Mechanisms of Drug-Receptor Interaction Flashcards
What does pharmacology include?
There are two main domains of pharmacology: medical pharmacology and toxicology, and environmental toxicology.
Medical pharmacology and toxicology can be further divided into pharmacokinetics (PK) and pharmacodynamics (PD)
Describe the history of pharmacology
Our first drugs most likely came from roots, berries, leaves and tree bark, etc. as evidenced by ancient well drawings and carvings.
We learned through trial and error.
Now we have evidence-based medicine (controlled clinical trials)
What is a drug?
Drug defined as any substance that brings about a change in biologic function through its chemical actions
What’s a substance?
A chemical species, pure element or species of matter
Describe the naming convention of drugs
Chemical name: e.g., acetylsalicylic acid
Code name: short hand method for defining a drug
Generic name: given by the government (Health Canada, FDA)
Trade/Brand name: given by the company
What is pharmacodynamics?
The actions of the drug on the body
Drug-receptor interaction
What is pharmacokinetic?
The actions of the body on the drug
ADME (main pillars of PK)
What are the two main mechanisms of drug action?
Non-receptor mechanisms (e.g., anti-infectives) Receptor mechanisms (e.g., NDMA)
What are 3 characteristics of a receptor?
- They determine the relationship between dose and effect
- Receptors are responsible for selectivity (if it’s not selective, you’re going to have all these other, most likely unwanted, biological responses)
- Receptors are responsible for the agonist or antagonist activity
What are the classifications of receptors?
Ion channels
G-protein-coupled receptors
Enzyme-linked receptors
Steroid receptors
Describe ion channel receptors
There’s a receptor that goes through the lipid bilayer. It’s selective as to what can pass through it. Most ion channel receptors have a gaiting mechanism (they only open when stimulated). E.g., NMDA is closed by the presence of Mg ion. When activated, the Mg ion dissociates and the receptor opens, allowing calcium to flow through
Describe G-protein-coupled receptors
When a ligand binds to the receptor, this causes the activation of a G-protein. The alpha subunit of the G-protein acts on the effector protein, causing a change in the cell
What are the three subtypes of enzyme-linked receptors?
Guanylyl cyclase
Tyrosine kinase receptors
Tyrosine kinase-associated receptors
Describe guanylyl cyclase
The receptor is located within the cell (not in the lipid bilayer) which means the drug has to get passed the lipid membrane (filtering process). It binds to the binding domain and the catalytic domain has some enzymatic conversion
Describe tyrosine kinase receptors
The span the membrane
Activation causes phosphorylation of a Tyr residue on a second messenger
Describe tyrosine kinase-associated receptors
Drug binds to a receptor that then activates a tyrosine kinase (common in the immune system)
Describe steroid (nuclear) receptors
The drug has to cross the membrane AND enter the nucleus (via nuclear pores).
This type of receptor is involved in DNA transcription (and gene expression)
Explain the duration of effect of activated receptors
The effect typically only lasts as long as the drug is bound to the receptor. So if the drug dissociates from the receptors, the process is terminated. There are, however, examples where the effect might continue to last
How do enantiomers affect the binding of drugs?
The + form might bind better than the - form just because of the chiral molecule is a little different (affects affinity). This can change the potency and effectiveness
What are the factors determining drug properties?
Affinity - the degree of attraction between drug and receptor
Efficacy - maximal response
What is an agonist?
Drugs that bind to activate the receptor
What is a partial agonist? Describe them
Drugs that bind to the same receptors and activate them in the same way with a lower response.
They have affinity for the receptor but have low efficacy
What is an antagonist?
Drugs that bind to the receptor, compete with and prevent binding by other molecules
What is a competitive inhibitor?
It binds to the active site of a receptor, blocking other molecules from binding
What is an allosteric activator/inhibitor?
It binds to a site other than the active site. This often causes conformational change leading to increased activation/inhibition
What is the law of mass action?
When a drug combines with a receptor, it does so at a rate which is dependent on the concentration of the drug and the concentration of the receptor.
What is the EC50?
The concentration of drug that causes 50% of its maximum effect. To determine the EC50, we often log transform the ligand concentration to give a sigmoidal relationship
What does effect equal, mathematically?
Effect = Emax x D/(D+EC50)
What is potency?
Potency refers to the concentration or dose of a drug required to produce maximal effect (x axis)
What is an inverse agonist?
Causes the efficacy to reduce (creates a new response in the opposite direction
What happens when you administer a partial agonist?
When administered alone, partial agonists activate the receptor
When administered in the presence of a full agonist, the partial agonist reduces the effects of the full agonist
Name the different types of antagonists
Competitive reversible antagonists Irreversible antagonists Physiological "antagonists" Chemical "antagonists" Allosteric modulators
How do competitive reversible antagonists work?
They make the drugs less potent. The EC50 is shifted to the right. Emax doesn’t change.
How do irreversible antagonists work?
Via covalent bonds, they diminish the number of receptors available. The Emax is reduced
How do physiological “antagonists” work?
The effects of one agonist counteracts the effects of another agonist (no drug-receptor interactions)
How do chemical “antagonists” work?
A chemical interaction reduces the effect of the agonist (the effect of the drug is lost).
No receptors are involved
How do allosteric modulators work?
They do not bind to the agonist binding site of the receptor
They do not compete with the agonist for binding; they do not interfere with agonist binding
Allosteric modulators may increase or decrease agonist-induced response
What is desensitization?
Receptor response to agonist wanes over time. Response recovers after wash-out of agonist. The process is turned off because of a lysosomal interaction
What is tachyphylaxis?
Tissue response to agonist wanes over time
