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1

Tricyclic Antidepressants

Mechanism of Action (general) and Names of drugs

NE, 5-HT reuptake inhibitor

Also muscarinic receptors block, a1 block, H1 block

Imipramine
Amitriptyline
Desipramine
Nortriptyline
Doxepin
Clomiphene
Amoxapine

2

Tricyclic Antidepressants

Uses (including specific drugs)

General: Major depression chronic pain, obsessive- compulsive disorder

- Imipramine: bed-wetting
- Desipramine: least anticholinergic
- Clomipramine: OCD
- Amitriptyline: Neuropathic pain, migraine
- Amoxapine: some D2 blockade

3

Tricyclic Antidepressants

Toxicities

Antimuscarinic: mydriasis, cycloplegia, urinary retention, sedation.
Alpha1 block: hypotension, orthostasis.
Histamine1 block: sedation, weight gain

Overdose: coma, convulsion, cardiotoxicity (Respiratory depression, fever, prolonged QT interval)

Treating TCA tox: Sodium bicarbonate attaches to sodium channel to decrease cardiovascular effects

CYP drug interactions; polymorphism a/w slow metabolism of TCAs

Serotonin Syndrome

4

Bupropion

Mechanism of Action

- Reuptake inhibition of dopamine and norepinephrine.

- Noncompetitive antagonist at nicotinic receptor (smoking cessation potential)

- SEPARATE-> Varenicline: partial nicotinic receptor agonist (erratic behavior, suicide). Not related to bupropion mechanism

5

Bupropion

Use

- Major depression
- Smoking cessation

6

Bupropion

Toxicities

Lowers seizure threshold, caution in bulimic patients.

No sexual dysfunction
Little M, H1 effects

7

Mirtazapine

Mechanism of Action

Alpha2 block to
increase NE and 5-HT release.

Opposite clonidine mechanism

8

Mirtazapine

Use

Major depression
sedation

9

Mirtazapine

Toxicity

Weight gain, sedation

10

Serotonin-Norepinephrine
Reuptake Inhibitors
(SNRI)

MOA, examples of drugs

Inhibits reuptake of 5HT and NE

Duloxetine, Venlafaxine, Desvenlafaxine, Milnacipran

11

Serotonin-Norepinephrine
Reuptake Inhibitors
(SNRI)

Use

Major Depression, chronic pain, fibromyalgia, neuropathic pain

12

Serotonin-Norepinephrine
Reuptake Inhibitors
(SNRI)

Toxicities

Mechanism like tricyclics. No blockade of H1, alpha1, Muscarinic

Overdose: coma, convulsion, cardiotoxicity.

Serotonin Syndrome

13

Selective Serotonin
Reuptake Inhibitor (SSRI)

MOA and Examples

Inhibits 5HT reuptake
At least 4 weeks for full effect

Fluoxetine
Fluvoxamine
Citalopram
Paroxetine
Sertraline
Escitalopram

14

SSRIs

Use

- Major depression
- anxiety
- panic disorder
- OCD
- post- traumatic stress disorder
- premenstrual dysphoric disorder
- bulimia
- social phobias

15

SSRIs

Toxicities

Insomnia, headache
Nausea, vomiting
Bleeding abnormalities (platelets)
Impotence (use phosphodiesterase 5 inhibitor)

Serotonin syndrome

Drug interactions (most w/ fluoxetine CYP450 2D6) -->least with sertraline, citalopram, and escitalopram

16

Serotonin Syndrome

Symptoms

3 As: Increased activity (neuromuscular), Autonomic stimulation, Agitation

Specific symptoms:
- MYDRIASIS
- hyperthermia
- hypertension
- tachycardia
- myoclonus
- tremor
- delirium
- confusion
- within 24 hrs, unlike NMS
- GI symptoms

17

- Trazodone
- Nefazodone

MOA

Serotonin reuptake inhibitor and blocker (SARI); Alpha1 and H1 block

18

- Trazodone
- Nefazodone

Uses

- Major depression
- Sedation
- Sleep aid

19

- Trazodone
- Nefazodone

Toxicities

- Alpha1 block (priapism, possible sedation)
- H1 block (sedation)

Increased levels of trazodone w/ CYP 3A4 inhibitors
- Nefazodone is hepatotoxic

20

Phenelzine
Tranylcypromine
Isocarboxazid

Mechanisms of Action

Monoamine oxidase A inhibitors (prevents breakdown of (NE, Epi, 5-HT, DA, tyramine)

Exception:
Selegiline (MAOIb, prevents dopamine breakdown) --> Tx for Parkinson’s disease

21

Phenelzine
Tranylcypromine
Isocarboxazid

(MAOIs toxicity)

- Hypertension with tyramine-containing foods or sympathomimetics (cold medicine)

- Must avoid tyramine foods: Aged cheese and meats, red wine, chocolate, avocado.

Serotonin syndrome (W/ SSRIs, TCAs, meperidine, dextromethorphan, triptans, linezolid, St. John’s Wort)

22

Lithium

MOA

Blocks inosine 5’monophosphatase (Gq), PKC and decreases DAG, IP3 and therefore Ca2+

23

Lithium

Use

Bipolar disorder

24

Lithium

Toxicity

- Na+ loss promotes Li+ reabsorption (toxicity with diuretics)

- NSAIDs, ACEI facilitate Li+ reabsorption in PCT
Amiloride (enhances Li+ excretion)

- Narrow therapeutic index (1.5 mEq vs. 2mEq)

- Tremors (use a beta blocker)

- Leukocytosis

- Polyuria, polydipsia (Loss of ADH response). Amiloride benefit here.

- Hypothyroidism

- Ebstein anomaly, a congenital heart condition (use lamotrigine in pregnancy)

25

Valproate

MOA

Broad-spectrum:

1. Blocks Na+ channels and T-type calcium channel

2. Decrease glutamate at NMDA receptors

3. Increases GABA receptor action

4. Increases GABA synthesis

5. Blocks degradation of GABA

26

Valproate

Use

Alternative to lithium in bipolar mania

Tonic-clonic, absence, and partial seizures, migraine prophylaxis

27

Valproate

Toxicity

"Valproate Syndrome” includes spina bifida, neural tube defects, autism.

- Weight gain
- Hepatitis
- Inhibitor of CYP2D6 and 3A4

28

Carbamazepine

MOA

Blocks sodium channels, blocks NE reuptake

29

Carbamazepine

Use

Bipolar disease

Tonic-clonic and partial seizures, trigeminal neuralgia

30

Carbamazepine

Toxicity

- Drowsiness
- Ataxia
- Diplopia

- SIADH (water “intox”)
- Aplastic anemia
- Teratogen (neural tube defects)

- Stevens-Johnson syndrome (HLA allele in ethnic population).
- Inducer of CYP 3A4

31

Lamotrigine

MOA

Potentiates GABA, blocks voltage-gated Na+ channels, glutamate blockade

32

Lamotrigine

Use

Manic phase of bipolar syndrome

Partial, tonic-clonic, and absence seizures, Lennox-Gastaut syndrome

33

Lamotrigine

Toxicity

Black Box Warning for Stevens-Johnson syndrome= rash

CNS effects

34

Atypical Antipsychotics

General Mechanism

5-HT2A >>>D2; D3 and D4 block

35

Atypical Antipsychotics

General MOA and ADEs

- Increase DA release to relieve negative symptoms of psychosis (and positive too)
- Few EPS effects
- Hyperprolactinemia
- All prolong QT interval, contraindicated with certain cardiovascular issues

36

Risperidone

MOA and Use

5-HT2A >>>D2; D3 and D4 block

- Atypical antipsychotic, approved for mania

37

Risperidone

Toxicity

- Hypotension from alpha1 blockade.
- Increase prolactin, hyperlipidemia, hyperglycemia

Palperidone is active metabolite

38

Olanzapine

MOA and Use

Blockade of
5-HT2A > H1 > D4 > D2 > α1 > D1

Approved in combination with fluoxetine for mania
Atypical antipsychotic

39

Olanzapine

Toxicity

- Less ANS effects.
- Fewer extrapyramidal effects (EPS)
- Weight gain
- Sedation
Metabolic changes like risperidone - hyperglycemia, hyperlipidemia

40

Quetiapine

MOA and Use

Blockade of
H1 > α1 > M1,3 > D2 > 5-HT2A

D2 blockade, BUT binds for a short time.

- Atypical antipsychotic, approved for mania

41

Quetiapine

Toxicity

- Minimal muscarinic block
- H1 (sedation)
- alpha1 (orthostasis)

42

Aripiprazole

MOA and Use

- Partial D2 agonist
- 5-HT2A antagonist

Approved for mania, atypical antipsychotic

43

Aripiprazole
Toxicity

- Weight gain
- Akathisia

44

Ziprasidone

MOA and Use

Blocks 5-HT and NE reuptake

Atypical antipsychotic, approved for mania

45

Ziprasidone
Toxicity

Skin reactions, eosinophilia

46

Chlorpromazine
MOA and use

D2>> 5HT2 antagonist

- Typical antipsychotic; treats positive symptoms of psychosis
- low potency, inexpensive, used most often; phenothiazine

47

Chlorpromazine
Toxicity

- H1 block (sedation), a1 block (orthostasis)
- M1 block
- Parkinsonian effects - EPS, dystonias, tardive dyskinesias
- Deposits in cornea and lens
- Neuroleptic malignant syndrome
- Increased prolactin

48

Fluphenazine
MOA and use

D2>> 5HT2 antagonist, High clinical potency

Typical antipsychotic; A phenothiazine/piperazine

49

Fluphenazine
Toxicity

High incidence of tardive dyskinesias, parkinsonian effects

less autonomic toxicities

50

Thiothixene
MOA and use

D2>> 5HT2 antagonist, clinically most potent antipsychotic

Typical antipsychotic; a thioxanthene

51

Thiothixine
Toxicity

- Mid level tox. of extrapyramidal symptoms
- Injectable form— less tardive dyskinesias, less upreg of D2 receptors
- Sedation and hypotension

52

Haloperidol
MOA and use

D2>> 5HT2 antagonist; very potent antipsychotic

Typical antipsychotic; Also for Tourette’s

A butyrophenone

53

Haloperidol
Toxicities

Most severe EPS: parkinsonism, akastheisa, akinesia, dystonias

54

Thioridazine
MOA and use

More 5HT2 antagonist, less D2
low potency (M block)

Typical psychotic

55

Thioridazine
Toxicity

-Low eps effects
- ocular toxicity- brown vision from deposits in retina
- cardiotoxic effects: t wave, AV block, arrhythmias
HIGHEST risk of prolonged QT interval
- Na+ channel block

56

Tardive dyskinesias
Characteristics

- Drugs that decrease dopamine release will cause upreg of receptors
- occurs months to years later
- tongue protrusion, lip smacking, abnormal mvmts, “ rabbit nose”
- typically not reversible
- manage by starting with lowest dose, assess Pt periodically

57

Neuroleptic Malignant Syndrome
Characteristics and Tx

Life threatening effect of typical antipsychotics, inhaled anesthetics, and succinylcholine
- occurs weeks to months later, unlike serotonin syndrome

S and S: muscle rigidity, hyperthermia, tachycardia, altered consciousness, rhabdomyolysis.
- CK is elevated syndrome
DECREASED reflexes

Treatment: d/c drug, supportive care, and dantrolene or bromocriptine
- manage EPS and dystonias with anticholinergics or amantidine
- manage akasthesia (restlessness) with propranolol

58

Dantrolene
MOA and use

- interferes with release of Ca2+ from sarcoplasmic reticulum via ryanodine receptor bind
- used IV for NMS, skeletal m. Relaxant, malignant hyperthermia

59

Dantrolene
Toxicity

Hepatotoxicity
GI effects
CNS effects

60

Clozapine
MOA and use

D4 = a1 > 5HT2a > D2 = D1

Atypical antipsychotic, not approved for mania

61

Clozapine
Toxicity

-Nighttime drooling (paradox, ? M block)
-Weight gain
-Agranulocytosis- weekly blood counts for first 6 mo of Tx, every 3 wks after that
-Hypotension

62

Barbituates
General MOA and Use
- Short acting v. long acting?

- Bind to the Cl- channel and facilitate GABA action (prolong duration of channel opening)
- open channel in absence of GABA (independent)

Use: anxiety and insomnia (fallen out of use), seizures (phenobarbital), induction of anesthesia (thiopental)

Pentobarbital, Secobarbital- Short acting
Phenobarbital- long acting
Amobarbital, Thiopental - middle

63

Barbituates
Toxicities

- Can induce FULL respiratory effect (b/c GABA independent)- "No ceiling effect"
- Highly sedative with a hangover effect
- Tolerance, physical dependence, and withdrawal. Taper slowly!
- Highly abused (pentobarbital esp., b/c short acting)

- CYP450 inducers
- Lipid-soluble (thiopental): redistributed from brain.
- Elderly/ liver disease may see an increase in t1/2.

64

Benzodiazepines
MOA and General use

- Potentiates GABA by increasing frequency of
Cl- channel opening
- Needs GABA to open channel ("Ceiling effect", safer than barbs)

Use: anxiety, sedative-hypnotic, insomnia, anterograde amnesia, muscle relaxant, anticonvulsant.

65

Benzodiazepines
Use of Specific drugs

- Chlordiazepoxide and Diazepam (long acting drugs): EtOH detoxification.
- Alprazolam: Panic disorder. Most abused b/c short acting.
- Lorazepam, Clonazepam, Diazepam: Seizure disorder.
- Midazolam: anesthesia
- Estazolam and Flurazepam: insomnia

- Oxazepam, temezepam, and lorazepam are the safest for the elderly --bypass phase I metabolism (Only undergo glucuronide conjugation, which is ).

- Flunitrazepam (Rohypnol)- "date rape" drug bc antergograde amnesia

66

Benzodiazepines
Short acting v. Long acting

- Alprazolam (aka Xanax), Oxazepam- short acting
- Chlordiazepoxide, diazepam (aka valium), flurazepam: metabolites make drug long acting
- Lorazepam (aka Ativan), Temazepam- intermediate acting

67

Benzodiazepines
Toxicities

- Respiratory depression ONLY when combined with other CNS depressants
- Drowsiness, hangover
- Mild euphoria (abuse potential)
- Anterograde amnesia
- Physical dependence, can built tolerance
- Withdrawal: rebound anxiety, insomnia, seizures (esp. with alprazolam)
- Fetal malformations (hypotonia)

68

Ethanol
MOA and Toxicity

- Potentiates GABA. Euphoria (small doses)
- Reward center (release of dopamine)
- Increased norepinephrine release (cardiovascular effects)

- Zero-order elimination; CYP 2E1 induction- toxic with acetominophen
- Fetal Alcohol Syndrome (teratogen)
- Wernicke’s (thiamine deficiency)
- Loss of liver function; lose glutathione so unable to get rid of Reactive Oxidative Species
- ? Increased inflammation resulting in malignancy

-treat abuse with long-acting benzo, naltrexone (opioid blocker), or acamprostate (Glu blocker that increases GABA)
- Benzo for delirium tremens

69

Flumazenil
MOA and Use

- Antagonist at BDZ binding site at the GABA receptor

- Blocks actions of benzos and “zz” drugs but not for other sedative-hypnotic drugs.
- IV increases recovery following BDZ administration in anesthetic procedures.

70

Flumazenil
Toxicities

Agitation, confusion, and withdrawal symptoms (in chronic BDZ users)

71

Zolpidem, Eszopiclone, Zaleplon
MOA and Use

- "Zzz" drugs; Ambien aka Zolpidem
- Benzo-like action on Cl- channels (Binds specific GABAa subunit)

- Sleep aid; Minor effect on REM sleep
- Shorter duration of action
- Less hangover effect and daytime sedation
- Potentiated by EtOH

72

Zolpidem, Eszopiclone, Zaleplon
Toxicities

- Anterograde amnesia
- Hallucinations
- Delusions
- Impaired judgement
- Sleepwalking

73

Ramelteon
MOA and Use

- MT-1, MT-2 melatonin receptor agonist

- Sleep aid; Not addictive (not a controlled substance); No GABA transmission

-No significant toxicity; Substrate for CYP 1A2

74

Suvorexant
MOA and Use

- Orexin antagonist (blocks orexin normal action, which indicates arousal/wakefullness)

- Sleep aid/sedative

- No significant toxicity

75

Amphetamine and Dextroamphetamine
MOA and Use

- CNS stimulation, inhibits reuptake of NE and DA
- increases release of these catecholamines from nerve terminals

Use: Narcolepsy

76

Amphetamine and Dextroamphetamine
Toxicity

Sympathomimetic effects (cardiostimulation/CV, insomnia, weight loss)

77

Methylphenidate, Modafanil
MOA and Use

- Inhibit DA reuptake
- Use: Narcolepsy

78

Methylphenidate, Modafanil
Toxicity

- Less anxiety and anorexia than amphetamines
- Cardiovascular effects

79

Propranolol
MOA and Use

- Beta-1, Beta-2 antagonist
- Blocks SANS contribution to anxiety
- “situational anxiety”

80

Propranolol
Toxicity

- CNS depression
- Fatigue
- Bradycardia
- Asthma
- Hypoglycemia because of B2 blockade

81

Buspirone (Buspar®)
MOA and Use

- 5-HT1 Agonist
- Generalized anxiety; No sedation or addiction

82

Buspirone (Buspar®)
Toxicity

- Headache, dizzy, nervous
- Several weeks (3-4) for full effect

83

Sominex®, Unisom® Tylenol-PM®
MOA and Use

- All have Diphenydramine as an active ingredient
- OTC Sleep aid/sedative

84

Sominex®, Unisom® Tylenol-PM®
Toxicity

- H1 block: orthostasis
- Lipophilic, cross the blood brain barrier
- Muscarinic dryness: Dryness, constipation, mydriasis, urinary retention, increase AV and SA node conduction
- Muscarinic blockade is not indicated in BPH and glaucoma.

85

Disulfiram
Use

- Inhibits aldehyde dehydrogenase
- Anti-EtOH abuse
- CANNOT use with alcohol

86

Clonidine
MOA and Use

- Alpha 2 agonist
- Reduce sympathetic NS effects following EtOH, opioid, and nicotine withdrawal

87

Treatment of stimulant overdose

- Acidify urine
- Supportive therapy (lorazepam and haloperidol)

88

Typical Antipsychotic Toxicities

- M, H1, alpha1 blockade
- EPS (dystonia, pseudoparkinsonism)
- Akathisia
- Menstrual irregularities (prolactin
release)
- Tardive dyskinesia
- Neuroleptic malignant syndrome

89

Hypertensive crisis symptoms

Occipital headache
Stiff neck
Nausea/vomiting
Photophobia
Palpitations

Due to drug interaction with tyramine and MAOI-A