Drug Binding

Question 1

Depot Binding:

Answer 1

• Drugs bind to silent receptors that aren’t the target receptors
○ Albumin (carries free fatty acids in plasma)
○ Muscles
○ Bone
○ Fat
• While bound to silent receptors, drugs can’t reach active sites or be metabolized
Reversible, can unbind, re-enter circulation, and bind to target site or be metabolized

Question 2

Effects of Depot Binding:

Answer 2

• Binding to depots before reaching target tissue -> slower onset and reduced effects on drug
• High amount of depot binding (i.e. high amounts of adipose tissue results in more depot binding)-> less free drug, need higher dosage
• Low amount of depot binding -> more free drug, individuals seem more sensitive
• Competition among drugs for depot- binding sites -> Higher than expected blood levels of the displaced drug, causes side effects, toxicity
○ Silent receptor for one drug is the target receptor for another drug, depot binding causes the other drug to be displaced back into the blood stream, can cause overdose
• Bound drug not metabolized -> Drug remains in body for a longer period of time
• Binding to depots follows rapid action at targets (Drug binds to target, unbinds, binds to depots) -> rapid termination of drug action (now bound to depot, can’t rebind to target and cause a response)
Causes a shorter response

Question 3

Pharmacodynamics:

Answer 3

Study of physiological and biochemical interactions between drug molecules and receptors

Question 4

Transmembrane Receptors:

Answer 4

• Embedded in membrane
	• Most common, most ligands (molecule that bind to receptors) bind to transmembrane receptors 
	• 2 types
		○ Ionotropic
			§ Opens ion channel
			§ Immediate effect
		○ Metabotropic
			§ Activates second messengers via g proteins
Long lasting effect

Question 5

Intracellular Receptors:

Answer 5

• Located in the cytoplasm (i.e. glucocorticoids) or in the nucleus (i.e. sex hormones)
Hormones must be lipid soluble to enter target cell

Question 6

Ligand Affinity:

Answer 6

• Ability for a ligand to fit to the binding site of a receptor
• Can be agonists or antagonists
○ If agonist binds-> drug action/effect
If antagonist binds -> no drug action/effect (Competitive antagonist)

Diagram

Question 7

Ligand Efficacy:

Answer 7

• Ability of ligand to alter the 3D structure of the receptor and initiate intracellular changes (maximum effectiveness of a drug)
Can be agonists or antagonists

Question 8

Up/Down Regulation of Receptors:

Answer 8

• Binding of ligand changes the number of receptors available and the sensitivity of those receptors
  
  • i.e. Drug tolerance- receptors become less sensitive, decrease in number, need more of the drug

Question 9

Receptor Variability:

Answer 9

• Ligands can bind to different sites and initiate different effects
i.e. serotonin

Question 10

Law of Mass Action:

Answer 10

• Ligand binding is temporary and reversible
• D + R DR*
• Drug and Receptor combines to form active complex (DR) which induces a cellular response
• Response is proportional to the number of occupied receptors (higher number of occupied receptors-> high response)
Active DR complex is in equilibrium with inactive components (drug associates with receptor and then dissociates again)

Question 11

Dose- Response Relationship:

Answer 11

When number of available receptors is constant, the DR* will increase when D concentration increases, resulting in an increase in response of the drug until the maximum effect is achieved

Diagram + Explanation

Question 12

Potency:

Answer 12

• Effects of drugs at any arbitrary dose (how much of a drug you need to achieve a certain response
Determined by accessibility and affinity
• Hydromorphine, morphine, and codeine have the same efficacy, but different potencies
• Hydromorephine is the most potent drug (need much less of it to get to ED 50, ED 100)
• Aspirin is less potent, but also less efficacious (won’t get the same result no matter how much you take)
• Most potent drug not always the best, can have other size effects (codeine may be less potent, but might have fewer side effects)
Shape of aspirin’s curve compared to the others indicates that it acts through a different mechanism

Diagram

Question 13

Therapeutic Index:

Answer 13

• Safety window in which the dosage to get the desired effect does not cause a side effect
TI= TD 50/ ED 50

	• Sedation Effect: TI= 10/8 =1.2 (small safety window, dosage required to suppress anxiety also likely to cause sedation)
	• Respiratory Depression Effect-: TI= 30/8=3.75 (large safety window, dosage required to supress anxiety unlikely to cause respiratory depression)
Lethal Dose (LD50)- Dosage of drug that kills 50% of the population, used to establish the safety of a drug

Diagram + Explanation

Question 14

Affinity:

Answer 14

• Fit between ligand and receptor
• Ability of the ligand to alter the receptor to fit to the ligand
Ligands with better affinity will bind more easily and for longer periods of time, but will (usually) eventually unbind

Question 15

Competitive Antagonists:

Answer 15

• Binds to same binding site as the agonist
• Can be displaced from the receptor by an excess of the agonist
• A + R AR (no *, not an active complex) —> no effect
• Often doesn’t do anything else other than occupy the binding site
• Usually reversible, but sometimes the receptor and antagonists can form covalent bonds, or affinity between the antagonist and receptor is so strong that the rate of dissociation is 0
○ Permanently deactivates receptor
Only way to recover function is for the neuron to make more of the receptor, can take time

**Diagram + Explanation*

Question 16

Non-Competitive Antagonists:

Answer 16

• Antagonisms cannot be overcome by increasing the amount of agonist
• Antagonist prevent agonist from binding, but binds to a different binding site on the same receptor or to a different site along the neural pathway of the final response
Causes a change in the receptor, prevents agonist from binding

Diagram + Explanation