the drug
-Shape, charge, size
Cells recieve multiple stimulatory and inhibitory signals simultaneously. How are they interpreted?
second messengers
Another defintion for pharmacodynamics?
Induce changes within the cell to produce a biochemical or physiologic response
What do second messengers do?
Help in translating the message from the bound drug into a cellular response
Examples of second messengers?
Cyclic adenosine monophosphate (cAMP)
Cyclic guanosine monophosphate (cGMP)
Inositol trisphosphate (IP3)
What does inositol triphosphate do? (IP3)
Aids in release of calcium from within the cell
Where do the drug and recepetor pair in the cytosolic-nuclear receptors and where do they go?
they bind in the cytosol and move into the nucleus. When they get there they bind to DNA and create RNA making specific proteins.
Examples of cytosolic-nuclear receptors?
glucocorticoids and sex hormones
Drugs compete for selective receptor sites
Favorability of the interaction is based on what?
Chemistry Biochemical affinity (attraction) Intermolecular interactions (compatibility)
What does affinity refer to ?
Chemical forces that cause the drug to associate with the receptor
Bond Forces
If there is a higher affinity how does that affect the drug and receptor interaction?
tighter drug binding to the receptor
What does drug efficacy refer to?
Extent of functional change imparted to a receptor upon binding of a drug
What is the benefit of having a better knowledge of a receptor structure?
increased ability to design a drug selective for a certain receptor this could perhaps cause fewer side effects
Describe basal activity and what is another name for it?
- Also called constitutive activity
- Activity of a cell in the absence of a ligand (either endogenous or exogenous)
- Or the “natural” activity of a cell
How does an agonist affect activity?
What mediums?
increases activity
Natural ligand Exogenous compound (drug)
How does an inverse agonist affect activity?
Decreases activity
Describe the process of agonism?
3
- Drug binds to receptor
- Interaction activates signal cascade
- Leads to function within the cell
Describe epinephrines role with beta-1 receptors in cardiac tissue?
3 steps
5 things total to remember
Its an alpha/beta receptor agonist so….
1. Epi attaches to beta-1 receptors →
2. increases calcium level in the cell →
3. increases force of contraction of cardiac muscle
Useful in cardiac arrest
What are partial agonists?
Drug that cannot produce a full response, regardless of the concentration
What are some factors that make agonists partial agonists?
2
number of receptors on the cell membrane
Drug history
What is Buprenorphine?
opioid analgesic used to treat acute and chronic pain
What is Buprenorphine role as a partial agonist?
Partial agonist of mu receptor in central nervous system → pain relief
Used to deccrease withdrawl symptoms
Whats can partial agonists be used for?
utilized in opioid treatment programs to decrease withdrawal symptoms in patients but not provide as much euphoria as a full opioid agonist (Ex: Heroin)
Can be displaced from receptor by opioids with higher affinity
What are inverse agonists?
- Drug that can stabilize receptors in the inactive state
- Binding to a receptor by an inverse agonist produces an effect opposite that of an agonist
Examples of inverse agonists?
diphenhydramine
Gaba receptors
How does an anti-histamine work as a inverse agonist?
3
- Anti-histamine is an inverse agonist for the H1-receptor
- Blocks the release of histamine from mast cells
- Decreases symptoms caused by histamine release
How does a GABA receptor work as an inverse agonist?
- When bound by natural ligand (GABA) →
- allows chloride into the cell, which causes sedation
- Inverse agonist of GABA receptor will cause anxiety and seizure
Look at illustrations for agonists in the slide show
More agonists binding = more saturation = more active unbound drug
What is ED50?
The point where 50% of patients have a therapeutic effect from the medication
-directly in between threshold and and ceiling levels
What is potency?
Dose of drug necessary to produce a specified effect
What determines potency?
- receptor density,
- efficiency of the stimulus-response mechanism
- affinity
- efficacy
What is intrinsic efficacy?
And what is it determined by?
Power of a drug to induce a response
Number of receptors in the target tissue
How do you determine if one drug is more potant than the other?
If it requires less drug to get the same effect
How os relative potency calculated?
ED50b/ED50a
What is a competitive antagonist?
2
- Drug that binds to a receptor but does not initiate a response
- Compete for active sites with agonists
What is an active site?
aka?
- Site where the drug recognizes and binds to the receptor
- Also called substrate binding site
How does propranolol act as a competitive antagonist?
3
Whats its end result on the heart?
Look at competitive antagonists picture slides and explain them
- Its a beta-blocker so it binds to beta1 receptor preventing epinephrine, a beta agonist, from binding to the same receptor
- Does not initiate a response
- Blocks epinephrine from initiating its response → decreasing rate and contractility in the heart
What is a non-competitive antagonist?
Drug that binds to receptor and does not produce an effect
Binds to a different site other than the drugs active site but that binding creates a conformational change in the binding of the active site.
What is the site called that a non-competitive antagonist binds to?
an allosteric site
Describe the steps in non competitive antagonists processes?
3
- Antagonist binds to this site ➔
- changes the conformation of the receptor ➔
- impossible for an agonist to bind
What is chemical antagonism?
Example?
Drug (antagonist) interacts directly with the agonist drug and renders it inactive
Example: Digibind® - binds to the drug digoxin
What is Functional/Physiologic Antagonism?
Example?
Antagonist acts through a completely different mechanism to counteract the effect of the agonist
Example: Calcium channel blockers reduce effects of epinephrine
Describe the selectivity of aspirin?
Not very selective. It does it job by inhibiting COX1 and COX 2 receptors to stop inflammation but also interfers with other processes like platelet, kidney function, and stomach issues
Describe the selectivity of Celecoxib or Celebrex?
Pretty selective. It only inhibits COX2 and works primarily at the site of inflammation. It also has fewer side effects
Why is drug selectivity an important concept to understand when selecting drug therapy for patients?
Mitigate side effects of drugs being used
What does cellular regulation accomplish?
Prevention of over-stimulation that could lead to cellular damage
What are the four kinds of cell regulation?
Up regulation
Down regulation
Desensitization or (tachyphylaxis)
Refractory
What is up regulation?
Cells may add receptors to the cell membrane
What is down regulation?
Repeated stimulation of receptor → cell begins to remove receptors from the cell membrane
What is Desensitization or (tachyphylaxis)?
- not getting the same effect that you used to
- Diminished effect of drug over time
- Decreased ability of drug to stimulate receptor
Like caffeine if you drink too much
What is refractory regulation?
Period of time during receptor simulation before another interaction can produce an effect
What are the two borders of the acceptable therapeutic range?
Minimum Toxic Concentration
(MTC) -top border
Minimum Effective Concentration
(MEC)- bottom border
Therapeutic Window/Range can best be described as?
Doses of a drug which elicit a therapeutic response without unacceptable toxicity
What does the Therapeutic index provide?
2
- Method for quantifying therapeutic window
2. Provides a relative safety margin of a drug
How does the TI affect the safety of the drug?
2
Greater the TI the safer the drug
Greater degree of dosage flexibility means more convenience
Why does warfarin require a lot of monitoring?
It has a small therapeutic window.
If the INR is below two then risk of clotting. If INR is above 3 then they are at risk of bleeding.
Describe penicillin’s therapeutic window?
Large therapeutic window. Toxic level is high
What is the LD50?
LD 50-50% of patients die(or experience toxic effects) from this dose
What is the equation for figuring out the TI?
LD50/ED50
Examples of TI equations?
Diazapam?
Digoxin?
TI = 100/1 = 100 TI = 2/1 = 2
Example of digoxin TI calculations:
Therapeutic range at 0.6_1.5ng/mL
Toxic concentration at 1.5 ng/mL
TI?
TI = (toxic concentration / therapeutic range) = 2.5
What three drugs have very narrow theraeutic windows that we talked about?
Warfarin
Digoxin
Lithium
Drug A has a TI of 100 and drug B has a TI of 14. Based on therapeutic index alone, which is the safer drug?
Drug A
