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pharmacology > Autonomic nerous system > Flashcards

Autonomic nerous system Flashcards

1
Q

what are the 2 divisions of the nervous system ? and explain the components that make up each divisions

A
  1. central nervous system -> which is composed of the brain and the spinal cord
  2. peripheral nervous system -> which composed of the neurons that are located outside the brain and the spinal cord , that interconnect the CNS to the ordans of the body
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2
Q

explain the divisions of the peripheral nervous system and their functions .

A
  • the peripheral nervous is divided into somatic autonomic nervous systems
    1. SOMATIC -> involved in voluntary control of functions such as contraction of skeletal muscle for movement.
    2. AUTONOMIC NS->The ANS regulates the everyday requirements of vital bodily functions without the conscious participation of the mind.
  • Such as : involuntary ,. Innervate smooth muscle of the viscera, cardiac muscle, vasculature, exocrine glands, thereby controlling digestion, cardiac output, blood flow, and glandular secretions. (All the functions of the body you don’t have to think about).
  • the autonomic NS consists of sympthathetic, parasympathetic and the enteric system.
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3
Q

name the 3 devisions of the AUTONOMIC nervios system

A
  1. Sympathetic nervous system
  2. parasympathetic nervous system
  3. Enteric system
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4
Q

explain the main 2 fuctional pathways of the peripheral nervous system

A
  1. Efferent (E for Exit) - carry signals away from CNS to peripheral tissues
  2. Afferent divisions - bring information from periphery to the CNS. Afferent neurons provide sensory input to modulate the function of the efferent division through reflex arcs or neural pathways that mediate a reflex action.
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5
Q

explain the anatomy of the syspathetic nervous system and the main function .

A

Sympathetic: Orginates from thoracic and lumbar segments of spinal cord .
-Thoracolumbar (T1-L2)
-produce “fight or flight” response.

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6
Q

explain the anatomy of the parasyspathetic nervous system and the main function .

A

Parasympathetic: Originates from craniosacral segments of cord .
-Craniosacrall (CN III,VII,IX,X AND S2,3,4)
-produces “rest and digest” functions.

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7
Q

explain the anatomy of the Enteric autonomic nervous system and the main function

A

Enteric ANS: “brain of the gut”, entirely independent of CNS/not arising in the CNS.
-Collection of nerve fibres found in walls of the GIT tract and innervate GIT organs
-function : to control motility, exocrine and endocrine function, the microcirculation of GIT.
-Is also modulated by PS and Sympathetic Nervous system.

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8
Q

explain the anatomy of the ANS (the two neuron system ) including the functions of the 2 functional pathways of the ANS

A

the 2 neurons = pregangionic nad postgaanglionic neurons
they synapse at the Ganglia
ANATOMY OF THE ANS :
1. Efferent pathway (exit): the nerve impulses carried from the CNS to effector organ by efferent neurons .
- with the efferent neurons ,the cell bodies of the preganglionic neurons are located in the CNS
-The preganglionic neuron emerges from the CNS in brainstem or spinal cord and meets at a synapse in the ganglia.
-Cell body of the post ganglionic neuron originates in the ganglion. Post ganglionic neuron terminates at effector organ.
2. Afferent pathway (towards CNS): the afferent neurons of the ANS are important in the reflex regulation /sensory feedback of the autonomic nervous system (for example, baroreceptors sensing pressure in the carotid sinus and aortic arch)
and in segnaling the CNS to influence the efferent branch of the system to respond .

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9
Q

How is the sympathetic nervous system structured ?

A

-The preganglionic neurons of the sympathetic system come from the thoracic and lumbar regions (T1 to L2) of the spinal cord,
- and they synapse in two cord-like chains of ganglia that run close to and in parallel on each side of the spinal cord - sympathetic chain
-These nerves have short preganglionic fibres and long postganglionic fibres. (the pregangionic are close to the spinal cord and then the post ones are long ecause they terminate at the target organ)
-All neurons in sympathetic nervous system can be activated simultaneously because of numerous neuronal interconnects within the paravertebral chain
- receptors : adrenegic receptors
- neurotransmitters : noradrenaline at receptors on most effector organs.
- Release of NA and A from adrenal medulla into blood during sympathetic stimulation also integral to sympathetic response.

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10
Q

whatt are the functions of the SNS?

A

SKIN :- Gives goose bumps, chicken skin, duck skin – piloerection, arrector pilli muscle in the skin is innervated primarily by sympathetic nerves
EYES:Dilates pupil by stimulating the iris dilator muscle
MOUTH : - inhibits salivation by producing viscous saliva
HEART :Accelerates heart rate – stimulates beta 1 receptors in the heart
LUNGS :Relaxes bronchi stimulates Beta 2 receptors in the airway
STOMACH :Inhibits peristalsis and secretion – tonic inhibitory influence on GI muscles
PANCREAS:Stimulates glucose production and release – promotes glycogenolysis
KIDNEYS:Secretion of adrenaline and noradrenaline (catecholamines) from the adrenal gland preganglionic sympathetic nerve endings release acetylcholine, which causes calcium-dependent exocytosis of these cytoplasmic storage granules and release of the catecholamines.
BLADDERR : Inhibits bladder contraction - it causes relaxation of the destrusor muscle -> promoting urinary retention, and closes the mouth of the bladder (the sphincter )

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11
Q

How is the Parasyspathetic nervous system structured ?

A
  • nerves arise from the craniosacral region of the spinal cord ( CN III,VII,IX,X AND S2,3,4)
    -Ganglia are close to innervated organs and have long preganglionic fibres and short post ganglionic fibres.
    -There are few or no interconnections between ganglia, so innervated organs can be controlled independently.
    -Receptors: (general the term for receptors that ACh acts on are cholinergic receptors, may either be muscarinic in PS or nicotinic in skeletal muscle/ganglia.)
    *Nicotinic receptors – found in the CNS and the skeletal neuromuscular junction.
    *muscarinic receptors.
  • neurotransmitters : Parasympathetic NS uses ACh
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12
Q

what are the effects of the parasympathetic nervous system in the body ?

A

REST AND DEGEST
EYE : contraction of pupillary muscle (constrictor papillae), contraction of cilliary muscles to change shape of lens in ocular accommodation.
CVS: slow HR, decrease force of contraction, vasodilation

GIT: increased peristalsis, increased gastric and pancreatic secretions

EXOCRINE GLANDS : increased sweating, saliva, bronchial secretions, histamine release.

SMOOTH MUSCLE : bronchial contraction, bladder smooth muscle contraction

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13
Q

How do this 2 ANS divisions (Sympathetic autonomic NS and the parasympathetic autonomic NS) work with each other ?

A
  • these systems are opposite each other( have oppposites effects on the organ function )
  • many organs are innervated by both ofthese ,which causes a fine balance .
    -Example: urination - Brought about by decrease sympathetic activity on sphincter muscle and increased PS activity on bladder wall muscles.
    -At resting conditions predominant drive to major organs is parasympathetic , then the sysmathetic produces more transiet (short-lasting) but higly coordinated responses.
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14
Q

what is ganglion ?

A

Are functional relay stations between two neurons, are an aggregation of nerve cell bodies located in peripheral nervous system

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15
Q

list cholinergic agents that are direct acting (agoists )and where are they found or used in

A
  1. Methacholine -> may be used to assess airway reversility in the diagnosis of asthma
  2. Pilocarpine -> used for management of glucoma (in consultation with a specialist )
  3. Muscarine->this is a alkaloid toxin that can be found in wild mushroomsm

1.

muscarine poisoning insouth africa most commun inWestern cape and KZN

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16
Q

classify the direct acting cholinergic agonists underr reversible and irrersible

A

REVERSIBLE :
1. Methacholine -> may be used to assess airway recersility in the diagnosis of asthma
2.Pilocarpine -> used for management of glucoma (in consultation with a specialist )
3. Muscarine->this is a alkaloid toxin that can be found in wild mushroomsm
IRREVERSIBLE : N/A

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17
Q

List the indirect acting cholinergic agents (anticholinesterases ) and where they are used

A
  1. Neostigmine (diagnosis and treatment of myasthenia gravis. Reversal agent for non-depolarising muscle relaxants following surgery-> used in anaesthesia)😁
  2. Physostigmine (Myasthenia gravis)
  3. Pyridostigmine (treatment of myasthenia gravis. Reversal agent for non-depolarising muscle relaxants following surgery)
  4. Edrophonium (diagnosis of myasthenia gravis)
  5. Rivastigmine (management of Alzheimer’s disease)
  6. Organophosphorus compounds
    (Organophosphate containing insecticides)

Exposure can be:
occupational – agriculture
accidental – gardening
intentional overdose in self-harm

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18
Q

classify the indirect acting anticholinesterases based on their reversibility

A

REVERSIBLE :
1.Neostigmine
2. Physostigmine
3.Pyridostigmine
4.Edrophonium
5.Rivastigmine
6. other :donepezil, galantamine(used in alzheimer’s )
IRREVERSIBLE : (binds irreversibly)
1.Organophosphate compounds (organophosphate containing insecticides )

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19
Q

what is the function of the acetycholinesterase?

A

Acetylcholinesterase (AChE) – is the enzyme that metabolises / hydrolyses acetylcholine back into acetic acid and choline. The enzyme aborts the action of the acetylcholine (Ach) at the synapse.

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20
Q

what is implied by the direct acting and indirect acting cholinergic agents ?

A

Direct acting implies - direct action by the drug on the cholinergic receptors (nicotinic and/or muscarinic receptors).

Indirect implies action via inhibition of acetylcholinesterase – AChE

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21
Q

explain the mechanism of action ofthe cholinergic agonists

A

they bind to the cholinergic receptors (muscarinic or nicotinic ) and exert the action of Ach

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22
Q

explain the mechanism of action of anticholinesterases

A
  • The anticholinesterases (indirect acting cholinergic agents) prolong the availability and actions of acetylcholine at all its receptors as inhibition of the enzyme results in increase in endogenous Ach (acetylcholine).
  • These agents increase ACh at nicotinic receptors at the neuromuscular junction but also increases ACh mediated effects produced via the muscarinic receptors resulting in parasympathetic effects such as bradycardia and increased secretions.
    -These unwanted effects of ACh on the muscarinic receptors can be blocked by coadministration of an anticholinergic agent such as glycopyrrolate.
  • example : Anticholinesterases such as neostigmine can be used to overcome reversible neuromuscular blockade by non-depolarizing muscle relaxants used in general anaesthetic following surgery
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23
Q

Anticholinesterases that bind irreversibly are commonly encountered in poisoning situation such as in organophosphates poisoning that present with cholinergic crises.List the features /signs in cholinergic crises

A

SLUDGE
1.S-SALIVATION
2.L- LACTIMATION
3.U-URINATION
4.D-DIARRHOEA/DEFECATION
5.G- GESTROINTESTINAL UPSET AND CRAMPS
6.E?
puls the 3Bs and 2Ms

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24
Q

Additional effects of excessive acetylcholine are 3Bs and 2Ms, list these effect in full

A

Bronchospasm, Bradycardia; Miosis, Muscle fasciculations and weakness respectively.

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25
Q

what is the Management of cholinergic crises (acetylcholine excess)?

A
  • ABCDEFG approach (all cases of poisoning )
  • Atropine, an anticholinergic
  • Pralidoxime, acetylcholinesterase activato
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26
Q

what is the effect of the cholinergic agents both agonists and anticholinesterases ?

A

The effects of these drugs will be cholinergic as they both increase acetylcholine at the synapse:
CVS: slow HR, decrease force of contraction, vasodilation
Smooth Muscle: bronchial contraction, bladder smooth muscle contraction
GIT: increased peristalsis, increased gastric and pancreatic secretions
Exocrine glands: increased sweating, saliva, bronchial secretions, histamine release
Eyes: contraction of pupillary muscle (constrictor papillae), contraction of cilliary muscles to change shape of lens in ocular accommodation

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27
Q

list the principle of neurotransmitters

A
  • Synthesis of a neurotransmitter
  • Storage of a neurotransmitter
  • Release of a neurotransmitter
  • Interaction of a neurotransmitter with receptor on effector cells
    -Removal/Degradation/Recycling of a neurotransmitter
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28
Q

Explain the principles of neurotransmitters

A
  1. NT get synthesized in the presynaptic axon terminal
  2. and stored within membrane vesicles
  3. AP is generated by cell body in response to appropriate stimulus.
    AP is conducted along the axon by the opening of of voltage-gated Na channels and the influx of Na.
    When the AP reaches the presynaptic nerve terminal, it results in influx of Ca through voltage gated channels.
    Ca influx results in the fusion of NT containing vesicles with the presynaptic membrane and release of stored NT into synaptic cleft.
  4. Released NT binds to the appropriate postsynaptic membrane and generates biochemical changes in the receptor cells and basically instruct the cells to increase/decrease their activity.
    The released neurotransmitter may also stimulate auto receptors in the presynaptic membranes and modulate further release of NT.
  5. NT is degraded by enzymes or taken back into presynaptic neuron for reuse.
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29
Q

list the neurotransmitter that we ahve in our bodies

A
  1. Acetycholine
  2. Noradrenaline /Adrenaline
  3. Non-Ach /non -Adrenergic e.g . serotonin, dopamine, GABA, histamine, nitric oxide
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30
Q

which areas of the nevous system is Ach the neurotrasmitter and which receptors does it acts on ?

A
  1. Preganglionic- All(ACh is the NT present at all synapses of preganglionic neurons (whether PS or Sympathetic)
  2. Postganglionic
  3. Parasympathetic - muscarinic R (Parasympathethic postganglionic receptors - ACh acts on muscarinic R)
  4. Postganglionic Somatic - nicotinic R (Postganglionic Somatic nervous system the NT is ACh acting on Nicotinic N1 receptors)
  5. Adrenal medulla - NE/E
  6. (Postganglionic Sympathetic in sweat glands)
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31
Q

which areas of the nevous system is NA the neurotrasmitter and which receptors does it acts on ?

A

Sympathetic postganglionic fibres release NA, that acts on alpha and beta adrenoreceptors (adrenergic neurons), except for sympathetic innervation of sweat glands which is cholinergic
In the somatic nervous system, transmission at the neuromuscular junction (the junction of nerve fibers and voluntary muscles) is also cholinergic

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32
Q

explain the synthesis,storage,transportation,release ,and degradation of ACh

A
  • Choline (derived from the diet) is transported into nerve terminal by high affinity Na-choline co-transporter.
    (Positively charged, does not readily cross cell membranes, needs a specific transporter to be taken up into cell - inhibited by hemicholinium)
  • ACh is synthesized within the cytosol of the cholinergic neuron from choline and AcetylCoA by choline acetyltransferase (CAT).
  • Once synthesized, ACh is taken up into membrane vesicles by vesicular ACh transporter (VAChT) for storage (inhibited by Vesamicol)
    -Acetylcholine in vesicles is released into synaptic cleft by calcium-dependent exocytosis of vesicles
  • ACh in the synaptic cleft can stimulate the nicotinic or muscarinic receptors
  • Presynaptic and postsynaptic membranes are rich in acetylcholinesterase (enzyme responsible for the metabolism/breakdown of ACh). ACh is rapidly hydrolysed back to choline and acetate. Choline undergoes reuptake into presynaptic neuron and the process of synthesis continues.
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33
Q

what are the effects of inhibiting ACh vesicular release into the synapse ? and how does this happen ?

A
  • Inhibition of sweating, giving symptoms of a dry, warm skin
  • Inhibition of salivation with symptoms of dry mouth
  • Pupillary dilatation
  • all the symptoms and signs of sypathetic stimulation
    HOW DOES THIA HAPPEN ?
    Effects of decreasing ACh release into synapse via inhibition of influx of calcium into nerve terminals results in less Ach. Less ACh in synapse to bind to and act on cholinergic receptors thus less cholinergic effects and this can result in effects similar to sympathetic/adrenergic effects.
    (Less ACh, less cholinergic effect, opposite effects similar to sympathetic stimulation and less effects on skeletal muscles)
    Effects of inhibiting acetylcholine release are similar to effects of sympathetic stimulation
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34
Q

Effects of anti AChE

A

Clinical effects:

Effects: sweating, salivation, bradycardia, hypotension, muscle fasciculation, paralysis, lacrimation, urinary incontinence, diarrhoea, constricted bronchi

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35
Q

Give example of drugs that inhibit Ach and their effects

A
  1. Aminoglycoside antibiotics such as Amikacin, Gentamycin, Streptomycin , Neomycin - may cause NMBlockade and respiratory paralysis, especially if given soon after anaesthesia or muscle relaxants
  2. Botulinum toxin/BOTOX blocks release of ACh at sweat glands (reduced sweating), and at NMJ (muscle paralysis) causes paralysis
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36
Q

what is the function of Butyrylcholinesterase also called pseudocholinesterase and where is it found in the body ?

A
  • found in the liver,brain and GIT
  • function : Responsible for inactivation of some drugs such as the muscle relaxant –Suxamethonium
37
Q

list Cholinergic Antagonists / Anticholinergics

A
  1. Atropine
    2.Glycopyrrolate
    3.Ipratropium bromide
    4.Oxybutinin
    Anti-cholinergics, Cholinergic antagonists - block muscarinic receptors - less parasympathetic effects, more sympathetic effects
38
Q

what type of drug is Atropin ,what is it used for ,and what the the MOA?

A
  • it is tertiary amine
  • competitive cholinergic anatagonist- it competitively bind to muscarinic receptors
    used to treat organophasphate poisoing ( and also used in anaesthesia with the reversal drug ,neostigmine )
    MOA:
  • organophosphate is an anti AChE agent , it bind irreversibly to the AChE
  • this then increases Ach in the synaptic cleft , prolonging the effect of ACh
  • therefore, Atropine competes with ACh for the cholinergic receptors ,prevents teh axcesss ACh from binding
  • effects : Antispasmodic, antisecretory, mydriasis and cycloplegia
39
Q

what type of drug is Glycopyrrolate ,what is it used for ,and what the the MOA (clinical application )?

A

-Quaternary amine, preoperative medication
-Ophthalmology to produce mydriasis and cycloplegia

Some Clinical Applications:
Glycopyrrolate – Glycopyrrolate is a cholinergic antagonist/anticholinergic at the muscarinic receptor. It is used in perioperative medicine for reduction of secretions, prevention of bronchoconstriction and bradycardia.
In anaesthesia, neuromuscular blockade is reversed/overcome with neostigmine/pyridostimine (indirect acting cholinergics aka anticholinesterases). During this neuromuscular blockade reversal process there are cholinergic side effects at the muscarinic receptors as well which may cause effects of bradycardia, increased secretions and bronchoconstriction.

40
Q

what Ipratropium Bromide it used for ,and what the the MOA (clinical application )?

A
  • used in as bronchodilator in Asthma/COPD
  • MOA: cholinergic stimulation causes bronchospasm, therefore anticholinergic acts as bronchodilator
41
Q

what Oxybutinin used for and MOA?

A
  • usually used in older patients forurge incontinance
  • and in post -oparative urinary spasms
    – cholinergic stimulation of bladder leads to detrusor muscle contraction, therefore blocking cholinergic stimulation will have urinary antispasmodic effect.
42
Q

what is Imipramine used for?

A
  • tricyclin antidepressents
    -impramine TCA with strong antimuscarinic action, reduced bladder contraction, reduces incontinence
43
Q

list the cholinergic receptors and their location in the body

A

Muscarinic receptor :
- M1= CNS,ganglia
-M2= heart,nerve,smooth muscle
-M3= Glands ,smooth muscle ,endothelium
-M4&M5= CNS
NICOTINIC RECEPTORS:
- Nm= skeletal muscle ,NMJ
-Nn= postganglionic cell body,dendrites,CNS

44
Q

List the adranergic receptors and their location in the body and the effect they have.

A

ALPHA RECEPTORS :
Alpha receptors : Alpha 1 are post synaptic, alpha 2 are presynaptic and postsynaptic.
-Major effects on vascular smooth muscle.
Alpha 1: vasoconstriction, GIT muscle relaxation, salivation, hepatic glycogenolysis.
Alpha 2: smooth muscle contraction, decreased NE release via autoreceptor inhibitory action, inhibition of insulin release, platelet aggregation.(its effects are kinda ihibiting sympathetic sytem ?)
BETA RECEPTORS :

B1: mainly located in the heart ,but also found in the GIT presynapitically ( also in heart,thyroid gland and in the kidney )->increased HR and force of cardiac muscle contraction
B2: heart,thyroid gland ,kidney ,blood vessels,airways,smooth muscle ,pancrease,GIT,Liver -> bronchodilator, vasodilation, visceral smooth muscle relaxation, hepatic glycogenolysis.
B3: adipose tissue ->fat cell lipolysis.

45
Q

eplain the sysnthesis of sympathetic NT( noradrenaline )-> until release

A

diet -> tyrosine -> dopa-> dopamine -> NE
1. Tyrosine is oxidized by tyrosine hydroxylase in the presence of pteridine cofactor into L-Dopa (levodopa) within the neuron-> This step is both rate limiting and is subject to negative feedback by catecholamines that are subsequently produced.
2. L-Dopa is catalyzed into Dopamine by the cytosolic enzyme known as Dopa decarboxylase. This is the end of the process in Dopaminergic neurons.
3. In adrenergic neurons, Dopamine is taken up into vesicles by a specific transporter termed the vesicular monoamine transporter 2 (VMAT2). The vesicles contain the enzyme dopamine beta hydroxylase within vesicular membrane, which then further generates Noradrenaline from dopamine.

  1. The remaining dopamine is converted to VMA (Vanilly mandelic acid / homovalinic) and excreted in the urine
  2. NE may be further converted to adrenaline via methyl transferase in adrenal glands
  3. Release is once again in response to a nerve impulse that occurs following calcium (Ca2+ influx and Ca mediated fusion of NE containing vesicle with cytoplasmic membrane-> NE released into synaptic cleft.
46
Q

explain how NE is removed from the synapse

A
  1. Principal mechanism of removal of NE from the synapse is uptake into presynaptic neuron by specific high affinity carrier called uptake 1 or the NET (Norepinephrine transporter).
  2. It also takes up dopamine but not adrenaline. NA can then be transferred from the cytosol into the vesicles by VMAT2.
  3. Some of the noradrenaline remaining in the synapse is taken up into non-neuronal tissues by low-affinity carrier called uptake 2 (extra neuronal monoamine transporter (which can also transport adrenaline).
    4.NE bind to presynaptic receptors that negatively feedback and decrease the release of further NE. The rest of the NA and Adrenaline is metabolized.
47
Q

which 2 main ezymes are involved in the initial steps in the catabolism of NE? and HOW?

A
  • 2 main enzymes involved in the initial steps in the catabolism of NE : MAO (monoamine oxidase) and catechol-O-methytransferase (COMT).
    1. MAO is present on the surface of mitochondria of presynaptic neuron and in GIT epithelium and liver.
    It metabolizes NE via oxidative removal of amino group, preventing binding to the postsynaptic receptor.
    Metabolism of NE by MAO and COMT results in the formation of Vanillylmandelic acid (VMAs) - which is mainly a urinary metabolite
48
Q

what is the clinical importance of the VMA (Vanilly mandelic acid / homovalinic)

A
  • The remaining dopamine is converted to VMA (Vanilly mandelic acid / homovalinic) and excreted in the urine
  • in clinical practice you may encounter a request of ‘urinary VMAs or urinary catecholamines when a tumour called phaechromocytoma is suspected)
  • This is an adrenal tumour that results in excess production of catecholamines i.e adrenaline and noradrenaline and leads to effects of excess sympathetic nerve stimulation.
49
Q

explain the 4 ways in which adrenergic homeostasisi is maintaned 1.

A
  1. When high levels of cytosolic NE – there is negative feedback with inhibition of Tyrosine hydroxylase. (Decreased conversion of tyrosine to L-Dopa)
  2. Stimulation Presynapsic autoreceptors : NE can be modulated its own neuronal release by stimulation of presynaptic autoreceptors, which can be either inhibitory or excitatory. Binding of NE to auto receptors also leading to negative feedback and decreased NE production. Alpha 2 adrenergic receptors are inhibitory receptors and reduce NE release. B1 adrenoceptors are excitatory auto receptors and increase NE release. Presynaptic heteroreceptors also exist. Dopamine and ACh can inhibit the release of NE by stimulating D2 and cholinergic M2 receptors.
  3. Action of NE in the synaptic cleft is also terminated by reuptake into the presynaptic nerve terminal by 2 transporters: neuronal uptake 1 and extraneuronal uptake 2. Reuptake back into the nerve terminal accounts for removal of 70% of NE released into the synaptic cleft. (Excess NE may accumulate in the synaptic cleft when drugs that inhibit the uptake 1 mechanism of NE via NET - increased adrenergic effects (Cocaine))
  4. Metabolism via MAO in mitochondria, COMT in the cytoplasm. 5HT, Dopamine, NE and E follow similar degradation pathways.
50
Q

list sympathomimetics

A
  1. Ephindrine
  2. Adrenaline /epinephrine
  3. Noradrenaline /norepinephrine
  4. Dopamine
51
Q

classify the sympathomemitic drugs into direct acting ,indirect and mixed

A

Direct acting : also non selective
- Adrenaline
-Noadrenaline
-Dopamine
MIXED ACTING :
-Ephedrine

52
Q

how does Ephedrine work and what are the side effects ?

A

MOA: acts primarily on alpha and beta adrenergic receptors but with less potency.Acts directly on alpha and beta receptors

  • Causes release of endogenous ->Also displaces NE from vesicles and reverses neuronal uptake transport of NE leading to increased NE in synaptic cleft.
  • . Previously used as a nasal decongestant by inducing vasoconstriction in nasal mucosa. Due to its potential to release NE as well, it is classified as banned substance in competitive sport.
    side effects : HPT, insomnia, cardiac dysrhythmias
53
Q

How does Adrenaline works ?

A

Alpha 1 receptor activation - peripheral vasoconstriction
Beta 1 receptor activation - inotropic effect
Beta 2 receptor activation - *Bronchodilation
Lower doses - predominantly Beta, higher doses - alpha effects.

54
Q

what happens in low doses of adrenaline ?

A

Low doses of epinephrine increase cardiac output because of beta 1 adrenergic receptor inotropic and chronotropic effects, while alpha adrenergic receptor induced vasoconstriction is often offset by beta 2 adrenergic receptor vasodilation
- Result is increase cardiac output, decrease systemic vascular resistance and variable effects on MAP.

55
Q

what happens in high doses of epinephrine ?

A

At higher epinephrine (such as used in anaphylaxis) doses alpha adrenergic receptor effect predominates, producing increased SVR in addition to increased CO, as well as stimulation of B2 receptors inducing bronchodilation

56
Q

How and why is epinephrine used in anesthesia ?

A
  • used in local anesthesia ->there lignocaine with epinephrine .
    -Its alpha receptor stimulation with vasoconstrictor effects, is exploited in coadministration of local anaesthetic, where it prolongs the duration of action by reducing tissue perfusion and preventing dispersal of LA.
56
Q

list topical uses of Epinephrine

A
  1. Adjuvant o local anesthesia
    2.Bleeding
    3.Glaucoma
57
Q

List systemic uses of epinephrine

A
  1. Cardiac arrest
  2. Anaphylactic shock
  3. Acute Bronchial asthma
58
Q

How does norepinephrine works ?

A

Acts on both alpha 1 and beta 1 adrenergic receptors producing potent vasoconstriction via alpha 1 and B1 receptors with modest increase in cardiac output.
net effect : Increase BP; preferred vasopressor in septic shock
- Negligible effects on alpha 2 and beta 2. (Also preferred in atypical antipsychotic overdoses)

59
Q

When are the Dopamine receptos located ? and what happen in activation of these receptors ?

A
  • Dopamine receptors present in renal, mesenteric, coronary and cerebral vascular beds.
  • Activation of theses leads to vasodilation. A subtype of dopamine receptors induces NE release causing vasoconstriction.
60
Q

How does Dopamine works ?

A

the effect of dopamine is dose related .
1. Low doses - D receptors -renal, mesenteric, cerebral and coronary vasodilation (some patients may actually develop hypotension at lower doses).

  1. Mod. Doses(5-10mcg/kg) - Beta-1 - inotropic effect (increases cardiac output, predominantly by increases stroke volume, with variable effects on heart rate. Some mild alpha adrenergic activation may increase systemic vascular resistance and increase MAP)
  2. High Doses - Alpha 1 - vasoconstriction and increased SVR.
61
Q

name the areas in the body where it is not advisable to use local anesthesia containing epinephrine and why is that ?

A
  • sites : fingers,toes ,ears and nose
  • this is due to vasoconstriction in these areas that already do not have collateral blood supply (they have end arteries,arteries that are the only blood supply to that organ ) -> leading to-> reduced blood supply in these areas -> ischemia
62
Q

what are sympathomometics and sympatholytics drugs ?

A
  • sympathomemitics -> drugs that activate adrenergic receptors
  • Sympatholytics -> Drugs that inhibit adrenergic receptor activation
63
Q

what are effects of Alpha 1 adrenoceptors ?

A
  • Vasocontriction
    -increased peripheral resistance
    -Mydriasis (pupillary dilation )
    -increased closure of internal sphincter of the bladder
64
Q

what are effects of Alpha 2 adrenoceptors ?

A

⍺2-adrenoceptor
1. located primarily on sympathetic presynaptic nerve endings.
- control the release of norepinephrine.
- Stimulation of ⍺2-adrenoceptors causes feedback inhibition and inhibits further release of norepinephrine from the stimulated adrenergic neuron.
- This acts as local mechanism for modulating norepinephrine output when there is high sympathetic activity.
- Act as inhibitory autoreceptors.
2. Also found on presynaptic parasympathetic neurons.->inhibiting Ach release .
3. Inhibition of insulin release

65
Q

what are effects of Beta 1 adrenoceptors ?

A
  • chronotropic effect -> tachycardia
  • inotropic effect -> increased myocardiac contractility
  • increased release of renin
66
Q

what are effects of Beta 2 adrenoceptors ?

A

-Bronchodilation
-Vasodilation
-decreased peripheral resistance
-relax uterine smooth muscle
-increased release of glucagon.
-increased muscle and liver glycinolysis

67
Q

what is Tamsulosin and what is it used for ?

A

Background : there’s ⍺1A, ⍺1B, ⍺1C, ⍺1D adrenoceptors
- alpha 1a mostly in the urinary tract and the prostate.
- alpha 1b found in vessels
Tamsulosin -> competitive selective ⍺1A antagonist used to treat benign prostatic hypertrophy
This drug has fewer cardiovascular side effects because it targets ⍺1A, and, ⍺1D. less on ⍺1B

68
Q

what is Finasteride ,and what is it used for ?

A

Finasteride – is a 5⍺-reductase inhibitor an enzyme that converts testosterone to DHT (Dihydrotestosterone). It is used to treat benign prostatic hyperplasia

69
Q

what is Prazosin ,and what is it used for ?

A

Prazosin – selective alpha 1 receptor antagonist. Relaxes both arterial and venous vascular smooth muscle, in the prostate there are also alpha-1-receptors, it also relaxes the smooth muscle in the prostate.

70
Q

what is Terazosin ,and what is it used for ?

A

Terazosin – reversible alpha-1-receptor antagonist that is effective in hypertension. It is also approved for BPH.

71
Q

what is Doxazosin ,and what is it used for ?

A

Doxazosin – is efficacious in the treatment of both hypertension and BPH. It has a longer half-life than both terazosin and prazosin, it is 22hours. Has active metabolites

72
Q

what is phentolamine ? and what is it used for ?

A

Phentolamine - nonselective alpha antagonist. Antagonises alpha 1 receptors. This reduces peripheral resistance.

73
Q

List adrenergic antagonists [10]

A

1.Finasteride
2.Doxazosin -alpha blocker
3.Prazosin
4.Terazosin
5.Tamsulosin
6.Phentolamine
7. Propranolol (Non-selective - β1 and β2)- B blocker
8. Atenolol (β1 selective) – ischaemic heart disease and hypertension -B blocker
9. Carvedilol (hypertension, stable congestive heart failure)-both
10.Labetalol (hypertensive crisis)- both

74
Q

list selctive direct acting adrenergic aginists and which recepto they actt on[7]

A
  • Oxymetazoline - A1
    -phenylephrine -A1
    -Clonidine -A2
    -Methyldope -A2
  • Dobutamine -B1
    -Salbutamol (short acting )-B2
  • Salmeterol (long acting )- B2
75
Q

what is phenylephrine used for ?

A

Phenylephrine - used in anaesthetics (particularly regional/spinal anaesthesia - where blockade of sympathetic outflow leads to vasodilation and drop in BP). PEP is selective for Alpha 1 receptors (virtually no Beta activity - no effect on cardiac inotropy or chronotropy) - causing peripheral vasoconstriction and raising BP. Also used in nasal decongestants.

76
Q

what is oxymetazoline used for ?

A
  • stimulates alpha 1 receptors in nasal mucosa and eye, causing vasoconstriction for relief of nasal congestion and ocular erythema. Worth noting that many agents that are alpha 1 - agonist have at least some mixed alpha and beta-agonistic activity
77
Q

what is Clonidine used for ?

A

stimulates A2 receptors in the brain stem ,which has inhibitory efect on sympathetic outflow outflow from CNS (responsible for negative feedback loop with resultant reduced NE release). Reduced sympathetic outflow leads to decrease in heart rate and blood pressure.
- not the typical sympathomemitic

78
Q

what is methyldopa used ?

A
  • similar to clonidine , it is a central acting anti hypertensie
  • it acts on the alpha1 receptors in the brain stem
  • which has an unhititory effectt on sympathetic outflow from CNS
    -(responsible for negative feedback loop with resultant reduced NE release). Reduced sympathetic outflow leads to decrease in heart rate and blood pressure.
79
Q

How does Dobutamine works ?

A

Synthetic analogue of dopamine. used primarily for cardiogenic shock (when cause of shock related to pump failure). Primarily stimulates beta 1 receptors in myocardium resulting in increased contractility (inotropic) > heart rate (chronotropic), without any vasoconstriction.

80
Q

what are salbutamol and Salmeterol used for ?

A

they are beta 2 agonists
- short acting -> Salbutamol
- long acting ->Sameterol
- used in treatment of asthma. Mechanism of action is bronchodilation via B2 receptor stimulation. Salbutamol also used in the prevention of preterm labour by reducing uterine contractions.

81
Q

list 3 indirect acting adrenergic agonist

A

1.Cocaine
2.Amphetamine
3.Tyramine

  • they increase BP and heart rate
82
Q

Explain the MOA of Cocaine

A
  • acts by encouraging release o endogenous NE,E or by increasing the levels at the synapse
    -Cocaine binds and blocks monoamine reuptake transporters (dopamine, norepinephrine, epinephrine and serotonin).
  • Monamines then accumulate in synaptic cleft with enhanced and prolonged sympathomimetic effect.
83
Q

what is the clinical importance of cocaine ?

A
  • Principle action of cocaine (and clinical use) is on the mucosa - causes vasoconstriction (previously used in treatment of epistaxis).
  • Systemic effects may occur via alpha and beta receptor stimulation leading to increase in systemic arterial pressure and myocardial contractility.
    Cocaine toxicity can precipitate myocardial ischaemia
84
Q

explain the MOA of amphetamines

A

-Amphetamines are CNS stimulants and indirectly acting sympathomimetics.
It increases the cytoplasmic NE by displacing NE at VMAT2 (vesicular monoamine transporter 2 that’s responsible for uptake into vesicles) and by slight inhibition of MAO (less MAO to metabolize catecholamines).
- Binds to presynaptic membrane transporters responsible for the reuptake of NE (NET) and reverses NE transport. Also affects dopamine via dopamine transporter (DAT) and serotonin reuptake transporter (SERT). There is uptake of amphetamine in exchange of NE release at the presynaptic membrane.
There is amphetamine uptake into vesicles in exchange of this efflux of monoamines with a resultant increase in the cytoplasmic pool of NE.

Net effect: Amphetamine increases the release of norepinephrine, dopamine and serotonin from nerve terminal into the synaptic cleft in the CNS.
This leads to central stimulant effects of wakefulness, euphoria, anorexia, hallucinations.
Peripheral effects include hypertension crises, tachycardia, cardiac arrhythmias and even death.

85
Q

Explain the mechanism of action of Tyramine

A
  • Mechanism of action:
    Tyramine is found naturally in foods. (Particularly fermented, aged, cured foods such as cheese)
    When consumed in large amounts causes CVS effects, via indirect catecholamine releasing properties.
    So called “cheese effect” refers to hypertensive crises after tyramine ingestion - rare.
  • MAO enzymes are responsible for metabolism/breakdown of tyramine and NE.
    Normally the bioavailability of dietary tyramine (present in red wine and cheese) is relatively low due to the expression of MAO in the GUT tract and liver.
  • However, in patients taking MAOi – monoamine oxidase inhibitors, MAO expression/availability is reduced.

Tyramine is taken up by NET transporter in exchange of NE. Tyramine can lead to increased release of NE, E and dopamine from the cytoplasmic pool, leading to increased adrenergic receptor stimulation which causes an increased heart rate, vasoconstriction and raised raised blood pressure.

86
Q

explain the clinical relavance of tyramine and the tyramine cheese reaction .

A

Clinical relevance:
Patients on MAOi – MONOAMINE OXIDASE INHIBITORS such as listed below,
Selegiline – MAOi used in -Parkinson’s
-Phenelzine
-Tranylcypromine
when exposed to tyramine-containing products such as cheese, wine, other fermented products can result in a hypertensive crises also called ‘The Tyramine Cheese Reaction’.

87
Q

Sympathomimetics or Adrenergic agonists: very important class of drugs in management of cardiovascular and respiratory diseases.
Can function in 3 ways: explain these 3 ways

A

(target receptors alpha and beta receptors)
1. Indirectly by enhancing release of NE/catecholamines from vesicles.
2. Direct acting. Directly activate the adrenoceptors mimicking the action of NA/A. This category includes catecholamine and non-catecholamines. Examples of non-catecholamines are alpha 1 and 2 agonist, beta agonists. Catecholamines can be endogenous (NE, E, Dopamine) or synthetic.
3. Mixed acting , acts both directly and indirectly.

88
Q

explain how MOA of beta blockers is beneficial in pts with heart ailure with reduced ejection fraction

A

They reduce the detrimental efct from catecholamine stimulation
1. Reduction in detrimental effects of catecholamines on myocardium. Restoration of beta receptor responsiveness, chronic beta receptor stimulation reduces responsiveness to beta agonist due to down regulation and desensitisation of receptor and its signalling pathways. Beta blockade up regulates myocardial beta 1 receptor density in patients with heart failure, helping to restore inotropic and chronotropic responsiveness of the myocardium and improving contractile functioning.

2.Heart rate lowering - which is a therapeutic target. Since patients with elevated HR, have worse CVS outcomes. Detrimental effects of elevated HR, include HR related increases in myocardial energy demands and decreased myocardial perfusion.
Improving the balance of myocardial supply and demand (esp in ischaemic cardiomyopathy). Improves function in regions of hibernating myocardium by reducing myocardial oxygen consumption and increasing diastolic perfusion.
3. Beta blockade acutely depresses cardiac function due to decreases in SV and HR (hence contraindication in acute HF). But when given chronically to patients with HF,
4. improves cardiac structure and function. It has a beneficial effect on reversal of LV remodelling.
Reduction of vasoconstrictor levels - normally vasoconstriction increases afterload and therefore the rate of progression of cardiac dysfunction.
5. Decrease frequency of ventricular premature beats and incidence of sudden cardiac death. , decrease likelihood of development of atrial fibrillation.

pharmacology (12 decks)

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