Autonomic Nervous System Flashcards
ANS Pharmacology
The study of drugs that act on receptors and neurotransmitters in the ANS to alter nervous system function.
Drugs acting on the ANS are important in the treatment of which diseases?
- eye
- cardiovascular system
- respiratory tract
- GI and urinary tract
What are the 2 branches of the Nervous System?
- Central (brain and spinal cord)
2. Peripheral (Somatic and autonomic)
Describe the Peripheral Nervous System.
Efferent Neurons (Motor) and Afferent Neurons (Sensory) -Efferent Nervous system divided into somatic (conscious) and autonomic (unconscious)
What are the 3 divisions of the ANS?
- parasympathetic
- sympathetic
- enteric- collection of neurons that regulates the GI tract
How do ANS fibers interact with their target neurons (3 steps)?
- cell body of the first neuron resides in brain/spinal cord (pre-ganglionic neuron)
- pre-ganglionic neuron synapses w/ post ganglionic neuron in a ganglia (autonomic ganglion)
- ganglionic neuron innervates the target organ (cardiac muscles, smooth muscles, exocrine glands)
In what 3 ways do the PNS and SNS differ in their organization?
- Preganglionics in different regions of CNS
- Different location of ganglia
- Different lengths of preganglionic fibres
SNS v PNS: From what region of the CNS do the preganglionics originate?
PNS-cranial and sacral SC region
SNS-thoracic and lumbar SC region
SNS v PNS: Where is the ganglia located?
PNS-close to target tissue
SNS-close to spinal cord in a chain
SNS v PNS:What length is the pre-ganglionic fibre?
PNS-long
SNS-short
How do SNS and PNS affect the heart?
SNS= increased rate and contractility
PNS=decreased rate
How do SNS and PNS affect the intestine?
SNS=decreased motility
PNS=increased motility
How do SNS and PNS affect the pupil?
SNS=dilate
PNS=constrict
How do SNS and PNS affect the respiratory system?
SNS=bronchodilation
PNS=bronchoconstriction
How do SNS and PNS affect the LUTS?
SNS= stimulates ejaculation/voiding
PNS=stimulates erection/voiding
Explain PNS neurotransmission?
- Releases Ach at autonomic ganglion, neuronal nicotinic R
- releases Ach at post ganglionic neuron, muscarinic R
- affects cardiac and smooth muscle, gland cells, nerve terminals
Draw out diagram of SNS transmission-include neurotransmitters and receptors.
See ANSI lecture
Explain ANS regulation in the eye
PNS: Ach causes sphinctor pupillae to contract-Miosis
SNS: Noradrenaline cause dilator pupillae to contract-Mydriasis
Explain organ level integration of the ANS.
See ANSII
Cholinergic Agonists
-drugs that mimic the action of Ach at cholinergic R and increase PNS responses
Cholinergic Antagonists
-drugs that inhibit the action of Ach at cholinergic R and decreases PNS response
Cholinergic Receptors (2)
- muscarinic-high affinity for muscarine, low affinity for nicotine
- nicotinic-high affinity for nicotine, low for muscarine
Acetyl cholinesterase
-breaks down Ach in the synaptic cleft, choline is recycle back to axon terminal
Draw the pathway for cholinergic neurotransmission.
See ANSII
Vesamicol
Inhibits Ach uptake into synaptic vesicles
Botulinum toxin
Inhibits vesicular release of Ach
Describe the Muscarinic Receptor Subtypes (3)
M1: CNS, ANS
M2: acts on heart, decreased heart rate
M3: smooth muscle contraction, exocrine gland-increased secretion
Describe the Nicotinic R Subtypes (2)
Nn: Autonomic ganglia- stimulate both SNS and PNS Adrenal Medulla-releases Adr/NA Nm: skeletal muscle contraction
Muscarinic Agonists
-activate muscarinic R directly
What is a non-selective muscarinic agonist?
ACh
-dont see long duration of action due to ACh esterase
What is a selective muscarinic agonist (2)?
- muscarine
- pilocarpine
What is a synthetic analogue of Ach?
-bethanechol
What are uses of direct muscarinic antagonists?
- stimulate tone in bladder after surgery
- increase gut motility
- glaucoma
How do muscarinic agonists work in the treatment of glaucoma?
Activate M3 receptors on the ciliary muscle to cause contraction and increase fluid drainage
What are the side effects of muscarinic agonists (5)?
- stimulate all muscarinic R
- GI disturbances (eg nausea and vomiting)
- miosis
- effects on heart rate (bradycardia)
- salivation and bronchoconstriction
* overstimulation of the PNS
Muscarinic Antagonists
-bind to muscarinic R preventing Ach from binding
Give 2 examples of muscarinic antagonists.
Atropine-naturally occurring alkaloid
Ipratropium bromide-synthetic analogue
3 Uses of Atropine
- Dilate eye pupil for ophthalmic exam
- treat bradycardia
- to reduce secretion during surgery
What is the effect of muscarinic agonist on the eye?
- ciliary muscles contract
- refractive power of the lens increases, able to focus on near
- miosis
What is the effect of muscarinic antagonist on the eye?
- block the PNS
- make the lens thinner for far vision
- mydriasis
Uses of ipratropium bromide (Atrovent)
- to reduce cholinergic bronchoconstriction
- non-selective for all muscarinic subtypes (i.e. M1-M3)
- used to treat asthma and COPD
Name 2 nicotinic agonists?
Nicotine-selective
Non-selective-Ach
What are the uses of nicotinic agonists?
- to treat nicotine addiction
- patch, gum aerosol
What are the side effects of nicotinic agonists?
- CNS
- tremor, convulsions, coma
Ganglionic Blockers
- nicotinic R antagonist
- block nicotinic nerve R at autonomic ganglia
- not used
Neuromuscular Blockers
-block nicotinic muscle receptors at the neuromuscular junction on skeletal muscles
What are the 2 classes of neuromuscular blockers?
- Non-depolarizing (competitive) antagonists
2. Depolarizing (non-competitive) antagonists
Non-depolarizing (competitive) nicotinic antagonists
- binds in the place of Ach, doesn’t cause sodium influx
- can overcome blockade using acetylcholine esterase inhibitor
Curare
- Non-depolarizing (competitive) nicotinic antagonist
- used to produce skeletal muscle paralysis during surgery and in ICU
- side effects = paralysis
- selective at the neuromuscular junction, doesn’t bind at the ganglion due to differences in structure
Depolarizing (non-competitve) nicotinic antagonists
- binds in the place of Ach and remains bounds
- causes depolarization
- receptor becomes desensitized
Succinylcholine
- Depolarizing (non-competitve) nicotinic antagonist
- used to produce skeletal muscle paralysis during surgery and in ICU
- takes time to wear off
Cholinesterase Inhibitors
Enhance duration of action of Ach by prevent its metabolism in the synapse
Reversible cholinesterase inhibitors
- weakly bind Ach esterase
- neostigmine and physostigmine
Uses of Reversible cholinesterase inhibitors (3)
- loss of tone in bladder and gut (increases gut and bladder motility)
- glaucoma (same as muscarinic agonists)
- myasthenia gravis
What are side effects of reversible cholinesterase inhibitors?
- same as for direct muscarinic agonists
- salivation, miosis, bronchocontriction, bradycardia
Irreversible Cholinesterase Inhibitors
-covalent bond w/ Ach esterase
Pralidoxime
-compound that can break down covalent bond of irreversible cholinesterase inhibitors
Treatment for irreversible cholinesterase inhibitors
- support respiration
- decontamination
- use muscarinic antagonist (atropine)
- use pralidoxime
Examples of irreversible cholinesterase inhibitors (2)
- insecticides (parathion and malathion)
- nerve gases (sarin)
Effects of irreversible cholinesterase inhibitors
- effects at both muscarinic and nicotinic R
- initial signs are muscarinic (bronchoconstriction, salivation, GI symptoms)
- followed by central and peripheral nicotinic signs (e.g. persistent activation of skeletal muscle, paralysis)
Adrenergic Agonists (sympathomimetics, adrenergics)
Mimic the action of epinephrine and norepinephrine at adrenergic R, increases SNS responses
Adrenergic Antagonists (sympatholytics, antiadrenergics)
Inhibit the action of NA at adrenergic receptors and decrease SNS responses
Localization of Adrenergic R
- alpha1 and beta2 on smooth muscle
- beta1 in heart
- alpha1 and beta2 on blood platelets, adipose, endocrine tissue
- alpha2 on presynaptic terminal of sympathetic neuron
Draw the pathway for adrenergic neurotransmission
ANS III
Cocaine
Inhibits NE reuptake
Amphetamine
Stimulates release of NE
What are the 3 ways that adrenergic agonists mimic the actions of NE?
- Direct acting
- Selective
- Indirect acting
Direct Acting Adrenergic Agonists
Non-selective -bind to pre or post synaptic adrenergic Rs eg NE (alpha1, alpha2, beta1)
Phenylephrine
-direct adrenergic alpha1 agonist
What is phenylephrine used to treat (3)?
- Nasal congestion
- constricts blood vessels in nasal mucosa - to dilate pupils
- activates alpha1 R on iris radial muscle - combine w/ local anaesthetic
- to constrict blood vessels and prolong nerve block
What is a side effect of phenylephrine?
-can increase bp due to vasoconstriction
SNS regulation of Vascular tone
NE acts on alpha1, causes vasoconstriction
- circulating epinephrine for adrenal medulla causes vasodilation mediated by beta2R
- ANSIII diagram
Direct Alpha2 agonists
- alpha2 R (autoreceptor) on pre-synaptic nerve terminal
- decreased NE release via inhibition of adenylate cyclase and cAMP signalling
clonidine
- direct alpha2 agonist
- has CNS actions
- used to treat hypertension by reducing SNS outflow from the brain to the periphery
- side effects are sedation
Direct beta1 agonists
- acts in the heart
- increased Ca influx
- increased force of contraction cardiac muscle
- dobutamine
Direct beta2 agonists
- beta2 in airway smooth muscle
- decreased contraction of smooth muscle (bronchodilation)
- salbutamol
Direct Adrenergic Agonists (at multiple subtypes)
-adrenaline
What is adrenaline used to treat? How?
- anaphylaxis
- activates alpha1 R in vascular smooth muscle and beta1 R in cardiac muscle to increase cardiac output, leading to increased BP
- reduces mucous membrane congestion by activating alpha1
- activates B2 in smooth muscle of respiratory system
What are the 2 mechanisms of indirect adrenergic agonists?
- inhibition of reuptake (cocaine)
2. cause release of NE (amphetamine)
Cocaine
- indirect adrenergic agonist
- blocks reuptake
- useful as local anaesthetic in nasopharyngeal surgery (blocks sodium channels in nerves)
What are the side effects of cocaine?
- powerful CNS stimulant
- increased HR, bp, force of contraction
- arrhymias due to Ca influx into tissue
Amphetamine/Ephedrine
- indirect adrenergic agonist
- causes release of noradrenaline from sympathetic nerve terminals
What is the mechanism of action of amphetamine?
- amphetamine and NE taken up by same transporter
- increases presence of cytosolic NE in the pre-synaptic nerve terminal, NE can’t be stored
- Monoamine transporter works in reverse and moves NE into synapse
What is amphetamine used to treat?
- narcolepsy, ADHD
- appetite suppressant
Tyramine and the Cheese Reaction
- by product of tyrosine metabolism can be produced in protein rich foods
- metabolized by MAO in liver
- indirect agonist causing release of stored NE
- inhibition of MAO produces increased tyramine levels and release of NE
- patients taking MAO inhibitors (depression) must avoid tyramine rich food to prevent high bp
Phentolamine
- alpha adrenergic antagonist
- non selective for alpha1 and 2
- increased heart rate b/c NE can still act on beta2
Prazosin
- alpha adrenergic antagonist
- selective for alpha1
- used to treat high bp b/c doesn’t block alpha2 so NE can still feedback
Propanolol
- direct beta antagonist
- non selective
Metropolol
- direct beta antagonist
- cardioselective, beta1
What are the uses of metropolol and propanolol?
- high bp, angina, arrhythmias
- glaucoma, decrease aqueous humour secretion in the eye
What are the side effects of metropolol and propanolol?
- exercise tolerance
- asthma
Beta AR blockers and glaucoma
- aqueous humour is secreted by the ciliary epithelium
- beta AR blockers act at Beta AR receptors on the epithelium and decrease aqueous humour secretion leading to a decreased pressure in the eye
- used topically so non selectivity is ok
