L8 Autonomic Pharmacology Flashcards
What are the principal transmitters in the autonomic nervous system (ANS)?
Acetylcholine and Noradrenaline
These transmitters act upon nAChRs, mAChRs, α- and β−adrenoceptors.
What are the two main ways that drugs can target ANS receptors?
Indirectly (synthesis, storage, breakdown) or directly (agonists, antagonists)
Understanding the systems controlled by these receptors helps predict drug action.
What is the role of G proteins in receptor signaling?
G proteins modulate effector proteins, which can be ion channels or enzymes
This modulation helps predict cellular effects.
What are the effects of Gαs protein activation?
Increases adenylyl cyclase, cAMP levels, and protein kinase A (PKA)
Gαs is considered stimulatory.
What does Gαi protein activation lead to?
Decreases adenylyl cyclase, cAMP levels, and protein kinase A (PKA)
Gαi is considered inhibitory.
What is cAMP?
A second messenger, moves freely in cytoplasm
What are kinases?
Enzyme that Adds phosphates to molecules/proteins
Explain how G protein- coupled receptor signalling works
1) Hormone or neurotransmitter binds to receptor which causes a conformational change
2) Activates G heterotrimeric G protein (Gαi/ Gαs)
3) This interacts with adenylyl cyclase
4) Adneylyl cyclase converts ATP to cAMP which activates PKA
What effect does Gαq have on intracellular calcium levels?
Increases intracellular Ca2+ levels through phospholipase C
This results in increased IP3 and DAG.
What are gαs, gαi and gαq all types of?
They are all different types of G protein alpha subunits
What effect does Gβy have in membrane potential?
They can directly influence membrane potential by interacting with and activating ion channels, specifically potassium channels
What are the two types of subunits within the Gi protein?
Gαi (inhibitory effects for cAMP)
Gβγ (activates potassium channels)
What are the main subtypes of muscarinic receptors?
M1, M2, M3, M4, M5
M1, M3, and M5 are coupled to Gq, while M2 and M4 are coupled to Gi.
Which subtypes of muscarinic receptors are coupled to Gq and Gi?
- M1, M3, M5 are coupled to Gq ( Increase calcium conc)
- M2 and M4 are coupled to Gi (inhibitory cAMP) and increases potassium channel opening
The effects of Muscarinic actions closely resembles what?
It closely resembles the effects of parasympathetic innervation
Where are Muscarinic receptors primarily located?
They are located postsynaptic to the parasympathetic ganglion neuron and in the sweat glands
What are Muscarinic receptors?
They are a type of GPCR that are activated by the neurotransmitter acetylcholine
Where are M2 (cardiac) located?
M2 receptors are located in nodal tissue and atria.
Where are M3 (glandular/smooth muscle) generally located?
- Exocrine glands: salivary, etc
- Smooth muscle: gastrointestinal tract, eye, airways, bladder
- Blood vessels: endothelium
What is M3’s (glandular/ smooth muscle) main functional response?
- Gastric, salivary secretion
- Gastrointestinal smooth muscle contraction
What is the primary function of M2 muscarinic receptors?
Decreases heart rate and slows atrioventricular conduction (decrease force of atria contraction)
Cardiac inhibition
How does M2 decrease heart rate?
- M2 activation via ACh
- Gαi protein activation
- βγ subunits open potassium channels
- Potassium ions move out of the nodal cell into the ECF
- More negative membrane potential which makes it more difficult for cell to reach threshold potential
What physiological response is stimulated by M1 and M3 muscarinic receptors?
Contraction of smooth muscle and secretion from exocrine glands
This includes bronchoconstriction and gastrointestinal motility.
What is a common effect of muscarinic agonist overdose?
Death from cardiac and respiratory failure
Symptoms may include decreased blood pressure, increased saliva, tearflow and sweating
What is atropine and its primary function?
A non-selective muscarinic antagonist that inhibits secretion and relaxes smooth muscle
It can also cause pupillary dilation and modestly increase heart rate.
What happens if anticholinesterase drugs enter the brain?
These drugs will affect ALL cholinergic transmission including CNS
What can reverse poisoning by anticholinesterases?
Muscarinic antagonists
What are the effects of β1 adrenergic receptor activation?
Increased heart rate and contractility
β1 receptors are coupled to Gαs and located in nodal tissue and ventricular myocytes.
What are the main subtypes of adrenergic receptors?
-α1
-α2
-β1
-β2
-β3
All β adrenergic receptors coupple to gαs (muscarinic) and thus increase cAMP levels
Where is noradrenaline and adrenaline synthesised from?
Noradrenaline - sympathetic neurons
Adrenaline - chromaffin cells of the adrenal medulla
What happens when activation of β1 adrenergic receptors occurs?
- 𝛽1 activation via NA
- Gαs protein activation
- Increases adenylyl cyclase, cAMP and PKA
- This increases phosphorylation of calcium channels
- Increase calcium ions into myocytes
- Increases contraction
NA - norepinephrine
What is the role of β2 adrenergic receptors in the respiratory system?
Causes smooth muscle relaxation in the bronchioles by increased PKA
This is important for bronchodilation, especially in asthma treatment.
Which drugs can treat hypertension and heart failure?
Adrenoceptor antagonists
These drugs can also alleviate anxiety symptoms.
What are the unwanted effects of adrenoceptor antagonists?
Bronchoconstriction - beta blockers are avoided in asthma patients
Cardiac depression - particularly in the elderly
Give me 2 examples of adrenoceptor agonists
- Adrenaline
- 𝛃2 selective respiratory system
What’s the difference between antagonists and agonists?
Agonist - A substance that binds to a specific receptor and activates it, triggering a biological reponse
Antagonist - A substance that binds to a specific receptor but does not activate it
What are the clinical uses of adrenoceptor agonists?
- Adrenaline:
Cardiac arrest, Anaphylaxis - 𝛃2 selective respiratory system:
Bronchodilator to treat asthma
What is the function of acetylcholinesterase (AChE)?
Breaks down acetylcholine
This is crucial for terminating cholinergic transmission.
True or False: All β adrenergic receptors couple to Gαs.
True
This leads to increased cAMP levels.
Fill in the blank: Muscarinic antagonists can be used to reverse poisoning by _______.
Anticholinesterases
These drugs affect all cholinergic transmission.
What physiological consequences depend on a drug’s specificity for particular receptors?
The drug’s effects and clinical uses
This includes whether the drug acts as an agonist or antagonist.
