CIS Neuropharmacology Capstone (Linger)

Term
1 / 74
The DSAs are meant to give an overall preview. So the DSA is broad and the lecture is more specific
Click the card to flip 👆
Terms in this set (74)
The DSAs are meant to give an overall preview. So the DSA is broad and the lecture is more specific
...
LOBS
CNS:
1.List the 10 major sites of drug action in the CNS.
2.Identify the primary excitatory and inhibitory neurotransmitters in the CNS.
3.Describe the modulatory effects of small molecule neurotransmitters in the CNS.
4.Compare and contrast the pathophysiologic effects of glutamate, GABA, acetylcholine, dopamine, norepinephrine, and serotonin in the CNS; identify clinical indications that may benefit from therapeutic modulation of these neurotransmitter systems.
5.Apply the presented information to clinical scenarios and case studies.

ANS:
1.List the various types and subtypes of cholinergic and adrenergic receptors and their ganglionic nerve terminal and effector organ distribution.
2.Describe the physiological functions and effects of cholinergic and adrenergic stimulation at effector organs (the big table included in the DSA packet under subheading 8).
3.Describe sympathetic and parasympathetic tone.
4.Compare and contrast the sympathetic and parasympathetic effects in response to the administration of cholinergic agonists, cholinergic antagonists, adrenergic agonists, and adrenergic antagonists.
5.Apply the information presented to clinical scenarios and case studies.
CNS has two main divisions:

PNS has three main divisions:
Central Nervous System
1. Brain
2 Spinal Cord

Peripheral Nervous System
1.Autonomic Nervous System
-Parasympathetic Division
-Sympathetic Division
2. Somatic Nervous System
3. Enteric Nervous System
What are the ten (10) possible places of drug action in the CNS?
1. Action potential propagation
2. Synthesis
3. Storage
4. Metabolism
5. Release
6. (Re)Uptake
7. Degradation
8. Receptor
9. Ion conductance
10. Retrograde Signaling
Image: What are the ten (10) possible places of drug action in the CNS?
Monoamines are a group of chemicals including serotonin and catecholamines.

What is their primary mechanism for signal termination?
Reuptake via presynaptic transporters
Image: Monoamines are a group of chemicals including serotonin and catecholamines. What is their primary mechanism for signal termination?
What are pharmacological therapies for:

ADHD? (2)
Depression? (3)
Therapeutic applications:

ADHD: methylphenidate, amphetamine
Depression: SSRIs, SNRIs, TCAs
Image: What are pharmacological therapies for: ADHD? (2) Depression? (3)
What is the reuptake transporter for Norepinephrine?
NET
What presynaptic transporters do SNRIs and TCAs act on?
NET and Serotonin reuptake transporters
Image: What presynaptic transporters do SNRIs and TCAs act on?
Amphetamine MOA?
Amphetamine shown on left diagram, represented by black circles

-Uses NET transporter or simple diffusion to get into presynaptic neuron

-Once inside, can use VMAT to displace NE from inside vesicles

-Phosphorylation events that lead to reversal of NET, so the NE that's floating around in the neuron because it's been displaced now flows out into the synapse
Image: Amphetamine MOA?
Cocaine MOA?
Cocaine shown on the right diagram, represented by gray polygon

Blocking NET transporter
Image: Cocaine MOA?
A 75 yo man with atrial fibrillation experiences a stroke when an embolus lodges in the proximal portion of his left middle cerebral artery. He immediately loses his ability to talk and experiences paralysis of his right arm and leg. A small portion of his left cortical hemisphere has substantially reduced blood flow for several hours and is irreversibly damaged. Excess of which neurotransmitter contributes most to the cell death of neurons in this case? A.Acetylcholine B.Dopamine C.GABA D.Glutamate E.SerotoninD. GlutamateWhat is the primary excitatory NT? Inhibitory NT?Excitatory - Glutamate Inhibitory - GABAWhat is the mechanism for Glutamate?1. Glutamate released from vesicles 2. AMPAR (Na+ influx), NMDAR mGluR receptors bind glutamate in synapse 3. Signal terminated by reuptake by neighboring Glial cells 4. Glial cell converts glutamate into glutamine via glutamine synthetase 5. Glutamine shuttled back into the presynaptic cell 6. Glutamine converted to glutamate via glutaminase 7. Glutamate packaged into vesiclesWhat are some pathophysiologies linked with Glutamate? (4)Pathophysiology of glutamate: •Ischemic injury, stroke •Migraine •Alzheimer's disease •Lou Gehrig's diseaseHow is Glutamate linked with ischemia and cell injury?All of the processes with glutamate reuptake and processing are active, so when there's no oxygen or energy for glutamate to be taken back out of the synapse, then cytotoxicity by glutamate occurs Additionally, NMDA receptors get calcium entry, which can act as a second messenger linked to some apoptosis pathwaysA 35 yo chronic alcoholic, after consuming up to 2 quarts of vodka a day for several weeks, runs out of money and alcohol and presents to the ED in acute alcohol withdrawal. He is extremely agitated, trembling violently, and an hour after arriving at the ED, experiences the first of several grand mal seizures. Phenytoin, a Na+ channel blocker, is given as a loading dose to control his seizures. A drug acting at which of the following receptors is indicated as additional treatment in this EtOH-withdrawal case? A.α2 adrenergic B.D2 dopaminergic C.GABAA GABAergic D.5-HT3 serotoninergic E.M1 muscarinic cholinergicC. GABAA GABAergicWhere is GABA used a lot? (3)Neurons in striatum, globus pallidus, and Purkinje cells of cerebellumWhat is the primary NT of interneurons?GABAWhat are the roles of GABA? (3)Roles of GABA: •Balances excitatory activity of glutamate •GABA dysfunction leads to hyperexcited states •GABA-mimetic drugs are used to induce sleep and control anxiety and seizuresHow does alcohol affect Glutamate and GABA receptors?Alcohol inhibits Glutamate receptors, and stimulates GABA receptorsWhat is the mechanism for how alcohol affects brain anatomy?Adaptive mechanisms occur from chronic alcohol use 1. Alcohol shuts down glutamate signaling, so the brain adapts by increasing glutamate receptor expression 2. Alcohol is increasing GABA signaling, so the brain adapts by upregulating GABA receptor expression When you take away alcohol, now you have all of these extra glutamate receptors that will lead to cytotoxicity from glutamate signalingHow do we control alcohol withdrawl?GABA-mimetic drugs -mimics the effect of endogenous GABA Specifically for the case, we would use a GABA-A receptor -ionotropic receptor for Cl- entry into the cell -Cl- hyperpolarizes the cell via IPSP, preventing firingA 66 y/o woman is diagnosed with Alzheimer disease, with symptoms being described as mild-to-moderate. Studies suggest that impaired cortical cholinergic function may contribute to the pathophysiology of disease. Which pharmacologic approach is most likely to restore cortical cholinergic function and alleviate her symptoms? A.Inhibit acetylcholinesterase B.Inhibit choline acetyltransferase C.Inhibit monoamine oxidase D.Prescribe acetylcholine E.Prescribe succinylcholineA. Inhibit acetylcholinesteraseWhat is the lifecycle of released ACh (acetylcholine)?i) Synthesis occurs in the presynaptic terminal from choline and acetyl-CoA by the enzyme choline acetyltransferase ii) Storage: ACh is loaded into vesicles by the vesicle-associated transporter (VAT) iii) Release occurs in response to nerve impulses iv) Inactivation: Enzymatic degradation by acetylcholinesteraseWhat are the functions of ACh in the body? (3)Functions: •Wakefulness •Motor control •MemoryWhat can occur if ACh receptors are blocked? (3)•Drowsiness, sedation, and memory loss can occur when central ACh receptors are blockedDuring an annual physical exam, an internist notes that a 65 y/o woman appears depressed. She admits to persistent feelings of hopelessness. She feels she is nothing but a burden to her husband. She doesn't seem to enjoy anything anymore. She sleeps poorly, tending to wake up at 3-4 am. Her appetite is diminished and she has lost 10 lb over the past 2 months. She has frequent crying spells. She denies suicidal ideation but wishes she could just quietly die. Which of the following neurotransmitter systems could be modulated pharmacologically to address her psychological symptoms? A.Acetylcholine B.Dopamine C.Glutamate D.Norepinephrine E.SerotoninE. Serotonin Secondarily, she said B. Dopamine and D. Norepinephrine are correctWhy don't we modulate dopamine for mood disorders?Too much dopamine can precipitate psychosis and movement disorders Additionally, a dopamine drug could be potentially very addictiveSubstantia Nigra striatum regulates ________ movementSubstantia Nigra striatum regulates voluntary movementWhat neurons degenerate in Parkinson's Disease?Substantia Nigra DA neurons degenerate in Parkinson's diseaseHow does cocaine affect dopamine (DA) reuptake? How do amphetamines affect DA release?•Cocaine blocks DA uptake •Amphetamines increase DA releaseDopamine activity is (increased/decreased?) in schizophenia How do antipsychotics affect this?Dopamine activity is increased in schizophenia Classical antipsychotics work (in part) by blocking dopamine D2 receptorsSerotonin (5-Hydroxytryptamine, 5-HT) mediates affective processes such as _______ behavior and ______ Serotonin affects _______ pain pathwaysSerotonin (5-Hydroxytryptamine, 5-HT) mediates affective processes such as aggressive behavior and arousal Serotonin affects descending pain pathwaysDepression is associated with (increased/decreased?) 5-HT functionDepression is associated with decreased 5-HT functionEctasy (MDMA), LSD and other hallucinogens probably act in part by interacting with _______ receptorsEctasy (MDMA), LSD and other hallucinogens probably act in part by interacting with 5-HT receptorsNorepinephrine modulates what four major things?sleep, wakefulness, attention, and feeding behaviorsGlutamate is the primary FAST excitatory NT. GABA is the primary FAST inhibitory NT. Serotonin, norepinephrine, and dopamine have what type of effect?Modulatory (I think she just wants us to know NE is modualtory based on this slide, but it's hard to tell)KNOW LITERALLY EVERYTHING ABOUT THIS FIGURE. SHE LOVES THIS FIGURE.SERIOUSLY. LEARN IT.Parasympathetic •Neurotransmitter: (1) •Receptors: (2) Sympathetic •Neurotransmitters: (3) •Receptors: (5)Parasympathetic •Neurotransmitter: ACh •Receptors: nAChR, mAChR Sympathetic •Neurotransmitters: NE > Epi (DA); ACh •Receptors: α, β, (D), nAChR, mAChRNicotinic receptors are what type of receptors? Muscarinic?Nicotinic - ion channels that gate sodium Muscarinic - metabotropicAll of the ganglia have what type of receptors?Nicotinic ACh receptors -both sympathetic and parasympathetic ganglionThe tissues that receive parasympathetic innervation have what type of receptors?Muscarinic ACh receptorsThe primary NT of sympathetic system is what? Acts through what receptors?Norepinephrine -alpha and/or beta receptorsWhat are the 2 major exception in the sympathetic nervous system that you SHOULD FOR SURE KNOW?-Sweat Glands are sympathetically innervated, BUT the nerves innervating them are cholinergic (ACh), which stimulates the muscarinic receptors in those sweat glands -Sympathetic innervate the adrenal glands via preganglionic sympathetics (nACh), afterwards the adrenal glands release catecholaminesBeta1 (β1) receptors •Regulate ______ function •Regulate ______ release Beta2 (β2) receptors •Relax all _______ muscle •Vaso______ •Dilate ________ •EXCEPTION: β2 receptors in the heart increase _______ •Regulate metabolic functionsBeta1 (β1) receptors •Regulate cardiac function •Regulate renin release Beta2 (β2) receptors •Relax all smooth muscle •Vasodilation •Dilate bronchioles •EXCEPTION: β2 receptors in the heart increase contractility •Regulate metabolic functionsThe adrenal medulla is a modified ______ Receives what type of innervation?The adrenal medulla is a modified ganglion -sympathetically innervated via cholinergic (ACh) sympathetic neuronsAlpha1 (α1) receptors Stimulate contraction of all ________ muscle Vascular smooth muscle - vaso_______Alpha1 (α1) receptors Stimulate contraction of all smooth muscle Vascular smooth muscle - vasoconstrictionMuscarinic receptors (M2, M3) Contract ________ muscle M2 and M3 act via different signaling pathways M2 regulate ______ functionMuscarinic receptors (M2, M3) Contract smooth muscle M2 and M3 act via different signaling pathways M2 regulate cardiac function (Sketchy pharm makes this real easy)A 2 y/o female presents to the ED after an accidental overdose of antihistamines. Her temperature is 102.5° F and pupils are fixed and dilated. Heart rate is 160 bpm (normal 120 bpm). She shows signs of delirium and is noted to have marked cutaneous vasodilation upon physical exam.term-0 She is exhibiting symptoms of over activity of which division of the nervous system? A.Central nervous system B.Parasympathetic nervous system C.Somatic nervous system D.Sympathetic nervous systemD. SympatheticWhat syndrome was causing the symptoms presented in the previous case?Anticholinergic ToxidromeWhy is an antihistamine causing Anticholinergic Toxidrome?Cross-talking receptors Specifically something like diphenhydramine (brand name benadryll) is a "dirty" drug -not actually very selective for its intended drug receptor target -so it does block Histamine receptors, but is ALSO blocks muscarinic ACh receptors, so you can get anticholinergic symptoms!!!!! additionally it crosses the BBB (blood-brain barrier), which can result in drowsiness -this is why diphenhydramine is used in Tylenol PMSo why does an anticholinergic drug give you symptoms that look like overactivation of the sympathetic nervous system?Decreased parasympathetic tone from blocking muscarinic ACh receptorsWhat are the symptoms of Sympathetic (aka: adrenergic)(aka: anticholinergic) tone?Sympathetic Adrenergic (anticholinergic) •Cutaneous vasodilation •Pupil dilation (mydriasis) •Increase in HR •Reduction/elimination of the desire to urinate •Decreased secretion and motility ØFight or flight ØCardiac stimulation ØSmooth muscle relaxation (β2) and contraction (α1) (Target cell in the diagram is a heart pacemaker cell)What are the symptoms of Parasympathetic (aka: cholinergic) tone?Parasympathetic Cholinergic •Salivation, lacrimation •Pupil constriction (miosis) •Decrease in HR •Urination, defecation •Increased secretion and motility ØRest and digest ØCardiac depression ØSmooth muscle contraction (Target cell in the diagram is a heart pacemaker cell)A 2 y/o female presents to the ED after an accidental overdose of antihistamines. Her temperature is 102.5° F and pupils are fixed and dilated. Heart rate is 160 bpm (normal 120 bpm). She shows signs of delirium and is noted to have marked cutaneous vasodilation upon physical exam. Stimulation of which receptor will most likely correct her symptoms? A.Alpha-1 receptor B.Beta-1 receptor C.Beta-2 receptor D.Muscarinic acetylcholine receptor (mAChR) E.Nicotinic acetylcholine receptor (nAChR)D.Muscarinic acetylcholine receptor (mAChR)Nicotinic receptors are highly susceptible to what?Desensitization -this is why we don't really have many good nicotinic agonists clinically available -you start to actually inhibit them, rather than stimulate them like you wantAnticholinergic toxidrome is caused by what kind of drugs?•Caused by antimuscarinic drugs •1st generation antihistamines (diphenhydramine) have antimuscarinic actionHow can you differentiate anticholinergic toxidrome from sympathomimetic toxidrome? (3) KNOW THIS PLEASEAnticholinergic toxidrome differs from sympathomimetic toxidrome by: •DRY skin •DECREASED bowel sounds •PUPILS will not respond to lightA healthy 68 y/o male presents to an ophthalmologist complaining of double vision, droopy eyelids, and difficulty chewing due to jaw fatigue. The neurologic examination revealed ptosis of the left eye after a sustained upward gaze (Panel A). The movements of the extraocular muscles were normal. The ice-pack test was performed with the placement of an instant cold pack over the left eye (Panel B). After 2 minutes, the ptosis was substantially diminished (>5 mm), indicating a positive test (Panel C). Antibodies to which of the following would most likely cause this patient's presenting symptoms? A.Acetylcholinesterase B.Alpha-1 adrenergic receptor C.Muscarinic acetylcholine receptor D.Nicotinic acetylcholine receptor E.Vesicular monoamine transporter (VMAT-2)D.Nicotinic acetylcholine receptorWhat tissue is being impacted in the previous case? What's going on in this tissue to cause this presentation? Why is the ice pack having this effect? What is this condition of antibodies against nicotinic ACh receptors called?Skeletal muscle Weakness in the skeletal muscle Ice pack is slowing the ability of the antibody to bind to its target, resulting in recovery of that muscle weakness Myasthenia GravisWhich of the following is most appropriate to treat this droopy eye patient's symptoms? A.Acetylcholinesterase inhibitor B.Alpha receptor agonist C.Beta-2 receptor agonist D.nAChR agonist E.SNARE-complex inhibitorA.Acetylcholinesterase inhibitor -remember that a nicotinic receptor agonist would cause desensitizationThe droopy eye patient is prescribed an AChE inhibitor. Which of the following adverse effects is most likely? A.Anhydrosis (lack of sweating) B.Decreased urination frequency C.Diarrhea D.Dry mouth E.Mydriasis (pupil dilation)C.DiarrheaWhy does AChE inhibitor acute intoxication cause diarrhea?Muscarinic ACh receptors of the parasympathetic nervous system are being stimulated from increased levels of ACh at the nerve synapseWhat is the acronym to remember the AChE inhibitor acute intoxication effects?SLUDGEM Salivation, Lacrimation, Urination, Defecation, GI distress, Emesis, MiosisWhich of the following types of agents is most likely to reduce the patient's symptoms of diarrhea? A.AChE inhibitor B.Alpha receptor antagonist C.Beta receptor antagonist D.mAChR antagonist E.nAChR agonistD. mAChR antagonistWhat are two antidiarrheal agents used?Example of an antidiarrheal: diphenoxylate and atropine (Lomotil) •Diphenoxylate - weak opioid receptor agonist (schedule V narcotic); inhibits excessive GI motility •Atropine - added to discourage abuse Opioids are great at treating diarrhea, but atropine is added to hopefully avoid abuseA 32 y/o female presents with intermittent attacks of headache, perspiration, palpitations, and anxiety. During these attacks, she reports having feelings of impending doom and tremors. She notes that the attacks often occur after exercise or drinking coffee. Laboratory values are unremarkable. A plasma fractionated free metanephrine test is positive and a 24-hour urine specimen supports a diagnosis of pheochromocytoma (tumor of chromaffin cells) If propranolol is administered, which of the following is most likely to occur? A.Bronchial smooth muscle constriction B.Diarrhea C.Increase in heart rate D.Uncontrollable urination E.Worsening of hypertensionPropranolol blocks both Beta-1 and Beta-2 receptors E.Worsening of hypertension is the right answer because blocking the beta receptor leads to unopposed vasoconstriction by alpha-1 receptorsWhat receptors cause constriction of the lung bronchioles?M2 and M3 receptorsPheochromocytoma Treatment •Pharmacologic control of hypertension and volume expansion in preparation for surgical resection of the pheochromocytoma •The use of a nonselective beta-blocker in a patient with a pheochromocytoma will result in symptoms of 'unopposed alpha' stimulation (i.e., vasoconstriction) •Although nonselective adrenergic antagonists (e.g., labetalol) can be used to block both alpha- and beta-receptors, use as the initial antihypertensive agent may cause paradoxical hypertension •The preferred agent for controlling blood pressure is an irreversible, long-acting, nonspecific _____ ______ _____ some protocols utilize ______•Pharmacologic control of hypertension and volume expansion in preparation for surgical resection of the pheochromocytoma •The use of a nonselective beta-blocker in a patient with a pheochromocytoma will result in symptoms of 'unopposed alpha' stimulation (i.e., vasoconstriction) •Although nonselective adrenergic antagonists (e.g., labetalol) can be used to block both alpha- and beta-receptors, use as the initial antihypertensive agent may cause paradoxical hypertension •The preferred agent for controlling blood pressure is an irreversible, long-acting, nonspecific alpha adrenergic antagonist (phenoxybenzamine); some protocols utilize prasozinWhat does sympathomimetic toxidrome look like? REVIEW BECAUSE IMPORTANT: How does it differ from anticholinergic toxidrome? (3)Mydriasis Hyperthermia Diaphoresis Hypertension Tachycardia Tachypnea Increased bowel sounds Remember for anticholinergic toxidrome, you'd have •DRY skin •DECREASED bowel sounds •PUPILS will not respond to lightAutonomic Effects on the Heart and Blood VesselsWhich agent may be used in this patient to differentiate between a diagnosis of pheochromocytoma and false-positive increases in plasma catecholamines and fractionated metanephrines? (i.e., which agent will reduce catecholamine release in a patient without pheochromocytoma but will produce little-to-no physiological effects in a patient with a pheochromocytoma?) A.Beta-1 selective agonist B.Beta-2 selective antagonist C.Centrally-acting alpha-2 receptor agonist D.mAChR antagonist E.Monoamine oxidase inhibitorC.Centrally-acting alpha-2 receptor agonistWhat is using a centrally-acting alpha-2 receptor agonist as a test for pheochromocytoma called? How does it work?Clonidine suppression test •Clonidine activates central pre-synaptic alpha-2 receptors and suppresses the release of catecholamines from neurons •Clonidine has no effect on catecholamine secretion from a pheochromocytoma A patient who has pheochromocytoma is not going to shut down the sympathetic drive because the epi/norepi being secreted is in the blood -so using a centrally-acting (CNS) alpha-2 receptor agonist in the brain will NOT turn it off In a patient with something ELSE going on, then it will shut down the sympathetic toneAdrenergic synapse signaling diagram for previous question