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PMCOL 200 > Lecture 13+ > Flashcards

Lecture 13+ Flashcards

1
Q

Psychosis

A

refers to mental disorders in which there is a loss of contact with reality, affecting a persons ability to think, feel, and act

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2
Q

Core clusters of schizophrenia

A
  • positive symptoms: mental phenomena that are absent in healthy individuals (hallucinations and delusions)
  • negative symptoms: loss or impairment of normal psychological function (ex: loss of motivation and social withdrawal)
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3
Q

Cognitive symptoms of Schizophrenia

A

poor concentration, disorganized thinking, poor memory, etc.

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4
Q

Dopamine hypothesis

A
  • symptoms of schiz due to hyperactivity of dopamine system
  • inferential evidence: drugs that increase synaptic dopamine (amphetamine, cocaine, cannabis) can cause delusions and hallucinations at high doses; drugs that block dopamine receptors are effective antipsychotics (first gen antipsychotics)
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5
Q

largest population of dopamine neurons are located in the …

A

midbrain (ventral segmental area and substantial nigra)

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6
Q

Mesocortical/mesolimbic system

A

dopamine neurons located in the ventral tegmental area project to striatum and the PFC

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7
Q

Dopamine receptors

A

GPCR; two classes:

  • D1: stimulate adenylate cyclase via Gs… (although target for drugs, they are unlikely to contribute to the therapeutic action of many antipsychotics)
  • D2: Gi (inhibit adenyl cyclase); blocking D2 directly related to clinical antipsychotic potency
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8
Q

Serotonin Hypothesis

A

symptoms of schizophrenia due to increased serotonin signalling

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9
Q

5HT-2A antagonists

A

block glutamate release in cortex = reduces hallucinations and other positive symptoms

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10
Q

First generation antipsychotics

A
  • typical
  • targets both D1 and D2 (D2 antagonism = efficacy!)
  • haloperidol, chlorpromazine
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11
Q

Second generation antipsychotics

A
  • atypical
  • antagonists at both 5HT and D2 receptors
  • bind looser (lower affinity) to dopamine receptors than first gen = produce less dopamine related side effects
  • clozapine, risperidone
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12
Q

This has a unique affinity for D4 receptors ad causes a serious side effect called agranulocytosis (WBC loss)

A

Clozapine ; not considered a first line therapy bc of the rare side effects

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13
Q

Alcohol distribution

A
  • throughout tissues
  • leaner ppl = there’s more water to dissolve into = lower BAC
  • larger people = larger body vol = lower BAC
  • alcohol seems to favour water than adipose tissue (doesn’t retain alcohol well)
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14
Q

T or F. Females have a greater BAC

A

T, they tend to be smaller (small size allows passage into brain) and less lean

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15
Q

Acute effects of ethanol consumption

A
  • inhibited decision making
  • unstable mood/heightened emotions
  • decreased anxiety
  • increased aggression
  • increased addiction
  • less REM sleep
  • impaired memory
  • impaired balance and coordination, vision impeded and taste and smell too
  • reduced perception of pain
  • dilated blood vessels of skin
  • reduced blood clotting
  • increased HDL levels
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16
Q

Acute effects of ethanol

A
  • Biphasic*
  • BAC rises = stimulant
  • BAC declines = depressant
  • metabolism causes phases
  • increased sociability, decreased anxiety
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17
Q

Why does alcohol affect perception?

A

interacts with brain receptors!

  • ethanol modulates glutamate and GABA receptor activity
  • tilts balance of neuronal activation towards hyper-polarization => inhibition
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18
Q

Heteropentameric receptors of GABA receptors

A

most have 2 alpha and 2 beta and one other

- conduct negative chloride current into neurons

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19
Q

Heterotetrameric receptors of NMDA receptors

A
  • all contain 2 NRI subnuits and either 2 NR2 or 2 NR3 subunits
  • conduct positive currents into neurons; depolarizing
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20
Q

Physiological effects of EtOH

A
  • vasodilation (warm skin but low core temp = autonomic brainstem nuclei)
  • loss of stomach mucosal lining = ulcers
  • spins (endolymph and cupula)
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21
Q

Metabolic tolerance of alcohol

A

due to liver adaptation

- up-regulation of enzymes, especially in heavy drinkers

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22
Q

Congener

A

minor chemical constituent, especially one that gives a distinctive character to a wine or liquor or is responsible for some of its physiological effects

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23
Q

Beer belly

A
  • ethanol is calorie-dense so problem if also malnutrition
  • 50% of caloric intake; complex carbs, especially beer!!!
  • metabolic changes in E usage -> brain metabolizes acetate not glucose
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24
Q

Acetate

A

calorie-dense product of ehtanol; can enter CAC and generate energy (not nutritional)

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25
Q

FASD

A

3rd trimester most vulnerable; affects synaptogenesis, facial development

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26
Q

Affected liver function due to disease

A
  • Steatosis (fatty liver) = lipid buildup in liver = yellow colour
  • Cirrhosis = nodules, fatty deposits, essentially all fibrous
  • scar tissue = liver has lost its ability to properly filter blood and metabolize toxins
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27
Q

Brain health after excessive alcohol consumption

A
  • acetaldehyde (ethanol metabolite) is reactive
  • modifies proteins = dysfunction = affects glucose metabolism, protein synthesis and myelin formation
  • damages neurons and cause cell death
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28
Q

Acetaldehyde

A

carcinogen; impairs DNA synthesis

- especially upper GI tract bc microflora metabolizes ethanol too ; can reach 10-100x higher conctns than in the blood

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29
Q

Disinhibition

A

release a neuron from inhibition - you’re activating it!!

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30
Q

Explain how the cupula affects brain’s position in space

A

whichever way the cupula deflects in the endolymph, it tells brain position in space ; ethanol leaves cupula first ( cupula a lot denser than endolymph); if lying down, cupula will be deflected but it’s supposed to be straight up ; brain perceives deflection as movement

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31
Q

the Limbic brain

A
  • circles the brainstem
  • ‘old’ neocortex that includes amygdala, hippocampus basal ganglia, and cingulate gyrus
  • connections to FC and hypothalamus
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32
Q

monoaminergic neurotransmitters

A

dopamine, norepinephrine ,and serotonin

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33
Q

Depression results from inadequate monoamine neurotransmission especially…

A

serotonin and noradrenaline in the brain

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34
Q

inadequate monoamine neurotransmission may be due to: (3)

A
  • fewer receptors
  • less neurotransmitter release
  • impaired signal transduction
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35
Q

Reserpine

A

antihypertensive drugs that block transporter necessary for moving dopamine into vesicles = depression symptoms

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36
Q

Ipronazid

A

anti-tubercular drug that alleviated depression by inhibiting MAO

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37
Q

Problems with amine hypothesis

A
  • drugs that restore
    monoaminergic levels are only moderately effective
  • inconclusive evidence that serotonin and noradrenergic systems are disrupted in depression
  • antidepressants = several weeks before effect is seen despite immediate effects on synaptic neurotransmitter levels
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38
Q

Monomine antidepressants

A
  • increase synaptic levels of monoamine neurotransmitters (ser and norepi)
  • MAO inhibitors
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39
Q

Tyramine cheese reaction

A
  • tyramine is a sympathomimetic monoamine (acts like noradrenaline)
  • naturally found in aged cheese
  • also degraded by MAO
  • combo with antidepressant = acute hypertension rxn caused by tyramine binding to adrenergic receptors on blood vessels and in heart
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40
Q

Transporters

A

move neurotransmitters from the synapse to the intracellular space

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41
Q

SSRIs

A
  • inhibit SET and NET
  • blocking transporters increase the extracellular concentration of neurotransmitters
  • inhibit both NET and SET = SNRI
  • fluoxetine
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42
Q

limitations of Monamine antidepressants

A
  • moderately effective in 30-50% of patients
  • several weeks before clinical effect is seen
  • MAOIs, SSRIs, and SNRIs affect levels throughout body = side effects such as nausea, indigestion, dizziness, dry mouth, weight loss, etc.
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43
Q

Ketamine

A

noncompetitive NMDA receptor antagonist

  • dissociative anesthetic w/ hallucinogenic properties
  • also possibly antidepressant
  • binds to an allosteric binding site ; within pore of the glutamate (NMDA) receptor ; blocks its ability to open and pass positively charged ions; acts as an antagonist
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44
Q

Glutamate antidepressant

A
  • ketamine
  • causes transient burst in glutamate resulting from blockage of NMDA receptors on GABA interneurons
  • glutamate burst = synaptic remodeling and resetting of systems
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45
Q

Ketamine clinical trials and limitation

A
  • showed promise in patients with treatment-resistant depression
  • very narrow therapeutic index
  • administered intravenously within hospital setting
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46
Q

SSRI vs Ketamine

A
  • SSRI = ~15% improvement after 8 weeks

- Ketamine = ~25% improvement after 1 day

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47
Q

Future treatments for Depression

A
  • targeting downstream effects
  • to increase cAMP, inositol, and CREB
  • ex: Rolipram
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48
Q

Heterogenous disease with multiple overlapping mechanisms

A

Depression

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49
Q

Transient alteration of behaviour due to abnormally excessive and synchronous neuronal activity in the brain

A

Seizures

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50
Q

Epilepsy

A

disorder of brain function characterized by the periodic and unpredictable occurrence of seizures

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51
Q

Occurrence of spontaneous, unprovoked seizures

A

Epilepsy

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52
Q

Other things that can look like seizures which are not

A

movement and sleep disorders, migraines (often predicted by aura - also seen in seizures)

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53
Q

T or F. Normally neurons fire asynchronously n the brain

A

T, spread of electrical activity is maintained by changes in membrane potential following depolarization (refractory period) and surround inhibition

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54
Q

Surround inhibition

A

physiological mechanism that focuses neuronal activity in the CNS

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55
Q

Three steps of seizures

A

initiation
propagation
termination

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56
Q

Seizure initiation characterized by two events:

A
  • high-frequency bursts of action potentials
  • hyper-synchronization of a neuronal population

**sustained neuronal depol = burst of APs driven by Ca influx through NMDA receptors

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57
Q

(SEIZURES) With sufficient activation, can overcome intact hyperpolarization and surround inhibition by: (3)

A
  • increasing extracellular potassium = blunts hyperpolarizing outward potassium
  • accumulation of Ca in presynaptic terminals = enhances neurotransmitter release
  • depolarization induced activation of the NMDA receptor = more Ca influx and neuronal activation
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58
Q

Mechanism that terminate a seizure are not well known but likely involve: (4)

A
  • loss of ionic gradients
  • depletion of ATP
  • depletion of neurotransmitters like glutamate
  • activation of inhibitory circuits (GABA)
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59
Q

Status epilepticus

A
  • seizure lasting longer than 5 mins
  • OR more than 1 seizure within a 5 minute period
  • life-threatening!
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60
Q

Postictal period

A
  • lasts 5-30 minutes after a seizure and is characterized by drowsiness, confusion, depression/anxiety, and sometimes psychosis (includes hallucinations and delusions)
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61
Q

Types of seizures characterized by:

A

location in brain they initiate and how widely they propagate

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62
Q

Focal seizures

A
  • may be simple (retain consciousness)
  • complex (loss)
  • jerking may start in specific muscle group then spread to surrounding muscle groups (Jacksonian March)
  • automatisms
  • may become generalized overtime
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63
Q

Automatisms

A

unusual activities that are not consciously created, like smacking the lips

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64
Q

Generalized seizures

A
  • tonic-clonic: sustained contractions of muscles throughout the body followed by periods of alternating muscle contraction and relaxation (previously: grand mal)
  • myoclonic: brief (~1s) shock like contraction of muscles that may be localized or generalized

**all involves loss of consciousness

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65
Q

Non-convulsive seizures

A
  • absence and atonic seizures
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66
Q

Absence seizures

A

abrupt onset of impaired consciousness

  • can be subtle with only a slight turn of the head or staring
  • loss of consciousness but person does not fall over
  • may return to normal right after seizure ends
  • there may be period of postictal disorientation (previously petit mal)
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67
Q

Atonic seizures

A

characterized by sudden loss of muscle strength

- consciousness maintained usually though person may fall down

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68
Q

Benzodiazepines vs Barbiturates (on GABA receptor)

A
  • benzodiazepine = no effect on GABA receptor without GABA

- barbiturates = can act as GABA agonists at higher conctns

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69
Q

Benzodiazepines vs Barbiturates (effect)

A
  • Benzodiazepines = increase frequency at which the GABA receptor opens ; increases potency of GABA
  • Barbiturates increase duration at which GABA receptor is open ; increases efficacy of GABA
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70
Q

Risks for Benzodiazepine and Barbiturates

A
  • overdose for both is possible
  • riskier for barbiturates bc of direct gating at GABA receptor
  • symptoms: sluggishness, incoordination, faulty judgment, and death
  • additive risk when taken with CNS depressants like alcohol and opioids
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71
Q

Vigabatrin

A
  • anti-seizure

- inhibit GABA-T

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72
Q

Tiagabine

A
  • anti-seizure

- inhibit GAT-1

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73
Q

Carbamazepine

A
  • anti-seizure
  • block voltage-gated Na channels in neuronal membranes
  • cause conformational change of inactivation gate
  • rate dependent = block increases with increased frequency of neuronal discharge = prolongation of inactivated state of Na channel and refractory period of neuron
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74
Q

Gabapentin

A
  • GABA covalently bound to a lipophilic cyclohexane ring
  • crosses BBB
  • little activity at GABA receptor (developed to be a centrally active GABA agonist) but inhibits voltage-gated Ca channels
  • binds to alpha-2-delta subunit of Ca channel (not a direct block; disrupts regulatory function)
  • blocking Ca influx reduces neurotransmitter (glutamatergic) release
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75
Q

Pharmacokinetic considerations of seizure drugs

A
  • used for long time to prevent recurrence so consider pharmacokinetic profile to avoid toxicity and drug interactions
  • despite wide variety, most exhibit similar pharmacokinetic properties = well-absorbed, good bioavailability, and cross BBB, low extraction rxns (long-acting)
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76
Q

T or F. Anti-seizure drugs can accumulate in fat tissues

A

T, lipophilic!

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77
Q

Can take these drugs once every few days, etc. better pharmacokinetic profiles than other lectures

A

Anti-seizure meds

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78
Q

Cannabinoids

A

class of chemical compounds that act at the cannabinoid receptors

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79
Q

Cannabis contains hundreds of phytocannabinoids:

A 
particularly delta-9 tetrahydrocannbinol (THC)
and cannabidiol (CBD)
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80
Q

Cannabis contains hundreds of non-cannabinoid constituents

A

including terpenoids which give plant characteristic smell

- anti-inflammatory, anti-bacterial and anti-anxiety effects??

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81
Q

THC Absorption

A
  • aka bioavailability
  • fraction of drug that reaches effectors (plasma, CNS)
  • smoking = rapid and efficient delivery from lungs to brain
  • bioavailability of smoked THC is 25%, reaching peak plasma conctn in 6-10 mins
  • vs. ingested = 6%; 2-6 hours
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82
Q

THC Distribution

A
  • highly lipophilic
  • tissues with less blood flow accumulate THC more slowly and release it over a longer period of time (ex: adipose tissue)
  • THC stored in fat in chronic users can be released into blood for days
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83
Q

THC Metabolism

A
  • liver by cytochrome P450 2C9 enzyme producing the metabolites 11-OH-THC and THC-COOH
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84
Q

THC Excretion

A
  • within 5 days, 80-90% of THC dose is excreted as metabolites mostly
  • 65% feces
  • 25% urine
  • can detect in urine (2-5 days for low dose THC)
  • weeks in chronic daily cannabis smokers bc lipophilic)
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85
Q

Cannabinoid receptors

A

Gi

CB1 and CB2

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86
Q

CB receptors lead to decrease in …

A

cyclic adenosine monophosphate (cAMP) accumulation which inhibits influx of Ca in firing neuron and inhibits neurotransmitter release
- decrease synaptic transmission = inhibit neurotransmitter release

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87
Q

T or F, THC is a full agonist at CB1

A

F! partial agonist!

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88
Q

Among the most abundant GPCRs

A

CB1

  • found on glial cells (non-neuronal cells of brain)
  • also found in peripheral organs (heart, liver fat, stomach, testes) and peripheral nerves
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89
Q

CB2 receptor distribution

A

mostly on immune cells

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90
Q

Potential therapeutic effects of THC

A

attenuation of nausea, increased appetite, decreased intraocular pressure, chronic pain relief

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91
Q

Adverse effects of Cannabis

A
  • acute effects: panic attacks, severe anxiety, psychosis, paranoia, convulsions, hyperemesis ; rare but associated with high THC doses
  • prenatal effects: neurodevelopment of fetus affected; dose-relationship not identified
  • lung cancer: especially smoked cannabis
  • driving: increases motor vehicle accident; THC impairs perception, psychomotor performance, cognitive functions, and affective functions; also decreased rxn time
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92
Q

COMT

A

enzyme important in degrading monoamine neurotransmitters particularly noradrenaline and dopamine

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93
Q

Tolerance

A

decreased response to the effects of the drug, necessitating ever larger doses to achieve the same effect

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94
Q

Psychological dependence

A

compulsive drug-seeking behaviour in which the individual uses the drug receptively for personal satisfaction, often in the face of known risks to health

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95
Q

Physiological dependence

A

revealed when withdrawal of the drug produces symptoms and signs that are frequently opposite of those sought by the user

96
Q

Substance use disorder

A

inability to control the use of legal or illegal substances despite negative consequences
- diagnosed by 11 diagnostic crieteria

97
Q

A manufactured compound whose properties imitate those of the active constituents of cannabis

A

Synthetic cannabinoids

- act in a similar way as THC but different structure

98
Q

Why synthetic cannabinoids?

A
  • increased specificity
  • decreased off target effects
  • easier dosing
  • better controlled studies
99
Q

Nabilone

A

partial agonist at CB1; synthetic analog of THC

100
Q

Dronabinol

A

partial agonist at CB1; (-) trans isomer of delta 9-THC, approved for nausea and vomiting in patients who undergo chemotherapy and anorexia in AIDS wasting syndrome

101
Q

Nabixmols

A
  • sativex
  • botanical drug (cannabis extract)
  • 1:1 mixture THC and cannabinol
  • sublingual spray
  • Canada; for pain relief (MS or cancer)
  • less psychotropic effects than smoked cannabinoids
102
Q

Rimonabant

A
  • inverse agonist at CB1 receptor

- obesity treatment but withdrawn due to serious adverse effects of depression and suicide ideation

103
Q

Endocannabinoid synthesis

A
  • similar types of molecules to arachidonic acid

- made from phospholipid bilayer of cell membrane

104
Q

Endocannabinoid signalling

A
  • AEA & 2-AG = retrograde neurotransmitters
  • not stored in vesicles; synthesized on demands when and where they are needed!!
  • act on CB receptors which are on PRESYNAPTIC membranes
105
Q

Endocannabinoid metabolism

A
  • AEA and 2AG are rapidly cleared from the synapse and inactivated by fatty-acid amide hydrolase (FAAH) monoacylclycerol lipase (MAGL)
  • suppression of these enzymes prolongs activity of endocannabinoids
106
Q

Opium

A

dried latex obtained from the poppy

107
Q

Opiates

A

any drug derived from opium

108
Q

Opioid

A

any drug that binds to an opioid receptor

- includes opiates, synthetic opioid agonists (fentanyl, heroin, oxycontin)

109
Q

Narcotic

A
  • Greek; “narco” = to make numb
  • originally referred to any drug with sleep-inducing properties
  • now usually used by law enforcement to refer to illegal use of opioids for non-medicinal purposes
110
Q

Opioid receptors

A
  • Gi

- leads to neuronal inactivation and reduced transmitter release

111
Q

Ligand specificity of opioid receptors

A
  • extracell loops = controls which ligand binds = form pocket that confers cell activity of ligand binding
  • intracell tail = which G proteins bind, how well, intracell signalling processes

least homology = extracell and intracell = happens in important regions = specificty

112
Q

Effects of mu opioid agonists

A
  • analgesia
  • reward
  • antitussive
  • respiratory depression
  • constipation
  • morphine, codeine, heroine
113
Q

Effects of mu opioid antagonists

A
  • aversive
  • prevent reward
  • block overdose
  • naloxone
114
Q

Naloxone

A

treatment for opioid addiction and overdose; antagonist is intensely unpleasant (counters positive mood) ; effective in acute overdose

115
Q

Effects of delta opioid agonists

A
  • not rewarding
  • no analgesia (except chronic pain, migraine)
  • some seizure-inducing (not commercially available, under investigation)
116
Q

Effects of delta opioid antagonists

A

no obvious effects

117
Q

Effects of kappa opioid agonists

A
  • aversive
  • hallucinogenic
  • anxiogenic (causes/increases anxiety)
  • Salvia (isolate form a plant; some ppl steep for tea; ppl use this recreationally)
118
Q

Effects of kappa opioid antagonists

A
  • potential antidepressant/anxiolytic
119
Q

Full mu opioid agonists include

A

morphine, methadone, fentanyl, and heroin

120
Q

T or F. Codeine is a full agonist at the mu opioid receptor

A

F, partial!

121
Q

This mu opioid agonist has a mild to moderate analgesic efficacy but a SAFER therapeutic index

A

Codeine; less likely to overdose

122
Q

T or F. Codeine is more potent than morphine

A

T!

123
Q

Buprenorphine

A
  • partial agonist at mu
  • antagonist at delta and kappa
  • common treatment for pain and opioid addiction - opioid agonist therapy
124
Q

opioid agonist therapy

A

Buprenorphine

125
Q

Beta-arrestins

A

family of intracellular proteins important for regulating signal transduction at GPCRs

126
Q

These proteins arrests G protein signalling that leads to tolerance following chronic opioid use

A

Beta arrestin ; also activates its own intracellular signalling pathways that contribute to some of the drug effects

127
Q

Receptor selectivity

A

selectivity for different receptor subtypes

128
Q

Functional selectivity

A

selectivity for different signalling pathways coupled to the same receptor

129
Q

Mu opioid receptor G-protein signalling pathway

A

drives analgesia

130
Q

Mu opioid beta arrestin signalling pathway

A

drives respiratory depression

131
Q

“tickling” the receptor

A

possibility of designing ligands that activate one pathway over the other to maintain analgesia without the respiratory depression (safer opioid?)
beta-arrestin vs GPCR

132
Q

T or F. Most mu opioids are well absorbed when taken orally

A

T! But morphine undergo extensive first-pass metabolism

& codeine avoids first pass so more effective orally!

133
Q

Morphine metabolized by …

A

phase II glucuronidation and morphine-6-glucuronide (M6G)

134
Q

Most important glucuronidation enzyme

A

UGT2B7 (morphine)

135
Q

morphine-6-glucuronide

A

an active metabolite

- can prolong morphine effects

136
Q

Addition of large polar bodies that makes them more likely to be excreted (it inactivates them)

A

Glucuronidation

137
Q

Codeine is metbaolized into morphine by …

A

CYP2D6; codeine is a prodrug!

138
Q

Slow vs fast metabolizers of CYP2D6

A

Slow CYP2D6 = Poor metabolizers = lower responses to codeine ; will require much higher doses to get same effect

Fast metabolizers of CYP2D6 = more analgesic but also susceptible to side effects

139
Q

These are excreted mainly in the urine (includes M3G and M6G)

A

polar metabolites; small amounts of unchanged drug also in urine

140
Q

Three types of endogenous opioid peptides

A

beta endorphins
enkephalins
dynorphins
- widely distributed neurotransmitters that mediate pain, reward, learning and memory, and cognition

141
Q

All opioid peptides share common AA sequence of:

A

Tyrosine, Glycine, Phenylalanine

Tyr-Gly-Gly-Phe

**various extensions are added during post-translational modification yielding opioid peptides from 5 to 31 AAs in length

142
Q

Beta endorphins

A

unbiased! GPCR and beta arrestin signalling

143
Q

Serine proteases

A

degrades endogenous opioids
by blocking the enzyme that degrades or metabolizes the neurotransmitters = increased levels of compound ; promoting effects of beta endorphins
Beta endorphins = mu opioid primarily and delta –> activation of mu = pain -> analgesia also euphoria

144
Q

T or F. Delta agonists are not effective in treating acute pain

A

T! If consistently in pain = delta receptors move to membrane so more delta on nociceptors so available to bind to agonists

145
Q

Opioid receptors are localized in the brainstem

A

rostroventral medulla

146
Q

Opioid receptors in rostroventral medulla

A

they increase diffuse noxious inhibitory control

147
Q

Dopamine neurons are located primarily in the …

A

ventral tegmental area (VTA)

148
Q

Mu opioid receptors in the VTA are located on …

A

inhibitory GABAergic interneurons

- so opioids inhibit inhibition (disinhibition) leading to dopamine release

149
Q

inhibitory GABAergic interneurons

- so opioids inhibit inhibition (disinhibition) leading to dopamine release

A

1) decreasing nociception at the level of the nociceptor, in the spinal cord, and in the brain stem
2) decreasing the emotional and cognitive aspects of pain (make the pain bother you less)

150
Q

Most opioid agonists used for pain are

A

mu agonists

151
Q

These opioid agonists are being developed for chronic migraines

A

delta agonists (seizures side effects)

152
Q

TRV250

A

delta opioid receptor biased agonist currently under development by Trevena

153
Q

Why are delta agonists not as effective at treating acute pain?

A

bc expressed very low in pain pathways in a normal individual not in pain… BUT conditions of chronic pain like migraines = up-regulation of expression of delta receptors on pain pathways

154
Q

Why have kappa agonists that penetrate brain not been developed for pain?

A

due to dysphoria/hallucinogenic effects (SALVIA)

155
Q

These kappa agonists do not cross the BBB

A

peripherally restricted kappa agonists

156
Q

These drugs bind kappa receptors in the skin and inhibit pain transmission while avoiding CNS adverse events

A

peripherally restricted kappa agonists

157
Q

CR845

A
  • peripherally restricted kappa agonists
  • potent analgesic
  • anti-inflammatory
  • anti-itch
  • little CNS effects
  • under development by Cara Therapeutics
158
Q

Tolerance

A

decreased response to the effects of the drug, necessitating even larger doses to achieve the same effect

159
Q

Desensitization to opioid agonists

A
  • following agonist binding and G-protein signalling, beta arrestin is recruited to shut off signalling
  • receptor+agonist is pulled off the membrane and recycled in an endosome (degraded or recycled back to membrane)
  • repeated opioid use leads to less receptors on the membrane = reduced agonist effect (tolerance)
160
Q

This develops following chronic opioid use and is revealed following abrupt discontinuance of drug as withdrawal

A

physical dependence

161
Q

Brain disease driven by dysfunction in reward, motivation, memory circuitry

A

Addiction

162
Q

Addiction characterized by: (5)

A
  • inability to abstain consistently
  • behavioural control impairment
  • drug craving
  • diminished recognition of significant problems with ones behaviours and interpersonal relationships
  • dysfunctional emotional response
163
Q

Agonist replacement therapy

A

comprehensive treatment approach including maintenance of an opioid agonist and cognitive behavioural therapy

164
Q

This blunts the symptoms of opioid withdrawal

A

Agonist replacement therapy

165
Q

T or F. Replacement agonists have longer half-lives, so avoid the repeated high/crash cycle

A

T

166
Q

Advantages to agonist replacement therapy

A
  • reduced drug cravings
  • better participation in addiction treatment (behaviour therapy) since withdrawal symptoms aren’t a distraction
  • improved socials functioning
  • reduction in infectious disease/death associated with illicit drug use
167
Q

Methadone

A
  • long-term acting full agonist at mu opioid receptor
  • first replacement therapy approved for opioid use disorder
  • disadvantage = full agonist so overdose still possible
168
Q

Partial agonist at mu opioid receptor and an antagonist at kappa and delta opioid receptor

A

Buprenorphine

  • safer agonist profile
  • antagonist activity at kappa may improve mood
  • marketed as suboxone (buprenorphine+nalaxone)
169
Q

T or F. Buprenorphine risk of abuse is much higher than methadone

A

F! much lower (partial agonist at mu)

170
Q

A psychoactive agent that causes changes in perception

A

hallucinogen

171
Q

Associated with substantial changes in thoughts, emotions, and consciousness

A

Hallucinogens

172
Q

Criteria for a drug to be classified as a hallucinogen: (5)

A
  • in proportion to other effects, changes in thought, perception, and mood should be predominate
  • intellectual or memory impairment should be minimal
  • stupor, narcosis, or excessive stimulation should be an integral effect
  • ANS side effects should be minimal
  • addictive craving should be absent
173
Q

Hallucinogenic effects of LSD is mediated by

A

5HT-2a

- mice knockout did not show head bobs to LSD

174
Q

High affinity partial agonist at 5HT-2a receptors

A

LSD

175
Q

Why don’t all 5HT-2a agonists cause hallucinations?

A

biased agonism

  • LSD activates phospholipase A2 instead of phospholipase C (like serotonin does)
  • leads to regulation of different genes
176
Q

Is pretreated with this it blocks hallucinogenic effects of LSD

A
  • Ketanserin

- 5HT-2a antagonist

177
Q

LSD effects

A
  • dilated pupils, increased heart rate and BP
  • sensory perception distortion
  • sometimes feeling of enlightenment
  • adverse psychiatrics effects such as anxiety, paranoia, and delusions are possible
  • hallucinogen persisting perception disorder (HPPD)
178
Q

HPPD

A
  • hallucinogen persisting perception disorder
  • distressing visual hallucinations that appear following drug use
  • rare!
  • can persist for months, years after a bad trip and harm a person (heavily distressing)
  • can be deadly ; don’t know true mechanism driving the perception differences but maybe involves changes in serotonin signalling and visual cortex changes
179
Q

LSD Tolerance

A
  • single dose can lead to profound tolerance that lasts for several days
  • accompanied by down-regulation of 5-HT2 but not other 5-HT receptors
  • cross-tolerance of LSD w/ other hallucinogens acting at serotonin receptors (psilocybin and DMT)
180
Q

Analogue to serotonin

A

psilocybin

181
Q

What happens when psilocybin mushrooms are ingested?

A
  • euphoria
    • visual and mental hallucinations
  • changes in perception
  • distorted sense of time
  • spiritual experiences
  • adverse: nausea and panic attacks
182
Q

One of the few hallucinogenic drugs that are self-administered in animals (addiction liability)

A

Phencyclidine

183
Q

Exception to rule – addictive and drug of abuse through its activity at the dopamine transporter (hallucinogens)

A

Phencyclidine

184
Q

Analgesia of nitrous oxide might be due to

A

release of dynorphin and activation of kappa opioid receptor

185
Q

Atropine and scopolamine

A
  • tropane alkaloids from Datura plant

- competitive antagonists at the muscarinic cholinergic receptors

186
Q

Leading cause of disability worldwide, particularly in those under 50

A

Migraine

187
Q

Visual disturbances consisting of flashing lights or zigzag lines moving across the field of vision

A

Aura

188
Q

T or F. Migraines affect more men than women

A

F! More women than men

- increase incidence in women due to hormones?? (after puberty)

189
Q

Familial hemiplegic migraine

A
  • includes weakness of half of the body
  • autosomal dominant inheritance
  • mutations associated with FHM (P/Q-type Ca channel, Na+/K+ ATPase, Na+ channel subunit)
  • mutations lower threshold for cotrical spreading depression
190
Q

Largest cranial nerve

A

Trigeminal nerve

191
Q

Peripheral processes of the trigeminal system is divided into three branches

A

Ophthalmic, maxillary, and mandibular

192
Q

3 purposes of trigeminal system

A
  • sense pain and temp in head region
  • innervates dura matter
  • controls cerebral blood vessels (trigeminovascular system)
193
Q

Serotonin and Migraine

A

Vessels have serotonin receptors and release of serotonin = vasoconstriction particularly the 5HT-1D receptors on vessels

194
Q

Calcitonin gene-related peptide (CGRP)

A
  • trigeminal peripheral afferents
  • released from afferents in response to pain => vasodilation
  • CGRP elevated in those with migraine
195
Q

Potent vasodilators that are tuned to pain detection (primarily in nociceptors)

A

CGRP; elevated levels in those with migraines

196
Q

Prophylactic vs Abortive strategies for migraines

A
  • Prophylactic: give drug before someone has migraine chronically to reduce likelihood (taken daily)
  • Abortive: taken once an attack occurs (to avoid severity or to avoid when feel coming on)
197
Q

Propanolol for migraines

A
  • beta blockers
  • antagonist at beta adrenergic receptors
  • works by decreasing BP to have less pressure on cerebral blood vessels = reduce trigger of migraines within cerebral vasculature
198
Q

Anticonvulsants for migraines

A
  • gabapentin
  • works by inhibiting Ca channels which can reduce neuronal activity that can promote seizures
  • may also inhibit cortical spreading depression in migraine
  • shown to be effective at blocking pain transmission - first line therapies or chronic pain treatments
199
Q

Antidepressant for migraines

A
  • increasing levels of serotonin in synapse
  • works to normalize serotonin levels to normal levels to remove risk factor that could be contributing to development of migraine
200
Q

Medication overuse headache

A

severe cases of migraines; emergency room -> give opioids; can be effective short-term but risk of med overuse headache - constant use of opioid drug = make headaches worse!

  • someone with headaches greater than 15days/month
  • regular overuse >3mos
  • headache has developed or markedly worsened during medication overuse
201
Q

First specific anti-migraine agents

A 
ergot alkaloid (like LSD)
- no longer first line therapy
202
Q

Treatment strategies under development for migraines

A
  • small molecule CGRP antagonists

- monoclonal antibodies to CGRP/CGRP receptors

203
Q

Pathway to drug development

A
  • preclinical
    (approved for human testing)
  • safety
  • efficacy
  • larger population = confirm findings (rare side effects more detectable with more ppl)
  • FDA revirew to confirm safety and effectiveness
  • drug approved
204
Q

Rimegepant (Nurtek)

A
  • one of few remaining small molecule CGRP receptor antagonists that remains in clinical development
  • effective migraine treatment
  • less effect on liver aminotransferase levels (safer for longterm use)
  • FDA approved
205
Q

Peptidoglycan structure

A
  • alternating glycan strands: GlcNAc and MurNAc
  • cross-linked by peptides
  • indiv strands polymerized by enzyme glycosyltransferase in to pg chain
  • transpeptidase cross link the strands (penicillin binding protein)
206
Q

therapeutic index

A

ratio of minimum concentration likely to produce an adverse effect to the minimum concentration needed to produce a desired effect

207
Q

ability to penetrate

A

delivery of antibiotics to site of infection is most difficult challenge of antibiotic delivery

208
Q

Acremonium

A

Fungus that provided cephalosporins

209
Q

Penicillium notatum

A

fungus for Penicillin

210
Q

Beta lactams

A
  • unusual 4 member rings of penicillins and cephalosporins
  • inhibit cell wall synthesis by inhibiting DD-transpeptidase (responsible for cross-linking)
  • bacteriocidal
  • also called PBP
  • originally only effective on gram + (still work better on them though)
211
Q

Beta-lactamases

A
  • made by many gram negs that hydrolyze beta-lactam ring

- Staph

212
Q

Beta-lactamase inhibitors

A
  • Calvulanic acid
  • potent inhibitors of beta-lactamases used in combinations to protect hydrolyzable penicillins from inactivation
  • given together with beta-lactams for protection
213
Q

Vancomycin

A
  • NOT a beta-lactam (no 4 ring)
  • also inhibits peptidoglycan cross-linking
  • Actinobacteria
214
Q

Bacteria use this to synthesize nucleic acids that make up their DNA

A

folic acid

215
Q

A nutrient obtained from the environment that is the precursor for folate in bacteria

A

PABA (metabolic pathway that is unique to bacteria)

216
Q

These resemble PABA and dihydrofolic acid respectively, and interfere with PABA metabolic pathways

A

Sulfonamides and trimethoprim

217
Q

Usually given together to block sequential steps in synthesis of folic acid

A

Sulfonamides and trimethoprim

218
Q

This adds AA to growing AA chain

A

transpeptidase (tRNA)

219
Q

Chloramphenicol and Macrolides

A

bind to 50S subunit and block transpeptidation

220
Q

Tetracyclines

A

bind to 30S subunit to prevent binding of incoming tRNA

221
Q

Aminoglycosides

A

bind 30S ribosomal subunit

  • blocks initiation of complex
  • cause misreading of the code on mRNA template
  • inhibit translocation
222
Q

Aminoglycosides block protein synthesis at multiple levels

A
  1. Two ribosomal subunits have to come together before RNA can be translated into protein so aminoglycosides blocks this
  2. Wrong amino acid added to growing change or none at all (nonsense sequence)
  3. Block translocation; after protein is made, need to be released to cell so it can float around intracell space; process of releasing = translocation = aminoglycosides block the release/translocation of mature peptide/protein form ribosome
223
Q

T or F. Eukaryotes can synthesize folic acid from PABA

A

F! they can’t; only prokaryotes can

224
Q

Bacterial resistance

A
  • drug inactivation or modification (beta lactamases)
  • alteration of binding site (MRSA alteration of PBP)
  • alteration of metabolic pathways (sulfonamide resistant bacteria begin to use pre-formed folic acid)
  • reduced drug accumulation (efflux pumps)
225
Q

Stevens-Johnson syndrome and toxic epidermal necrolysis

A

rare conditions in which the skin becomes detached from the underlying tissue and sloughs off the body
**Lower dermis detached from epidermis(upper layer of skin)
Not known why antibiotics cause these effects = autoimmune rxn maybe ?

226
Q

Anticholinergic medication can ________ _______

A

impair vision

= falls!

227
Q

High risk medications for seniors

A
  • proton pump inhibitors
  • benzodiazepines
  • natural opium alkaloids
228
Q

Potentially inappropriate medication

A

Beers Criteria

229
Q

T or F. Women tend to use more meds and also more PIMs

A

T

230
Q

Excessive use of medication

A

polypharmacy

231
Q

Changes in organ system when aging

A

5h decade; 40s

232
Q

T or F. Less CO when aging

A

T! more sensitive to CV meds in terms of vasodilation = dizziness!

233
Q

For medications oxidatively metabolized, _______ dose

A

reduce

234
Q

Drug dose adjustments in older adults is mostly due to

A

renal function

235
Q

Paradox of exposure for older adults

A

the more exposed to meds = the more sensitive

PMCOL 200 (4 decks)

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