Pharmacodynamics (MECHANISM OF DRUGS)

Question 1

Drugs can induce a tissue response through ……………. & ……….. mechanisms

Answer 1

receptor mediated
Non receptor mediated

Question 2

DEF receptors

Answer 2

specific Cellular macromolecules (proteins), that interact w/ a ligand producing a response.

Question 2

What are types of ligands ? diff betw ?

Answer 2

Agonists (full, partial, inverse)
Antagonists (Chemical, physiological, competetive & noncompetetive).

DIFF :
Agonsit : binds to receptor (Affinity) & produces a response (efficacy).
Antagonist : binds to receptor (Affinity) but w/o response (no efficacy)

Question 3

Diff btew : full, partial, inverse Agonists

def & Examples

Answer 3

Full :
Affinity & Efficacy 100%.

EX: ACH on nicotinic receptors => depolarization => skeletal muscle contraction.
Partial :
Abscence of a full agonist : the partial binds to empty receptors w/ lower efficacy than that of the full agonist.
Presence of Full agonist : the partial acts as antagonist.

EX: Buprenorphine w is a partial agonist for opioid receptors while the full agonist is the morphine.
Inverse
- Stabilizes the receptor away from the constitutional state.
- Produces opposite effects than the pharmacological effect of the receptor

*EX: Anti-hitaminics /// Beta Carboline *

Question 4

What are ccc of receptors ?

Answer 4

Sensitivity : small conc. is enough to elicit the action
Specificity : the receptor will induce the same response each time it binds to the ligand
Selectivity : the receptor has its type of ligand that can interact w/.

Question 5

The 3-state model of receptor activation suggests that receptors exist in 3 conformational states ……… // ………. // ……….. states that are in ………. equilibrium.
Explain each state.

Answer 5

Inactive, active, constitutional, reversible.

in Constitutional state : the receptor has some activity even in the absence of a ligand.
Active : presence of agonist
Inactive : presence of antagonist.

Question 6

Diff betw Competetive & Non competetive antagonist.

def // duration of antagonsim // consequ on log dose reponse curve // EX

Answer 6

Competetive
DEF : Antagonsit competes w. the agonist for the same recognition site of the receptor.
Duration of Antagonsim depends on plasma conc of agonist & antagonist.
Consequences on log Dose-Rponse Curve: right shoft w/ increase in EC50 and no change in Emax.
EX: Curare, an antagonist of ACH on nicotini NM receptors

Non competetive
DEF : Antagonsit binds irreversibly to the recognition site of the receptor (prevent the binding of agonist) or to the allosteric site (=> conformational change).
Duration of Antagonsim depends on turnover of the receptor.
Consequences on log Dose-Rponse Curve: down shift w/ decrease in Emax
EX: phenoxybenzamine (alpha blocker)

Question 7

Can antagonists act w/ the agonist AWAY from the agonist’s receptor ?

Answer 7

Chemical : antagonist interact chemically w/ the agonist away from the receptor.

EX: Protamine sulfate is an Heparin antidote, its antagonist. _ve charges on heparin are neutralized w. +ve charges on protamine sulfate.

Physiological : Antagonist binds to a different receptor than that of the agonist producing th opposit action of the agonist.

EX: Epinephrine is an antagonsit to histamine.
the B2-bronchodilator & Aplha-vasoconstrictor effects of epinephrine antagonizes the H1 bronchoconstriction & vasodilator effects of Histamine.

Question 8

What’s meant by receptor recycling or turnover ?

Answer 8

Nb of receptors isn’t cte but some are internalized inside the cell and others are externalized outside.
Binding of Agonist => Increases internalization => decrease in nb of recruited receptors => down regulation.
Binding of Antagonist => increase in nb of recruited receptors => up regulation.

Question 9

What are the most signal transduction system ?

Answer 9

1. ion channels
2. Receptors linked to tyrosine kinase
3. G protein coupled receptors
4. Receptors regulating transcription
5. Nitric Oxide receptors

Question 10

Describe ion channels in the context of receptor families.

Answer 10

Ion channels are receptors that are ion-selective channels in the plasma membrane, responding very rapidly to fast neurotransmitters by opening upon agonist binding, leading to alterations in membrane potential or intracellular ion concentration,both will lead to change in cell activity.

Question 11

What are examples of ion channels in major receptor families?

Answer 11

Examples include Nicotinic Ach receptors (combined Na+/K+ channels) and GABAa receptors (Cl- channels).

Question 12

How do ion channels in major receptor families respond to neurotransmitters?

Answer 12

Ion channels respond very rapidly, enduring for a few milliseconds, upon binding of agonists, leading to changes in cell activity.

Question 12

Define the role of ion channels in major receptor families.

Answer 12

Ion channels play a crucial role in altering membrane potential or intracellular ion concentration, thereby influencing cell activity in response to neurotransmitters.

Question 12

Describe the structure of receptors linked to Tyrosine Kinase (RTKs).

Answer 12

RTKs consist of two domains: an extracellular domain for ligand binding (e.g. insulin) and an intracellular domain for binding the tyrosine kinase enzyme.

Question 12

What is an example of a ligand that binds to receptors linked to Tyrosine Kinase (RTKs)?

Answer 12

Insulin is an example of a ligand that binds to RTKs.

Question 13

What happens when insulin binds to Tyrosine Kinase receptors?

Answer 13

Insulin binding causes two single tyrosine-kinase receptors to aggregate into a dimer, leading to autophosphorylation and activation.

Question 13

Define the role of relay proteins in the signaling pathway of Tyrosine Kinase receptors.

Answer 13

Activated-phosphorylated dimers of Tyrosine Kinase receptors bind to relay proteins, which are then activated to trigger cellular responses.

Question 13

How do Tyrosine Kinase receptors initiate cellular responses?

Answer 13

Through either the production of a second messenger or by turning on gene expression, triggered by relay proteins activated by the phosphorylated dimers of the receptors.

Question 14

Describe G protein-coupled receptors.

def

Answer 14

G protein-coupled receptors are cell surface receptors that are linked to G proteins, which are trimers consisting of α, β, and ɣ subunits.

Question 15

What is the function of Gs, Gi, Gq protein in G protein-coupled receptors?

Answer 15

Gs protein is stimulatory => linked to β-receptors => an increase in cAMP levels.
Gi protein is inhibitory => linked to α2 and M2 receptors => decrease in cAMP levels.
Gq => linked to α1, M1, and M3 receptors => liberation of DAG & IP3.

Question 16

What happens when an agonist binds to a G protein-coupled receptor?

Answer 16

Agonist binding causes the dissociation of the α subunit of the G protein, which then regulates the activity of various effectors.

Question 17

What are the effectors upon w the G protein coupled receptor actions alter ?

Answer 17

1. Adenylyl cyclase => forms the 2nd messenger cAMP => activated protein kinase A (PKA) → phosphorylation cascade.
2. Phospholipase C, => liberates the 2nd messengers: diacyl-.glycerol (DAG) and inositol triphosphate (IP3):
   - DAG activates protein kinase C (PKC) → phosphorylation cascade.
   - IP3 stimulates Ca2+ release from sarcoplasmic reticulum → change in cell activity.
3. Channels: M2 receptors coupled to Gi → K outflux → hyperpolarization

Question 17

Define the term ‘effector’ in the context of G protein signaling.

Answer 17

In G protein signaling, effectors are proteins or molecules that are regulated by G proteins and mediate the cellular response to extracellular signals.

Question 17

Describe the process of how drugs interact with intracellular receptors to regulate transcription.

Answer 17

Drugs enter the target cell and combine with intracellular receptor proteins associated with nuclear chromatin to activate or inhibit transcription of nearby genes.

Question 18

Explain the impact of activating or inhibiting transcription on protein production and target tissue.

Answer 18

Modifying protein production through transcription regulation can cause changes in the structure or function of the target tissue.

Question 18

What are some examples of agonists that regulate transcription very slowly?

Answer 18

Steroid hormones, estrogen, progesterone, thyroid hormones, and vitamin D.

Question 19

where do nitric oxide receptors exist ?

Answer 19

inside the cell

Question 19

Define the main protein receptor for Nitric Oxide (NO) and its function.

Answer 19

The main protein receptor for NO is soluble guanylyl cyclase enzyme, which generates the second messenger cyclic GMP (cGMP) within the cell.

Question 20

What is the role of phosphodiesterase inhibitors like sildenafil in relation to Nitric Oxide (NO) receptors?

Answer 20

Phosphodiesterase inhibitors increase the level of the second messenger c-GMP, mimicking the action of NO on the receptors.

Question 20

What drugs can activate the NO receptors that increase NO levels ?

Answer 20

• nitrovasodilators : nitrites, nitrates (nitroglycerine & sodium nitropusside)
• muscarinic M3-agonists : release endothelial NO

Question 21

What happens when binding of NO to NO receptors proteins ?

Answer 21

Binding of NO→ triggers allosteric change in the protein→ the formation of a “2nd messenger” within the cell.

Question 21

How can drugs affect plasma memb ?
EX ?

Answer 21

Drugs may affect permeability, carrier systems, transport processes or enzyme systems in the plasmatic membrane.

EX:
1. Cardiac glycosides inhibits membrane-bound ATPase.
2. Polyene antifungal drugs ↑ permeability of fungal plasmatic membrane.

Question 22

What is an example of a drug acting via enzyme inhibition?

Answer 22

1. Monoamine oxidase inhibitors (MAOIs) inhibit the MAO enzyme, preventing the destruction of biogenic amines like norepinephrine (NE).
2. Aspirin inhibits cyclooxygenase (COX), leading to a decrease in prostaglandin (PG) synthesis.
3. Choline esterase inhibitors inhibit ChE, thereby preserving acetylcholine (Ach) levels.

Question 23

What type of mechanisms do drugs acting on enzymes fall under?

Answer 23

Non-receptor mediated mechanisms.

Question 23

Describe drugs effect on enzymes.

Answer 23

Drugs can either inhibit (-) or activate (+) enzyme systems.

Question 24

Drugs acting on subcellular structures ?

mitochondria // microtubules

Answer 24

1. Mitochondria : salicylates uncouple oxidative phosphorylation
2. Microtubules : Colchicine disrupts microtubules => (-) mitosis

Question 25

Drugs acting on genetic apparatus ?

Answer 25

1. Antibiotics (e.g. aminoglycosides, chloramphenicol & tetracyclines) (-) bacterial protein synthesis.
2. Anticancer drugs affect DNA synthesis or function.

Question 26

Drugs Acting by Physical Means ?

Answer 26

1. Demulcents (soothing): bismuth salts coat intestinal mucosa.
2. Adsorbents: charcoal adsorbs gases and toxins in intestine.
3. Lubricants: liquid paraffin is used in constipation.
4. Osmosis: osmotic diuretics.

Question 27

Drugs Acting by Chemical Action

Answer 27

1. Antacids neutralize HCL in peptic ulcer.
2. Citrates interact with calcium to (-) blood coagulation.
3. Protamine neutralizes heparin by its +ve charge in treatment of heparin overdose.
4. Chelation; is the capacity of organic compounds to form complexes with metals (chelates). The chelate may become more water-soluble and easily excreted. It is useful in treatment of heavy metal poisoning

Question 28

EX of chelators ?

Answer 28

1. Ethylene diamine tetra acetic acid (EDTA) chelates lead & calcium.
2. Dimercaprol (BAL) chelates arsenic, gold & copper.
3. Penicillamine chelates copper in Wilson’s disease.
4. Deferoxamine chelates iron and is used in iron toxicity