Pharmokinetics 1 Flashcards
How do all drugs exert their effects?
By binding to a target
What are the majority of drug targets?
Proteins, with some exceptions
Give an example of an exception to drug targets being proteins
Some antimicrobial and antitumour drugs bind DNA
What do must drugs bind with?
Receptors
Is drug binding to receptors reversible?
Usually
What is binding of drugs to receptors governed by?
Association and dissociation rates
Give 7 targets for drugs
Enzymes GPCRs Ion channels Nuclear hormone receptors Integrins Other receptors
What % of drug targets are enzymes?
47%
What % of drug targets are GPCRs?
30%
What % of drug targets are ion channels?
7%
What % of drug targets are transporters?
4%
What % of drug targets are nuclear hormone receptors?
4%
What % of drug targets are other receptors?
4%
What % of drug targets are integrins?
1%
What is critical in determining drug action?
The concentration of drug molecules around receptors
What do drugs of equivalent molar concentrations have?
The same concentration of drug molecules
Do drugs of equivalent concentrations by weight have the same concentration of drug molecules?
They may not
How much does 1 mole contain?
6x10^23
What does 1 molar solution contain?
1 mole in 1 litre
How do you calculate grams per litre?
Molecular weight x molarity
What do agonists do?
Bind to receptors and cause a response
What do agonists have?
Both affinity and efficacy
What do antagonists do?
Bind to receptors, but do not cause a response
What do antagonists have?
Affinity only
What is affinity?
The likelihood of a ligand binding to its target
What is efficacy?
The likelihood of activation
How is binding information often obtained?
By the binding of a radioligand
What is a radioligand?
A radioactive version of the ligand
What is Bmax?
The maximum binding capacity
What does Bmax give?
Information about the number of receptors
What is Kd?
The dissociation constant
What is Kd a measure of?
Affinity
How is Kd worked out?
It is the concentration needed for 50% occupancy
What does a lower Kd value relate to?
A higher affinity
On what scale is [drug] usually shown
Logarithmic
Where in concentration response curves used?
In measured in a response in cells/tissues
When are dose response curve used?
When measuring a response in a whole animal
What is Emax?
The maximum response
What is EC 50 ?
The effective concentration giving 50% of the maximal response
What isEC 50 a measure of?
Potency
What is potency?
A combination of both affinity and efficacy
What governs potency?
The number of receptors
In what terms is efficacy measured?
Relative- no absolute scale
What may agonists with different Emax value have?
Different efficancy
Do agonists with the same Emax values have identical efficacy?
Not always
Why may two drugs with the same Emax values not have the same efficacy?
They may differ in affinity, meaning that the relationship between occupancy and response will be different- one may be more able to convert binding into function
What is the treatment goal is asthma?
To activate ß2-adrenoceptors to relax the airways
What is the problem with activating ß-adrenoceptors to treat asthma?
There are ß-adrenoceptors elsewhere in the body
Give an example of where ß-adrenoreceptors are found elsewhere in the body?
ß1 in the heart increase the force and rate of contraction
What is salbutamol?
A ß2-adrenoagonist
What is the Kd of salbutamol?
20µM for ß1
1µM for ß2
What is the result of the lower Kd for ß2?
It has a higher affinity
Why can salbutamol be used in treatment of asthma?
Because of the higher affinity for ß2-receptors, as well as ß2 selective efficacy and route of administration- this limits ß1 activation and side effects
What is the route of administration of salbutamol in the treatment of asthma?
Oral spray
What is salmeterol?
A longer acting ß2-adrenagonist than salbutamol
How does salmeterol differ from salbutamol?
It has no selective efficacy
How does salmeterol prevent ß1 activation and side effects?
Purely through differences in affinity
What is the Kd of salmeterol?
1900nm for ß1
0.55nm for ß2
What will less than 100% receptor occupancy give in some cases?
100% response
What is true when 100% receptor occupancy gives 100% response?
EC50 is less than Kd
Describe the relationship between receptor occupancy and response?
Non-linear
What is the relationship between receptor occupancy and response influenced by?
Both the transduction system/amplification produced by second messengers, and the properties of the tissue
What is meant by spare receptors?
Some tissues have more receptors than required to produce a maximal response
What is the advantage of spare receptors?
It increases sensitivity, allowing for responses at low concentrations of agonist
What does number of receptors have an effect on?
Potency
What is a partial agonist?
A drug that cannot produce a maximal effect, even with full receptor occupancy
How can a partial agonist be identified?
By comparing the ability of different agonist to evoke responses in a tissue
What is the EC50 of a partial agonist equal to?
Its Kd
What is the potency of a drug dependent on?
Both its affinity and efficacy
Are partial agonists more or less potent than full agonists?
Can be either
Is a partial agonist always so?
No
What does wether an agonist is partial or not depend on?
The tissue and the biological response
What are opioids used for?
Pain relief Recreationally
What can opioid cause?
Respiratory depression, leading to death
How do opioids act?
Primarily through the µ-opioid receptor (GPRC)
How do morphine and buprenorphine differ?
Morphine is a full agonist of the receptor
Buprenorphine is a partial agonist, with a higher affinity but lower efficacy
Why is buprenorphines high affinity and low efficacy advantageous?
If it provides adequate pain control it is preferable, as there is less respiratory depression
What are the types of antagonist?
Reversible competitive
Irreversible competitive
Non-competitive
What is the most common form of antagonist?
Reversible competitive
Where is reversible competitive antagonism important?
In therapeutics
What does reversible competitive antagonism rely on?
A dynamic equilibrium between ligands and receptors
What is IC50?
The concentration of antagonist giving 50% occupancy
How can reversible competitive antagonists be overcome?
By high concentrations of agonists
Give a therapeutic example of a reversible competitive antagonist?
Naloxone
What is naloxone?
A high affinity, competitive antagonist of µ-opioid receptors
What is naloxone used to do?
Reverse opioid mediated respiratory depression
Why can naloxone be used to reverse opioid mediated respiratory depression?
Its high affinity means it will compete effectively with other opioids for receptors
When does irreversible competitive antagonism occur?
When the antagonist dissociates slowly, or not at all
What do irreversible competitive antagonisms cause to the concentration-reponse curve?
A permanent shift to the right
What do irreversible competitive antagonists do at high concentrations?
Suppress the maximal response
Why do irreversible competitive antagonists suppress the maximal response at higher concentrations?
As spare receptors are filled by the antagonist, not leaving enough receptors free to illicit a maximal response
Give a therapeutic example of irreversible competitive antagonism?
Phenoxybenzamine
What isPhenoxybenzamine?
A non-selective irreversible α1-adrenoreceptor blocker
Where isPhenoxybenzamine used?
In hypertension episodes in pheochromocytoma
What is pheochromocytoma?
A tumour of the adrenal gland, which causes excessive NA/Adrenaline secretion leading to vasoconstriction
What is non-competitive antagonism?
The allosteric binding of an antagonist to a receptor (not the ligand binding site)
