Autonomic physiology and pharmacology Flashcards
What is the autonomic nervous system?
Part of the nervous system responsible for control of the bodily functions not consciously directed
What are the two divisions of the efferent autonomic nervous system?
Sympathetic
Parasympathetic
*enteric nervous system is a third division under the influence of the other two
What are the branches of the sympathetic nervous system?
Spinal roots T1-L4 emerging from the spinal cord
What are the branches of the parasympathetic nervous system?
Cranial nerves
Spinal roots S2-S4
Describe the symmetry that is seen throughout the ANS
The system is constantly controlled by the opposing actions of the sympathetic and parasympathetic branches
Example of a tissue only innervated by one of the two branches of the ANS
Vasculature
Only innervated by the sympathetic nervous system
Ciliary muscles of the eye
Only innervated by the parasympathetic nervous system
What is the difference between the afferent and efferent nervous system?
The afferent nervous system carries information to the CNS - sensory neurons
The efferent nervous system carries information from the CNS to the peripheral targets - motor neurons
What is the division of the afferent ANS?
Not split up into parasympathetic and sympathetic like efferent
Autonomic sensory information is conducted by general visceral afferent fibres
Less is known about this system
What is a consensual response?
Reflex observed on one side of the body when the other has been stimulated
For example, if an individual’s right eye is shielded and light shines into the left eye, constriction of the right eye will also occur
What is an autonomic ganglion?
Cluster of nerve cell bodies in the autonomic nervous system
Ganglia = where two nerves meet
What determines what type of neurotransmitters are released in the autonomic ganglia?
Whether it is the sympathetic or parasympathetic nervous system
Autonomic ganglia are closer to organs in the parasympathetic nervous system
TRUE or FALSE
TRUE
Which neurotransmitter is predominantly released in the efferent parasympathetic nervous system ganglia?
Acetylcholine
Binds to nicotinic receptors
Which neurotransmitter is predominantly released in the efferent parasympathetic synapse?
Acetylcholine
Binds to muscarinic receptors
Which neurotransmitter is predominantly released in the efferent sympathetic nervous system ganglia?
Acetylcholine
Binds to nicotinic receptors
Which neurotransmitter is predominantly released in the efferent sympathetic nervous system synapse?
Noradrenaline
Binds to alpha or beta adrenergic receptors*
*exception = sweat gland, acetylcholine is released which binds to muscarinic receptors
Which was the first discovered neurotransmitter?
Acetylcholine
Otto Loewi
Describe how the first neurotransmitter was discovered
Lowei wasn’t convinced that the action of nerves at the NMJ was electrical
He placed two hearts in water connected through a tube
The stimulation of one heart through the vagus nerve caused the same response in the heart in the separate beaker
Concluded that the chemical produced had travelled through the water and affected the other heart
How were the two receptors ACh acts through discovered?
Dale extracted the ACh
When placed on targets, it was discovered these two NT cause similar reactions as nicotine and muscarine
Concluded that acetylcholine acts on two different receptors - muscarinic and nicotinic
How did scientists conclude that adrenaline and noradrenaline acted on different receptors?
Ahlquist knew they were different structurally
Same molar concentrations of adrenaline had more of an effect on the heart than noradrenaline
Isoprenaline was artificially produced, and had strong effects on the heart without any effect on the vasculature
Concluded this was because adrenaline and noradrenaline works on different receptors
What are the two receptors of the sympathetic nervous system?
Alpha
Beta
What are the subtypes of alpha and beta receptors?
Alpha 1 and alpha 2
Beta 1, beta 2, beta 3
Describe the action of the parasympathetic nervous system
Pupil constriction
Decreased heart rate
Bronchoconstriction
Increased motility and secretion of the GI tract
Smooth muscle contraction
Describe the effect of the sympathetic nervous system
Pupil dilation
Heart
Describe the branches of the nervous system
The NS is split up into the CNS and PNS
Within the PNS you have the ANS and the somatic NS
Within the CNS you have the Brain and the Spinal Cord
Describe the adrenergic system in the brain
The locus coeruleus uses adrenaline and noradrenaline
Important in controlling mood and synchronization of physiological responses to stress and pain
Describe the cholinergic system in the brain
Acetylcholine is involved in memory formation and higher cognitive functions
Why is it complicated to use adrenergic or cholinergic agonists/antagonists to modulate the autonomic system?
These transmitters are not specific to the ANS and are used in other non-autonomic systems
- Motor system uses Ach in the NMJ
- ACh and NA are involved in CNS functions
List drugs used to modulate the autonomic nervous system
Reserpine
Physostigmine
Atropine
Describe the action of Reserpine
Used to treat hypertension
Irreversibly blocks the monoamine transporter, depleting the vesicles of adrenergic NTs by blocking vesicular transport mechanisms
Why is Reserpine not used more widely?
Serious side-effects = suicide
Describe the action of Physostigmine
Natural Acetylcholinesterase inhibitor
Causes a build up of acetylcholine
Potentiates the effect of ACh
What have been the uses of Acetylcholinesterase inhibitors?
Irreversible inhibitors have been used as pesticides and chemical warfare due to their effect on the ANS
Reversible inhibitors have been used for treatment of myasthenia gravis, Alzheimer’s and control of bladder in stroke patients
How must Acetylcholinesterase inhibitors be given in order to be used as treatment?
Low doses
Be reversible
Due to potentially dangerous effects
What is the main NT of the parasympathetic nervous system?
ACh
What is the main NT of the sympathetic nervous system?
Noradrenaline and Adrenaline
Describe the advantage of Atropine compared to Reserpine and Physostagmine
It is selective antagonist of muscarinic receptors
What are the medical applications of atropine?
Treatment of poisoning by nerve agent
Cardiac arrest
Decrease salivary secretion during anaesthesia
What are the three beta receptors?
Beta 1: heart muscle - positive ionotropic and chronotropic agent
Beta 2: bronchial smooth muscle, skeletal smooth muscle vasculature
Beta 3: adipose tissue
How have beta 1 receptors been targeted for therapy?
Treatment of hypertension
Safer for asthma sufferers with hypertension
How have beta 2 receptors been targeted for therapy?
Selective agonists for asthma sufferers
Bronchodilator
Salbutamol
Little effect on the heart - poisitve
What are the different types of alpha receptors?
Alpha 1
Alpha 2
Where are alpha 1 receptors expressed?
Vascular smooth muscle cells
Causes vasoconstriction in all the blood vessels but those expressed in the cardiac vasculature and skeletal muscle vasculature
Where are alpha 2 receptors expressed?
Presynaptic autoreceptor
Modulates the release of neurotransmitters
How have alpha 2 receptors been targeted for therapy?
Alpha 2 receptor agonists inhibit the release of norepinephrine
Used to decrease blood pressure
Acts as an antihypertensive drug
What are other neurotransmitters than NA, A and ACh called?
NANC (non-adrenergic, non-cholinergic neurotransmitters)
List NANC neurotransmitters
Nitric oxide
Serotonin
ATP
Neuropeptide Y
Substance P
Vasoactive intestinal polypeptide
How were NANC NT discovered?
Upon the continued smooth muscle contraction despite the blockade of both adrenergic and cholinergic synapses
What did the discovery of NANC NT reveal?
Neurons can release more than one neurotransmitter at a time
What percentage of hypertension cases is caused by secondary conditions?
5%
Conditions like pheochromocytoma
What is allostasis?
The process of achieving homesostasis through physiological change
Why do alpha-1 antagonists and alpha-2 antagonists have differing effects on blood pressure?
Because alpha 2 receptors are found in the presynaptic membrane
Decreases the release of noradrenaline when the concentration has reached a certain threshold in the synaptic cleft
Blocking this causes the increased release of NA and therefore more vasodilation, leading to decreased blood pressure
Which alpha receptor antagonist causes an increase in blood pressure?
Alpha 1 antagonist
Receptor binding to noradrenaline causes vasodilation
If this is blocked, the vasculature undergoes decreased vasodilation
Why have many different types of antihypertensive drugs been developed?
The heterogeneous presentation of patients upon the use of drugs
The unknown cause of the disease
Many side effects
What are 4 classes of drugs used to treat hypertension?
ACE inhibitors
Angiotensin II blockers
Calcium channel blockers
Potassium channel openeners
How do ACE inhibitors alleviate hypertension?
Targets the renin-angiotensin system
Causes a blockage of active compounds further down the pathway
What is the major side effect of ACE inhibitors?
Importance of ACE in the modulation of bradykinin action
Causes a chronic cough
How do Angiotensin II blockers alleviate hypertension?
Inhibits the action of angiotensin II in the vasculature, leading to vasodilation
More specific than ACE inhibitors, and do not cause cough
Which patient population is advised against Angiotensin II blockers?
Pregnant women
Angiotensin II is involved in the genesis of the kidney in the embryo
How do calcium channel blockers alleviate hypertension?
Block the entry of calcium, which is used for muscle contraction
Decreases blood pressure by decreasing the contractility of cardiac and vascular smooth muscle cells
Does not affect skeletal muscle, since their calcium channels are different that those targeted by this blocker
Which patient population is advised against calcium channel blockers?
Patients with congestive heart failure who have experienced a heart attack
More difficult for their heart muscle to start pumping again
How do potassium channel openers alleviate hypertension?
Cause the release of potassium
Hyperpolarising the membrane
Makes it more difficult for the smooth muscles to contract
What is the major complication of potassium channel openers?
Potassium channel openers influence insulin release from the pancreas
Induces periodic diabetes
What is mydriasis?
Pupil dilation
What is miosis?
Pupil constriction
What is the best way to examine the autonomic nervous system?
Pupils
You can stimulate miosis and mydriasis through altering the muscarinic or adrenergic receptors
How do you stimulate mydriasis?
a-adrenergic agonists
Muscarinic blockers
What is the role of the muscarinic blockers when stimulating mydriasis?
Cilliary muscles change the lense shape upon contraction
No innervation from the sympathetic nervous system, but muscarinic receptors are present
Blocking these allows us to dilate the pupil
Describe the actions of the ANS
Regulates smooth muscle tone
Regulates cardiac function
Actions on exocrine and endocrine secretions
Actions on intermediate metabolism
Only efferent autonomic pathways are targets for drug action
TRUE or FALSE
TRUE
What are the two neurons that make up the efferent autonomic pathways?
Preganglionic fibres
Postganglionic fibres
Describe the enteric nervous system
Neurons with cell bodies in the plexuses of the intestinal wall
Autonomic nerves terminate on these cells
System can operate autonomously in the control of peristalsis and secretion
Where is acetylcholine released from?
Postganglionic parasympathetic neurons
Preganglionic neurons
Motor nerves
Where is noradrenaline released from?
Postganglionic sympathetic neurons
What is the function of NANC?
Primary transmitters in the enteric and sensory neurons
Co-transmitters with NA and ACh in autonomic nerves
What are co-transmitters?
Released together with neurotransmitters
Commonly have different response speeds to neurotransmitters
Which co-transmitter is released with ACh?
ATP
Which co-transmitter is released with NO?
NA
Which co-transmitter is released with VIP?
NPY
Where do sympathetic ganglia lie?
Far away from target site
Where do parasympathetic ganglia lie?
Close to target organs
Compare the responses evoked from sympathetic and parasympathetic nerves
Sympathetic responses are more diffuse
Preganglionic fibres branch and synapse with postganglionic neurons in several segments above and below their origin in the spinal cord
Also release of catecholamines from the adrenal medulla increases the effect radius
Parasympathetic responses are more localised
Connect with only a few postganglionic fibres
Describe the storage and release of noradrenaline
Stored in dense-core storage vesicles
Released by calcium-mediated exocytosis
What is another name for adrenaline?
Epinephrine
What is another name for noradrenaline?
Norepinephrine
Alpha receptors are specific for NA, and do not react to adrenaline
TRUE or FALSE
FALSE
These receptors act to both, but to different extents
What type of receptors are alpha receptors?
G-protein coupled
a1 = Gq a2 = Gi
What type of receptors are beta receptors?
G-protein coupled
All Gs
How do a1 receptors carry out their function upon binding to their agonist?
G-protein mediated
Second messengers IP3 and DAG generate
Increase Ca2+
Activates the contractile mechanisms in smooth muscle cells
How do a2 receptors carry out their function upon binding to their agonist?
Inhibit adenylate cyclase
Reduces cAMP
Inhibits opening of Ca2+
Promote opening of K+ channels
What is the main antagonist used clinically?
a1-selective antagonists
What is the effect of a1-selective antagonists?
Fall in blood pressure
Rise in heart rate
Decreased tone of the smooth muscle at the bladder neck
What are the unwanted effects of a1-selective antagonists?
Extension of their pharmacological effects
Increased heart rate
Postural hypotension
Congestion of the nasal blood vessels
What is the effect of beta-1 agonists?
Increase in heart rate/force
What is the effect of beta-2 agonists?
Dilation of bronchioles and arterioles
Relaxation of bladder muscle
Glycogenolysis
What is the effect of beta-3 agonists?
Lipolysis
Describe the mechanism of function of beta receptors
G proteins
Activate adenylate cyclase
Increase cAMP
Activates protein kinase A
PKA inactivates the myosin light chain kinase, reducing the contraction
In heart, PKA phosphorylates Ca2+ channels, increasing he inward Ca2+ current and the force of contraction
What are the main effects of b-antagonists?
Antihypertensive effect
Antianginal effect
Limited action in normal individual, main action seen in pathological conditions
How do b-antagonists cause antihypertensive effects?
Reduces cardiac output
Decreases release of renin
Central decrease in sympathetic action
How do b-antagonists cause antianginal effects?
Slowing of the heart muscle
Decreased metabolic demand
How are uptake 1 inhibitors used ?
Increase the effects of NA through interfering with the main method of terminating NA action
How do sympathomimetic amines work?
Taken by uptake 1 and into vesicles
Exchange with NA
NA is released from the neuron as a response
Increases alertness and decreases appetite
What is carbidopa used for clinically?
Reduces the peripheral sympathetic activity when used as an adjunct with levodopa
How does methyldopa work as an antihypertensive?
Taken up by amino acid transporter
NA-producing enzymes transforms it into methylnoradrenaline
Acts on a2-adrenoreceptors to reduce the release of NA
Antihypertensive
