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Pharmacology Exam #4 > Pharm Exam #4 > Flashcards

Pharm Exam #4 Flashcards

1
Q

Schizophrenia Symptoms

A

Positive symptoms: “additional” things not seen in healthy individuals
-Delusions: ongoing false beliefs pertaining to one’s self
-Hallucinations: seeing or hearing things that are not really there
Negative Symptoms: characteristics that are lacking in schizophrenic individuals
-flat effect
-alogia: decrease in speech fluency
avolition: decrease in initiation of goal directed behavior
-anhedonia: lack of ability to derive joy
Cognitive symptoms: decreased executive function
-Working memory
-Planning
-Prefrontal cortex of brain

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2
Q

What causes schizophrenia?

A
  • Unknown: likely genetic and environmental factors
  • 50% concordance in monozygotic twins
  • Possibilities of infection of malnutrition before birth or during early childhood
  • No objective test, and it probably better thought of as many closely related disorders
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3
Q

Structural changes of the brain in schizophrenia

A
  • Typically have larger ventricles
  • Atrophy of some parts of cerebral cortex
  • Decreased synaptic connections and activity in prefrontal cortex
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4
Q

Dopamine hypothesis: schizophrenia

A
  • Amphetamines, which cause massive DA release, can cause psychosis
  • Levodopa can cause hallucinations
  • PET scans show increased mesolimbic activity
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5
Q

Typical antipsychotics

A
  • Older drugs

- Primarily block D2, no 5-HT receptor blockade

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6
Q

Atypical antipsychotics

A
  • Block D2 and 5-HT receptors

- Different side effect profile; fewer extrapyramidal symptoms

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7
Q

Haloperidol, chlorpromazine

A

Typical (1st gen) antipsychotics

  • Efficacy of typical antipsychotics is directly correlated with amount of D2 receptor blockade
  • Primarily alleviate the positive symptoms of schizophrenia (delusions, hallucinations)
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8
Q

Quetiapine, risperidone

A

Atypical (2nd gen) antipsychotics

  • Block D2 receptors, but less than typicals
  • Block serotonin 5-HT receptors
  • Less serious effects on nigrostriatal DA signaling
  • Alleviate positive and negative symptoms
  • Generally fewer adverse effects
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9
Q

Clozapine

A

Clinical effectiveness:
-30% of patients resistant to other antipsychotics will respond to clozapine
-Not a first line medication due to side effects
-effective against positive, negative and cognitive defects
Side effects:
-Orthostatic hypotension
-Agranulocytosis; regular monitoring of white blood cell counts required
-Sedation
-Seizures

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10
Q

Adverse effects related to antipsychotics

A
  • Generally more severe with 1st gen due to higher DA blockade
  • Extrapyramidal symptoms: problems related to motor function –> parkinsonism due to blockade of basal ganglia dopamine receptors, akathisia (restlessness of the legs)
  • Galactorrhea due to blockade of pituitary DA receptors
  • Metabolic syndrome –> obesity, elevated triglycerides, reduce HDLs, elevated BP, elevated fasting glucose levels
  • Neuroleptic malignant syndrome –> some symptoms attributed to D2 blockade, autonomic nervous system collapse, muscle rigidity - tx = stop antipsychotic, dopamine agonist and dantrolene may help
  • Tardive dyskinesia and perioral tremor - involuntary movements of the face and extremities that occurs after longer term use
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11
Q

Major neurotransmitters of the CNS

A
  • Acetylcholine
  • Catecholamines: dopamine, NE, Epi
  • Amino acids: glutamate, glycine, GABA
  • Peptides: opioids such a Beta-endorphin
  • Glutamate is the most prevalent neurotransmitter in the CNS
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12
Q

Ionotropic receptors

A
  • Work by directly passing ions across the membrane
  • Inhibitory neurotransmitters open channels that allow negative ions (usually Cl-) to enter cells and cause hyperpolarization
  • Excitatory neurotransmitters open channels that allow positive ions (Na+, Ca2++) to enter cells and cause depolarization
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13
Q

Metabotropic receptors

A
  • G protein-coupled receptors - work through second messenger pathways inside the cell
  • Downstream actions can open/close ion channels and/or lead to changes in gene transcription
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14
Q

Nigrostriatal pathway

A
  • Substantia nigra to striatum

- Important in posture and movement, main area of Parkinson’s disease pathology

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15
Q

Mesolimbic/mesocortical pathways

A

Complex behavior, psychosis, schizophrenia

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16
Q

Ventral tegmental area to nucleus accumbens

A

Reward-driven behavior/addiction

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17
Q

Tuberoinfundibular

A

Regulates pituitary gland

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18
Q

Parkinson’s Disease

A
  • Neurodegenerative disease
  • Loss of dopamine-producing neurons in the substantia nigra that project to the striatum (nigrostriatal neurons)
  • Cause unknown except small percentage of cases with clear genetic mutation –> age-related, association with farm occupations, more common in men and whites, cigarette smoking linked with lower incidence of PD
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19
Q

Parkinson’s neuropathology

A
  • Normally, nigrostriatal neurons inhibit inhibitory neurons and stimulate excitatory neurons –> overall excitatory effect
  • This causes symptoms related to an inability to initiate and properly perform movement
  • By the time symptoms emerge, 60-80% of substantia nigra neurons are gone –> remaining ones filled with clumps of protein called Lewy bodies
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20
Q

Parkinson’s hallmark symptoms (TRAP)

A
  • Tremor
  • Rigidity
  • Akinesa/bradykinesia
  • Postural instability
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21
Q

Ropinirole

A

Dopamine agonist

  • Can be used alone or in combination with levodopa
  • Lower overall efficacy compared to levodopa, but also fewer motor fluctuations
  • Adverse effects: similar to levodopa
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22
Q

Rasagiline

A

MAO-B inhibitor - decrease breakdown of dopamine

  • Reduces the breakdown of dopamine by monoamine oxidase-B
  • Can be used alone, but effect is small and not seen by all patients
  • Adverse effects: may cause confusion in older patients
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23
Q

Tolcapone

A

COMT inhibitors - decrease breakdown of dopamine –> accessory to levodopa treatment

  • Reduced breakdown of levodopa and dopamine
  • Not effective as individual agent
  • Extends action of levodopa in patients who experience “wearing off” phenomenon
  • Adverse effects mainly related to levodopa
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24
Q

Levodopa (L-DOPA)

A
  • Dopamine is synthesized from tyrosine
  • DOPA: intermediate between Tyr and DA
  • Levodopa taken up by dopaminergic neurons and converted into dopamine
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25
Q

Carbidopa/Levodopa

A
  • Levodopa is extensively metabolized in the body by peripheral decarboxylase enzymes (AADC)
  • Peripheral conversion of levodopa into dopamine causes systemic side effects and limit the desired therapeutic effect
  • Therefore, levodopa almost always given with carbidopa, an AADC inhibitor
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26
Q

Treatment strategy for Parkinson’s

A
  • Dopamine agonists (ropinirole) and MAO-B inhibitors (rasagiline) are modestly effective and can be used as monotherapy in early PD
  • Some clinicians believe that benefit from levodopa is finite; therefore, delay starting it
  • In patients with more severe symptoms, carbidopa/levodopa is treatment of choice, possibly combined with other drugs
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27
Q

Levodopa Side Effects

A
  • Nausea, drowsiness, dizziness, headache most common but not usually severe
  • Older patients: delusions, hallucinations, orthostatic hypotension
  • Movement related –> motor fluctuations (wearing of phenomenon and on-off phenomenon) and dyskinesias (involuntary abnormal movements)
  • Dopamine dysregulation syndrome –> addictive-like behavior toward dopaminergic dugs, mood and behavioral changes, compulsive behaviors, punding
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28
Q

Duration of levodopa therapy

A
  • Optimal therapeutic effect for 3-5 years in most patients

- Over time, positive effects diminish –> side effects, particularly dyskinesias, become more severe

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29
Q

Alzheimer’s Disease

A
  • Most cases are age-related (>65) and sporadic (not linked to specific gene mutation)
  • Memory loss, personality/behavioral changes; progressive
  • Risk Factors: family history, head injuries, poor cardiovascular health
  • Much remains unknown about pathology
  • Accumulation of amyloid beta plaques outside neurons, and neurofibrillary tangles of tau protein inside neurons
  • Neuronal death –> cholinergic neurons particularly affected, overstimulation of NMDA (glutamate) receptors
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30
Q

Donepezil

A

Anticholinesterases

  • Generally more beneficial early in disease
  • Modest overall effect
  • Typical anticholinesterase side effects
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31
Q

Memantine

A

NMDA antagonist

  • Approved for moderate to severe disease
  • Modest overall effect
  • Fewer side effects compared to anticholinesterases
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32
Q

Seizures: Terms

A
  • Seizures –> abnormal function of ion channels and neural networks leading to rapid, synchronized and uncontrolled spread of neural activation - classified according to clinical manifestations rather than underlying biological mechanisms
  • Convulsions –> outward manifestations of sudden, excessive, neuronal activity in the cerebral cortex
  • Epilepsy: recurrent spontaneous seizures, common neurologic disorder
  • Status epilepticus: 30+ minutes of continuous seizure activity or a series of seizures without return to full consciousness between the seizures
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33
Q

Seizure Pathophysiology

A

-Surround inhibition: keeps action potentials from spreading outside appropriate neural pathway
Seizures:
-Failure of surround inhibition
-Rapid, uncontrolled firing of action potentials
-Synchronous firing of neuronal populations

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34
Q

Focal seizures

A
  • Restricted to one hemisphere
  • Effects depend on parts of brain involved (visual cortex - flashing lights; motor cortex - involuntary movement of part of body)
  • Aware and impaired awareness variants
  • Focal to bilateral tonic-clonic –> begins as a focal seizure that spreads to the other hemisphere (tonic-clonic = full body muscle contraction followed by rhythmic shaking of limbs)
  • Focal seizures may be preceded by an aura: characteristic sensations/perceptions that vary between individuals
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35
Q

Primary Generalized seizures

A

-Involves both hemispheres
-Signals between thalamus and cortex
Variants:
-Motor - i.e. tonic, clonic
-Nonmotor (absence) - sudden, brief interruption of consciousness, blank stare

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36
Q

Absence seizures

A
  • Characterizes by abnormal activity of T-type Ca++ channels
  • Normally, these channels are active during sleep and prevent sensory information from the thalamus from being transmitted to the cortex
    1. Hyperpolarization of relay neuron opens T-type calcium channels leading to depolarization and burst firing
    2. Activates glutamatergic neurons projecting from cortex to GABA interneurons in the thalamus
    3. Activation of GABAergic cells in the thalamus hyperpolarized relay cell and reinitiates the cycle
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37
Q

Ethosuximide

A

Treatment of absence seizures

  • Mechanism of action: blocks T-type calcium channels on thalamic relay neurons that underlie absence seizures
  • Clinical Use: Only effective in treating absence seizures. First choice for uncomplicated absence seizures.
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38
Q

Tonic-clonic seizures

A
  • Tonic phase initiated by a sudden loss of GABA-mediated surround inhibition
  • Rapid train of action potentials leading to tonic contraction of muscles
  • As GABA activity is restored, it oscillates rhythmically with the excitatory component
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39
Q

Carbamazepine

A
  • Mechanism of action: prolongs the inactive state of sodium channels following an action potential - decreases repetitive firing of action potentials
  • Note: it does not alter spontaneous activity. Thus, it can exert antiseizure activity in the absence of general depression of CNS activity
  • Clinical Use: First choice in the treatment of focal seizures as well as primary generalized tonic-clonic seizures
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40
Q

Phenytoin

A
  • Mechanism of action: prolongs recovery from inactivated to resting state; use-dependent
  • Clinical Usage: efficacious in the treatment of focal or generalized tonic-clonic seizures, elicits severe and somewhat predictable side effects: movement and coordination problems, gingival overgrowth, anemia
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41
Q

Valproic Acid

A
  • Mechanism of action: prolongs the inactive state of voltage-gated sodium channels, produces small reductions of activity in T-type calcium channels
  • Clinical Usage: very effective in epilepsy with mixed seizure types; while ethosuximide is the drug of choice for absence seizures alone, valproic acid is the drug of choice when the patient has concomitant absence and generalized tonic-clonic attacks
  • Notable adverse effects: teratogenic
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42
Q

Lamotrigine

A
  • Mechanism of action: similar to phenytoin and carbamazepine, but effective against more types of seizures, likely other mechanisms of action
  • Clinical usage: focal or generalized tonic-clonic seizures, also effective in absence seziures
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43
Q

Topiramate

A
  • Mechanism of action: prolong the inactive state of voltage-gated sodium channels, inhibits voltage-gated calcium channels, activates GABA receptors and inhibits NMDA glutamate receptors
  • Clinical Usage: used to treat focal or generalized tonic-clonic seizures, also FDA approved for weight loss, prescribed (off label) for the treatment of migraine
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44
Q

Benzodiazepines: diazepam, midazolam

A
  • Mechanism of action: primary site of action is GABA-induced influx of chloride via GABA receptors (increase inhibitory signaling)
  • Clinical Use: to abort seizures acutely, tolerance and side effects (dizziness, drowsiness) limit use in seizure management
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45
Q

Gabapentin

A
  • Mechanism of action: increases GABA content of GABA neurons - however, the main antiseizure activity of the drug is blocking HVA calcium channels
  • Clinical Use: not a first-line agent for seizures due to lack of efficacy, does have other indications: neuropathic pain, restless legs
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46
Q

Levetiracetam

A
  • Mechanism of action: believed to inhibit neurotransmitter vesicle release by binding to a synaptic protein
  • Clinical Use: adjunct for partial seizures
47
Q

Barbiturates: phenobarbital

A
  • Mechanism: enhances activity of GABA receptor
  • Clinical Use: effective in focal and tonic-clonic seizures, use limited by sedation, use has decreased as better options available
48
Q

Migraine headache

A

-May be preceded by sensory or visual aura
Thought to be due to neurovascular dysfunction:
-Vasoconstriction and ischemia associated with serotonin release
-Vasodilation and pain due to release of substance P and calcitonin gene-related peptide (CGRP) from trigeminal neurons

49
Q

Drugs used to prevent migraine headaches

A
  • Antidepressants
  • Anticonvulsants
  • Beta Blockers
  • NSAIDs
  • Calcium channel blockers
  • CGRP receptor antibody: erenumab
50
Q

Drugs used to abort migraine headaches

A
  • Serotonin 5-HT receptor agonists: sumatriptan
  • Ergot alkaloids: ergotamine
  • NSAIDs
  • Tramadol
51
Q

Erenumab

A
  • Mechanism: monoclonal antibody that binds and blockers CGRP receptor
  • Monthly subcutaneous injection
  • Adverse effects: minimal in clinical trials, long term effects of CGRP blockade unknown
52
Q

Sumatriptan

A
  • Mechanism: 5-HT agonist, inhibition of CGRP release through action of autoreceptors, direct stimulation of vasoconstriction
  • Generally first-line for aborting migraines
  • Adverse effects: contraindicated in coronary artery disease, paresthesia, dosage must be limited due to vasoconstriction and other adverse effects
53
Q

Ergot alkaloids

A
  • Produced by Claviceps purpurea, a fungus that grows on grain
  • Contains psychoactive compounds, vasoconstrictors and stimulators of muscle contraction: extreme peripheral vasoconstriction results in gangrene, abnormal body movements, pregnancy termination
  • Historically associated with mass poisonings
54
Q

Ergot alkaloid: ergotamine

A
  • Mechanism of action: anti-migraine effects similar to triptans, also acts on other serotonin receptors
  • Available in combination with caffeine
  • Adverse effects: long-lasting and cumulative vasoconstriction limits dosage, pregnancy category C due to stimulation of uterine smooth muscle
55
Q

Attention Deficit Hyperactivity Disorder

A
  • Characterized by the inability to volitionally control attention and impulsive behavior leading to problems with inattention and/or hyperactivity-impulsivity
  • Treatment generally involves low-dose stimulants that help to drive focus and attention
  • Dose-dependent effects: high doses of these drugs are cognition-impairing and induce hyperlocomotion
  • Enhance transmission of NE (and other neurotransmitter)
56
Q

Norepinephrine from the Locus Coeruleus

A
  • Promotes the activity states necessary for acquisition of sensory information (NE is high during wake states and low during resting states)
  • Within the waking state, NE modulates the processing of salient sensory information
  • Given the wide distribution of LC-NE projections, dysregulation of the LC-NE system may result in deficits in a variety of cognitive and affective processes that are, in turn, associated with numerous cognitive and affective disorders such as: ADHD, narcolepsy, stress-related disorders
57
Q

Methylphenidate

A
  • Derivate of amphetamine (most effective agents are derivatives of amphetamine)
  • Blocks reuptake of dopamine (DA) and norepinephrine (NE)
  • Adverse Effects: abuse potential, insomnia, nausea, decreased appetite
58
Q

Atomoxetine

A
  • NE reuptake inhibitor
  • Lower abuse potential compared to amphetamines
  • General contraindications for drugs that affect NE: CVD, MAOIs, sympathomimetics
59
Q

Modafinil

A
  • Weak effects on several neurotransmitter systems
  • Exact mechanism for increased alertness is unknown
  • Primary approved use: narcolepsy
60
Q

Anxiety Disorders

A
  • Generalized anxiety disorder: disorder characterized by chronic anxiety, worry and tension, often in the absence of a precipitating event
  • Social phobia/social anxiety disorder: disorder characterized by overwhelming anxiety and excessive self-consciousness in everyday situations
  • Agoraphobia: fear/avoidance of public spaces and other situations where one might feel trapped
  • Situational anxiety: state of uneasiness and apprehension triggered by a variety of stimuli including drugs, disease and environmental stressors
61
Q

Drug treatments for anxiety disorders

A
  • SSRI antidepressants usually best choice for long-term management of anxiety disorders
  • Buspirone: alternative monotherapy or added to SSRI
  • Benzodiazepines: patients should have low depressive symptoms and low substance abuse potential can be used, can be used short term for situational anxiety, can be used as bridge to effectiveness of SSRI of therapy
62
Q

Pharmacological targets for anxiolysis

A
  • Sedative/hypnotic drugs –> increase GABA signaling
  • Buspirone –> acutely inhibits firing of serotonin neurons
  • Selective serotonin reuptake inhibitors (SSRIs) –> target serotonin signaling/ acute administration; acute administration can increase anxiety, more effective following long-term treatment
  • Antiadrenergic Agents: target NE signaling to inhibit peripheral manifestations mediated by the sympathetic nervous system
63
Q

Dose dependent effects for sedative-hypnotic drugs

A

Anxiolysis (decreased anxiety) –> Sedation (calmness) –> Hypnosis (sleepiness) –> Aesthesia (unconsciousness) –> Death

64
Q

GABA(A) Receptor

A
  • Five subunits; composition is variable
  • Different pharmacological profiles based on subunit composition
  • Non-benzodiazepine hypnotics such as zolpidem bind a more restricted set of GABA(A) receptors compared to benzodiazepines
65
Q

Benzodiazepine anxiolytic drugs

A

Mechanism of Action:
-Bind to an allosteric site on GABA(A) receptor that increases channel affinity for GABA
-Positive allosteric modulator that increases frequency of channel opening
-Produces CNS depression but with a ceiling effect
BZD uses: anxiolysis, sleep, sedation, anti-seizure, muscle relaxant, ethanol withdrawal

66
Q

BZD Drug Choice (short acting, intermediate, long acting)

A
  • Short acting: triazolam, midazolam
  • Intermediate: alprazolam
  • Long acting: diazepam
67
Q

BZD Adverse Effects

A
  • CNS depression: excess sedation, ataxia, amnesia
  • Respiratory depression: usually not serious with BZD alone, serious risk when combined with alcohol, opioids, other CNS depressants, other specific drugs that alter BZD metabolism
  • Tolerance and physical dependence
68
Q

Flumazenil

A

BZD antagonist: can reverse overdose

69
Q

Pentobarbital

A

Barbiturates

  • Mechanism of action: Bind GABA(A) at a site distinct from BZD, cause increase in opening duration of channel
  • More powerful CNS depressant effects compared to BZD
  • Uses: anxiety/insomnia (rarely), emergency treatment of seizures
70
Q

Zolpidem

A

Non-BZD hypnotics (Z-drugs)

  • Mechanism: bind a more restricted set of GABA(A) receptors compared to BZD, leading to hypnotic effect
  • Use restricted to insomnia
  • Less alteration of sleep cycles and hangover effects compared to BZD
  • Adverse effects: amnesia, sleep-walking/driving/eating
71
Q

Buspirone

A

Azapirone

  • Mechanism of action: 5-HT(1A) partial agonist, found in several brain regions; pre and post-synaptic, effects take 2-3 weeks to develop
  • Moderate anxiolytic
  • No sedation or abuse potential
72
Q

Melatonin

A
  • Available as a supplement - not an FDA-approved drug

- Hormone that promotes sleep

73
Q

Ramelteon

A
  • First approved insomnia treatment that targets melatonin receptors
  • Advantages: no affinity for GABA receptors, limited interactions with other CNS depressants, little abuse potential
  • Disadvantages: post-marketing reports of reduced testosterone or elevated prolactin, overall effect is modest
74
Q

Phenelzine

A

Monoamine oxidase inhibitor

  • Mechanism: inhibit MAO-A and MAO-B irreversibly
  • Adverse effects: serious potential for hypertensive crisis with sympathomimetics and tyramine-containing foods (processed meat, hard cheeses, red wine), two-week washout required before using sympathomimetic or other classes of antidepressants
75
Q

Imipramine

A

Tricyclic antidepressants (TCAs)

  • Mechanism: block monoamine reuptake, specific TCAs preferentially block either NE or 5-HT - but clinical efficacy is similar
  • Adverse effects: most serious is blockage of cardiac NA+ channels leading to conduction block, can also cause blockade of muscarinic, histamine and adrenergic receptors
76
Q

Fluoxetine, citalopram

A

Selective serotonin reuptake inhibitors (SSRIs)

  • Mechanism: blockade of serotonin reuptake
  • SSRI similar in efficacy to TCAs and to one another
  • Overall better tolerated that TCA, less severe side effects
77
Q

SSRI Side Effects

A

-Sexual effects: decreased libido, delayed orgasm
-GI symptoms: diarrhea, constipation
Drug interactions: some SSRIs inhibit CYP enzymes )i.e. fluoxetine is a potent CYP2D6 inhibitor)
-Serotonin syndrome: if combined with MAOI or other drugs that increase 5-HT levels –> hyperthermia, muscle rigidity, myoclonus, rapid fluctuations in mental status and vital signs
-Note: SSRI active metabolites can persist for weeks (long 1/2 life)

78
Q

Suicide risk of SSRIs?

A
  • Controversial: conflicting evidence, possible small effect
  • In FDA review no suicides but 4% thought about or attempted: this was double the rate of placebo group
  • Main counterpoint: untreated depression is definitely linked to suicide
79
Q

Duloxetine, venlafaxine

A

Serotonin norepinephrine reuptake inhibitors (SNRI)

  • Some patients who do not respond to SSRI respond to SNRI
  • Some evidence to support choosing SNRI over SSRI in severe depression
  • Fairly similar adverse effect profile compared to SSI including potential for serotonin syndrome if combined with other serotonergic drugs
80
Q

Bupropion

A

Atypical Antidepressant

  • Mechanism not fully understood
  • Weak monoamine reuptake inhibitor
  • Metabolites block nicotinic Ach receptors
  • Lowers seizure threshold
  • Lowest rate of sexual dysfunction for antidepressants
81
Q

Mirtazapine

A

Atypical Antidepressant

  • Blocks alpha-2 autoreceptors and interacts with some 5-HT receptor types
  • Anxiolytic and hypnotic effects
  • Causes slightly more weight gain compared to other antidepressants
82
Q

Clinical response to antidepressants

A
  • SSRI are first line treatment due to best efficacy and fewest side effects
  • Maintenance treatment indicated for 6-12 months
  • Taper dos when stopping drug
83
Q

Monoamine hypothesis

A

Depression caused by altered monoamine (5-HT, NE) signaling

  • Drugs that decrease reuptake or reduce breakdown of monoamines improve depressive symptoms
  • A drug (reserpine) that inhibits monoamine packaging into vesicles was found to induce depression in some patients
84
Q

Newer hypothesis for antidepressant drug action

A

Depression related to abnormal neural circuitry

  • Altered receptor/neurotransmitter levels, leading to altered synaptic activity
  • Neurogenesis: depressed brain has less new neuron formation
  • G(s)-coupled GPCRs can regulate gene transcription through the cAMP response elements binding protein (CREB)
  • This signaling maintains proper cell structure in neurons
  • Thought to be deficient in depression
85
Q

Evidence for neurogenesis

A
  • In certain brain regions, particularly hippocampus, new neurons proliferate throughout life
  • Impaired by stress, stress hormones
  • In animal models, preventing neurogenesis blocks the effect of antidepressant drugs
  • Exercise releases growth factors that promote neurogenesis; exercise also relieves depression in some patients
86
Q

Proposed mechanism for drugs that affect monoamine signaling

A
  • Observation: antidepressant effects take up to 8 weeks to develop
  • Initial treatment causes increased monoamine levels, leading to increased auto-receptor activation and decreases neurotransmitter release
  • After chronic treatment, autoreceptors are downregulated. Monoamine release is now enhanced.
87
Q

Reward and Reinforcement in the brain

A
  • Addiction involves activation of, and maladaptive changes to, the “reward” pathway of the brain
  • Neurons from the ventral tegmental area (VTA) release dopamine in the nucleus accumbens (NAc)
  • Produces a rewarding stimulus and positive reinforcement - drives a desire to repeat the behavior
  • Why does our brain have this pathway? Provides motivation for necessary survival activities: eating, reproduction, etc.
  • VTA_NAs activated by rewarding stimuli and all addictive drugs
  • Many inputs affect VTA activation: including brain centers for learning/memory, stress and novelty
88
Q

Brain changes in addiction

A
  • Over time, dopamine release in the NAc occurs due to cues associated with the reinforcer
  • Thought to provide motivation and drive behavior toward seeking the reinforcing stimulus
89
Q

Differences between natural reinforcers and drugs

A

-Natural reinforcers: sensory stimuli are associated with a necessary survival activity and produce a modest dopamine release
-Drugs of abuse act on neurons in the reward pathway to activate it
-The brain regards any activity that activates reward pathway as one that should be repeated
Ways drugs activate the reward pathway:
-Directly mimic dopamine
-Inhibit DA reuptake
-Inhibit GABAergic transmission in VTA (disinhibition)

90
Q

Endocannabinoid system

A

eCG system summary
-At least two receptors (GPCR)
-CB1: neurons, presynaptic, decrease neurotransmitter release
-CB2: immune system, generally anti-inflammatory
At least two lipid transmitters:
-Anandamide
-2-arachidnylglycerol

91
Q

Effects of cannabinoid receptor activation

A 
CB1
-Euphoria, disinhibition, memory impairment, appetite stimulation, activation of reward pathway
CB2
-Reduce immune cell activation
-Anti-inflammatory
92
Q

Components of cannabis

A
  • Active ingredient for psychotropic effects is delta-tetrahydrocannabinol (THC)
  • However, dozens of active compounds and metabolites
93
Q

Dronabinol

A
  • Synthetic TCH, taken orally
  • Approved in U.S. for treating chemotherapy nausea
  • Also for appetite loss in AIDS
94
Q

Cannabidiol

A
  • FDA approved in 2018 for treatment-resistant seizure disorders
  • Exact mechanism unknown, weak interactions with several receptors
95
Q

Areas where cannabinoid drugs might have therapeutic value

A
  • Antitumor activity
  • Anxiety/depression
  • Obesity/metabolic syndrome
  • Additional types of pain
  • Seizure disorders beyond current FDA approved uses
96
Q

Synthetic cannabinoids

A
  • Originally synthesized for research
  • Discovered in “herbal incense”
  • Now on schedule I of controlled substances act
97
Q

Side effects/harmful effects of cannabinoid drugs

A
  • Pleasurable “high” for one person is adverse side effect for medical user
  • Lung cancer: difficult to study, but smoked marijuana contains many carcinogens
  • Cardiovascular: increased CO, possibly causing heart attacks, cardiac arrest
  • Addiction: it is reinforcing, but less than many other drugs of abuse
  • Difficult to establish correlation/causation: gateway drug, schizophrenia link
98
Q

Issues related to medical use

A
  • Deliver methods
  • Standardization
  • Cannabinoid hyperemesis syndrome
  • Diversion for illicit use
  • Ability to perform accurate testing for intoxication
  • Withdrawal
99
Q

Tobacco (nicotine)

A
  • Mechanism of action: stimulates central, peripheral and neuromuscular ACh receptors
  • Effects: dopamine release in NAc, increased level of arousal, appetite suppression, elevated blood pressure, can alleviate depression/anxiety
  • Most addictive drug: only 5-10% of unassisted addicts successfully quit smoking
100
Q

Varenicline

A
  • Nicotinic receptor partial agonist

- 1 year abstinence rate of ~25%

101
Q

Bupropion

A
  • Atypical antidepressant that inhibits the uptake of monoamines (NE and DA)
  • Stabilize dopamine levels following tobacco withdrawal
  • Antagonizes nicotinic receptors
  • 1 year abstinence rate of 22%
102
Q

Ethanol

A
  • Ethanol is only moderately toxic, while other alcohols are very toxic
  • Mechanism of action –> increases effects of GABA, blocks effects of glutamate, endogenous opioid release, activates reward pathway
103
Q

Physiological effects of ethanol

A
  • Disinhibition at low doses –> excitement, increased sociability
  • Depressant at moderate doses –> ataxia, respiratory depression, blackouts at higher doses
  • Anesthetic at high doses –> unconsciousness
  • Death at 0.4-0.5% in non-tolerant individuals
  • Disturbances in sleep and memory consolidation, even at low doses (2-3 drinks)
  • Hangover is due to combined effects of sleep changes, dehydration, acidosis, GI irritation
104
Q

Pharmacokinetics of ethanol

A
  • Mostly intestinal absorption due to favorable surface area - influence of gastric emptying time
  • Gender differences in ADME - first-pass metabolism, total body water
  • Doses are In gram (14g ethanol in 1 drink) as opposed to most drugs taken in milligram or microgram doses
  • Approximate BAC for men –> women add 20-30%
105
Q

Metabolism of ethanol

A
  • Metabolism follows zero-order kinetics - essentially linear
  • Process saturates at low BACs (due to limited NAD+ supply, ADH and ALDH breakdown ethanol)
106
Q

Health effects of alcohol

A
  • Most current analysis: there is no safe amount of alcohol consumption
  • 1990s-recently: moderate alcohol consumption reduced mortality –> J-curve
  • Alcohol does appear to slightly reduce risk of cardiovascular disease and possibly diabetes, but these effects are offset by increased mortality from other causes
107
Q

Potential reasons for the original J-curve

A
  • Moderate drinkers generally have healthy lifestyles and higher socioeconomic status
  • People in poor health advised not to drink
  • Moderate alcohol intake may: reduce stress and anxiety, lower the risk of cardiovascular events
  • Red wine contains antioxidants but amounts are fairly small
108
Q

Ethanol is clinical use

A
  • An older method to treat methanol poisoning

- Competes for ADH metabolism

109
Q

Fomepizole

A

-Pharmacological inhibitor or ADH that is now the preferred treatment for methanol poisoning

110
Q

Risk of Excessive Alcohol Intake

A
  • Contributes to 5 of the 10 leading causes of death in North America: heart failure, cancers, cirrhosis of liver, MVA accidents and other accidents, suicide
  • Selected harmful effects of alcohol
  • Liver damage –> increased NADH leads to fatty acid synthesis, release of endotoxin in gut leads to inflammation
  • Wernicke-Korsakoff syndrome –> caused by thiamine deficiency, confusion & ataxia (W), memory problems & hallucinations (K)
  • Dependence with severe, life-threatening withdrawal syndrome –> delirium tremens: delirium, tremors, seizures, agitation - withdrawal symptoms treated with BZD or other anticonvulsants
  • Genetic variant seems to allow some people to survive many years of heavy alcoholism, while others cannot
111
Q

Naltrexone

A

Tx of alcoholism

-Opioid antagonist; decreases rewarding properties

112
Q

Disulfiram

A

Tx of alcoholism

  • ALDH inhibitor
  • Aversive treatment
  • Accumulation of acetaldehyde results in flushing, headache, nausea/vomiting, general dysphoria
113
Q

Acamprosate

A

Tx of alcoholism

-Thought to work on glutamate signaling to reduce craving and relapse

Pharmacology Exam #4 (1 decks)

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