1
Q
Zuclopenthixol
A
- moderate potency
- Blocks D1 and D2 receptors
- Has three main forms:
1. Zuclopenthixol dihydrochloride - used for patients who are compliant with oral men’s
2. Zuclopenthixol acetate - used in a true sedation of psychotic patients (2-3 days sedation)
3. Zuclopenthixol decanoate - long acting IM injection for poor compliant patients (weekly) - Has only dopamine related side effects: Extrapyramidal symptoms, hyperprolactinemia, anti0emetic, tardive dyskinesia
Typical
2
Q
Haloperidol
A
High potency
Blocks D1 and D2 dopamine receptors
Only dopamine related side effects:
- extrapyramidal symptoms, hyperprolactinemia, anti-emetic, tardive dyskinesia
Typical
3
Q
Chlorpromazine
A
- DA antagonist: affect extrapyramidal system, pituitary, chemoreceptor trigger zone, can illicit tardive dyskinesia
- Weak alpha-adrenergic antagonist (postural hypotension)
- Muscarinic antagonist (constipation, sedation, hypotension, anxiolytic)
- Histamine antagonist (sedation, itching, etc.)
In some countries, such as the United States, injections of antipsychotics such as haloperidol can be ordered by a court at the request of a psychiatrist
Typical
4
Q
Atypical
A
Substantially lower risk of extrapyramidal side effects
5
Q
Positive Symptoms
A
Symptoms that most individuals do not normally experience but are present in the disorder. It reflects an excess or distortion of normal functions (i.e., experiences and behaviours that have been added to a person’s normal way of functioning
Example: Hallucinations, Delusions, Bizarre behaviour
6
Q
Negative Symptoms
A
symptoms that are not present or that have diminished in the affected persons but are normally found in healthy people. It reflects a diminution or loss of normal functions (i.e., something that has been taken away from a person’s normal way of functioning)
Example: Poverty of Speech, social inattentiveness
7
Q
Clozapine (Clozaril)
A
- D1, D2, and 5-HT (Serotonin) antagonist
- effective on both positive and negative symptoms
- little or on extrapyramidal symptoms but weight gain
- BUT bone marrow suppression produces agranulocytosis and death
- Mandatory weekly blood testing
Atypical
8
Q
Risperidone (Risperdal)
A
- D2 and serotonin antagonist
- at optimal doses, reduces positive and negative symptoms with little or no EPS or other side effects
First line atypical antipsychotic
9
Q
Olanzapine (Zyprexa)
A
- D2 and serotonin antagonist
- reduces positive and negative symptoms with little or no side effects (other than weight gain, dizziness, and dry mouth)
- Seems to halt progression of schizophrenia
First line atypical antipsychotic
10
Q
Quetiapine (Seroquel)
A
- D1, D2, and serotonin antagonist
- actions similar to risperidone and olanzapine but cheaper
First line atypical antipsychotic
11
Q
Tardive Dyskinesia
A
- Repetitive painless, involuntary, tic-like movements of face, eyelids, mouth, tongue, extremities, or trunk
- frequently appears after long-term or high-dose is of antipsychotic drugs
12
Q
Neuroleptic Malignant Syndrome (NMS)
A
- Due to massive DA black; increase incidence with high potency and depot neuroleptic
- Fever, muscle rigidity, unstable blood pressure, lactic acidosis, shock and dehydration
Treatment: stop drug, hydrate, cool, Dantrolene (inhibits calcium release in muscles which inhibits contraction), bromocriptine (dopamine agonist) (5% mortality)
13
Q
Neurosis
A
- A class of functional mental disorders involving distress with neither delusions nor hallucinations, whereby behaviour is not outside socially acceptable norms
- maladaptive learned behaviour
14
Q
Psychosis
A
- Psychosis is given to the more severe forms of psychiatric disorders, during which hallucinations, delusions and impaired insight may occur:
1. Loss of contact with reality (lack of reality testing)
2. Disruption of brain function
3. Neurochemical imbalance induced by: drugs/chemicals, neurodegeneration, genetic abnormality
15
Q
Alzheimer’s Disease
A
- A neurodegenerative disease of the elderly
- 1/12 of the population 65-75 years of age
- 1/3 of the population >85 years of age
- Accounts for 60-80% of all dementias
16
Q
Dementia
A
- Short term memory loss
- Impaired memory retrieval
- impaired ability to generate ideas and to manipulate concepts mentally
- impaired judgement and evaluation
- Labile and inappropriate emotions
- Motor functions are generally intact until late stages of the disease
17
Q
Donepezil
A
- Reversible AChE inhibitor
- Indicated for mild-moderate AD
- Half-life of 70 hours
- Dosing must be titrated over weeks to months
- 100% oral bioavailability and crosses the BBB easily with 40% plasma protein binding
18
Q
Galantamine
A
- Reversible AChE inhibitor
- Indicated for mild-moderate vascular and Alzheimer’s type dementia
- Half-life of 7 hours
- Dosing must be titrated over several weeks
- 80-100% oral bioavailability and crosses BBB easily with 18% plasma protein binding
- Sleep aid (enhances dreaming), memory enhancer
19
Q
Rivastigmine
A
- Butyrylcholinesterase and AChE inhibitor
- Indicated for mild-moderate Alzheimer’s type and Parkinson’s related dementia
- Half-life of 1.5 hours
- Dosing must be titrated over several weeks
- 40% oral bioavailability and crosses BBB easily with 40% plasma protein binding
- Bypasses cytochrome P450 pathways for reduced drug-drug interactions (reduced adverse effects)
20
Q
Tranylcypromine
A
- Half life: 2 hours but binds irreversibly to MAO, so 1 dose lasts about 7 days
- Inhibits both MAO-A and MAO-B, this increases the levels of 5-HT, NE, and DA in neurons in the brain
- increases the absorption of dietary tyramine from the gut into the blood stream
MAO inhibitor
21
Q
Moclobemide
A
- Half-life: 2 hours but binds reversible, competitive binding
- is a selective inhibitor of MAO-A: increases levels of serotonin and noradrenaline in brain without affecting blood tyramine
- the ‘wine-cheese’ reaction is usually not a problem because moclobemide has a short half-life, is taken after meals, is reversible, and does not alter MAO-B in the liver
Anti-depressant
22
Q
Imipramine and Amitriptyline
A
Imipramine: half life 17 hours
Amitriptyline: half life 38 hours
- Inhibit both noradrenaline and serotonin reuptake
- broad spectrum
- also block muscarinic and alpha one adrenergic receptors producing impaired memory, etc., and postural hypotension, respectively.
NSRIs
Antidepressant
23
Q
Fluoxetine
A
- Half life of 3 days
- has active metabolite norfluoxetine, total biological half-life about seven days
- lacks affinity for neurotransmitter receptors
- inhibits cytochrome P450 2D6 (and others) causing potentially fatal drug interactions with narcotics, beta blockers, etc.
- inhibits only serotonin reuptake
SSRI
Antidepressant
24
Q
Fluvoxamine and Paroxetine
A
Fluvoxamine: Half-life of 15 hours Paroxetine: Half-life of 24 hours - Inhibit Serotonin reuptake - lack active metabolites - Have less serious P450 related drug interactions than fluoxetine SSRIs Antidepressant
25
Sertraline and Citalopram
```
Sertraline: Half-life of 26 hours
Citalopram: Half-life 35 hours
- Inhibitors of serotonin
SSRIs
Antidepressants
```
26
Desipramine
- Half-life: 38 hours
- is the active metabolite of imipramine
- has less affinity for muscarinic and alpha one receptors than imipramine
- selective noradrenaline reuptake inhibitor
SNERI
Antidepressant
27
Nortripyline
- Half-life: 55 hours
- is the active metabolite of Amitriptyline
- has less affinity for muscarinic and alpha one receptors than Amitriptyline
- selective noradrenaline reuptake inhibitor
Antidepressant
SNERI
28
Maprotiline
- Half-life: 36 hours
- tetracyclic antidepressant
- side effects comparable to tricyclic antidepressants
- noradrenaline reuptake inhibitor
SNERI
29
Amoxipine
- Half-life: 8 hours
- Moderate and strong reuptake inhibitor of 5-HT and NE respectively
- Antagonist of select 5-HT, NE, and DA receptors (antagonist/inverse agonist)
Atypical Antidepressant
30
Nefazodone
- Half-life: 3-4 hours
- selective inhibitor of NE uptake
- block 5HT2A high potency
- Can be hepatotoxic (contraindicated in patients with liver disease)
Atypical Antidepressant
31
Trazodone
- Half-life: 4-8 hours
- weak inhibitor of serotonin uptake and antagonizes serotonin and alpha adrenergic receptors
Atypical Antidepressant
32
Bupropion
- Half-life: 4-8 hours
- weak inhibitor of DA uptake (NE reuptake as well)
- Nicotinic acetylcholine receptor antagonist
- Effective alone, but often added to cases to incomplete responses with SSRIs
Atypical antidepressant
33
Mirtazapine
- Half-life: 30 hours
- blocks pre-synaptic alpha 2- receptors that inhibit release of noradrenaline and serotonin (increase both noradrenaline and serotonin release)
- also blocks several types of post-synaptic serotonin receptors
- Blocks NE-dependant alpha 2 receptor mediated analgesia
- generally mild side effects )increased appetite ad weight gain)
- Atypical antidepressant
34
Bipolar Disorder
- Affects 1-2% of the population (much higher in professionals and entertainers)
- mood swings that cycle between depression and mania (cycle lengths vary from hours to years in different patients)
- Several different genes have been identified (onset at any time of life, typically younger)
35
Lithium
- Half-life: 8-30 hours
- Cornerstone treatment option as it can abort manic episode, prevent future magic episodes, and exerts a mild antidepressive effect
- Long term patient compliance poor due to side effects (nausea, diarrhea, drowsiness, weight gain, fine hand motor tremor, polyuria)
- Low therapeutic index (0.6-1.2 meg/L vs 1.4meg/L for toxicity) Nausea and vomiting are early signs of overdose
- Very dangerous in conjunction with other meds (diuretics Na+)
- Interferes with receptor-activated Phosphatidylinositol turnover
- Antagonizes 5-HT1A and 5HT-1B autoreceptors, preventing feedback inhibition of 5HT release
- Enhances glutamate reuptake, clearing glutamate from synapse
36
Carbamazepine
- Half-life: 15-30 hours
- decreases voltage-gated Na channels
- potentiates GABA receptor currents
- Exhibits antimanic, antidepressant, and prophylactic effects equivalent to lithium with fewer adverse effects in may patients
- Adverse effects include: dizziness, ataxia, double vision
Bipolar drug
37
Valproic Acid (Bipolar)
- Half-life: 13-21 hours
- decreases voltage-gated Na Channels
- potentiates GABA receptor currents
- additional effects as a histone deacetylase inhibitor (epigenetic effects)
- Especially useful in patients with rapid cycling of manic and depressive episodes
- Adverse effects include: nausea, vomiting, diarrhea, headache, tremor, double vision, drowsiness, dizziness
38
Lamotrigine
- Half-life: 13 hours
- Decreases voltage gated Na channels
- It also blocks L-, N-, and P-type calcium channels and has weak 5-HT3 receptor inhibition. These actions thought to inhibit glutamate release in cortex and striatum/limbic areas - these neuroprotective and antiglutamatergic effects are promising contributors to its mood stabilizing activity
- Is effective in the treatment of the depressed phase of bipolar disorder, where as other sodium channel blocking channel blocking antiepileptic drugs are not
- Adverse effects include: dizziness, ataxia, double vision
39
Phenytoin
- Zero order kinetic (metabolism saturation)
- P450 metabolism: Beware of toxicity
- Enzyme inducer
- Side effects: Gum hypertrophy, Cerebellar atrophy: imbalance, Teratogenic: fetal hydantoin syndrome
Voltage-Gated sodium Channels
40
Carbamazepine and Oxcarbazepine
- P450 metabolism
- Enzyme inducer (lower for Oxcarb): induces its own metabolism, dose adjustment is required, may lower other medication levels (e.g., oral contraceptives)
- Side Effects/Interaction: Rash (for both), Hyponatremia (higher in Oxcarb), Hepatotoxicity (higher in Carb), bone marrow suppression (higher in Carb), Osteoporosis (higher in Carb), teratogenic (not as bad as phenytoin)
- voltage gated sodium channel blockers
41
Lamotrigine
- Metabolized predominantly by glucuronic acid conjugation
- sodium gated channel blockers
- if combined with valproic acid, slowly increase VPA to avoid toxicity/side effects (VPA decreases metabolism (glucuronidation) resulting in 2-fold increases in lamotrigine half-life)
- Levels decrease significantly in pregnancy or with oral contraceptives as glucuronidation is induced by estrogen so an increase in dose is required.
- Side Effects: severe skin rash (to avoid, titrate dose slowly for a few weeks), believed to be safe in pregnancy (a few casesk of cleft lip are reported, try not to combine with other AEDs in pregnancy (always add folate)
42
Lacosamide
- Prolongation of cardiac conduction (PR interval)
- may lead to heart block
- Do baseline ECG in patients with known cardiac disease or conduction defects
- voltage gated sodium channel blocker
43
Valproic Acid (Anticonvulsant)
- Heavy protein binding, displaces other protein bound medications -> toxicity (e.g., phenytoin)
- Blocks liver metabolism leading to an increase in lamotrigine and phenobarbital levels
- VPA level is decreased by P450 inducers (e.g., phenytoin)
- Side Effects: tremor, platelet dysfunction, hepatotoxicity, pancreatitis, hair loss, wight gain, polycystic ovaries -> infertility in young women, high teratogenicity (never use in young women if other choices available
- voltage gated sodium channel
44
Benzodiazepines (GABA potentiation)
- increase the frequency of the opening of Cl- channels
- Lorazepam and Midazolam: intravenous forms are used in emergency situations to treat ongoing seizures or status epilepticus (don't want to use long term)
- Lorazepam sublingual can be used by the patient at aura to avoid seizure generalization
- Rectal Diazepam (diastat) is used in children by their parents at home to stop seizures
- Only Clobazam and Clonazepam are used as adjunctive AEDs for long term seizure treatment
- Benzodiazepine withdrawal may cause seizures even in non-epileptic persons
- Side Effects: respiratory suppression and respiratory arrest at higher doses
45
Barbiturates (GABA Potentiation)
- Phenobarbital is used in neonatal seizures
- in adults, they are rarely used
- phenobarbital withdrawal may cause prolonged seizures even in non-epileptic persons
- Primidone is occasionally used to treat tremors and not used for seizures any more
- Vigabatrin inhibits GABA transaminase, side effects: retinitis and loss of vision, baseline and frequent visual assessments required
- Tiagabine inhibits GABA transporters, side effects: depression and psychosis
- Both lead to increase GABA in extracellular space
- Side Effects: respiratory suppression and respiratory arrest at higher doses
46
Ethosuximide
- Blockade of T-Type calcium channels in thalamic relay neurons (TR)
- specific for absence of seizure treatment
- Also may use Valproic Acid for absence
47
Gabapentin and Pregabalin
- molecular structure similar to GABA but no direct activation of receptor
- Bind to alpha 2 gamma subunit of presynaptic voltage dependant calcium channel leads to decrease in calcium entry, leading to decrease in excitatory neurotransmitter glutamate release
48
Anxiolytics (Benzodiazepines)
- Anxiolytics
- Hypnotic
- Anticonvulsant
- Muscle relaxant
- Amnesia
Neurochemical effects:
- increase GABA inhibition
- down-regulated benzodiazepine receptors
- up-regulate downstream receptors for NA, 5-HT etc.
(Increasing GABA reduces the release of NA, 5HT etc., which up regulates the receptors for NA, 5HT
- overdose with benzodiazepines is not lethal but benzodiazepines do potentiate the lethal actions of other compounds like alcohol and narcotics
49
Anxiolytic Benzodiazepine Examples
```
Diazepam
Flurazepam
Lorazepam
Midazolam
Oxazepam
Temazepam
Triazolam
```
50
Beta-Carbolines
- Interact with GABA(a) receptor at the Benzodiazepine allostérie binding site
- Decrease affinity of GABA for its binding site (inverse agonist)
- No Therapeutic use, but are found in nature (psychedelic plants)
- Are endogenous beta-Caroline's in the pineal gland (pinoline)
51
Diazepam
Half-life: 50-100 hours
- 1.5-2.0 hours until max effect
- 5 to 40 mg daily in divided doses
- low potency
52
Triazolam
2-3 hours half life
1.5-2 hours until max effect
0.25 mg before retiring
Relative potency: high
53
Buspirone
- acts as a partial agonist at serotonin 5HT inhibitory presynaptic autoreceptors
- seems to be a selective anti-anxiety drug
- lacks hypnotic, anti-convulsant or muscle relaxant effects
- does not potentiate the respiratory depressant actions of alcohol, narcotics, etc.
- Little or on withdrawal syndrome
- Best first line drug, hands down but it takes 2-3 weeks for its anti anxiety effects, most patients wont wait that long
54
Temazepam
- Half life of 8 to 10 hours
- Used as a hypnotic agent
- max effect in 2-3 hours
- 30 mg before retiring
- Low potency
55
Zopiclone (Imovane)
- half life of 5 hours
- have less effects on EEG than benzodiazepines
- Hypnotic agent
56
Zolpidem (Ambien)
- Half life of 2 hours
| - Hypnotic Agent
57
Flurazepam
- Hypnotic agent
- 50-100 hour half-life
- max effect in 1 hour
- 15-30 mg before retiring
- Low relative potency
58
Caffeine
- metabolized by liver CYP450 (CYP 1A2)
- plasma half-life is about 6 hours
- metabolites excreted in urine
- both water and lipid soluble, easily crosses the BBB
- Adenosine receptor antagonist (indirectly increases monoamine/acetylcholine release)
- inhibits phosphodiesterase which leads to increased cAMP (similar to beta-adrenergic receptors)
- 1 cup contains 100-200mg
59
Amphetamine
- structurally related to NE/DA
- plasma half life is about 20 hours
- stimulates the releases blocks the reuptake of NE and DA with lesser effects on 5-HT
- inhibits MAO at higher concentrations
- is a direct agonist at NE receptors
- Adverse Effects: vertigo, hypertension, insomnia, confusion, potential for addiction, nausea, diarrhea.
60
Methylphenidate
- neurochemically similar to amphetamine
- plasma half life is about 2 hours
- blocks reuptake of DA and NE
- also known as Ritalin
- used for narcolepsy treatment
61
Phentermine
- pharmacology similar to amphetamine
- Excreted unchanged by the kidneys
- generally well tolerated
- Available in immediate and sustained-release formulations
- plasma half life is about 2 hours (10 hours for sustained-release)
- promote NE and DA release
- suppress appetite through satiety center in the hypothalamus
62
Ephedrine
- plasma half life is about 3-4 hours
- Sympathomimetic acting on SNS
- Indirectly increases activity of NE on adrenergic receptors
- CNS stimulant similar to amphetamines (less pronounced)
63
Narcolepsy
- Affects 0.3 to 0.5% of the population
- is a neurological disorder characterized by: Sleep attacks (enter REM sleep almost instantly, even during the day), excessive daytime sleepiness (EDS), hallucinations as falling asleep or waking up, loss of muscle tone occurs without loss of consciousness in response to strong emotions (cataplexy)
64
Treatment guidelines for Bipolar
- 20-40% of people don't respond to lithium or tolerates its adverse effects
- Therefore -> anticonvulsants: Valproate, Carbamazepine or lamotrigine
- Atypical antipsychotics may be used for treatment of acute mania or mixed episodes
- Antidepressants may precipitate mania, and thus combination therapy of Olanzapine with fluoxetine can be used for the treatment of depression associated with bipolar disorder
65
Memantine
Non-competitive low affinity antagonist at NMDARs
At therapeutic doses, only partial blockade (low potency)
Non-competitive antagonist at the nAChRs
Memantine us recommended to manage moderate-severe AD in patients intolerant or contraindicated for AChE inhibitors
66
Zonisamide
Blocks NA channels and blocks calcium channels
67
Felbamate
NMDA blocker
68
Topiramate
AMPA blocker
69
Perampanel
AMPA blocker
