Drug Target Pharmacodynamics

Question 1

Question: How are drugs defined, and what is their primary purpose in a biological system?

Answer 1

Answer: Drugs are molecules that interact with a biological system to produce a biological response.

Question 2

Question: What characterizes most drugs in terms of molecular weight and origin?

Answer 2

Answer: Most drugs are ‘small molecules’ with molecular weights less than 600 and are not endogenous.

Question 3

Question: Provide examples of emerging therapeutic agents categorized as ‘biologics.’

Answer 3

Answer: More ‘biologics’ entering the clinic include antibodies and proteins as therapeutic agents.

Question 4

Question: What is emphasized regarding drug safety, and what factor determines it?

Answer 4

Answer: No drug is entirely safe; the balance between efficacy and toxicity is crucial. Drug safety depends on its therapeutic index, which varies for all drugs, making the administration of the right dose essential.

Question 5

Explain this graph

Answer 5

• This graph shows what happens to plasma concentration (mg/ml) over time (s) when a patient takes one tablet.
  -The peak of the graph is when the drug is absorbed into the patient
• The decrease shows the drug being removed from the system and gets metabolised until no drug is left.
• 2 dashed lines shown:
  Bottom line is the minimum effective concentration
  Top line is toxic concentration
• Between the MEC and TC is the therapeutic window and this is the range of effective doses that can be given to a patient.
• The wider the therapeutic window the wider the range of doses that can be given to a patient.
• The narrower the therapeutic window, the narrower the range of dosages, thus more caution taken when giving doses of drug.

Question 6

Question: What is the primary goal of administering drugs in the context of a biological response?

Answer 6

Answer: Drugs are administered to achieve a biological response that alleviates the symptoms or cause of an illness.

Question 7

Question: What is responsible for producing symptoms or causing illnesses at a biological level?

Answer 7

Answer: A biological process is responsible for producing the symptoms or causing the illness.

Question 8

Question: Describe the nature of a drug target at the molecular level.

Answer 8

Answer: At the molecular level, a drug target is usually a biomacromolecule such as a receptor, enzyme, or ion channel involved in the biological process.

Question 9

Question: What happens when a drug molecule interacts with its molecular target?

Answer 9

Answer: The drug molecule interacts with the molecular target and produces a response that is clinically beneficial.

Question 10

Question: Where is the drug target typically located, emphasizing its context in drug development?

Answer 10

Answer: The drug target is not in a test tube; it is buried somewhere in a physiological system, specifically within a patient.

Question 11

Question: How do drugs get to their target?

Answer 11

Answer: - In terms of taking the drug orally, the drug enters the mouth then down into the stomach.
- Drug must find a way to not get broken down by the highly acidic stomach acid.
- Assuming it survived, the drug moves int small intestine.
- Small intestine has large surface area, provides maximum absorption.
- Drug is absorbed across the lipid membrane of GI tract and enters bloodstream.
- Drug must avoid absorption of reflux pump.
- If survived, the drug moves through the lipid membrane into the systematic circulation.
- Drug enters the portal vein which leads into the liver.
- Drug must avoid metabolism of the liver.
- If avoided, the drug circulates in the blood to find its target.
- In order for the drug to reach its site of action, it may need to diffuse across another lipophilic membrane.

Question 12

Question: Name an example of a drug target enzyme involved in the inflammatory response.

Answer 12

Answer: Cyclo-oxygenase (COX) is an example of a drug target enzyme involved in the inflammatory response.

Question 13

Question: What role does COX play in the synthesis of prostaglandins (PGs) during inflammation?

Answer 13

Answer: COX initiates the PG synthesis cascade by catalyzing the cyclization and oxidation of its substrate arachidonic acid (AA) at the site of inflammation.

Question 14

Question: How do non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and flurbiprofen affect COX?

Answer 14

Answer: NSAIDs are competitive inhibitors of COX, binding to the catalytic site. This prevents arachidonic acid (AA) from binding and being converted to PGs.

Question 15

Question: What is the clinical consequence of inhibiting COX with NSAIDs?

Answer 15

Answer: Inhibiting COX with NSAIDs leads to a reduction in PG levels, resulting in a decrease in inflammation.

Question 16

Question: Describe a potential side effect associated with the non-specific inhibition of COX in the stomach.

Answer 16

Answer: Non-specific inhibition of COX in the stomach reduces prostaglandin levels, making the stomach susceptible to ulceration, as high prostaglandin levels typically protect the stomach wall from degradation by acid.

Question 17

Question: Identify an example of a drug target receptor involved in bronchial smooth muscle activation

Answer 17

Answer: β2 adrenoceptors are an example of drug target receptors involved in bronchial smooth muscle activation.

Question 18

Question: What initiates the activation of β2 adrenoceptors in bronchial smooth muscle?

Answer 18

Answer: Activation of β2 adrenoceptors in bronchial smooth muscle is initiated by adrenaline and noradrenaline.

Question 19

Question: How do drugs like salbutamol affect β2 adrenoceptors?

Answer 19

Answer: Drugs like salbutamol, as β2 adrenoceptor agonists, mimic the effect of the natural ligand and induce the same response.

Question 20

Question: Describe the clinical consequence of activating β2 adrenoceptors with drugs like salbutamol.

Answer 20

Answer: The bronchial smooth muscle relaxes, allowing asthmatic patients to breathe more easily.

Question 21

Question: What is the clinical context regarding maintaining the effectiveness of drugs like salbutamol?

Answer 21

Answer: To keep stimulating the β2 adrenoceptor and relax the airway, the clinically effective concentration of salbutamol must be maintained. Repeated dosing may not be required if the cause of the asthma attack is no longer present.

Question 22

Question: List the key intermolecular interactions that promote association between a drug and the amino acids in a target protein’s binding site.

Answer 22

Answer: Hydrogen bonding, Van der Waals forces (VDW or LDF), ionic/electrostatic interactions, π-π bonding, and dipole interactions are key intermolecular interactions.

Question 23

Question: What determines the types of interactions available for drug molecules?

Answer 23

Answer: The functional groups present in a drug molecule determine the types of interactions available.

Question 24

Question: How are physicochemical properties such as water solubility and membrane permeability influenced in drug molecules?

Answer 24

Answer: Physicochemical properties, including water solubility and membrane permeability, are dictated by the functional groups present in drug molecules.

Question 25

Question: What role does the tertiary structure of COX play in its function?

Answer 25

Answer: The tertiary structure of COX enables the enzyme to perform its function, maintaining the integrity of the active site where catalysis is performed.

Question 26

Question: In the case of COX as a drug target, what is the specific function related to its catalytic activity?

Answer 26

Answer: The catalytic activity of COX involves the oxidation and cyclization of arachidonic acid toward prostaglandin (PG) synthesis.

Question 27

Question: Regarding arachidonic acid being bound to COX, what effect do the amino acids bordering the active site of COX have on the substrate, arachidonic acid?

Answer 27

Answer: The amino acids that border the active site produce a particular 3D-shape, maximizing interactions between the enzyme and the substrate (arachidonic acid).

Question 28

Question: Why are these interactions between the enzyme and arachidonic acid crucial?

Answer 28

Answer: These interactions are crucial to ensure that the substrate (arachidonic acid) is held in the correct position within the active site, facilitating the catalysis of the reaction.

Question 29

Question: How is the tertiary structure of enzymes, such as COX, described?

Answer 29

Answer: Enzymes like COX have globular tertiary structures with a surface that excludes small molecules from penetrating their interior.

Question 30

Question: What is a characteristic feature of the active site in enzymes like COX?

Answer 30

Answer: The active site is flexible and can expand and contract, akin to a camera shutter, allowing substrates to enter and products to exit.

Question 31

Question: How does the movement of the active site contribute to the catalytic nature of enzymes like COX?

Answer 31

Answer: The movement of the active site lowers the activation energy of the reaction by forcing the substrate into a transition-state conformation, making the reaction catalytic.

Question 32

Question: What types of interactions occur between the amino acids bordering the active site and the substrate (arachidonic acid) when it is bound to the COX enzyme?

Answer 32

Answer: The interactions are a mixture of hydrogen bonds (H-bonds) and short-range van der Waals interactions. H-bonds are directional and specific for H-bonding groups on the substrate.

Question 33

Question: Why are hydrogen bonds considered specific in the context of substrate interactions with the COX enzyme?

Answer 33

Answer: Hydrogen bonds are considered specific because they are directional and form between specific hydrogen-bonding groups on the substrate and the amino acids bordering the active site.

Question 34

Question: What characterizes the short-range van der Waals interactions during the binding of arachidonic acid to the COX enzyme?

Answer 34

Answer: Short-range van der Waals interactions occur between the surface of the substrate (arachidonic acid) and the surface of the active site, contributing to the binding.

Question 35

Question: What role does flurbiprofen play in relation to the COX enzyme?

Answer 35

Answer: Flurbiprofen functions as a competitive inhibitor of the COX enzyme.

Question 36

Question: How does flurbiprofen block prostaglandin synthesis and reduce the inflammatory response?

Answer 36

Answer: Flurbiprofen binds in preference to arachidonic acid, blocking prostaglandin synthesis, which subsequently reduces the inflammatory response.

Question 37

Question: What structural resemblance is necessary for flurbiprofen to compete effectively with the substrate in the COX enzyme’s active site?

Answer 37

Answer: To compete with the substrate, flurbiprofen must have some structural resemblance, allowing it to match the 3D shape of the active site.

Question 38

Question: Why must flurbiprofen form stronger interactions with the active site to compete effectively with the substrate?

Answer 38

Answer: To compete effectively, flurbiprofen must form stronger interactions with the active site, binding in preference to the substrate.

Question 39

Question: How is the binding process described in the context of flurbiprofen as a competitive inhibitor?

Answer 39

Answer: The binding process is dynamic, involving regular association and dissociation of molecules. Effective inhibitors like flurbiprofen need to stay bound longer than the substrate to be effective.

Question 40

Question: How does the NSAID flurbiprofen interact with the COX active site in comparison to arachidonic acid?

Answer 40

Answer: Flurbiprofen binds in the COX active site with greater affinity than arachidonic acid.

Question 41

Question: What types of interactions occur between the amino acids bordering the active site and flurbiprofen during binding to COX?

Answer 41

Answer: The interactions are a mixture of hydrogen bonds (H-bonds) and short-range van der Waals interactions, similar to the types of interactions observed with the substrate arachidonic acid.

Question 42

Question: Why is it important for flurbiprofen to have greater affinity than arachidonic acid in the COX active site?

Answer 42

Answer: Having greater affinity ensures that flurbiprofen competes effectively with arachidonic acid, blocking prostaglandin synthesis and reducing the inflammatory response.

Question 43

Question: What characterizes the short-range van der Waals interactions between flurbiprofen and the COX active site?

Answer 43

Answer: Short-range van der Waals interactions occur between the surface of flurbiprofen and the surface of the active site, contributing to the binding process.

Question 44

Question: What is the physiological effect of the activation of β2 adrenoceptors in bronchial smooth muscle by adrenaline and noradrenaline?

Answer 44

Answer: Activation of β2 adrenoceptors in bronchial smooth muscle by adrenaline and noradrenaline dilates the airways, making it a treatment for asthma.

Question 45

Question: How does salbutamol function in relation to β2 adrenoceptors?

Answer 45

Answer: Salbutamol is a β2 adrenoceptor agonist, mimicking the effect of the natural ligand and inducing the same response more effectively.