Autonomic pharm Flashcards
Neurotransmitter
Small amounts released from the nerve terminals into the synaptic cleft
Action of neurotransmitter
Activates or inhibits the postsynaptic cell by binding to a receptor molecule
The cholinergic junction
- small vesicles contain Ach
- Ach synthesized within neuron
- Released is dependent on extracellular calcium
- metabolized by acetylcholinesterase.
structure of parasympathetic system
- very long, pre synaptic fibers, shorter post synaptic neuron in tissue
- normally not seen with ganglia.
structure of sympathetic system
-short pre synaptic fibers, to ganglia, and long post synaptic fibers that go to organs.
Sympathetic neurotransmitter
Norepinephrine
Parasympathetic neurotrnasmitter
Acetylcholine.
describe the somatic nervous system
- voluntary
- long fibers run from spinal cord to muscle tissue.
What are the 2 networks that make up plexus
- Myenteric plexus and submucosal plexus;.
How many cholinorecptors are there, and what are the types?
7 receptor types, 5 are muscarinic and 2 are nicotinic.
What determines agonist selectivity?
Is determined by the subtypes of muscarinic and nicotinic receptors present in a given cell.
What are catecholamines?
Neurotransmitters or drugs that affect the sympathetic nervous system
What is tyrosine?
A neurotransmitter where all catecholamines are synthesized.
Biosynthesis of catecholamines
- Tyrosine turns into dopa, which turns into dopamine and gets stored.
- When it is activated, it joins cell membrane and releases dopamine into synapse.
- End result is NE or epinephrine
- go to receptors on post synaptic membrane.
The Noradrenergic junction
- Release process similar to that of cholinergic terminals.
- NE is released with ATP, dopamine, peptide cotransmitters
Termination of noradrenergic transmission results from:
- Diffusion away from the receptor site with eventual metabolism in the plasma or liver
- Ruptake into the nerve terminal by NET (norepinephrine transporter)
Conversion of tyrosine to dopa can be inhibited by the ______
-tyrosine analog metyrosine
VMAT can be inhibited by ________
-reserpine, resulting in depletion of transmitter stores
NET can be inhibited by _________
-cocaine and tricyclic antidepressant drugs, resulting in an increase of transmitter activity in the synaptic cleft.
Release of NE blocked
guanethidine & bretylium.
What does a drug blocking a neurotransmitter do?
Decrease sympathetic function
How do antidepressants work?
Block reuptake, drug sits in synapse longer, and serotonin (etc) sits in the synapse longer, providing lasting effect.
Indirectly acting & mixed sympathomimetics can cause release of stored_____
NE
How many adrenoceptors are there?
Five. 2 alpha, and 3 beta
What are nonadrenergic, noncholinergic neurons?
Autonomic effector tissues contain nerve fibers that do not show no characteristics of cholinergic or adrenergic fibers.
- Both motor and sensory NANC fibers are present
- peptides are the most common transmitter substances found in these nerve endings
- they are poorly understood
Autonomic function is _____ and _____ at many levels, from the CNS to the effector cells.
Integrated, regulated
Important cooperative interactions occur between the parasympathetic and sympathetic systems at the level of the
Brain stem, medulla, and spinal cord.
Most regulation uses____
negative feedback. Negative feedback is particularly important in the responses of the ANS to the administration of autonomic drugs.
The sympathetic nervous system directly influences 4 major variables:
- Peripehral vascular resistance
- Heart Rate
- Force
- Venous tone
- Also directly modulates renin production.
The parasympathetic nervous system directly influences:
- Heart rate.
- stimulating aldosterone secretion
Choline esters
- hydrophillic
- poorly absorbed
- poorly distributed into CNS
- hydrolyzed in GI tract
Tertiary Cholinomimetic Alkaloids
Well absorbed from most sites of administration
-Nicotine is sufficiently lipid-solute to be absorbed across the skin.
Activation of the parasympathetic nervous system modifies organ function by 2 major mechanisms:
- Ach muscarinic receptors on effector cells to alter organ function directly.
- Ach interacts with muscarinic receptors on nerve terminals to inhibit the release of neurotransmitter (auto inhibition)
In what 2 ways do muscarinic receptors work?
By increasing second messengers or open ion channels.
Muscarinic signaling
- Ach is released from post-ganglionic cholinergic axon, act interacts with M2 receptor on a SA node cell, and opens K+ channels.
- Ach acts on an axonal muscarinic receptor to cause inhibition of Ach release.
Nicotinic agonists
- Nicotinic receptor binding opens ion channels that allow sodium and potassium ions to diffuse rapidly down their concentration gradients
- Cause depolarization of the nerve cell or neuromuscular end plate membrane
- paralytic drugs- paralyzing skeletal muscle.
Nicotinic signaling
- Ach released from the motor nerve terminal
- Ach interacts with subunits of the nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential.
- The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction.
Nicotinic agonists
- Prolonged agonist receptor occupancy abolishes the effector response
- prevents electrical recovery of the post junctional membrane cause “depolarizing blockade”
CNS effects of cholinergic agonists
- CNS contains both muscarinic and nicotinic receptors
- M1 receptors richly expressed in brain areas involved in cognition.
- nicotine stimulates the Ach receptors on dopamine-containing neurons: causes release of dopamine in the mesolimbic system
Indirect-acting cholinomimetics: Mechanism of action
- Ach actions are terminated by acetylcholinesterase
- indirect acting cholinomimetics exert their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors.
Hydrolytic enzyme presents in cholinergic synapses, 2 step process:
- Ach binds to the enzymes active site and is hydrolyzed, yielding free choline and the acetylated enzyme.
- The covalent acetyl-enzyme bond is split, with the addition of the water (hydration), producing choline and acetic acid.
How to irreversible agents work?
-By taking enzyme out of activity.
What is myasthenia gravis
An autoimmune disease affecting skeletal muscle neuromuscular junctions.
- Autoantibodies produced against the alpha 1 subunits of the nicotinic receptor.
- Severe disease may affect all the muscles, including respiratory.
- very sensitive to some drugs, such as curariform drugs.
MG clinical findings:
Ptosis(upper eyelid drooping), diplopia(double vision), difficulty speaking/swallowing, extremity weakness
Which are preferred in myasthenia graves therapy, cholinesterase inhibitors or direct acting acetylcholine receptor agonists?
Cholinesterase inhibitors
Diagnosis of myasthenia gravis
- Edrophonium.
- If patient has MG, an improvement in muscle strength that lasts about 5 minutes can usually be observed.
How does edrophonium work?
- Inhibits acetylcholinase
- when given, symptoms should improve because each competes with antibodies for receptor, by increased Ach, likelihood of binding act to receptor should increase and symptoms should improve
Why receptors are effected by myasthenia graves
nicotinic
Treatment of myasthenia graves
- long term therapy usually accomplished with pyridostigmine, neostigmine is an alternative.
- relatively short acting
- muscarinic side effects can be controlled with antimuscarinic drugs
How to determined difference between severe MG vs. Excessive drug therapy
-Give edrophonium, if nothing happens…drug problem
Alzheimer’s disease
A progressive, fatal neurodegenerative disorder manifested by: cognitive and memory decline, progressive impairment of activities of daily living, neuropsychiatric and behavioral symptoms.
Hallmarks of AD
- Deposition of neurofibrillary tangles
- Beta- amyloid plaques
Cholinergic hypothesis
- Proposes that AD is caused by reduced synthesis of acetylcholine
- Cholinergic neurons play a key role in memory and attentional function
- blockade of muscarinic cholinergic receptors result in cognitive dysfunction
- Widespread, progressive decline
- Decreased ACh synthesis
AD treatment options
-Acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine), NMDA receptor antagonists (memantine).
What kind of receptor are muscarinic receptors?
G protein- coupled receptors.
What do muscarinic antagonists do?
Block the effects of parasympathetic autonomic discharge.
What type of selectivity are antimuscarinic agents?
Non-selective, some newer agents are modernly more selective.
tertiary amines
- Lipophillic
- Most are well absorbed from GI tract and conjunctival membranes
- Widely distributed in the body
Quaternary amines
- Hydrophilic
- Distributed poorly into the CNS: limited ability to cross the blood brain barrier.
Anticholinergic side effects:
Decreased secretions (dry mouth), slow GI motility (constipation) urinary retention, dry eyes, visual distance.
Overactive bladder
Urgency (with or without urge incontinence)
Urgency= defined as a sudden and complaing desire to pass urine that is difficult to defer.
Nocturia= defined as walking one or more times per night to void urine.
Frequency definition
-Urination >8 times per
How many receptors have been identified in the bladder?
All 5
OAB SNS factor
-As bladder begins to fill & tension in bladder wall increases, activates spinal reflex pathways in the brainstem.
OAB PNS -
Responsible for bladder contraction and bladder outlet relaxation, mostly quiescent throughout the process of bladder filling.
Antimuscarinic agents in OAB
- Emerging evidence suggests competitive antagonism at urothelial muscarinic receptors during bladder filling (storage phase), decreasing urge and increasing bladder capacity
- Focus on M3 receptors
Darifenan is specific to ____
M3
Pathophysiology of Nonneurogenic OAB
- Excessive Ach release from urothelium during bladder filling
- Increased sensitivity of detrusor receptors to Ach
Pharmacotherapy of OAB
- Antimuscarinic agents
- Drugs that block Ach in the bladder
- Competitive antagonism at urothelial muscarinic receptors during bladder filling, decreasing urge and increasing bladder capacity.
Oxybutynin
- First drug used for OAB
- First pass metabolism
Oxybutynin characteristics (size etc).
Small size, highly lipophilic, neutral charge
-More likely to cross BBB than other antimuscarinic OAB agents.
Oxybutynin formulation
-Immediate release, extended release, transdermal patches and gel formulation.
Toletrodine
- Tertiary-amine, nonselective antimuscarinc agent
- First pass metabolism
- Low lipophillicity
- comparable to oxybutynin, but reduced side effects
- limited ability to distribute across BBB and cause CNS affects
Trospium
- Quaternary- amine, nonselective muscarinic agent
- first pass metabolism
- 60% excreted unchanged in urine
- May be concerned with renal patients
Fesoterodine
- Tertiary-amine, nonselective antimuscarinic agent
- First pass metabolism
- 70% really excreted as active and inactive metabolites
- low lipophillicity
- limited ability to distribute across BBB and cause CNS effects
Darifenacin
- Tertiary-amine, M3 selective receptor antagonist
- First pass metabolism
- 60% really excreted, 3% unchanged.
Solifenacin
- Quaternary-amine, nonselective muscarinic agent
- First pass metabolism
- low lipophillicity
Generally, _________ are associated with fewer side effects and adverse events.
Controlled-release medications.
For patients who have pre-existing constipation, which drugs are preferred?
-Non-selective antimuscarinics are preferable to M3 selective blockers.
Which drugs are best for patients with hepatic impairment?
- Trospium or fesoterodine
- Avoid darifenacin
Specific guidance for OAB treatment
- Begin with either tolterodine or oxybutynin
- If pt has cognitive issues, use darifenacin (ex. with constipation), tolterodine, or solifenacin.
