Lecture 1 - Drug-receptor interaction Flashcards
What is a drug?
- A substance used as a medicine to treat, prevent, or diagnose a disease
- A substance used with intent of producing a change within the body
What are pharmacokinetic processes?
- Absorption, distribution, metabolism, and elimination
- The actions of the body on the drug
What are pharmacodynamic processes?
- Receptor and signal transduction
- The actions of the drug on the body
What is a receptor?
A protein molecule in a cell that interacts with drugs and initiates a chain of events causing some form of cellular response
Where are receptors located?
- Cell membrane
- Cytoplasm
- Nucleus
What is the structure of receptors made from?
Proteins
What is the function of receptors?
Bind to ligands to activate or inhibit post-receptor signaling, which triggers a biological response
What is the main significance of receptors?
They transduce signals from outside a cell to inside a cell
What are the 4 receptor families?
1) G protein-coupled receptors
2) Ligand-gated ion channels
3) Enzyme-linked receptors
4) Intracellular receptors
What is the biggest family of receptors?
G-protein coupled receptors
Which receptors are the most common site of drug action?
GPCRs
What are the 2 subunits of a G protein?
1 alpha-subunit and 1 beta gamma-subunit
What does the alpha subunit of a G protein do?
Binds GTP and GDP
What does the beta gamma subunit of a G protein do?
Inhibits the alpha subunit
What are some second messengers?
- cAMP
- Ca2+
- IP3
- DAG
What happens when GPCRs are activated?
They either increase or decrease production of second messengers, depending on which G protein is activated
What are 5 examples of GPCRs?
1) Muscarinic receptors
2) Adrenergic receptors
3) Dopamine receptors
4) Serotonin (5-HT) receptors
5) Opioid receptors
What are drug examples of muscarinic receptors?
- Acetylcholine
- Drugs for parasympathetic NS
What are drug examples of adrenergic receptors?
- Alpha, beta receptors
- Norepinephrine, epinephrine
- Drugs for sympathetic NS
What are drug examples of dopamine receptors?
- Dopamine
- Antipsychotics
What are drug examples of serotonin (5-HT) receptors?
- Serotonin
- Antipsychotics
What are drug examples of opioid receptors?
- Endorphins
- Morphine and other analgesics
Which ions are more abundant on the INSIDE of a cell?
- K+
- H+ (equal on both sides)
- A- protein
Which ions are more abundant on the OUTSIDE of a cell?
- Na+
- Ca2+
- Cl-
- H+ (equal on both sides)
What does ligand binding trigger?
A conformational change in the receptor
What determines the direction of movement through an ion channel?
The electrochemical gradient
What are examples of ligand-gated ion channels?
- Nicotinic acetylcholine receptor
- Glutamate N-methyl-D-aspartate receptor
- Gamma-aminobutyric acid receptor
Which ion does the nicotinic acetylcholine receptor transfer?
Na+
Which ion does the glutamate N-methyl-D-aspartate receptor transfer?
Ca2+
Which ion does the gamma-aminobutyric acid receptor transfer?
Cl-
What is a drug example of a nicotinic acetylcholine receptor?
Succinylcholine
What is the function of a nicotinic acetylcholine receptor?
Muscle contraction
What is the function of a glutamate N-methyl-D-aspartate receptor?
Long-term potentiation
What are drug examples of a glutamate N-methyl-D-aspartate receptor?
- Memantine
- Ketamine
What is the function of a gamma-aminobutyric acid receptor?
CNS depression
What is a drug example of a gamma-aminobutyric acid receptor?
Benzodiazepines
What occurs in ion pumps?
Ions move across a membrane against their concentration gradient, using ATP
What occurs in ion channels?
Ions move down their concentration gradients
What is another name for cell membrane enzyme-linked receptors?
Tyrosine kinase receptors
Which receptors can form dimers?
Enzyme-linked receptors
What are functions of enzyme-linked receptors?
- Induce tyrosine phosphorylation
- Convert kinases from inactive to active form
- Metabolism, growth, and differentiation
What are drug examples of tyrosine kinase receptors and what do they treat?
- Imatinib (gleevec) - chronic myeloid leukemia
- Interleukin-2 (proleukin) - cancers
What is the most common intracellular enzyme-linked receptor?
Soluble guanylyl cyclase
Where is guanylyl cyclase located?
Cytoplasm
What is the structure of guanylyl cyclase?
- Forms a heterodimer composed of an alpha and a beta-subunit
- Contains a regulatory domain, a coiled-coil domain, and a cyclase domain
What activates guanylyl cyclase?
Nitric oxide
How are guanylyl cyclase and adenylyl cyclase different?
Adenylyl cyclase is activated by a G-protein; guanylyl cyclase is activated by nitric oxide
What are 2 drug examples of guanylyl cyclase and what do they treat?
- Nitroglycerin (glyceryl trinitrate) - angina
- Sildenafil (viagra) - hypertension and erectile dysfunction
Describe the structure of intracellular receptors
Ligand binding domain and DNA binding domain
Where are intracellular receptors generally located?
Nucleus
Receptor ligands for intracellular receptors are ____ soluble
Lipid
How are intracellular receptors regulated?
The ligand must diffuse into the cell to interact with nuclear receptor
What is the function of intracellular receptors?
Regulate gene expression
What are 2 examples of intracellular receptors?
- Steroid receptors
- Non-steroid nuclear receptors
What are drug examples of steroid receptors?
- Cortisone
- Estrogen
- Progesterone
- Testosterone
What are drug examples of non-steroid nuclear receptors?
- Retinoic acid
- Vitamin D
- Thyroid hormone
List the 4 families of receptors from shortest to longest duration of action
1) Ion channels (milliseconds)
2) GPCRs (seconds to minutes)
3) Enzyme-linked receptors (seconds to minutes, or minutes to hours)
4) Intracellular nuclear receptors (hours to days)
What are the 3 isoforms of the alpha subunit of a G protein and what does each do?
- G alpha s -> stimulatory -> adenylyl cyclase -> cAMP
- G alpha i -> inhibitory -> inhibits adenylyl cyclase -> inhibits cAMP
- Gq -> activates phospholipid-regulated signaling -> phospholipase C -> second messengers
Which ion has the greatest difference between intracellular and extracellular levels?
Ca2+
Where are ion channels abundant?
On excitable cells
What is Bmax?
The maximal specific binding of a ligand to a receptor
What does Bmax indicate?
The total concentration of receptor sites
What is Kd?
The equilibrium dissociation constant between ligand and receptor
What does Kd represent?
The concentration of drug at which half-maximal binding is observed
What is affinity?
The ability of a drug to bind to a receptor
What does affinity describe?
The strength of binding between a ligand and its receptor (how attractive a receptor is to its drug)
How are Kd and affinity related?
- Kd determines the affinity of a drug for its receptor
- Lower Kd means higher affinity
What is selectivity?
The degree to which a drug acts on a given site relative to other sites
What does selectivity describe?
Preference for one receptor over another
What is Emax?
The maximal effect induced by a drug (full agonist)
What is EC50?
The concentration of drug producing an effect that is 50% of the maximum
What is potency?
A measure of the amount of drug required to produce an effect of given magnitude
What is the relationship between EC50 and potency?
- EC50 determines potency
- Higher EC50 means a lower potency
What is efficacy?
A measure of the ability of a drug to elicit a biological response by agonist
What is the relationship between efficacy and Emax?
- Emax determines efficacy
- Higher Emax means higher efficacy
When selecting a drug, is efficacy or potency more important?
Efficacy (usually)
What are agonists?
Agents that can bind to a receptor and elicit a biologic response
What is a full agonist?
A drug binds to a receptor and produces a maximal biologic response that mimics the response of the endogenous ligand
Do full agonists have good or bad efficacy?
Good
What are some characteristics of partial agonists?
- Have affinity for the receptor but have low efficacy
- Binding site is the same as full agonist
What occurs when a partial agonist is administered alone?
It activates the receptor
What occurs when a partial agonist is administered in the presence of a full agonist?
The partial agonist reduces the effects of the full agonist
What are some characteristics of inverse agonists?
- Have affinity for the receptor but have negative effect
- Reverse the constitutive activity of receptors
What are some characteristics of antagonists?
- Drug has affinity for the receptor, but has no efficacy
- Can bind to a receptor but fails to produce a response
- Can decrease actions of agonist or endogenous ligands
What happens when an antagonist is used alone?
No biological effect is produced
What happens when a partial agonist is used alone?
Produces less of a biological effect
What happens when an antagonist is used with a full agonist?
Antagonist will reduce biological effect
What happens when a partial agonist is used with a full agonist?
Biological effect will be reduced
What happens when an antagonist is used with a partial agonist?
Antagonist will block partial agonist
What is the mechanism of competitive antagonists?
Bind to the same site on the receptor with the agonist
What is the function of a competitive antagonist?
Prevent an agonist from binding to its receptor
How can competitive antagonists be overcome?
By increasing the concentration of the agonist to the receptor
What happens to the dose-response curve of the agonist when a competitive antagonist is added?
The curve shifts to the right
What happens to the EC50 of the agonist when a competitive antagonist is added?
Increases
What is the mechanism of irreversible antagonists?
- Bind covalently or with very high affinity to the active site of the receptor
- Bind to an allosteric site
What happens to Emax of the agonist when an irreversible antagonist is added?
Decreases
What happens to the potency of the agonist when a competitive antagonist is added?
Decreases
What is an adverse effect?
An undesired harmful effect resulting from a medication
What are 4 examples of adverse effects?
1) Too much therapeutic effect
2) Poor tissue selectivity
3) Poor receptor selectivity
4) Drug interactions
What is TD50?
The drug dose that produces a toxic effect or adverse effect in 50% of patients taking the drug
What is ED50?
The drug dose that produces a therapeutic response in 50% of patients taking the drug
How can you determine therapeutic index (TI)?
TD50/ED50
What does a high TI mean?
A wide therapeutic window and a high safety
What will the therapeutic index be of a drug that has a high affinity and high selectivity?
High TI
What is hyporeactive?
Lower response to a drug than is usual
What is hyperreactive?
Higher response to a drug than usual
What is idiosyncratic?
Individuals exhibit an unusual drug response
What is tachyphylaxis?
An acute rapid loss of response to a drug
What is tolerance?
A decreased response to a drug when the drug is taken repeatedly
What is receptor desensitization?
A mechanism that reduces the receptor response to an agonist
What occurs in phase 1 of clinical trials?
- Screening for safety
- Find the maximum tolerated dose
What occurs in phase 2 of clinical trials?
Identify the therapeutic dose and study the efficacy
What occurs in phase 3 of clinical trials?
Further establish and confirm safety and efficacy
What occurs in phase 4 of clinical trials?
Monitor the safety of the new drug under actual conditions of use
