Exam 3 Flashcards
1
Q
Effects of Ach on CNS & PNS.
A
CNS: arousal, reward, and attention
PNS: skeletal muscle contraction, cardiac muscle relaxation, SLUDGE
2
Q
Effects of DA on CNS and PNS.
A
CNS: motor control, cognition, reward, sexual arousal, motivation, and mood.
PNS: increased renal clearance and decreased gut motility.
3
Q
Effects of glutamate.
A
most common excitatory NT which functions in learning/memory and cell death/ischemia.
4
Q
Effects of NE on CNS & PNS.
A
CNS: attention, alertness, energy, reward, cognition
PNS: sympathetic activation
5
Q
Effects of 5-HT on CNS & PNS.
A
CNS: relaxation, pleasure, obsession, and compulsion
PNS: blood clotting and increased GI motility
6
Q
What does VNT stand for? How does it work?
A
vesicular neurotransmitter transport - push NTs against their concentration gradient into acidified lipid vesicles via proton anti-porters
7
Q
Explain NT release.
A
Action potential –> Ca2+ opens –> binding activates SNARE complex which docks vesicles –> NTs squeezed out into synaptic cleft.
8
Q
Botulinum toxin effect.
A
blocks the SNARE complex & release of excitatory NTs, causing paralysis and sometimes respiratory failure.
9
Q
Tetanus toxin effect.
A
blocks the SNARE complex and release of inhibitory NTs, causing muscle spasms and lock jaw.
10
Q
What are the two classes of NT receptors?
A
- Ionotropic: ligand gated ion channels.
2. Metabotropic: g-protein coupled receptors.
11
Q
AcH receptors.
A
- Nicotinic: Na+ channels.
2. Muscarinic: M1/3/5 Gq coupled, M2/4 Gi coupled.
12
Q
DA receptors.
A
- D1/5 Gs coupled, D2/3/4 Gi coupled.
13
Q
GABA receptors.
A
- GABAa: Cl- channels.
2. GABAb: Gi coupled.
14
Q
Glutamate receptors.
A
- Na+/Ca2+ channels.
2. R1/5 Gs coupled, R2/3/4 Gi coupled.
15
Q
NE receptors.
A
- Beta: Gs coupled.
- Alpha-1: Gq coupled.
- Alpha-2: Gi coupled.
16
Q
5-HT receptors.
A
- 5-HT3: Na+ channels.
- 5-HT1/5: Gs coupled
- 5-HT2: Gq coupled.
- 5-HT4/6/7: Gi coupled.
17
Q
MAO function.
A
enzyme which metabolizes 5-HT, DA, and NE (1st step).
18
Q
COMT function.
A
Breaks down DA and NE (2nd step).
19
Q
Mechanism of Cocaine.
A
Competitive inhibition of DA reuptake transporters which enhances the synaptic duration of dopamine.
20
Q
Effects of cocaine.
A
- Mesocortical: stimulant effects.
2. Mesolimbic: changes within nucleus accumbens (reward center - addicting effect)
21
Q
Side effects of cocaine.
A
Stroke, heart attack, hyperthermia, arrhythmias, and death.
22
Q
Meth structure.
A
Phenethylamine
23
Q
Meth mechanism.
A
Acts as a substrate for monoamine transporters which results in reversal of the transporter & forced release of the NT (meth = dopamine, MDMA = serotonin).
24
Q
Meth effects.
A
- psycho-stimulant which enhances alertness and arousal.
2. MDMA has addition euphoric and empathogenic effects because it is mediated through serotonin.
25
Overall, what's the most important receptor targeted by psychedelics? What are the three classes of psychedelics?
5-HT. (specifically, 5-HT2a/c)
1. Phenethylamines.
2. Tryptamines.
3. Lysergamides.
26
What is the difference between phenethylamines and tryptamines from lysergamides regarding receptor activity?
What was 2,5 methoxy modeled after? What does lacking the 2 methoxy groups yield?
Lysergamides activates dopamine and alpha-2 receptors on top of 5-HT receptors.
2,5-methoxy was modeled after mescaline and produces hallucinogenic and psychedelic effects.
Lacking the 2 methoxy groups yields psycho-stimulant and/or empathetic effects.
27
What are the classes of cholinergic agents and what do they do?
1. Neuromuscular Blocking Agents: block activity of Ach receptors in the somatic system.
2. AchE Inhibitors: block Ach esterase.
3. Antimuscarinics: block muscarinic receptors.
28
What is curare and what is its function?
Alkaloid molecule originally used for hunting that acts as a reversible, competitive antagonist for nicotinic-Ach receptors at the NMJ.
Causes paralysis and asphyxiation.
29
Structure and action of depolarizing NMJ blockers.
1. Flexible, linear structures (close analogs to ach)
2. Initially activate (depolarize) the receptor. Persistent activation causes receptor desensitization and inactivation. Basically, Ca2+ gets sequestered and causes the muscle to relax.
30
What class is succinylcholine in? How does it work.
NMJ blocker.
NOT a substrate for Ach esterase and is instead metabolized by plasma cholinesterase. In order for it to be broken down, sux must diffuse out of the NMJ. This allows for longer duration activity at the NMJ necessary for receptor desensitization.
31
Structure and actions of non-depolarizing NMJ blockers.
1. Large, bulky, and/or rigid structures with hydrophobic surfaces. Common structure is two positively charged nitrogen atoms spaced apart.
2. Function as competitive inhibitors, similar to curare.
32
Name the 3 SAR modifications for NMJ blockers and what they cause.
1. Rigidity (non-depolarizing) increases potency.
2. Optimum distance from N+ to N+ is 2.1 nm. Larger molecules tend to be non-depolarizing.
3. Lipophilicity increases non-depolarizing likelihood.
33
Name the uses of NMJ blockers.
1. Paralytic agent during anesthesia.
| 2. Aids in intubation process.
34
Side effects of depolarizing NMJ blockers.
1. Hyperkalimia.
2. Pain from fasciculations.
2. cardiovascular effects (arrhythmias)
35
Side effects of non-depolarizing NMJ blockers.
1. can induce histamine.
| 2. tachycardia.
36
Acetylcholinesterase structure and function.
Contains anionic (binds to acetylcholine’s N+ group) and esteric/catalytic (catalytic triad composed of 3 amino acid residues glutamate, histidine, and serine which undergo the mechanism).
cleaves acetylcholine into acetate and choline.
37
Explain the mechanism of acetylcholinesterase.
1. Histidine activates the nucleophilic serine residue.
2. Serine binds to the Ach via nucleophilic attack, forming an acetylated intermediate.
3. Hydrolysis via H2O molecules releases acetate from the serine active site which completes the cycle.
4. Acetate and choline diffuse away from the enzyme which returns AchE to its active state.
38
Explain how AchE inhibitors.
Increases ach so that it can outcompete non-depolarizing NMJ blockers. (reverses their effects).
39
What are AchE inhibitors commonly given with? Why?
Atropine (non-selective antagonist of muscarinic receptors) to prevent bronchoconstriction caused from increased Ach.
40
What are the two families of AchE inhibitors?
1. Carbamates.
| 2. Organophosphates.
41
Explain how carbamates work.
1. Reversibly bind the anionic and esteric clefts of the active site by undergoing serine-mediated cleavage at the analogous bond.
2. Hydrolysis occurs more slowly than with Ach (longer duration of intermediate), which aids in enzyme inhibition
42
What are the side effects of carbamates?
SLUDGE, headache, nausea, blurred vision, and bradycardia.
43
Explain how organophosphates work.
1. Irreversibly bind the esteric cleft of the active site by undergoing serine-mediated attack at the phosphoester group.
2. Fluorine acts as a leaving group, and is substituted with the oxygen of serine.
3. Hydrolysis cleaves the O-P bond, permanently inhibiting the enzyme.
44
What are the side effects of organophosphates?
Severe parasympathetic effects which lead to cardiac/respiratory failure and death.
45
What is 2-PAM oxine?
Antidote to organophosphate side effects which cleaves thephosphorus intermediate. Must be injected before the inhibited AchE can undergo the aging process. Usually given with atropine to decrease parasympathetic effects
46
What is chantix and what is its function?
Nicotine mimic which acts as a partial agonist for the nictone receptor.
Partial agonism blocks full effects of nicotine.
47
What are the side effects of anti-muscarinic agents?
anti-SLUDGE, drowsiness/sedation, and possible cardiac effects.
48
What are the uses of anti-muscarinics?
1. Asthma: induce lung dilation.
2. Irritable bowel syndrome: slows GI motility.
3. Overactive bladder: decreases urination.
4. Motion sickness.
5. Sleep aids.
49
What are the places of origin for 5-HT, DA, and NE?
1. 5-HT:
2. DA:
3. NE:
50
What are the 3 anti-depressant mechanisms? What do they result in?
1. MAO inhibition (metabolic inhibition)
2. Reuptake transport inhibitors.
3. Antagonizing of NT auto-receptors on presynaptic cell.
Persistent signaling leads to adaptive changes. (neurotrophic factors = new synapses).
51
What are the reuptake inhibitors?
1. Selective serotonin reuptake inhibitors (SSRIs)
2. Serotonin norepinephrine reuptake inhib. (SNRIs)
3. Norepinephrine dopamine reuptake inhib. (NDRIs)
52
What do SSRIs treat?
Depression, anxiety, OCD, eating disorders, premature ejaculation.
53
What is the mechanism of SSRIs?
Competitive inhibition of primary 5-HT pocket. Bind the active site and prevent serotonin from binding. (does so indirectly).
54
SAR of SSRIs.
Lipid molecules. Notable structure is aryloxypropanamine with key chiral center.
55
What are the SAR modifications of SSRIs?
1. Para substitutions (Cl, F, and CF3) increase 5-HT selectivity/potency.
2. Ortho substitutions increase NE potency.
3. (S) enantiomer more potent.
56
What metabolizes SSRIs?
CYP2C9/D6 (phase 1) & glucoronodiation (phase II).
57
Why does clinical lag time occur in SSRIs?
Adaptive changes in the 5-HT neurotransmission.
58
What is serotonin syndrome? What does it cause?
Rare and life-threatening medical emergency resulting from excess serotonin levels caused by predictable (and preventable) drug-drug interactions and/or overdose. Other drugs involved include other anti-depressants, hallucinogens, stimulants, cough suppressants, and opioids.
causes mental state alteration and over-activation of the somatic and sympathetic systems.
59
What are some other side effects of SSRIs?
Sexual dysfunction, sleep disturbances, diarrhea, tremors, & increased suicidal thoughts/hostility (mainly in children/adolescents).
60
Which SSRI has most complaints of insomnia? Which one for tiredness complaints?
Prozac. Luvox.
61
What are the different treatments for serotonin syndrome?
1. Benzodiazepines: anti-anxiety agents which treat agitation.
2. Cyproheptadine: broad spectrum 5HT antagonist
3. Esmolol and/or nitroprusside: for cases of serious hypertension
4. Cooling measures for hyperthermia
5. Severe cases may require sedation, skeletal muscle paralysis, and mechanical ventilation
62
Which SSRIs cause most withdrawal?
Ones with shorter half lives. All have the ability to cause it though.
63
Are tricyclic antidepressants a 1st line depresssion therapy? Why?
No due to their side effects.
64
What do TCAs do?
Increase serotonin and norepinephrine.
65
What is the core structure of TCAs?
3 fused rings (6-7-6). Nitrogen can be substituted for carbon (attached to side chain) on the ring. Side chain must contain 2 or 3 carbons and terminate with an amine group.
66
What are the SAR modifications of TCAs?
1. Tertiary amines increase SERT potency as well as antihistamine and antimuscarinic activity.
2. Chlorine substitution increases CNS penetration and overall potency.
67
What are the typical side effects of TCAs? What about the side effects in overdose situations?
Antihistamine and antimuscarinic activity (results in sedation and anti-SLUDGE side effects. Inhibition of Na+ and L-type Ca2+ channels - can cause cardiotoxicity.
Overdose: hallucinations, twitching, delirium, coma, orthostatic hypertension, tachycardia, and arrhythmias.
68
What is the other chemical class of SNRIs besides TCAs? Why are they considered more safe?
Cyclohexanol Ethylamine. Side effects are similar to TCAs but less severe with low incidence rates.
69
What is the one example of NDRIs? What is its structure and what does it treat?
Wellbutrin®/bupropion. Phenethylamine (cathinone).
1. Depression: monotherapy or in combination with SSRI. 2. alternative option in ADHD.
3. smoking cessation: antagonizes central nAch receptors
70
What are the advantages and disadvantages of Buprupion?
Pros: less sedation and sexual side effects than SSRIs
Cons: carries the risk of seizures and agitation.
71
What is MAO? COMT?
Monoamine oxidase (breaks down all in first phase). Catechol o-methyltransferase (breaks down NE/DA in second phase).
72
How is 5-HT metabolized? What about DA/NE?
1. 5-HT: MAO --> aldehyde dehydrogenase.
| 2. DA/NE: MAO --> COMT.
73
What are the monoamine oxidase subtypes? Where are they found?
A: widespread.
B: exclusively found in platelets.
74
What do MAO inhibitors do?
Induce catecholamine release.
75
What are the side effects of MAO inhibitors?
1. potential for serotonin syndrome and hypertensive crisis.
2. Drug-diet interactions: when Tyramine (inducer for catecholamine release found in meat and cheese) is prevented from being metabolized, it causes an excessive sympathetic response and hypertension.
76
What are SARIs? What receptors do they target?
serotonin antagonist and reuptake inhibitors.
| 5-HT1A, 5-HT2A, and alpha-2.
77
What are the side effects of SARIs?
1. Trazadone: high fatigue, anti-muscarinic effects, and priapism (rare side effect where erection won’t subside).
2. Mirtazepine: increased appetite and weight gain
78
What are the anxiety treatments?
1. SSRIs are 1st line options. SNRIs and TCAs are other options.
2. Benzodiazepines: 2nd line therapy for short-term use due to cognitive impairment, overdose potential, and dependency.
79
What are the positive symptoms of schizophrenia? Why do they have that name?
Hallucinations, delusions, and disordered thinking. Respond well to typical treatments.
80
What are the negative symptoms of schizophrenia? What treats these?
Poor speech, flat affect, general lack of emotion, poor hygiene, issues with relationships and motivation. Atypical anti-psychotics.
81
What are the 4 pathways of dopamine in the brain? What is each involved with?
1. Mesocortical: negative symptoms.
2. Mesolimbic: positive symptoms.
3. Nigrostriatal: planned movement - site of neuron destruction in Parkinson’s disease and EPS.
Tuberoinfundibular: associated with galactorrhea, abnormal menstrual cycles, and erectile dysfunction (inhibits prolactin).
82
How do anti-psychotics work in general? What are the two types and how do they differ?
antagonize or partially agonize D2-dopamine receptors.
1. Typical (1st gen): high affinity for D-2 receptors with negligible inhibition of other NTs.
2. Atypical (2nd gen): interact with other NT receptors (serotonin, histamine, and adrenergic)
83
What is EPS? What is it caused from?
Altered motor control from antagonism of D2 receptors in the nigrostriatal pathway.
84
what are the different ways neuromotor effects can manifest? Which of these can be irreversible?
1. Parkinsonism: muscle rigidity, bradykinesia, tremor.
2. Dystonia: muscle twitching, abnormal posture.
3. Akathisia: motor restlessness.
4. Tardive dyskinesia: jerky movements, especially in face, lips, and tongue. This effect can be irreversible unlike the other effects.
85
What are the treatments for EPS?
1. switching to an atypical antipsychotic agent
| 2. anticholinergic drugs
86
What is neuroleptic malignant syndrome (NMS).
life-threatening side effect of anti-psychotics resulting from decreased D2 activity.
87
What are the symptoms of NMS?
severe muscle rigidity, tremors, and sympathetic system activation (similar to serotonin syndrome)
88
What are the treatments for NMS?
1. switching to an atypical antipsychotic agent
2. cooling blankets and/or ice packs for hyperthermia
3. support ventilation if necessary
4. dialysis if necessary.
89
What are the two types of typical anti-psychotics?
1. Phenothiazines.
| 2. Non-phenothiazines.
90
Which receptors do phenothiazines target?
1. D2 receptor antagonists with relatively low activity at the serotonin receptor.
2. can also antagonize other receptors such as histamine, muscarinic, and a1-adrenergic.
91
What are the side effects of phenothiazines?
sedation, dry mouth, constipation, hypotension, orthostasis, and dizziness
92
What is the core structure of phenothiazines?
tricyclic ring (6-6-6)
93
What are the 3 sub-types of phenothiazines based on the N10 position? What are their side effects?
1. Aliphatic: alpha chain substituent capped with a tertiary amine. Moderate EPS and other side effects.
2. Piperidine: contain a six-membered ring with one nitrogen. Low EPS but high sedation and anti-muscarinic effects.
3. Piperazines: contain a six-membered ring with two nitrogens. High EPS but low sedation and anti-muscarinic effects.
94
How are non-phenothiazines similar to phenothiazines?
Receptor affinity and side effects similar.
95
What are the benefits of non-phenothiazines?
fast onset, multiple dosage forms available (PO, IV, IM), extended-release formulations
96
What are the additional uses of non-phenothiazines?
drug-induced psychosis, hyperactivity/agitation (dementia), tic disorders (Tourette’s syndrome), personality disorders.
97
What is the receptor affinity of atypical anti-psychotics?
1. Retain activity as D2 antagonists but are 10-fold less potent than typical agents.
2. 100-fold higher potency against 5-HT receptors, in particular 5-HT2A,C.
3. Most also more potent at antagonizing M1-muscarinic, a-adrenergic, and/or H1-histamine receptors.
98
What are the side effects of atypical anti-psychotics?
1. Weight gain, increased risk of dyslipidemia, hyperglycemia and type II diabetes (Zyprexa®/olanzapine has highest risk).
2. Agranulocytosis: reduced white blood cells that occur in 1% of patients who take Clozapine. Almost always within 1st 3 months of therapy.
3. Although reduced, still carry risk of EPS and other D2-related side effects
99
What are the additional uses of atypical anti-psychotics.
bipolar disorder, dementia-related agitation, anxiety disorders, and OCD
