Pharm Autonomic I (7)
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7 - Autonomic Pharmacology I
- two cell types, endothelial cells & pericytes, that surrounded most areas of the brain & spinal cord (+ mast cells…)
- it prevents many harmful chemicals, environmental toxins AND NTs, hormones, or medications from entering the brain
- it regulates the flow of nutrients and ions into and out of the brain through a system of cellular transport mechanisms
What type of molecules pass most readily through the BBB?
lipophilic, small, and/or tend not to have a high electrical charge
Autonomic Nervous System
- the part of the peripheral nervous system that innervates ALL organs of the body acts as a control system, functioning largely below the level of consciousness to control visceral functions
- it affects heart rate, digestion, respiratory rate, salivation, perspiration, pupillary dilation, micturition (urination), & sexual arousal
- can be divided into 2 subsystems: PSNS & SNS
the relay stations between neurons that run through the sympathetic & the parasympathetic systems
ganglia of the parasympathetic nervous system
- located in close proximity to the end/effector organs (the first neuron is LONG and the second neuron is SHORT)
ganglia of the sympathetic nervous system
- form a chain, with divisions that occur closer to the spinal cord and farther from the end organs (first neuron is SHORT and second neuron is LONG)
Which NT & which receptor function at sympathetic nervous system ganglia?
- NT = acetylcholine (ACh)
- receptor = nicotinic
What are the eventual effector receptor types, NTs that work at said receptors, and the organ systems innervated in the post-ganglionic sympathetic nervous system?
- norepinephrine -> cardiac muscle, smooth muscle, & glands
- *norepinephrine is the main NT that innervates effector organs
- acetycholine activates muscarinic receptors on sweat glands, skeletal muscle, & blood vessels
How does the sympathetic nervous system stimulate the adrenal medulla?
- directly - there is no intermediate ganglion
- the NT acetylcholine (ACh) acts on nicotinic receptors on the adrenal medulla
- the adrenal medulla in turn releases norepinephrine or epinephrine
Which NT & which receptor function at parasympathetic nervous system ganglia?
- NT = acetylcholine (ACh)
- receptor = nicotinic
What is the eventual effector receptor types, NT that works at said receptor, and the organ systems innervated in the post-ganglionic parasympathetic nervous system?
- acetycholine activates muscarinic receptors on cardiac muscle, smooth muscle, & glands
- aka in the neuromuscular junction
SNS + PSNS Innervation Overview
What neurotransmitter functions at the preganglionic synapse for all autonomic nervous system neurons?
- acetylchonine (ACh) at nicotinic receptors
- *ganglionic nicotinic receptors are different than neuromascular junction receptors even though both respond to ACh
What does activation of the PSNS (parasympathetic nervous system) cause?
- constriction of the Pupils & Bronchi
- increased detrusor muscle activity (bladder wall)
- reduced heart rate
- increased tear & saliva production
- increased GI peristalsis
- increased sphincter tone
- increased blood flow to the GI tract
- the 2 glands are considered part of the sympathetic nervous system b/c they release epinephrine
- this release is unlike what occurs with the localized release from nerves close to an end organ because adrenals release it into the blood & it's carried throughout the body, acting like a hormone
Which has a greater affect on the body, the sympathetic nervous system or the parasympathetic nervous system?
- because it innervates the two adrenal glands, the output of the sympathetic division generally outweighs the output of the parasympathetic division
- epinephrine acts like a hormone instead of just NTs acting directly at neuromuscular junctions
What does activation of the sympathetic nervous system (SNS) cause?
- dilation of Pupils & Bronchi
- reduced detrusor muscle activity
- increased heart rate
- constriction of blood vessels
- increased blood pressure
- reduced gastrointestinal peristalsis
- piloerection (goose bumps)
Urinary Bladder Function & the ANS
- SNS: INHIBITS URINATION by relaxing the detrusor muscle so more urine can be accommodated & constricting the urinary sphincter which closes off bladder so urine can't be released
- PSNS: PROMOTES URINATION by constricting the detrusor muscle so less urine is accommodated & relaxing the urinary sphincter which opens the bladder so urine can be released
- (the end organ effects of parasympathetic or sympathetic innervations are often the opposite of each other)
Pupillary Function & the ANS
- NE: dilates pupils [SNS] through the superior cervical ganglion
- ACh: constricts pupils [PSNS] through the ciliary ganglion from the 3rd cranial nerve
What could cause unilateral pupil constriction on the affected side?
a lung tumor that blocks neuronal transmission (signaling pupil dilation)
“Bella dona” Alkaloids
dilates the pupil by blocking the action of acetylcholine (which normally constricts the pupil)
an enzyme that can degrade ACh once it's released into a synaptic cleft in both the parasymptathetic division or at a neuromuscular junction
- drugs that interfere with the effects of ACh by ANTagonizing receptors for acetylcholine, most commonly muscarinic (end-organ)
- eg. Atropine
- antihistamines (drugs that antagonize histamine receptors) can also antagonize muscarinic receptors
- eg. diphenhydramine (Benadryl)
Acetylcholine Receptor Antagonists
- Atropine: inhibits ACh-muscarinic receptors & treats AChase inhibitor overdose (too much ACh so it blocks the receptors it acts on)
- Tubocurarine: inhibits Ach-nicotinic (NMJ) receptors, causes flaccid paralysis, & is used for pre-op muscle relaxation
- Trimethaphan: inhibits Ach-nicotinic-ganglia receptors, & treats Malignant Hypertension
What are common symptoms of muscarinic receptor antagonism?
- dry mouth
- blurred vision
- urinary retention
- impaired cognition
Clostridium Botulinum Toxin
- inhibits ACh release -> causing flaccid paralysis
- [tetanus causes spastic paralysis]
neuromuscular blockers (NMBs)
interfere with nicotinic acetylcholine receptors located at neuromuscular junctions of the somatic motor system
- such agents bind competitively to nicotinic receptors & produce antagonism and flaccid paralysis
- blocking the binding of ACh to its receptors
- constitute the majority of the clinically relevant NMBs
- eg. tubocurarine, atracurium
- drugs that bind non-competitively to AChRs, depolarizing the plasma membrane of skeletal muscle fibers
- this produces overstimulation & spastic paralysis of muscle
- eg. succinylcholine
- drugs that mimic the action of ACh by either
- 1. acting like agonists at ACh receptors
- 2. inhibiting cholinesterase so ACh isn't degraded/sticks around longer (eg. organophosphates, or snake venom)
- a cholinomimetic drug that acts directly as a ACh agonist to promote gastrointestinal motility (useful after surgery)
- mimics ACh to treat "lazy gut syndrome"
- is administered orally
- a cholinomimetic drug that is a direct ACh agonist used for the treatment of glaucoma
- in eye-drop form it promotes drainage of the aqueous humor which lowers intraocular pressure
- constricts pupils during surgery or decreases pressure inside the eye after surgery
- a direct ACh agonist that stimulates sweat glands
- in a sweat test the concentration of chloride + sodium excreted in the sweat is used to diagnose cystic fibrosis
- is also sometimes administered as an oral tablet to promote saliva production in patients with dry mouth (eg. Sjogren’s syndrome)
- it's a cholinomimetic drug
- a non-selective muscarinic receptor agonist in the parasympathetic nervous system used to diagnose asthma
- causes pulmonary contraction so O2 capacity can be measured
- a cholinomimetic drug
- a depolarizing neuromuscular blocker that acts on nicotinic receptors resulting in persistent depolarization of the motor end plate
- it causes spastic paralysis & is used for pre-op muscle relaxation, intubation
- a cholinomimetic drug
- an autoantibody is made to the acetylcholine receptor (AChR) on muscle cells
- said Ig binds to the receptor & BLOCKS binding of acetylcholine (an NT) --> as result there can be no muscle activation
- additionally, the autoantibody induces complement activation, resulting in damage to the muscle end-plate destroying AChRs as the disease progresses; also the muscle cell itself phagocytoses the antibody-receptor complex, destroying AChRs
What type of drug is used to treat Myasthenia gravis?
- cholinesterase inhibitors (cholinomimetic drugs eg. edrophonium, neostigmine, pyridostigmine)
- without functional receptors, ACh cannot stimulate muscle leading to flaccid paralysis
- blocking acetylcholinesterase allows ACh to stay in the synapse longer & find a still-active receptor to bind + activate
- immune suppressors (azathioprine, Imuran) are also given to reduce the production of anti-AChR autoantibodies
- when a patient with myasthenia gravis presents with flaccid paralysis due to lack of sufficient treatment
- aka no Ach is stimulating neuromuscular receptors because of blocked receptors or a lack of receptors
- when a patient with myasthenia gravis presents with spastic paralysis due to too much ACh often accompanied by bradycardia & hypersalivation
- aka receptors are excessively stimulated due to too much Ach hanging around in synaptic junctions stimulating neuromuscular receptors
- (over-inhibition of acetylcholinesterase can lead to this as well)
How can you differentiate a patient in myasthenic crisis from one in cholinergic crisis?
- by giving Edrophonium, a short-acting AChase inhibitor
- this will only improve the patient in myasthenic crisis (aka it replenishes any working receptors w/ ACh)
- it will worsen the symptoms of cholinergic crisis, which can be alleviated by treatment w/ an anticholinergic medication (atropine)
- an AChase inhibitor that crosses the blood-brain-barrier useful for treating overdoses with anticholinergic medications that have large volumes of distribution
- is a type of cholinomimetic drug
- AChase inhibitors (so cholinomimetic) that can produce spastic paralysis
- the active ingredients in most insecticides (eg. parathion, malathion)
- can also be found in chemical warfare nerve gases (sarin)
What is the antidote for human poisoning due to organophosphates?
an anticholinergic drug (eg. Atropine) plus a medication that works to help restore Achase activity, pralidoxime (2-PAM)
What is one of the most common cause of pediatric poisonings due to accidental ingestion?
Organophosphates - in raw form they look similar to flour
What are the primary neurotransmitters of the autonomic nervous system?
- SNS NTs: dopamine, norepinephrine, & epinephrine
- tyrosine is the precursor for catecholamine synthesis
- Tyrosine -> Dopa -> DA -> NE -> EPI
Steps of Catecholamine Secretion
- 1. tyrosine is actively taken up into neurons via pump
- *tyrosine hydroxylase is rate-limiting step in catecholamine synthesis
- 2. NE & DO are formed in the cytoplasm
- 3. they're actively transported into secretory vesicles
- 4. NE is transported back into the cytoplasm & methylated to EPI, which is taken back up into the vesicles (occuring in the adrenal medulla)
- 5. NE is released via vesicular exocytosis (Ca2+ and energy dependent; Mg2+ inhibits)
- 6. NE binds to pre- & post-synaptic receptors
- 7. NE is actively reuptaken into neurons from synaptic
- 8. catabolism of NE & DO done by MAOs
Monoamine oxidase (MAO)
- enzyme primarily involved in the degradation of
- 1. dopamine
- 2. norepinephrine
- 3. epinephrine
- (monoamine-containing neurotransmitters of the SNS)
- 4. serotonin
- [which isn't a SNS NT, but is a monoamine containing NT degraded by MAO]
- MAO works in the cytoplasm of neurons after NT have been re-uptaken
What are the primary receptors for norepinephrine & epinephrine?
- alpha and beta receptors
- norepinephrine has a higher affinity for alpha receptors
- epinephrine has a higher affinity for beta receptors
- both may stimulate both types of receptors
- when stimulated: heart rate, contractility, & blood pressure increases
- when antagonized: heart rate, contractility, & blood pressure will decrease (eg. with a beta-blocker such as propranolol or metoprolol)
- a medication that's converted by decarboxylase enzymes to dopamine
- is helpful in the treatment of Parkison’s disease
- is given in conjunction with carbidopa because dopamine does not cross the BBB
- a drug given in conjunction with levodopa to maximize entry of levodopa into the brain
- it's a periperal decarboxylase INHIBITOR that doesn't cross the BBB
- it's presence prevents any L-dopa from being converted to dopamine outside the BBB
- a sympatholytic that reduces the endogenous synthesis & release of norepinephrine
- acts as anti-hypertensive therapy b/c it lowers NE, which increases blood pressure
How does norepinephrine increase blood pressure?
NE stimulates alpha-1 receptors which increases peripheral vascular resistance
- when those located on the surface of presynaptic neurons are stimulated they undergo auto-inhibition
- aka they SUPPRESS the release of NTs - mostly norepinephrine - from that neuron
- an alpha-2 receptor agonist; a sympatholytic that auto-inhibits the release of norepinephrine from a presynaptic neuron
- used to reduce blood pressure
What type of drugs should be avoided with clonidine?
- antidepressants that block norepinephrine reuptake into presynaptic neurons by inhibiting the membrane pump
- such drugs mixed w/ clonidine negate each other’s actions
What other substances preventing the reuptake of NE into presynaptic neurons?
- stimulant drugs - amphetamines, cocaine, & some nasal decongestants
- some are also weak agonists of AChRs
What is the fate of catecholamines after being released from a presynaptic neuron?
- the transmitter either binds to post synaptic receptors or is taken up in the pre-synaptic area by a pump
- some antidepressants act by inhibiting this pump (preventing reuptake of NTs) which provides higher levels of NTs in the synaptic cleft
- block both serotonin & norepinephrine reuptake into presynaptic neurons by inhibiting the membrane pump
- eg. amitriptyline (Elavil) or imipramine
selective serotonin reuptake inhibitors (SSRIs)
- antidepressants that block serotonin reuptake into presynaptic neurons by inhibiting the membrane pump
- eg. fluoxetine (Prozac)
Monoamine Oxidase (MAO) Inhibitors
- work by preventing catecholamine breakdown by mitochondrial MAO in the cytoplasm --> increasing amount of NT in the synaptic cleft
- medication used to treat depression
- eg. Phenelzine (Nardil)
a molecule found in many food products (aged cheeses, red wine, dark beer) that displaces NE or EPI from synaptic vesicles but has very little action on receptors once secreted from the vesicle
How can someone taking MAO Inhibitors go into hypertensive crisis if tyramine is ingested?
- MAO inhibitors would prevent catecholamine breakdown, resulting in an excess of synaptic catecholamines
- the presence of tyramine could obstruct any catecholamine breakdown that would occur in its absence, leading to overstimulation of receptors by NE
- excessive NE increases blood pressure, & if severe = hypertensive crisis
- patients prescribed MAO inhibitors are instructed to avoid tyramine-containing foods + sympathomimetics (medications that stimulate the sympathetic nervous system)
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