Pharm Test 1, Week 2

Neuropharmacology

the study of drugs that alter processes controlled by the nervous system

Compared to axonal conduction, synaptic transmission is a ________ ___________ process.

highly selective

Neuropharm drugs work by influencing _________ activity on target cells.

receptor

What are the three ways synaptic transmission is terminated?

1. Neurotransmitters can be reuptaked and removed from synaptic gap

2. Enzymatic degradation of neurotransmitter

3. Eventual diffusion away from gap

What is an enhancer?

a drug that enhances natural neurotransmitter effects

What are the two main branches of the peripheral nervous system and what are they responsible for?

Somatic Motor System (voluntary movements)

Autonomic Nervous System (involuntary processes)

What are the further two branches of the Autonomic Nervous System?

Parasympathetic Nervous System and Sympathetic Nervous System

The neuron pathways in the SNS and PNS are similar except for in the SNS, the ___________ acts as an additional postganglionic neuron

adrenal medulla

What neurotransmitter does the adrenal medulla use?

epinephrine

In the autonomic nervous system, both the PNS and SNS have two neuron pathways. This differs from the somatic nervous system where __________.

there is a single neuron pathway from spinal cord to muscles

Which site of action in the nervous system is the target site of action for a lot of paralysis drugs used by anesthesia?

the neuromuscular junction (the junction between the somatic motor nerve and the muscle) in the somatic motor system

What are the four neurotransmitters of the peripheral nervous system?

acetylcholine

norepinephrine

epinephrine

dopamine

What are the specific junctions acetylcholine is used in as a neurotransmitter?

• released by all preganglionic neurons of both parasympathetic and sympathetic systems

• all postganglionic neurons of parasympathetic neurons

• all motor neurons to skeletal muscles

• most postganglionic neurons of sympathetic system that goes to sweat glands

What are the specific areas norepinephrine is released as a neurotransmitter?

released by all postganglionic neurons of sympathetic system, except those going to sweat glands

What is the specific area epinephrine is used as a neurotransmitter?

released by the adrenal medulla

What are the two primary receptor types of the Peripheral Nervous System?

cholinergic receptors (for ACh) and adrenergic receptors (for epi/norepi)

What are the three cholinergic receptor subtypes?

NictonicN (neuronal)

NicotonicM (muscle)

Muscarinic

What are the five subtypes of adrenergic receptors?

a1, a2, b1, b2, and dopamine receptors

What is a receptor subtype?

receptors that respond to the same transmitter but have different actions from one another

Regarding the selectivity of drugs vs. natural transmitters, drugs have _________ structures from natural transmitters, allowing drugs to be more __________ for specific receptor subtypes.

different; selective

What are nicotinicN receptors, where are they located and what do they do (2)?

cholinergic receptor subtype

located in the cells bodies of all postganglionic neurons of the parasympathetic and sympathetic nervous systems

promotes ganglionic transmission in sympathetic and parasympathetic nervous systems

promotes release of epinephrine from adrenal medulla

What are nicotinicM receptors, where are they located and what do they do?

cholinergic receptor subtype

located in the skeletal muscle

causes contraction of skeletal muscle

What are muscarinic receptors and where are they located?

a cholinergic receptor subtype

found on all organs regulated by parasympathetic nervous system and sweat glands

What do muscarinic receptors do? (6 functions)

• increase glandular secretions

• slow heart rate

• contraction of smooth muscle in bronchi/Gi

• pupil constriction (miosis) and lens focusing for near vision

• vasodilation and lower bp

• promote bladder voiding

What are the four functions of a1 adrenergic receptors?

• Mydriasis (dilation of pupil)

• Vasoconstriction

• Ejaculation

• contraction of bladder -> urinary retention

What is the function of the a2 adrenergic receptors?

inhibition of transmitter release by suppressing norepinephrine release by binding to it

also modulates sympathetic outflow and pain perception in the CNS

What are the two functions of the b1 adrenergic receptors?

• increase hr and contractility

• releases renin from kidneys (leads to elevated BP)

What are the five functions of the b2 adrenergic receptors?

• bronchial dilation

• relaxes uterine smooth muscle -> prevents premature labor

• vasodilation of heart, lungs, smooth muscle

• increases blood glucose levels by promoting glycogenolysis

• enhances muscle contraction

What is the function of dopamine adrenergic receptors?

dilation of kidney vasculature

What receptors does epinephrine activate?

All a and b receptors but NOT dopamine

What receptors does norepinephrine activate?

a1, a2 and b1

What receptors does dopamine activate?

a1, b1 and dopamine receptors

What are muscarinic agonists and what do they do?

drugs that directly activate the muscarinic receptors of the parasympathetic nervous system

What is cholinesterase and what is the purpose of cholinesterase inhibitors?

the enzyme that breaks down ACh

inhibitors prevent the enzyme from doing that, thus increasing ACh availability

What is the effect of muscarinic agonist medications?

to mimic parasympathetic nerve stimulation

What is Bethanechol and what is it used for?

a direct acting muscarinic agonist

used to treat urinary retention, GERD, GI paralysis

What group of individuals is bethanechol contraindicated in and why?

asthma - d/t the effect of bronchial constriction

What is Cevimeline, what is it used for and what is the drug interactions associated with it?

A muscarinic agonist

used for relief of xerostoma (dry mouth) in patients with Sjogren syndrome

NO BETA BLOCKERS because they will intensify cardiac depression

What is Pilocarpine and what is it used for?

A muscarinic agonist

used for glaucoma & orally for tx of dry mouth resulting from Sjogren syndrome or salivary gland damage caused by radiation therapy

How can muscarinic poisoning occur?

from an overdose on:

direct acting muscarinic agonists

indirect acting cholinomimetics

or mushrooms

What is the treatment for muscarinic poisoning?

Atropine (a selective muscarinic blocking agent)

What does muscarinic poisoning look like?

“Sludge and the Killer Bs”

Salivation

Lacrimation (tears)

Urination

Diaphoresis/diarrhea

GI cramping

Emesis

Bradycardia

Bronchospasms

Bronchorrhea

What is myasthenia gravis?

autoimmune disorder that attacks post synaptic acetylcholine receptors

stops acetylcholine from activating these receptors resulting in severe muscle weakness

Signs and Symptoms of Myasthenia Gravis

ptosis, difficulty swallowing, respiratory muscle weakness

What is the general idea behind treatment of myasthenia gravis?

to overpower intact receptors with acetylcholine to promote muscle strength

What medication do we use to diagnose myasthenia gravis and how does it work?

Edrophonium

given IV or IM, will result in an increase in strength if the patient has myasthenia gravis

cannot be used for treatment bc of the short duration

What two medications are used for treatment of myasthenia gravis?

pyridostigmine or neostigmine

What medications are used in the treatment of glaucoma to specifically cause miosis with the intention of helping the fluid in the eye decrease, thus lowering intraocular pressures?

cholinesterase inhibitors, specifically echothiphate

What class of drug medications can be used to reverse a competitive neuromuscular blockage and how does it work?

cholinesterase inhibitors

blockade inhibits acetylcholine from binding -> give neostigmine/endrophonium to increase acetylcholine levels which competitively gets rid of the neuromuscular blockade

What medication is used as an antidote for muscarinic antagonist poisoning?

physostigmine

Donepezil, galantamine and rivastigmine åre all _____ and are all used for the treatment of ________.

cholinesterase inhibitors

Alzheimer’s disease

What is the only irreversible cholinesterase inhibitor?

echothiophate

What type of drug is pyridostigmine and what is the MOA?

a cholinesterase inhibitor used for tx of myasthenia gravis

act as a substrate for cholinesterase, preventing the breakdown of acetylcholine, thus increasing availability

What is neostigmine, what is it used for and can it cross the BBB?

a cholinesterase inhibitor used for tx of myasthenia gravis (in CA), reversal of paralytics

charged - so it cannot cross the BBB and has poor absorption in general

What is physostigmine and what differentiates it from neostigmine?

a cholinesterase inhibitor used for tx of atropine poisoning or muscarinic antagonist poisoning

it is uncharged and can cross the BBB

What is echothiophate, why is it dangerous and what medication is it’s antidote?

an irreversible cholinesterase inhibitor used for glaucoma and was previously a nerve agent

lipid soluble and crosses the BBB

administer pralidoxime to reverse cholinesterase inhibition

What are the four components of treatment of cholinesterase inhibitor toxicity?

• atropine (reduces muscarinic stimulation)

• pralidozime (to reverse cholinesterase inhibition)

• diazepam (to suppress convulsions)

• ventilator (for respiratory depression)

What is a myasthenic crisis?

an extreme muscle weakness d/t insufficient acetylcholine

NOT ENOUGH ACh

What is a cholinergic crisis?

muscle weakness and excessive muscarinic stimulation caused by an overdose of cholinesterase inhibitors

TOO MUCH ACh - over contracts receptors

How do you differentiate between a myasthenic crisis and a cholinergic crisis?

give edrophonium (a short acting cholinesterase inhibitor)

if symptoms improve, it’s a myasthenic crisis that needs more ACh

if person crumps, its a cholinergic crisis (too much ACh)

What do muscarinic antagonists do?

anticholinergic drugs that block muscarinic receptors = blocking the parasympathetic nervous system essentially

What is the most common example of a direct acting muscarinic antagonist ?

atropine

What type of drug is atropine, what does it cause and what is it used for?

a muscarinic antagonist that works as a competitive blockage of ACh at receptors

has no direct effect- but effect comes from blocking ACh = causing anticholinergic sx “seeing the bear”

prevents reflex bradycardia during surgery and reduces secretions

What are the adverse effects of atropine?

tachycardia and thickening in bronchial secretions which can lead to a bronchial plug (bad for asthma pts)

What are high risk patients to administer atropine to? (5)

non-bradycardic dysrhythmias

myocardial ischemia

glaucoma

MG

BPH

What is scopolamine, what is it used for and what is the effects of it?

anticholinergic, muscarinic antagonist

used for motion sickness

similar to atropine except it produces sedation, helps with motion sickness and emesis

What is ipratropium bromide and what is it used for?

anticholinergic, muscarinic antagonist

used for asthma, COPD, rhinitis caused by allergies/common cold

Dicyclomine (bentyl) - what is it and what is it used for

anticholinergic, muscarinic antagonist used for IBS

What are antisecretory anticholinergics?

anticholinergic drugs used to suppress gastric acid secretion in peptic ulcer disease

Glycopyrrolate (Robinul) - what is it, what is it used for, and what is a common side effect?

an anti-secretion anticholinergic

reduces severe drooling in children with neurological disorders and salivation caused by anesthesia

can cause tachycardia

M1 Receptor Subtype: Location, activation and blockade

location in salivary glands, CNS

activation = salivation, enhanced cognition

blockade = dry mouth , confusion, hallucinations

M2 Receptor Subtype: location, activation, blockade

location: heart

activation: bradycardia

blockade: tachycardia

M3 Receptor Subtype: location, activation, blockade

location = salivary glands, bladder, GI smooth muscle, eyes

activations = salivation, bladder contractions, increase GI motility, miosis/accomodation/tears

blockade = dry mouth, bladder relaxation, decrease GI motility, mydriasis/blurred vision/dry eyes

What is a highly selective M3 Muscarinic Receptor subtype drug?

Darifenacin (Enablex)

What is a primarily selective M3 Muscarinic Receptor subtype drug?

Oxybutynin

What is the cause of overactive bladder and what is used as treatment?

An over-contraction/stimulation of the bladder by the parasympathetic system

treatment first line by behavioral therapy, then by anticholinergics

What drugs are nonselective anticholinergics used for overactive bladder?

Solifenacin

Festerodine

Toiterodine

Trospium

What can cause muscarinic antagonist poisoning?

belladonna

antimuscarinic drugs

drugs with antimuscarinc properties like antihistamines

What are the symptoms of muscarinic antagonist poisoning?

dry mouth, blurred vision, photophobia, hyperthermia, CNS effects

What is the treatment of muscarinic antagonist poisoning and what is the antidote?

activated charcoal can minimize absorption but antidote is physostigmine

What are adrenergic agonists?

drugs that activate adrenergic receptors mimicking the effects of the sympathetic system (fight or flight)

What are the four mechanisms of adrenergic agonists?

Direct receptor binding

drugs bind directly to adrengeric receptors

ex. Dopamine, epi, isoproterenol, ephedrine

Promotion of norepinephrine release

drugs act on sympathetic nerve terminals to release norepinephrine

ex. Amphetamines, ephedrine

Blockade of Norepinephrine Reuptake

drugs that block reuptake = more NE in synaptic gap

ex. Cocaine, tricyclic antidepressants

Inhibition of Norepinephrine inactivation

drugs that inhibit monoamine oxidase (enzyme that breaks down norepinephrine) (MAO), increasing NE availability

ex. MAOIs

What are examples of catecholamines, what are the three properties of them, and what enzymes target their breakdown?

ex. Epi, norepinephrine, isoproterenol, dopamine, dobutamine

properties : cannot be used orally, brief duration, cannot cross BBB

rapidly inactivated by MAO and COMT enzymes

What are examples of noncatecholamines and what are three properties of them?

ex. ephedrine, albuterol, phenylephrine

can be used orally, longer half lives, can cross the BBB

Albuterol, a noncatecholamine, is highly selective for ______ receptors.

b2

Isoproterenol, a catecholamine, is selective for _________ receptors, and is basically a ___________ _________.

b1 and b2; chemical pacemaker

Selectivity is ______ __________, meaning it is maximal at _____ doses but decreases at ______ doses.

dose dependent; low; higher

A1 receptor activation is essentially used for

vasoconstriction

A2 receptor activation is used for

reduction of sympathetic outflow to heart and blood vessels, decreasing BP

and to reduce severe pain

What does epinephrine cause but not norepinephrine and why?

hyperglycemia, because epinephrine activates b2 receptors (causes glycogenesis)

Dobutamine activates which receptors?

b1 receptor ONLY

Phenylephrine, aka neo, activates which receptor?

a1 only - causes pure vasoconstriction

Dopamine receptor specificity is ______ _________.

dose dependent

dopamine targets which receptors?

dopamine, b1 and a1 depending on the dose

Which receptors does ephedrine target and what can it be used for (3)?

a1, a2, b1, b2

used for asthma, shock and anesthesia induced hypotension with low hr

Why might you choose to use Neo for a patient that’s hypotensive but has a high heart rate?

Neo, a1 agonist, will cause vasoconstriction, bringing the BP up, but can also trigger the baroreceptor reflex and bring the HR down

List the two non-selective a-adrenergic blocking agents.

phenoxybenzamine: blocks a1, a2

phentoalime: blocks a1, a2

What does a1 selective blocking agents end in?

-osin

ex. tamsulosin, prazosin, etc.

What are the five therapeutic applications of a1 blocking agents?

HTN

Reversal of a1 agonist toxicity (IV extravasation)

BPH

Pheochromocytoma

Raynaud Disease