Test 1- Pharmcodynamics Flashcards
(47 cards)
Pharmacodynamics
refers to the effects of drugs and their mechanism of action within the body. If pharmacokinetics are what the animal does to the drug then pharmacodynamics are what the drug does to the animal.
Therapeutic effects
Which is what we want
Side effects
Which are secondary to the intended effect and may be good or bad
Adverse effects
Which are unintended and unwanted, this includes NOT producing a desired clinical effect. The study and monitoring of adverse effects is called pharmacovigilance.
Toxic effects
Responses to a drug that are harmful to the health or life of the animal.
Physical interactions:
Nonspecific drug effects such as:
- Osmotic diuretics:
- Antacids (direct neutralizers):
- Radioactive iodine
Osmotic diuretics:
these molecules move through the body dragging water with them by osmosis until they are excreted.
Mannitol moves through the body dragging water with them until excreted in the urine
Antacids (direct neutralizers):
Given orally they directly interact with acid in the GI
tract, a form of physiologic antagonism.
Calcium carbonate tablets
Radioactive iodine:
The iodine is actively concentrated in the thyroid (as all iodine is) and the radiation will destroy all tissue within 2-3mm causing focal, controlled destruction
I-131 concentrates in the thyroid gland, the radiation will destroy all tissue within 2-3mm
Biological interactions with drugs:
Receptors (signal-transduction) – specific recognition sites for a ligand
- Ionotropic receptors:
- Metabotropic receptors
- Kinase-coupled receptors
- Nuclear receptors / Transcription factor receptors
- Receptor subtypes
- Receptors can undergo up- or down-regulatio
Ionotropic receptors:
LIGAND GATED ION CHANNELS
o These receptors are composed of several proteins embedded in the cell membrane creating a pore or tunnel. They are usually ligand-gated meaning that something has to bind to them causing a change in shape or ‘opening’ that allows a large influx of ions.
o Drugs can bind to these to activate them or prevent them from opening. This type of channel is often involved in fast neurotransmission (on the order of milliseconds).
- Nicotinic ACh receptors
- GABAA receptors
Metabotropic receptors
- G-protein coupled receptors or 7TM (seven transmembrane) receptors
- These transduce an extracellular signal to an intracellular one by activating the
G-protein second messenger system.
-The drug binds to the receptor on the outside of the cell causing G-proteins inside the cell to bind to the receptor and take up GTP, which gives them enough energy to move to a target enzyme or channel to cause an action.
- Use of these type of systems allow signal amplification and specificity
- These are common receptor types for secretory and smooth muscle functions (eg. muscarinic ACh receptors) where the changes occur over seconds.
Kinase-coupled receptors
o These transmembrane proteins have an extracellular receptor portion and an intracellular portion that has enzymatic activity (kinase domain).
- Phosphorylation and activation of proteins which then activate effectors
- There are enzymatic domains other than kinase
- Insulin receptors are of this type. Generally these are growth promoting hormones and factors—- METABOLIC CHANGES INSIDE THE CELL—- LONGER DURATION
Nuclear receptors / Transcription factor receptors
o Receptors are actually located in the cytoplasm but after the ligand binds the receptor they translocate to the nucleus of the cell and bind to a response element within the DNA to initiate specific gene transcription.- alters gene transcription
o Steroids and thyroid hormones are examples of these. New protein production starts over the course of hours.
Receptor subtypes
o Endogenous neurotransmitters often bind to more than one type of receptor.
The same signaling molecule can then cause different effects or have different affinity in different tissues or species.
-Adrenergic receptors for example, there are different subtypes (α, β) and differences in these subtypes between species.
Receptors can undergo up- or down-regulation
o Up-regulation is an increase in the number of receptors resulting in an increase
in the effect of the drug
o Down-regulation of the number of receptors and therefore a reduction in effect
- Down-regulation can be achieved by internalizing the receptors in lysosomes, recycling them, sequestering, or degrading.
- This may be part of the normal cellular metabolism (e.g. insulin) or can occur as part of developing tolerance (a gradual decrease in responsiveness to a drug over days to months) or tachyphylaxis (an acute tolerance to a drug).
Biological interactions:
Non-receptors
- Voltage-gated ion channels
- Enzymes
- Carrier proteins
Voltage-gated ion channels
o Blocking of ion channels can occur by the drug molecule physically obstructing the channel to impair ion movement
- Local anesthetics like lidocaine blocking Na+ channels
o The drug may also modulate the opening and/or closing of the channel
-Calcium channel blockers - amlodipine
Enzymes
o Drugs can be analogs that compete with the real substrate for binding to the enzyme (acetylcholinesterase inhibitors or organophosphates do this by binding to the active site of acetylcholinesterase)
o Prodrugs where the drug needs to be metabolized to its active form
o Drugs can also act as false substrates which will lead to the formation of abnormal metabolites instead of the active product that normally would have been produced
-Sulfonamides to Dihydropteroate synthase works on the sulfa instead of on PABA and does not produce it’s normal metabolites (nucleic acids)
Carrier proteins
Some small polar molecules do not cross cell
membranes and require transport proteins
Altering these proteins can remove molecules from their site of action and thus ending their effects
Fluoxetine is a selective serotonin reuptake inhibitor
Omeprazole targets the Na+/H+ proton pump in the gastric parietal cell
ligand
A ligand is anything that binds to a recognition site (this can be an endogenous ligand like a neurotransmitter or a drug). At any point if a ligand is bound to a receptor it prevents other ligands from binding as long as it is sitting there.
Agonist:
- Mimics the effect of the endogenous ligand
- There are differences in affinity and efficacy of agonists
o Full agonist: binds to the receptor to elicit a maximal response
o Partial agonist: will bind to the receptor but not cause as much effect as a full agonist, it does prevent anything else from binding to the receptor while it is ‘docked’ there.
This translates to a lower efficacy and is sometimes called a ceiling effect
o Reverse agonist: will bind to the receptor and cause the opposite effect as the endogenous ligand would (note that this is different from an antagonist)
Antagonist (or ‘neutral agonist’)
Binds to the receptor but does nothing on its own, however it sits there and prevents anything else (like an agonist) from binding and thus blocks the receptor.
Competitive antagonism
Competitive antagonism (most common) is when the antagonist ligand binds and releases as long as it is present and so if the antagonist is present as well as an agonist they will compete for the binding, who binds more often will be determined by concentration and affinity. Generally if you increase the concentration of either the agonist or antagonist enough you give that one a competitive advantage and can sometimes overcome the effect of the other. -This can be reversible or irreversible (a great example are the carbamate and organophosphate toxins, they both bind to acetylcholinesterase and antagonize it but carbamate does so reversibly and organophosphates do so irreversibly)
