autonomic and endocrine pharmacology

Question 1

what are the principle transmitters in the ANS

Answer 1

-acetylcholine and NA
-they act upon nAChR’s, mAChR’s, alpha and beta-adrenoreceptors

Question 2

what are the different ways drugs can target ANS receptors

Answer 2

-directly (agonist and antagonist)
-indirectly (synthesis, storage and breakdown)
-can only target them if we know the systems they control, you can predict the drug action

Question 3

how can we predict cellular effects

Answer 3

-by knowing which G proteins modulate which effector proteins
-effectors can be ion channels or enzymes
-examples of this is adenylyl cyclase and phospholipase C then the 2nd messengers are small diffusible molecules that spread the signal
-different types of G proteins activates the phospholipase C, this effects the amount of 2nd messenger that is produced depending if the G protein is activated or inhibited

Question 4

cholinergic receptors

Answer 4

-muscarinic receptors- 5 subtypes- a specific type of ACh receptors that responded specifically to muscarine
-postsynaptic to parasympathetic ganglion neurons and sweat glands

Question 5

what are the different types of mAChR’s couple

Answer 5

-M1, M3, M5:
-Gq= increased PLC =increased IP3
-increased intracellular Ca2+ -> contractile cells with M1, M3, M5 which when activated, Ca2+ is released and contraction occurs
-increase of Ca2+ causes contraction in smooth muscle cells
-M2, M4:
-Gi= decreased adenylyl cyclase= decreased cAMP
-increased K+ channel opening which causes increase in potassium inhibiting the cells
-decrease voltage gated Ca2+ channels which means a decrease in muscle contraction

Question 6

M1 (neural)

Answer 6

-main locations: autonomic ganglia, cerebral cortex, glands: salivary, lacrimal, gastric
-functional response: gastric secretion, CNS excitation (improved cognition)

Question 7

M2 (cardiac)

Answer 7

-main locations: heart-atria, CNS- widely distributed
-functional response: cardiac inhibition, neural inhibition, central muscarinic effects (e.g. tremors, hypothermia)

Question 8

M3 (glandular/ smooth muscle)

Answer 8

-main location: exocrine glands- salivary, smooth muscle- gastrointestinal tract and eye and airways and bladder, blood vessels
-functional response: gastric- salivary secretion, gastrointestinal smooth muscle contraction, ocular accommodation, vasodilation

Question 9

M4

Answer 9

-main location: CNS
-functional response: enhanced locomotion

Question 10

M5

Answer 10

-main location: CNS- substantia nigra, salivary glands, iris/ciliary muscle
-functional response: not known

Question 11

what does parasympathetic stimulation of the heart lead too- using the M2 receptor

Answer 11

-a decrease in heart rate via muscarinic M2 receptor activation
-M2 receptors are expressed in nodal tissue and atria
-M2 receptor activation causes : decreased heart rate, slowing of atrioventricular conduction, decreased force of contraction (atria only)

Question 12

how does the decrease in heart rate via muscarinic (M2) receptor activation via the beta-gamma subunit work

Answer 12

-M2 activation
-Gai protein activation
-beta-gamma open K+ channels
-increased K+ moves out of the nodal cell
-more negative membrane potential

Question 13

what do M1 and M3 AChR as Gq coupled receptors do

Answer 13

-stimulate contraction of smooth muscle e.g. bronchoconstriction (airway getting smaller), gastrointestinal motility, bladder voiding
-stimulate secretion from exocrine glands: mucus in the lungs, lacrimal glands, salivary glands, sweat glands

Question 14

lack of selective mAChR agonists, limits clinical use

Answer 14

-muscarine:
-effects depend on dosage but include: decreased blood pressure( due to decreased cardiac output), increased saliva, increased tear flow, increased sweating, abdominal pain, nausea (last 2 both contraction of GI tract which is unnatural)
-overdose= death from cardiac and respiratory failure
-topically applying them is the only way that they are clinically useful

Question 15

muscarinic antagonists

Answer 15

-atropine:
-non-selective mAChR antagonist
-inhibition of secretion- salivary, lacrimal, bronchial, sweat
-smooth muscle relaxant- bronchial, biliary, bladder
-pupillary dilation
-modest increase in HR
-decrease in GI motility, acid secretion
-drug selective for different mAChR can be used to treat peptic ulcers and overactive bladder

Question 16

drugs that act indirectly to enhance cholinergic transmission

Answer 16

-cholinomimetic
-acetylcholineesterase (AChE) which breaks down ACh
-anticholinesterase drugs: long acting (irreversible) anticholinesterases e.g. nerve gas (sarin)
-these drugs will affect ALL cholinergic transmission including CNS if they can enter the brain
-muscarinic antagonist can be used to reserve poisoning by anticholinesterases

Question 17

where are receptors for noradrenaline found

Answer 17

-found on tissues responding to postganglionic sympathetic neurons
-these receptors are GPCRs
-adrenergic agonists mimic sympathetic NS- opposite for antagonists

Question 18

what are the different subtypes of adrenoceptors

Answer 18

-alpha1 for blood vessel tissue, they contract and dilate
-beta1 and alpha2 for heart tissues, for tachycardia: increased contractility
-beta2 for bronchi tissue, effect is they relax the muscle

Question 19

what do all b adrenergic receptors couple to

Answer 19

-Gas therefore increasing cAMP levels

Question 20

what do the receptors signaling via Gas in the heart cause

Answer 20

-heart rate and contractility
-noradrenaline from sympathetic neurons and adrenaline for chromafffin cells
-receptor locations are nodal tissue and ventricular myocytes
-receptor type is beta1 adrenergic receptors and couple to Gas G proteins

Question 21

what does beta1 adrenergic receptor activation cause

Answer 21

-increased calcium current through phosphorylation of calcium channels
-beta1 activation via NA (noradrenaline) which causes Gas protein activation causes an increase in adenylyl cyclase which causes an increase in cAMP and thus causes an increase in PKA which causes a phosphorylation of calcium channels
-voltage gated calcium channels now have an increased channel open time which causes more Ca2+ into myocytes which causes an increased contraction

Question 22

what does beta2 adrenergic receptor activation cause

Answer 22

-smooth muscle relaxation in the bronchioles
-beta2 activated on broncial smooth muscle via adrenaline causes Gas protein activation causing an increase in adenylyl cyclase causing an increase in Camp, causing an increase in PKA causing phosphorylation of smooth muscle cell machinery

Question 23

what are the clinical uses of adrenoceptor agonists

Answer 23

-adrenaline (non-selective):
cardiovascular system - cardiac arrest and anaphylaxis uses adrenaline
-beta2 selective :
respiratory system
bronchodilator to treat asthma- salbutamol, beta2 selective, avoids cardiovascular consequences associated with beta1 effects (so doesn’t have a big effect on the heart)

Question 24

what are some clinical uses of adrenoceptor antagonists

Answer 24

-can be used to treat hypertension, heart failure, anxiety
-can have unwanted effects such as bronchoconstriction so the beta blockers are avoided in asthma patients, and cardiac depression (prevalent in the elderly)