Pharmacology CNS and PNS Flashcards
1
Q
Neurotransmitters Levels in Disease
-Acetylcholine, Dopamine, GABA, Glutamate, Norepinephrine, Serotonin (5-HT)
FA-OS p. 512
A
Acetylcholine
-Low in: Alzheimer’s
Dopamine
- Low in: Parkinson’s
- High in: Schizophrenia, mania, psychosis
GABA
-Low in: Anxiety, epilepsy
Glutamate
-High in: Alzheimer’s, Schizophrenia, epilepsy
Norepinephrine
- Low in: Major depressive disorder
- High in: Anxiety
Serotonin (5-HT)
- Low in: Major depressive disorder, bipolar disorder, anxiety
- High in: Schizophrenia
2
Q
Neurotransmitter Levels in Alzheimer’s
FA-OS p. 512
A
- Low Acetylcholine
- High Glutamate
3
Q
Neurotransmitter Levels in Schizophrenia
FA-OS p. 512
A
- High Dopamine
- High Glutamate
- High Serotonin
4
Q
Neurotransmitter Levels in Parkinson’s
FA-OS p. 512
A
-Low Dopamine
5
Q
Neurotransmitter Levels in Mania
FA-OS p. 512
A
-High Dopamine
6
Q
Neurotransmitter Levels in Psychosis
FA-OS p. 512
A
-High Dopamine
7
Q
Neurotransmitter Levels in Anxiety
FA-OS p. 512
A
- Low GABA
- High Norepinephrine
- Low Serotonin
8
Q
Neurotransmitter Levels in Epilepsy
FA-OS p. 512
A
- Low GABA
- High Glutamate
9
Q
Neurotransmitter Levels in Major Depressive Disorder
FA-OS p. 512
A
- Low Norepinephrine
- Low Serotonin
10
Q
Neurotransmitter Levels in Bipolar Disorder
FA-OS p. 512
A
-Low Norepinephrine
11
Q
An important site for the production of ACh in the brain
A
nucleus basalis of Meynert
12
Q
Important sites of dopaminergic neurons in the brain
A
- Substantia nigra pars compacta
- Ventral tegmental area
13
Q
Location of histaminergic neurons in the brain
A
-Ventral posterior hypothalamus (tuberomammillary nucleus)
14
Q
Primary site of norepinephrine synthesis in the brain
A
-Locus ceruleus (found in the upper pons)
15
Q
Area that releases serotonin to projections throughout the brain
A
-Raphe nucleus
16
Q
General characteristics of neuromuscular junction blocking agents
A
- Used for skeletal muscle relaxation
- Site of action = neuromuscular junction
- Do NOT cause analgesia or unconsciousness (only paralysis)
- Structurally resemble ACh
- Bind ACh receptors on muscle
- Two classes: depolarizing agents and nondepolarizing agents
17
Q
Depolarizing agent drug name
A
Succinylcholine
18
Q
Succinylcholine mechanism
A
- Short acting (works within 30 sec and last 10 min)
- Depolarizing agent
- ACh receptor agonist
- Resistance to AChE allows it to remain bound to the receptor
- Limited by diffusion away from endplate
- Metabolized by pseudocholinesterase before it reaches site of action
- Two phases:
1. drug binds aggressively to ACh receptor, triggering depolarization at the motor endplate. Remains bound, so Na channels cannot depolarize.
2. after the drug has been bound for a while, induces conformational change–>nondepolarizing block that is irreversible
19
Q
Succinylcholine uses
A
Temporary muscle paralysis in surgery and intubation
20
Q
Succinylcholine side effects
A
-Cardiovascular: low dose-nagative chronotropic and inotropic effects
high dose-positive chronotropic and inotropic effects, raises catecholamine levels
-Fasciculations during phase 1 (visible motor unit contractions)
-Myalgia
-Hyperkalemia- especially concerning in setting of burns, trauma, spinal cord injury, cardiac disease and metabolic abnormalities
-Malignant hyperthermia
21
Q
Nondepolarizing agent drug names
A
- Mivacurium (short acting)
- Vecuronium (intermediate acting)
- Rocuronium (intermediate acting)
- Atracurium (intermediate acting)
- Pancuronium (long acting)
- Doxacurium (long acting)
(obvious) NOTE: they all end in -curonium or -curium
22
Q
Nondepolarizing agent mechanisms
A
- ACh receptor competitive antagonists
- Bind to ACh receptor, but does not cause depolarization and blocks ACh from binding
- Most depend on hepatic or renal elimination to terminate effect (exception=mivacurium which is metabolized by pseudocholinesterase and thus safe for pts with renal or hepatic disease
- Can give AChE inhibitor to reverse effects
23
Q
Nondepolarizing agent uses
A
- Muscle relaxant during intubation, surgery
- Can be used in place of depolarizing agent
- Decreases the amount of required inhalational agents and helps maintain paralysis
24
Q
Nondepolarizing agent side effects
A
- Respiratory failure secondary to diaphramatic paralysis
- Tachycardia (pancuronium)
- Histamine release (Mivacurium)
25
Cholinesterase inhibitor drug names
- Neostigmine
- Pyridostigmine
- Edrophonium
- Physostigmine
26
Cholinesterase inhibitor mechanism
- Inactivate AChE by electrostatic or covalent binding
| - Prevents ACh degradation at the neuromuscular junction
27
Cholinesterase contraindications
-With depolarizing agents: by inhibiting cholinesterase and pseudocholinesterase, it prolongs the phase 1 block
28
Cholinesterase uses
- Reverse effects of nondepolarizing agents during surgery
| - Used to diagnose (edrophonium) and treat (neostigmine) myasthenia gravis
29
Cholinesterase side effects
- Bradycardia
- Bronchospasm
- Excitation (physostigmine)
- Intestinal spasm
- Increased bladder tone
- Pupillary constriction
30
Anticholinergic drug names
- Atropine
- Scopolamine
- Benztropine
- Glycopyrrolate (charged and cannot cross the BBB)
31
Anticholinergic drug mechanism
-Complete block of ACh receptors
32
Anticholinergic uses
- Primary use: anesthesiology
- Scopolamine is antiemetic
- Atropine: generally used for cardiovascular effects (reverses vagal-stimulated bradycardia, decreases respiratory secretions, relaxes bronchial smooth muscle, reversal of antipsychotic extrapyramidal effects) or with pralidoxime for organophosphate poisoning
33
Anticholinergic side effects
-CNS stimulation
-Cutaneous blood vessel dilation
-Urinary retention
-Cycloplegia (paralysis of ciliary muscle-->blocks eye accommodation)
-Decreased secretions
Mnemonic: "blind as a bat, dry as a bone, red as a beet, mad as a hatter and hot as a hare"
34
Barbiturate drug names
-Phenobarbital
-Pentobarbital
-Thiopental
-methohexital
-Secobarbital
Obvious NOTE: all end in -tal
35
Barbiturate mechanism
-Increase duration of Cl channel opening on GABAa receptors-->enhanced GABAergic transmission
Mneumonic: "BarbiDURATe increases the DURATion of GABAa receptor Cl channel opening)
-Can block excitatory glutamate receptors
-CYP450 inducer
-Phenobarbital is 75% metabolized in the liver and 25% excreted unchanged by the kidney
36
Barbiturate uses
- Short term agents (thiopental, methohexital) used in anesthesia
- Tonic-clonic seizure prevention, status epilepticus, exlampsia (phenobarbital)
- Mild sedative
- Relieve anxiety
- Insomnia (but not recommended because suppresses REM sleep>other stages)
37
Barbiturate side effects
- Dependence
- Synergy with alcohol and benzodiazepines (cross-tolerance)
- Respiratory, cardiovascular and CNS depression that can cause coma or death
- CYP450 induction alters other drug metabolism
38
Barbiturate contraindications
-Acute intermittent porphyria (barbiturates activate ALA synthase, the rate-limiting enzyme of heme synthesis)
39
Treatment of barbiturate overdose
- Manage symptoms (ABCs)
- Hemodialysis in severe cases
- Alkalization of urine to help with elimination (phenobarbital)
40
Symptoms of barbiturate withdrawal
- Anxiety
- Irritability
- Elevated heart and respiration rate
- Muscle pain
- Nausea
- Tremors
- Hallucinations
- Confusion
- Seizures
- Death if untreated
41
Benzodiazepine drug names
-Diazepam
-Lorazepam
-Triazolam
-Temazepam
-Oxazepam
-Midazolam
-Chlordiazepoxide
Alprazolam
NOTE: most end in -zolam
42
Benzodiazepine mechanism
- Increased frequency of Cl channel opening with binding to GABA receptors
- Cl entry-->hyperpolarization which reduces excitability
- Effect terminated through redistribution and excretion (metabolized by hepatic microsomal system into active metabolites)
- Can cross the placental barrier
43
Benzodiazepine uses
- Anxiolytics via inhibition of lymbic circuit
- Muscle relaxant to treat spasms
- Amnesic agents for endoscopy
- Anticonvulsant
44
Short acting benzodiazepines
(Not great) Mnemonic: "TOM thumb"
- Triazolam
- Oxazepam
- Midazolam
45
Benzodiazepine side effects
- Synergistic with alcohol and barbiturates (cross-tolerance)
- Respiratory depression and coma (much less than barbiturates)
- Drowsiness/confusion
- Tolerance
- Dependence
- Decrease latency to sleep onset and increase stage 2 sleep. REM sleep and stages 3 and 4 sleep are decreased
46
Benzodiazepine competitive antagonist
Flumazenil
47
Benzodiazepine withdrawal
-Confusion
-Anxiety
-Agitation
-Restlessness
-Insomnia
-Tension
Note: similar to barbiturate withdrawal, but less severe
48
Opiod drug names
- Morphine
- Hydromorphine
- Oxymorphone
- Methadone
- Meperidine
- Fentanyl
- Sufentanil
- Alfentanil
- Remifentanil
- Codeine
- Hydrocodone
- Oxycodone
- Buprenorphine
49
Neuroleptics (definition)
- Classified as first generation and second generation (atypical) anti-psychotics
- Block type 2 dopamine receptors (D2)
- Most effective against the positive symptoms of schizophrenia (such as hallucinations and delusions)
50
First-generation anti-psychotics drug names
```
Low potency group
-Chlorpromazine
-Thioridazine
High potency group
-Haloperidol
-Trifluoperazine
-Pimozide
-Perphenazine
```
51
Mechanism of first-generation anti-psychotics and difference between low and high potency drugs in this group
- All work in the mesolimbic system by blocking post-synaptic D2 receptors
- Low-potency drugs have an affinity for muscarinic ACh receptors, alpha-adrenergic receptors, and histaminergic receptors (note: this causes side effects)
- High potency drugs have a greater affinity for D2 receptors
52
Uses of first-generation anti-psychotic drugs
- Treatment of acute psychosis
- Treat of schizophrenia
- Treatment of bipolar disorder
- Haloperidol used in Tourette syndrome (to control tics) and Huntington disease (to control choreiform movements)
53
Side effects of first-generation anti-psychotic drugs
All 1st gen drugs:
- Neuroleptic malignant syndrome
- Hyperprolactinemia (amenorrhea, galactorrhea, gynecomastia)
High-potency anti-psychotics
- Extrapyramidal signs (Parkinsonism, akathisia, tremor)
- Movement disorders (tardive dyskinesia, dystonia)
Low-potency anti-psychotics
- Sedation
- -> *Blockade of histamine receptors causes weight gain, sedation, orthostatic hypotension, tremor, and sexual dysfunction
- Anticholinergic side effects
- -> *Blockade of muscarinic receptors causes facial flushing, dry mouth, urine retention, constipation
Thioridazine (additional side effects)
- Sudden death from prolongation of the QT interval, leading to torsades de points
- Irreversible retinal pigmentation
Chlorpromazine (additional side effects)
-Deposits in the lens and cornea
54
Second-generation (atypical) anti-psychotic drug names
-Clozapine
-Risperidone
-Olanzapine
-Quetiapine
-Ziprasidone
Aripiprazole
55
Mechanism of second-generation (atypical) anti-psychotic drugs
- Effects on the serotonergic, dopaminergic (with D2 affinity), and noradrenergic systems
- Each medication has a different neuroreceptor profile (leading to different therapeutic action and different side effects)
56
Advantages of second-generation (atypical) anti-psychotic drugs over first-generation anti-psychotic drugs
- Second-generation drugs are more effective with negative and chronic symptoms of schizophrenia (avolition, alogia, flattened affect)
- Second-generation drugs have a lower risk of tardive dyskinesia, neuroleptic malignant syndrome, and extra-pyramidal signs
57
Uses of second-generation (atypical) anti-psychotic drugs
- Treatment of schizophrenia
- Treatment of psychosis
- Treatment of bipolar disorder
- Risperidone used for antidepressant augmentation
58
Selective serotonin reuptake inhibitor side effects
- Few side effects, so safe in pregnancy
- Diarrhea
- Sexual dysfunction (decreased libido, erectile dysfunction, anorgasmia)
- Weight gain
- Fatigue
- Discontinuation syndrome (worse with short-acting): dizziness, vertigo, nausea, fatigue, headache, insomnia, shock-like sensations, paresthesia, visual disturbances, muscle pain, chills, irritability, agitation and suicidal thoughts
- Birth defects--most commonly ventral septal defects--can happen (greatest risk with paroxetine)
59
Monoamine oxidase inhibitor (MAOI) drug names
- Phenelzine
- Tranyleypromine
- Isocarboxazid
60
Opiod mechanism
- Analgesics that act on the CNS
- Endogenous endorphins are formulated from proopiomelanocortin (POMC), which is also the precursor for the formation of adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH) and lipotropin (LPH)
- Synthetic opiods structurally resemble endogenous opiods
- Most bind to the Mu-opiod receptor either as full or partial agonists
61
Opiod uses
- Local analgesia (regional nerve blocks, epidural nerve blocks, spinal nerve blocks)
- Systemic pain relief (patient controlled analgesia)
- Chronic pain management
- Used in antitussives (e.g. dextromethorphan)
62
Opiod side effects
- Tolerance
- Dependence
- Overdose potential
63
Buspirone mechanism
- Partial serotonin 1A agonist (5HT-1A) receptor agonist in the CNS
- Does not affect GABAergic receptors, so it does not interact with ethanol, is non-sedating and has low risk of dependence as it does not cause the euphoria associated with benzodiazepines and barbiturates
64
Buspirone uses
-Generalized anxiety disorder
65
Buspirone side effects
- May stimulate the locus ceruleus-->increased norepinephrine release-->increased anxiety
- May not work for patients with a history of benzodiazepine use or severe anxiety
66
Selective serotonin reuptake inhibitor drug names
- Citalopram
- Fluoxetine
- Paroxetine
- Sertraline
- Fluvoxamine
67
Selective serotonin reuptake inhibitor mechanism
- Prevent reuptake of serotonin by the presynaptic terminal-->increased availability of serotonin to the postsynaptic membrane
- Takes 3-6 weeks to get desired effect clinically
- Does not increase mood in non-depressed patients
68
Selective serotonin reuptake inhibitor uses
- First line for depressive and anxiety disorders
- Panic disorder
- obsessive-compulsive disorder
- Post-traumatic stress disorder
- Eating disorders
- Trichotillomania (impulsive hair eating)
- Prevents post-stroke depression and improves morbidity and mortality even in the absence of depression
69
Selective serotonin reuptake inhibitor side effects
- Few side effects, so safe in pregnancy
- Diarrhea
- Sexual dysfunction (decreased libido, erectile dysfunction, anorgasmia)
- Weight gain
- Fatigue
- Discontinuation syndrome (worse with short-acting)
- Birth defects can happen (greatest risk with paroxetine)
70
Monoamine oxidase inhibitor (MAOI) drug names
- Phenelzine
- Tranyleypromine
- Isocarboxazid
71
MAOI mechanism
- Irreversibly inhibits Monoamine oxidase-A from breaking down norepinephrine-->increased norepinephrine levels
- MAO-A also breaks down serotonin and tyramine, so there are increased levels of these neurotransmitters as well
72
MAOI side effects
```
Use with tyramine causes potentially fatal side effects and the following symptoms:
-Hypertensive crisis
-Diaphoresis
-Headache
-Vomiting
MUST AVOID: cheese (pizza), Pepperoni, Beer, Wine, Smoked/pickle meat, Liver, Spoiled foods
Use with SSRIs can cause serotonin syndrome:
-Confusion
-Hyperthermia
-Myoclonus
-diaphoresis
-Hyperreflexia
```
73
Side effects of second-generation (atypical) anti-psychotics
All 2nd generation drugs:
- Cardiotoxicity
- Abnormal ECG
- Neuroleptic malignant syndrome
- Hyperprolactinemia (gynecomastia, galactorrhea, and amenorrhea)
- Extrapyramidal signs (Parkinsonism, akathisia, tremor)
- Increased chance of seizures
- Insulin intolerance, T2D (unrelated to weight gain)
- Hyperlipidemia
Clozapine (additional side effects)
- Agranulocytosis
- Weight gain
Olanzapine (additional side effects)
-Weight gain
Risperidone (additional side effects)
-Especially prone to hyperprolactinemia
Ziprasidone (additional side effects)
-Prolongation of QT and PR intervals
Note: Ziprasidone and aripiprazole have fewer metabolic side effects than other 2nd-generation drugs
74
Names of Mood Stabilizing Drugs
Lithium
75
Mechanisms of Mood Stabilizing Drugs (Lithium)
- Exact mechanism of lithium unknown
| - It is believed that lithium interferes with monoamine synthesis, release, and reuptake
76
Uses of Mood Stabilizing Drugs (Lithium)
- Treatment of Bipolar Disorder
- Used to augment antidepressants in major depressive disorder
- May take 2-3 weeks for effects of lithium to manifest
77
Precautions with Lithium (lab tests to follow)
- Lithium has a low therapeutic index
- Must follow blood levels of lithium to keep them to the minimum therapeutic level
- Regularly follow creatinine (renal function) and TSH (thyroid function)
78
Side effects of Mood Stabilizing Drugs (Lithium)
- Hypothyroidism & goiter
- Thirst
- Renal dysfunction (nephrogenic diabetes insipidous results in increased creatinine kinase and eventual kidney failure)
- Tremor
- Diarrhea
- Increased appetite and weight gain
- Cardiac conduction problems
- Mild cognitive impairment
- CNS depression (at toxic levels)
- Congenital abnormalities
79
Anticonvulsants (definition and 3 basic mechanisms)
- These agents suppress uncontrolled neuronal discharge in epileptic seizures
- Anticonvulsants inhibit neuronal firing through 3 different mechanisms to reduce the likelihood that a seizure will occur:
1. Increasing GABAergic activity
2. Blocking voltage-gated sodium channels
3. Blocking voltage-gated calcium channels
80
Types of seizures (categories)
2 general categories: partial and generalized
Partial Seizures include:
- Simple seizure
- Complex seizure
- Partial seizure with secondarily generalized tonic-clonic seizure
Generalized Seizures include:
- Absence seizure
- Myoclonic seizure
- Tonic-clonic seizure
- Atonic seizure
- Status epilepticus
81
Names of anticonvulsants that target presynaptic and postsynaptic GABA and the GABA receptor (anticonvulsant mechanism #1: increase GABAergic activity)
- Vigabatrin (inhibit GABA-T, which metabolizes GABA)
- Valproate (inhibit GABA-T, which metabolizes GABA)
- Tiagabine (activate GAT-1, which reuptakes GABA)
- Barbiturates (GABA receptor)
- Benzodiazepines (GABA receptor)
Note: These drugs increase CNS inhibition and raise the seizure threshold
82
Names of anticonvulsants that target and extend sodium sodium channel inactivation (anticonvulsant mechanism #2: block voltage-gated Na+ channels)
- Carbamazepine
- Phenytoin
- Topiramate
- Lamotrigine
- Valproate
- Zonisamide
Note: All work on intracellular side of inactivated Na+ channel
Note: These drugs block the rapid successive firing of action potentials (which is classically associated with partial seizures and generalized tonic-clonic seizures)
83
Names of anticonvulsants that target and reduce current through T-type calcium channels (anticonvulsant mechanism #3: block voltage-gated Ca2+ channels)
- Ethosuximide
- Valproate
Note: These drugs on the extracellular side of the Ca2+ channel, specifically T-type calcium channels
Note: These drugs are used in treatment of generalized absence seizures
- These drugs reduce calcium current in thalamic neurons
- Thalamic neurons are responsible for the generation of the 3-Hz spike-and-wave rhythms seen in absence seizures
- Reduction of T-type currents in thalamic neurons stops the rhythmic discharge associated with absence seizures
84
Mechanism of Valproic Acid (or valproate, which is the ionized form)
-Mainly mechanism #2 for anticonvulsant drugs
- Binds to voltage-gated Na+ channels and favors the inactivated state
- Decreases Ca2+ influx across T-type Ca2+ channels in the membrane (this reduces the calcium current in thalamic neurons)
85
Uses of Valproic Acid
- Treatment of partial and generalized tonic-clonic seizures
- Second-line treatment for generalized absence seizures (ethosuximide is first line)
- Treatment of bipolar disorder (mood-stabilizing properties)
- Treatment of intermittent explosive disorder (a behavioral disorder characterized by extreme expression of anger that is disproportionate to the inciting cause)
- Used as prophylaxis for migraines
Note: Use of this drug is decreasing due to high # side effects and lower efficacy compared with other medications
86
Side effects of Valproic Acid
- GI upset (stomach pain, nausea, diarrhea)
- Increased appetite, leading to weight gain
- Tremor
- Sedation
- Alopecia
- Hepatotoxicity
- Decreased platelet count
- Possible polycystic ovarian sydrome (PCOS)
- Congenital neural tube defects (folate antagonist)
87
Mechanism of ethosuximide
-Mainly mechanism #3 for anticonvulsant drugs
- Decreases Ca2+ influx across T-type Ca2+ channels in the membrane (this reduces the calcium current in thalamic neurons)
- This is why ethosuximide is used for absence seizures (because absence seizures are associated with rhythmic discharge through T-type currents in the thalamus)
88
Uses of ethosuximide
-First-line treatment for absence seizures
89
Side effects of ethosuximide
- GI distress
- Lethargy
- Headache
- Urticaria
- Steven-Johnson syndrome
90
Mechanism of phenobarbitol
-Mainly mechanism #1 for anticonvulsant drugs
- Part of barbiturate drug class
| - Acts on the GABA-A receptor to increase CNS inhibition and raise the seizure threshold
91
Uses of phenobarbitol
-Many uses but role in anticonvulsant therapy is specific to treatment of status epilepticus
92
Side effects of phenobarbitol
- Sedation
- Tolerance
- Dependence
- Induction of cytochrome P450 system
93
Mechanism of carbamazepine
-Mechanism #2 for anticonvulsant drugs
- Reduces the rate of recovery of voltage-gated sodium channels (like phenytoin & lamotrigine)
- -> This blocks the rapid successive firing of action potentials that is classically associated with partial seizures and generalized tonic-clonic seizures)
94
Uses of carbamazepine
- First-line treatment for partial seizures and tonic-clonic seizures
- Treatment of bipolar disorder
- Treatment of trigeminal neuralgia
95
Side effects of carbamazepine
- Aplastic anemia
- Agranulocytosis
- Hyponatremia
- Induces cytochrome P450 system (increases metabolism of itself and oral contraceptives)
96
Mechanism of phenytoin
-Mechanism #2 for anticonvulsant drug
- Slows the rate of recovery of voltage-gated sodium channels (like carbamazepine & lamotrigine)
- -> this blocks the rapid successive firing of action potentials
97
Uses of phenytoin
- Treatment of all types of partial and generalized seizures (EXCEPT absence seizures)
- First line treatment for prophylaxis against status epilepticus
98
Side effects of phenytoin
Toxicity (at high levels)
- Nystagmus
- Diplopia
- Ataxia
- Sedation
- Gingival hyperplasia
- Megaloblastic anemia
- SLE-like syndrome
- Induction of cytochrome P450
- Fetal hydantoin syndrome
99
Mechanism of Lamotrigine
- Slows the rate of recovery of voltage-gated sodium channels (like carbamazepine & phenytoin)
- -> This blocks the rapid successive firing of action potentials
- May also reduce the amount of released glutamate
100
Uses of Lamotrigine
- Treatment of partial seizures and generalized tonic-clonic seizures
- Treatment of focal epilepsy
- Treatment of Lennox-Gastaut syndrome (type of childhood-onset epilepsy)
- Treatment of bipolar disorder
101
Side effects of Lamotrigine
- Dizziness
- Nausea
- Headache
- Skin rash (hypersensitivity reaction)
- Stevens-Johnson syndrome (avoided by increasing the dose very slowly)
102
Mechanism of Pregabalin
-Mainly anticonvulsant mechanism #1
- Binds to alpha2-delta subunit for high-voltage-activated Ca2+ channels
- Increases the density of GABA transporter protein and increases the rate of functional GABA transport
- Decreases pre-synaptic release of glutamate, NE, and substance P
Note: These mechanisms produce both anticonvulsant and anti-nociceptive effects
103
Uses of Pregabalin
- Treatment of neuropathic pain associated with diabetic neuropathy and post-herpetic neuralgia
- Adjunctive treatment of fibromyalgia
- Adjunctive treatment of partial seizures
Note: Compared to gabapentin, pregabalin is more potent, absorbs faster and has greater bioavailability
104
Side effects of Pregabalin
- Dizziness
- Somnolence
- Weight gain
105
Mechanism of Gabapentin
- Was designed to be a GABA analog, but it does not modulate GABA receptors
- Avidly binds to the alpha2-delta subunit for high-voltage-activated Ca2+ channels
- -> This may increase the synaptic concentration of GABA and enhances GABA responses at non-synaptic sites in neuronal tissues
- Decreases presynaptic release of glutamate
106
Uses of Gabapentin
- Treatment of partial seizures
- Treatment of pain (including neuropathic) and peripheral neuropathy
- Treatment of bipolar disorder
- Treatment of anxiety
- Used for sedation (because it is highly lipid soluble)
107
Side effects of Gabapentin
- Sedation
| - Weight gain
108
Tricyclic antidepressant drug names
-Amitriptyline
-Imipramine
-Amoxapine
-Clomipramine
-Desipramine
-Doxepin
-Nortriptyline
-Protriptyline
NOTE: All but Doxepin end in -ptyline or -ine
109
Tricyclic antidepressant mechanism
- Increase synaptic concentration of serotonin and NE in the CNS
- Inhibit serotonin and NE reuptake by presynaptic terminal
110
Tricyclic antidepressant uses
- Chronic pain
- Major depression
- Anxiety disorders
- Enuresis in children historically, but risk of sudden death means that this is not first line
111
Tricyclic antidepressant side effects
3 C's:
- Constipation
- Cardiac arrhythmias
- Coma (overdose potential)
Others:
- Sudden death in children (imipramine and desipramine)
- Sedation
- Tremor
- Insomnia
- Orthostatic hypotension
- Psychosis
- Seizures
- Weight gain
112
Bupropion mechanism
- Heterocyclic antidepressant
- Mechanism is mostly unknown--thought to have to do with blocking NE and dopamine reuptake (depression) and action on nicotinic ACh receptor antagonism (smoking cessation)
113
Bupropion uses
2nd and 3rd line for:
- Smoking cessation
- Major depression
114
Bupropion side effects
- Stimulant effects
- Tachycardia
- Insomnia
- Headaches
- Seizure risk is higher than other antidepressants
115
Bupropion contraindications
- Anorexia
- Bulimia
- Seizure disorders (lowers seizure threshold)
- MAO inhibitor treatment within the past 2 weeks
116
Venlafaxine mechanism
- Converted to active metabolite O-desmethylvenlafaxine
| - Inhibit presynaptic reuptake of serotonine>NE
117
Duloxetine mechanism
-Inhibit presynaptic reuptake of serotonine>NE
118
Venlafaxine uses
- Major depression
- Melancholia
- Anxiety disorders
- Chronic pain associated with depression
119
Duloxetine uses
- Major depression
- Anxiety disorders
- Chronic pain associated with depression
- Diabetic peripheral neuropathic pain
120
Duloxetine side effects
- Sedation
- Nausea
- Constipation
- Elevated bp
- Sweating
121
Venlafaxine side effects
- Sedation
- Nausea
- Constipation
- Elevated bp
- Sweating
122
Nefazodone mechanism
- Serotonin modulator
| - Blocks 5HT2 receptor and inhibit reuptake of 5-HT and NE
123
Trazodone mechanism
- Serotonin modulator
- Blocks 5HT2 receptor and inhibit reuptake of 5-HT and NE
- Antagonizes serotonin at low doses and acts as a serotonin agonist at high doses
- Effects histamine blockade
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Mirtazapine mechanism
- Serotonin modulator
- Blocks 5HT2 receptor and inhibit reuptake of 5-HT and NE
- Antagonizes histamine H1 receptors
- Weakly blocks peripheral alpha1-adrenergic and muscarinic receptors
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Nefazodone uses
- Major depression
| - Anxiety
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Trazodone uses
- Major depression
- Anxiety
- Insomnia
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Mirtazapine uses
- Major depression
| - Anxiety
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Nefazodone side effects
- Sedation
- Increased appetite
- Weight gain
- Dry mouth
- Hepatotoxicity
- Visual trails
- Postural hypotension
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Trazodone side effects
- Sedation
- Increased appetite
- Weight gain
- Dry mouth
- Priapism (persistent and painful erection of the penis)
- Postural hypotension
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Mirtazapine side effects
- Sedation
- Increased appetite
- Weight gain
- Dry mouth
- Postural hypotension
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Maprotiline mechanism
- Tetracyclic antidepressant
- Selectively prevents the reuptake of NE
- Unlike other antidepressants, does NOT prevent serotonin reuptake
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Maprotiline uses
-Major depression
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Maprotiline side effects
- Sedation
| - Orthostatic hypotension
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Define neuroleptics
- First and second-generation antipsychotics
- Block D2 (dopamine type 2) receptors
- Most effective against the positive symptoms of schizophrenia, such as hallucinations and delusions
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First generation antipsychotic drug names
- Chlorpromazine (low potency)
- Thioridazine (low potency)
- Haloperidol (high potency)
- Trifluoperazine (high potency)
- Pimozide (high potency)
- Perphenazine (high potency)
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First generation antipsychotic mechanism
- Work in the mesolimbic system
- Block postsynaptic D2 receptors
- The low potency drugs (Chlorpromazine and Thioridazine) also have affinity for muscarinic ACh, alpha-adrenergic and histaminergic receptors
- High potency drugs (e.g. Haloperidol) have greater D2 affinity
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First generation antipsychotic uses
- Acute psychosis
- Schizophrenia
- Bipolar disorder
- Tourette syndrome to control ticks (Haloperidol)
- Huntington disease (to control movements)
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First generation antipsychotic side effects
- Extrapyramidal signs (Parkinsonism, akathisia, tremor)--especially high potency
- Movement disorders (tardative dyskinesia, dystonias)--esp high potency
- Sedation (low potency)
- Neuroleptic malignant syndrome
- Hyperprolactinemia (amenorrhea, galactorrhea, gynecomastia)
- Anticholinergic side effects--low potency
- Sudden death from prolongation of QT interval--> torsades de pointes (thioridazine)
- Irreversible retinal pigmentation (thioridazine)
- Deposits in the lens and cornea (chlorpromazine)
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Drug classes used to treat Alzheimer's disease
1. Block NMDA receptors (which are activated by excess glutamate associated with disease)
-Memantine
2. Block AChE (AChE breaks down ACh into choline and acetate; ACh is low in AD)
-Tacrine, donepezil, rivastigmine, galantamine
Note: To date, no FDA-approved rug modifies the disease progression
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Mechanism of Memantine
- During depolarization of neuronal cells, the magnesium blockade of NMDA receptors is relieving, thus allowing calcium to enter the cell
- Over time, calcium influx leads to neuronal damage
- Memantine non-competitively blocks NMDA receptors in the CNS, thus preventing stimulating by glutamate. This results in less intracellular calcium. Less intracellular calcium prevents further damage to the neurons
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Uses of Memantine
- Used to treat moderate to severe Alzheimer's disease
| - May be used to treat vascular dementia
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Side effects of Memantine
- Agitation
- Insomnia
- Urinary incontinence
- Diarrhea
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Drug names of selective inhibitors of AChE in the CNS
- Tacrine
- Donepezil
- Rivastigmine
- Galantamine
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Mechanism of selective inhibitors of AChE in the CNS (tacrine, donepezil, rivastigmine, galantamine)
- By selectively inhibiting AChE in the CNS, levels of ACh increase, which has been shown to improve cognition
- Centrally acting AChE inhibitors improve efficacy and decrease peripheral side effects
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Uses of selective inhibitors of AChE in the CNS (tacrine, donepezil, rivastigmine, galantamine)
-Treatment of Alzheimer's disease (because they are centrally acting and can cross the BBB)
Note: Other AChE inhibitors, like those neostigmine used for myasthenia gravis, cannot cross the BBB, and thus, are not used for Alzheimer's disease
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Side effects of selective inhibitors of AChE in the CNS (tacrine, donepezil, rivastigmine, galantamine)
- Nausea
- Vomiting
- Diarrhea
- Insomnia
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Drug classes used to treat Parkinson's disease
Strategies to increase levels of CNS dopamine:
1. increase endogenous dopamine by preventing its degradation
- MAO-B inhibitors (selegiline, rasagiline)
2. add an exogenous precursor of dopamine that is converted to dopamine centrally
- Levodopa
3. give dopamine agonists that directly stimulate D2 receptors
- Bromocriptine, pergolide, ropinirole, pramipexole
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Cause of Parkinson's disease
- Loss of dopaminergic neurons in the substantia nigra pars compacta
- This results in lower levels of dopamine in the CNS
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Clinical manifestations of decreased dopamine
- Mask-like facies
- Bradykinesia
- Resting tremor
- Muscle rigidity
- Shuffling gait
- Postural instability
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Drug names of dopamine receptor agonists used in Parkinson's disease
- Bromocriptine
- Pergolide
- Ropinirole
- Pramipexole
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Mechanism of dopamine receptor agonists used in Parkinson's disease (bromocriptine, pergolide, ropinirole, pramipexole)
- These drugs all work as dopamine receptor agonists, but each drug has different effects on the different types of dopamine receptors
- Pergolide: agonist of D1 and D2 receptors
- Ropinirole and Pramipexole: agonist of only D2 receptors
- Bromocriptine: D2 receptor agonist and D1 receptor antagonist (can antagonize D1 receptors in the hypothalamus)
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Uses of dopamine receptor agonists (bromocriptine, pergolide, ropinirole, pramipexole)
- Used to treat Parkinson's disease
| - Bromocriptine can be used to reduce the rate of growth of pituitary adenomas (prolactinomas) and to treat acromegaly
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Side effects of dopamine receptor agonists (bromocriptine, pergolide, ropinirole, pramipexole)
- Headache
- Nausea
- Vomiting
- Epigastric pain
- Hypotension/syncope initially (leading to hypertension over time)
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Mechanism of Levodopa (L-Dopa)
- Levodopa is a metabolic precursor to dopamine that enters the brain through an L-amino acid transporter (dopamine itself cannot cross the BBB)
- Once in the CNS, levodopa is further decarboxylated to dopamine
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How does levodopa (L-dopa) appear in the urine?
-Appears as the metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC)
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Uses of Levodopa (L-Dopa)
-First-line treatment for Parkinson's disease
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What is Levodopa (L-Dopa) given with and why?
-Given with carbidopa to reduce peripheral conversion of L-dopa to dopamine, which decreases the side effects and increases the availability of L-dopa for the CNS
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Side effects of Levodopa (L-Dopa)
-Nausea and vomiting
-Tachycadia
-Atrial fibrillation
-Dyskinesias
-Agitation
-Confusion
Note: L-Dopa is CONTRAINDICATED in psychosis and close-angle glaucoma
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What are the two types of monoamine oxidase in the nervous system?
- MAO-A metabolizes NE and serotonin
| - MAO-B metabolizes dopamine
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Drug names of MAO-B inhibitors
- Selegiline
| - Rasagiline
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Mechanism of MAO-B inhibitors (Selegiline)
-Selegiline is an irreversible selective inhibitor of MAO-B (which is found in the striatum and metabolizes dopamine in the brain)
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Uses of MAO-B inhibitors (Selegiline)
- Treatment of Parkinson's disease
- Note: A selegiline preparation (Emsam) is available in a skin patch that allows the drug to bypass the GI tract. Its low dose does not have tyramine food interactions as seen with other MAO inhibitors
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Side effects of MAO-B inhibitors
-Serotonin syndrome (can occur when taken in combination with meperidine, TCAs, or SSRIs)
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Drug names of catechol-o-methyltransferase (COMT) inhibitors
- Tolcapone (central and peripheral)
| - Entacapone (peripheral)
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Mechanism of catechol-o-methyltransferase (COMT) inhibitors
-COMT inhibitors can prolong the action of levodopa by decreasing its peripheral (tolcapone and entacapone) and central (tolcapone) activity
Note: Entacapone is preferred to tolcapone even though it only has peripheral activity because it also has less hepatotoxicity
166
Uses of catechol-o-methyltransferase (COMT) inhibitors
-Used to increase the levels of levodopa in the treatment of Parkinson disease
167
Side effects of catechol-o-methyltransferase (COMT) inhibitors
- Dyskinesias
- Nausea
- Confusion
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What are general anesthetics?
- They cause analgesia, amnesia, and unconsciousness (essential to surgery)
- They also cause muscle relaxation and suppression of reflexes
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What are the four sequential stages of anesthesia?
Stage 1. Analgesia: "conscious and conversational"
Stage 2. Disinhibition: autonomic variations (changes blood pressure, heart rate, and respiratory rate)
Stage 3. Surgical anesthesia: Unconscious with relaxed muscles
Stage 4. Medullary depression: Respiratory and vasomotor center depression
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What are the methods of delivery of general anesthetics?
- Inhaled agents (volatile, halogenated hydrocarbons)
| - IV drugs (common property of rapid induction)
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Tradeoff between potency and speed of induction in general anesthetics
- Drugs with low solubility in blood have rapid induction and recovery times
- Drugs with high solubility in oil or lipids have increased potency
- "Anesthetics with greater solubility in oil tend to also have greater solubility in blood and vice versa, implying that there is a tradeoff between potency and speed of induction"
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Properties of inhaled anesthetics
-Depth of anesthesia can be rapidly altered by changing the inhaled concentration of the drug (making it suitable for maintaining anesthesia)
- Speed of induction of inhaled anesthetics depends on:
1. The alveolar gas and venous blood partial pressures
2. The solubility of the anesthetic agent in the blood
3. The alveolar blood flow
-The minimum alveolar concentration (MAC) is very similar to ED50 and is equal to the alveolar concentration of an inhaled anesthetic that stops movement in 50% of patients in response to incision
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Properties of drugs that cross the BBB
-Drug must penetrate through lipid membranes (lipophilic) or must be actively transported
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Drug names of inhaled anesthetics
- Halothane
- Isoflurane
- Sevoflurane
- Desflurane
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Mechanism of inhaled anesthetics (halothane, isoflurane, sevoflurane, desflurane)
- The mechanism of inhaled anesthetics is poorly understood
| - Derived from early research and clinical experience with ether and chloroform
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Side effects of inhaled anesthetics (halothane, isoflurane, sevoflurane, desflurane)
- Respiratory depression
- Nausea
- Emesis
- Hypotension
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Toxicity of inhaled anesthetics (halothane, isoflurane, sevoflurane, desflurane)
- Hepatotoxicity (halothane)
- Nephrotoxicity (methoxyflurane - no longer used in the US)
- Convulsions (enflurane)
- Malignant hyperthermia (all agents except nitrous oxide)
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What drug is used to treat malignant hyperthermia?
- Dantrolene
- This drug interferes with calcium release from the sacroplasmic reticulum of muscle cells by binding to ryanodine receptors
179
Properties of intravenous anesthetics
- Used to rapidly induce anesthesia
| - Propofol has the ability to both induce and maintain anesthesia
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Types of intravenous anestheics
- Barbiturates
- Benzodiazepines
- Ketamine
- Opiates
- Propofol
- Etomidate
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Properties of barbiturates (thiopental) for intravenous anesthesia
- Highly lipid-soluble and enters brain rapidly (making them suitable for induction of anesthesia and short surgical procedures)
- Redistribution from brain to other tissues causes loss of effects
- Not analgesic (therefore, they require a supplementary analgesic)
- IV barbituates can cause severe hypotension in patients who are hypovolemic or in shock
- Anesthetic concentrations of pentobarbitol block high-frequency sodium channels
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Properties of benzodiazepines (midazolam) for intravenous anesthesia
- Most common drug used for endoscopy
- Used with inhalation anesthetics and narcotics
- Midazolam can cause severe postoperative respiratory depression and amnesia
183
Properties of ketamine (arylcyclohexylamine) for intravenous anesthesia
- This is a PCP analog that acts as a dissociative anesthetic (very high affinity for NMDA receptors)
- It causes sedation, amnesia, immobility, disorientation, and hallucinations
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Properties of opioids (morphine, fentanyl, sufentanil) for intravenous anesthesia
- Used with other CNS depressants during general anesthesia
- Toxicity involves hypotension, respiratory depression, and muscle rigidity
- Opioids are reversed with naloxone or naltrexone (which antagonize the mu-opioid receptor)
185
Properties of propofol for intravenous anesthesia
- Used for rapid induction of anesthesia and short surgical procedures
- An excitatory phase may occur (causing muscle twitching, spontaneous movements, and hiccups)
- It can also reduce ICP
- Used in the resection of spinal cord tumors (since it has much less effect than volatile anesthetics on CNS-evoked potentials, it can be used when assessing spinal cord function)
186
OCD treatment
-Tricyclic antidepressants and SSRIs
Treatment of choice:
-Clomipramine (TCA)
-Fluoxetine
187
Meds to abort migraines
- Sumatriptan
- Almotriptan
- Rizatriptan
- Zolmitriptan
188
Which drug(s) should be given to reverse anesthesia caused by fentanyl, propofol and midazolam?
-Naloxone and Flumazenil
189
Mood stabilizers
- Lithium
| - Lamotrigine
190
Lithium
- Inhibits andrenergic, muscarinic adn serotonergic neurotransmission in the brain
- Alters serotonin, norepinephrine and dopamine neurotransmission
- Common adverse effects: acute lithium intoxication [nausea, vomiting, diarrhea, renal failure, ataxia, tremor), bradyarrhythmia, hypotension, hyperkalemia, nephrogenic diabetes insipidous, hypothyroidism, goiter, ECG and EEG abnormalities are rare, acne
191
Lamotrigine
- Inhibits neurotransmission by blocking neuronal Na channels
- Adverse reactions: rash, ataxia, somnolence, blurred vision
192
Methylphenidate
-Increase catecholamine release from the synaptic terminal
-Block catecholamine reuptake
-Weakly inhibit MAO
Adverse effects: hypertension, tachyarrhythmia, restlessness, loss of appetite, addiction potential
