Physiological Systems to Molecular drug targets Flashcards Preview

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Flashcards in Physiological Systems to Molecular drug targets Deck (37):

Define what the peripheral nervous system is? And what does it contain?

1. Represents the output of the CNS and usually acts "independently" to regulate the body's internal environment

2. Contains:
Autonomic nervous system
- largely outside of voluntary control

Somatic (motor) nervous system
- Conscious control
- Efferent nerves for movement
- Afferent nerves to external stimuli


Define what the autonomic nervous system is? And what does it contain?

1. The nervous system that's usually outside of voluntary control

2. Parasympathetic nervous system (rest and digest)
- Cranial-sacral output, synapse at ganglia close to innervated tissue

3. Sympathetic nervous system (fight or flight)
- Thoracic-lumbar output
- Synapse at ganglia either side of the vertebral column (sympathetic chain)
- Ganglia distal to innervated tissue


What are the main processes the autonomic nervous system regulates?

1. Heartbeat
- Rate and force of contraction increases
- Rate decreases (force unaffected)

2. Smooth muscle contraction and relaxation
- Eye pupils widening (dilation)
- Pupil becoming smaller (constriction)

3. All exocrine function (pancreas)

4. Some endocrine functions (hormones)

5. Some steps in Intermediate metabolism


What is cholinergic transmission?

1. All motor nerves release ACh which act on nicotinic acetylcholine receptors (nAChRs)

2. Postganglionic parasympathetic nerves release ACh to act on muscarinic acetyl choline receptors (mAChrs)

3. Presynaptic receptors:
ACh release is regulated by inhibitory presynaptic M2 mAChRs


What is the adrenergic transmission?

1. Most Postganglionic sympathetic fibres release noradrenaline to act on either:
- alpha or beta-adrenoceptors
(Exception is sympathetic innervation of sweat glands when ACh acts on mAChRs)

2. Presynaptic receptors:
Noradrenaline release is regulated by inhibitory presynaptic alpha2-adrenoreceptors


How is skeletal muscle activated in the somatic efferent system?

Acetyl Choline on the nicotinic receptors


How is are blood vessels, sweat glands, and adrenal medulla activated in the sympathetic nervous system?

1. Blood vessels: Acetyl Choline acting on the nicotinic receptors and the noradrenaline (vaso-constrict/contract)

2. Sweat glands: Acetyl Choline acting on the nicotinic receptors and the muscarinic receptors

3. Acetyl choline acting on the nicotinic receptors


How are salivary glands activated in the parasympathetic nervous system?

Acetyl choline acts on the nicotinic receptors and the muscarinic receptors


How can you block muscarinic and nicotinic receptors from causing a cellular effect?

1. Using an antagonist such as atropine to block muscarinic

2. Antagonist such as succinylcholine (nAChR) to block nicotinic ACh receptor


How does botulinum toxin work?

Prevents the vesicle from forming and going into the synaptic cleft


What happens if you block acetylcholine esterase? And what drugs do this?

1. You can increase the amount of acetylcholine into the synaptic cleft and it doesn't get broken down into choline + acetate

2. Doneprezilm rivastigmine and galantamine for Alzeheimer's disease act as Anticholinesterases


How does sarin and nerve gases work?

1. Prevent the acetylcholine from breaking down into choline and acetate

2. This is irreversible which means that the body stays in the parasympethic nervous system

3. This can slow down the heart and brain which leads to death


How does acetylcholine affect blood pressure? And how else can you reduce this effect and how do you raise the blood pressure?

1. ACh decreases blood pressure

2. Stabilises blood pressure if atropine (antagonist) is added as the muscarinic receptor is blocked - blocks ACh

3. ACh and atropine added cause stable response

4. Large dose of ACh with atropine causes an increase in blood pressure as the nicotinic receptor causes the response

3. Hexamethonium antagonist can be used to block and mediate the nicotinic receptor


What agonists stimulate the muscarinic receptors in the body?

1. Acetylcholine

2. Carbachol

3. Oxotermorine

4. Piliocarpine

5. Bethanechol


What antagonist blocks the muscarinic receptors in the body?

1. Atropine

2. pirenzepine (shows selectivity for cardiac muscarinic receptor)

3. darifenacin (shows selectivity for glands, smooth muscle and blood vessel muscarinic receptors)


What are the odd numbers of the Muscarinic receptors (all G protein) related to?

G alpha Q cause an ATP increase


What are the even numbers of muscarinic receptors related to?

G alpha inhibitory decease in cyclic AMP


How does the G protein coupled muscarinic receptor work?

1. Binding of an agonist to extracellular domain

2. Alpha and a gamma subunit

3. Binding activates G protein coupling domain

4. This activates second messenger and enzyme molecules and other effectors

5. These are like ion channels and other kinase enzymes


Explain the action of the M1/M3/M5 mACh receptor action?

1. PIP2 with phospholipase C and Alpha A GTP

2. Becomes IP3 + DAG


What can IP3 and DAG be used for?

1. Increase in intracellular calcium secretion, contraction, vasodilation


Explain the action of the M2/M4 mACh receptor?

1. GPCRS coupled to G alpha i/o to inhibit adenylate cyclase

2. ATP ---> cAMP (adenylate cyclase) (alpha i/o)

3. cAMP causes reduced heart rate (bradycardia)


What are the parasympathetic effects the actions of the mAChR agonists can have?

1. Bradycardia/reduced cardiac output

2. Vasodilation

3. Increases secretion (salivation, lacrimation, sweating)

4. Bronchoconstriction and bronchial secretion

5. Increased gut motility

6. Reduction of intraocular pressure (due to pupillary constriction)


What are the actions of atropine (mAChR antagonists)?

1. Block secretion- salivation, lacrimation, sweating, bronchial secretion

2. Tachycardia (increased heart rate)- modest effect

3. Inhibits gut motility

4. Paralysis of bladder

5. Smooth muscle (except gut) relaxation

6. CNS effects: excitatory


What are some of the indications of atropine?

1. Smooth muscle relaxant e.g. IBS

2. Cardiovascular e.g. treat bradycardia after heart attack

3. Anaesthesia: pre-medication and to prevent vagal inhibition of the heart

4. Ophthalmic use to paralyse eye to aid treatment of inflammation


What are the three Nicotinic ACh receptor subtypes?

1. Muscle

2. Ganglion

3. CNS


What are the agonists for each nicotinic ACh receptor subtype?

1. Muscle - acetylcholine, succinylcholine

2. Ganglion- acetylcholine, nicotine

3. CNS- nicotine, acetylcholine


Where are peripheral nAChRs present at?

1. Autonomic ganglia

2. Neuromuscular junctions


How do nAChRS work at the neuromuscular junction?

1. Competitive antagonists of nAChRs = competitive blockers

2. Agonists which cause a depolarising block of the muscle fibre endplate =
depolarising blockers


Describe a use of a competitive blocker for nAChRS and give an example of one and where it came from?

1. Used as a muscle relaxant as an adjunct to anaesthesia

2. Mainly obstetrics as these drugs do not pass the placenta

3. Examples: tubocurarine, pancuronium, vecuronium, atracurium

4. These are found in poison dart frogs as a poison


Explain the effect of depolarising blockers and how it works? Give an example of one and why it's used?

1. Works by continuously stimulating the neuromuscular junction by acting as an agonist
- Causes muscle paralysis

2. Muscles contract due to maintained depolarisation and cannot repolarise to relax

3. This causes loss of excitability as the sodium channels cannot inactivate


Give an example of a depolarising blocker and why it's used?

1. Suxamethonium (succinylcholine)

2. Used to cause paralysis during anaesthesia

3. Short acting (10 minutes) as it's rapidly hydrolysed by cholinesterases


How do cholinesterases work?

Act as an enzyme to catalyse the hydrolysis of acetylene choline to acetate acid and choline


How does botulinum toxin type A work and what can it cause?

1. Blocks the vesicle docking/release botulism caused by food poisoning

2. Causes dry mouth, blurred vision, can easily lead to respiratory paralysis


What are the therapeutic indications for botulinium toxin?

1. Muscle spasm
- For treatment of excessive spasm from stroke, brain or spinal cord injury
- Pain associated with continual muscle contraction

2. Migraine and headache treatment
- Facial muscle contraction stimulates headache

3. Excessive secretion
- Treatment of under arm swelling and salivation


What is the indication of donepezil and the MOA?

1. The treatment of mild to moderate Alzheimer's disease

2. Acetylcholinesterase enzyme inhibitor (anti cholinesterase)


What does an ion channel receptor look like?

1. Five transmembrane domains

2. Each domain has four subunits

3. Nicotinic acetylcholine receptor is a pentama, permeable to a cation sodium

4. Activate with ACh, causes a conformational change when it binds and causes excitation and a charge inside


What is the Nicotinic acetyl choline receptor permeable to? How is it activated? And what can we do with this?

1. Permeable to cation sodium

2. Activate with ACh that causes a conformational change which causes excitation

3. We can use this to selectively target specific pentameric subunits acetylcholine receptors