Antipsychotics

What are the theory for Schizophrenia and Psychosis?

-Hyperactive Dopamine transmission in Mesolimbic Pathway.

What are the drugs used to treat it?

- Typical Antipsychotics
 Phenothiazine: Chlorpromazine, Fluphenazine
 Thioxanthene: Thiothixene
 Butyrophenone: Haloperidol

- Atypical Antipsychotics
 Clozapine, Olanzapine, Risperidone

What are the mechanism of the drug action?

- Both drugs are D2-receptors antagonists, therefore able to suppress Positive Symptoms.

What are the undesirable side effects of Typical Antipsychotics?

- Suppression of Mesocortical Pathway: Exaggeration of Negative Symptoms.
- Suppression of Nigrostriatal Pathway: Extrapyramidal Syndrome (Symptoms?)
- Suppression of Tuberoinfundibular Pathway: Prolactinaemia (Symptoms?)
- Unpredictable: Neuroleptic Malignant Syndrome (Can you name the signs?)

How to treat EPS symptoms?

- Acute DystoniaAkathisiaParkinsonismTardive Dyskinesia (due to up reg. of D2-R)
- Use Anticholinergic agent Benzatropine

Which drugs have greater risk to cause the above NMS?

- Haloperidol, Chlorpromazine, Promethazine

In what ways are Atypical Antipsychotics better than the Typical one?
- High 5-HT2A-R : D2-R blocking ratio: Reduce risk of EPS
- Rapid dissociation from D2-R: Reduce risk of EPS
- Also improve Negative Symptoms
What are the undesirable side effects caused by Atypical Antipsychotics?
- Weight Gain
- EPS can still occur if daily dose of Risperidone is high
- Drug allergy
- Prolonged QT-interval by blocking K+channels (Clozapine and Risperidone)
- **Agranulocyosis of Clozapine**

Why do Clozapine and Olanzapine cause weight gain?

- Antagonize H1- R: Excessive eating, Food craving
- Antagonize Muscarinic –R: Reduce insulin secretion Hyperglycemia
- Affect adrenal activity: Reduce Lipolysis in adipose tissue.

When should you prescribe Clozapine to patients? What precaution measure should be taken?
- Only when the patient is not responding to conventional therapy or those who have Tardive
Dyskinesia. (Typical will worsen the TD)
- Regular Blood Monitoring is needed

What are general side effects for both Typical and Atypical Antipsychotics?
- Antagonizeα-adrenergic-R: Vasodilation Postural Hypotension
- Antagonize Histamine-R: Sedation, Drowsiness
- Antagonize Muscarinic-R: Dry mouth, Urinary retention etc.

What drug interactions do Antipsychotics have?

- Counteract Antiparkinsonian drugs
- Potentiate Sedative effect of Hypnotics, Anxiolytics and 1st gen. Antihistamine
 Antidepressants
What is the theory for Depression?
- Deficit of NA and 5-HT transmission between Limbic System and Prefrontal Cortex

What are the drugs used to treat depression?

- Selective Reversible MAO-A inhibitors (MAO-B is for DA metabolism)
 Moclobemide

- MA Reuptake Inhibitors
 Tricyclic Antidepressants: AmitriptylineNortriptyline, ImipramineDesipramine
 SSRIs: Fluoxetine, Citalopram
 NRIs: Bupropion
 SNRIs: Venlafaxine

- Special MA-R antagonists:

 α2- adrenergic-R antagonist: Trazodone
 5-HT2c-R antagonists: Mianserin
What is the mechanism of drug action of Selective Reversible MAO-AI?
- To inhibit Monoamine Oxidase A’s action, which is to metabolize NA, Adrenaline and 5-HT.

What is the importance of using selective inhibitor for type A MAO?

- To prevent inhibition of MAO-B useful for Tyramine metabolism. Accumulation of Tyramine 
Hypertensive Crisis ( Cheese Reaction)

What are the side effects of MAO-AI?

- Nausea, Insomnia, Agitation

What are the side effects of Tricyclic Antidepressants?

- Suppression on H1-R: Sedation (Coma)
- Suppression onα1- R: Postural Hypotension
- Suppression on Muscarinic-R: Cardiac Arrhythmia (Fatal)

What are the side effects of SSRIs, NRIs, and SNRIs?

-SSRIs: Sexual Dysfunction, Agitation, Insomnia
-SNRIs: Less severe side effects than SSRIs.
**SSRIs and others are known to increase Suicidal Tendency
What are the drug reactions between Antidepressants?
- SSRIs and Non-selective MAOIsSerotonin Syndrome (Too much)
- Fluoxetine (SSRIs) and TCAs: Fluoxetine is CYP2D6 inhibitors, TCAs are metabolized by CYP2D6
Serotonin Syndrome

Why is there a time lag for antidepressants’ actions?

- MAOI and MA Reuptake Inhibitors transient increase 5-HT and NA level in the synapse, which
activate the 5-HT1A and 5-HT1B Autoreceptors, as well as α2- adrenergic R. These autoreceptors in
response inhibit the synthesis of MA.
- In long term, these autoreceptors Desensitize and are Downregulated MA rises Effect

Why canα2- adrenergic R Antagonists display antidepressant effect?

- α2- adrenergic R on NA neurons as Autoreceptor
- α2- adrenergic R on 5-HT neuron as Inhibitory Receptor
- α1- adrenergic R on 5-HT neuron as Excitatory Receptor

Why 5-HT2c R antagonists work?

- Research shows Over-activation of 5-HT2c R is related to depression
- Causes Increase in DA and NA activity in Frontal Cortex

What is the other hypothesis for Depression besides MA deficit?

- Decreased expression of Neurotrophic gene BDNF Hippocampal atrophy, Loss of neuronal
growth and circuitry

What are the drugs used to treat Bipolar Disorder?

- Anti-epileptic drugs
- Antipsychotics
- Lithium**

What are the PROPOSED mechanism for Lithium?

- Inhibit Glycogen Synthase Kinase-3 (GSK-3), which inhibits the transcription and expression of
Neuroprotective, Neurogenic, and Mood-Stabilizing factors. (-/-=+)

Why is Lithium not easy to use?

- Narrow Therapeutic Window Easy to cause Acute Lithium Toxicity
- Renal Toxicity (DI) Especially with Thiazide Loop Diuretics
- Hypothyrodism
- Neurotoxicity With Typical Antipsychotics and Anticonvulsants (Carbamazepine)
 Hypnotics and Anxiolytics
What is the cause of Anxiety?
- Exaggerated output from Central Nucleus of Amygdala to different brain regions.

What are the drugs used to treat Anxiety?

- Benzodiazepines: “-----am”
- 5-HT1A-R Agonist: Buspirone
- Β- adrenergic blocker: Propranolol, Atenolol
- Antidepressants
- Atypical Antipsychotics
- Antiepileptics

What is the mechanism for Benzodiazepine action?

- Bind Selectively to GABA-A receptor to facilitate Cl- influx via Allosteric Modulation
- GABA-A R: Ligand-gated Ion Channel, GABA-B R: GPCR

What are the 3 most common Benzodiazepine?

- Diazepam
- Lorazepam
- Midazolam

What is the difference in usage between them?

- Long T1/2 used to treat Acute Anxiety State: Diazepam (Nordiazepam 36-99hr), Lorazepam (8-
12hr)
- Short T1/2 used to treat Insomnia: Midazolam (2-4hr) To prevent Hangover effect in the mrn

Which GABA-R subunits mediate which effect?

- α2 and α3 subunits mediate Anxiolytic effect.
- α1 mediates Hypnotic effect.

What is Z-drug?
- Same mechanism as Bezodiazepine
- But only Short-acting Hypnotic effect
- E.g Zolpidem, Zopiclone

What are the drug interactions of Benzodiazepine?

- BZD metabolized by P450, SSRIs Inhibit P450 Accumulation of BZD
- Potentiate CNS suppression by other drugs like Alcohol and Opioids Fatal Sedative effects on
 Vital Body Functions

How to treat Acute BZD Overdosing?

- BZD Antagonist Flumazenil

How can BZD cause Addiction?

- Withdrawal Symptoms: High excitatory Sig. between doses”Fake Return” of Anxiety
- Tolerance: Downregulation of GABA-A R
- Both of the above leads to Drug Seeking Behaviours

How to prevent BZD Addiction?

- Only used in acute anxiety treatment (e.g Recent Trauma)
- Long term treatment should use Antidpressants/ Antiepileptics

What is the mechanism for 5-HT1A R agonist (Buspirone)?

- Bind to 5-HT1A Autoreceptors to desensitize them Increase 5-HT
- No Sedative Effect
 Anticonvulsants
How many types of Seizures are there?
- 1. Partial Seizure: Simple (Only Conscious), Complex
- 2. Generalized Seizure: Tonic-clonic, Absence, Myotonic, Atonic
- 3. Status Epilepticus (>1 seizure within 5 mins)

What is the difference between Partial Seizure and Generalized Seizure?

- Partial Seizure starts in an area in a brain, then spreads to the whole brain
- Generalized Seizure has no onset area, starts in the whole brain simultaneously

What are the drugs used to treat Partial and Generalized Seizures EXCEPT for Absence Seizure?
- Voltage-gated Na+ channel blocker: Carbamezapine, Phenytoin
- GABA-A R Enhancer: Phenobarbital (Not BZD)
- GABA Transaminase Inhibitor: Vigabatrin

What are the undesirable side effects of Carbamezapine?

- Stevens- Johnson Syndrome in Han Chinese (Allele HLA-B 1502) (Super scary skin disease)
- Sedation
- Ataxia
- Blurred Vision
- Water Retention

What are the side effects of Phenytoin?

- Gingival Hyperplasia
- Confusion
- Skin Rashes
- Anemia
- Teratogenicity= Fetal Malformation

What are the side effects of Phenobarbital?

- Sedation
- Respiratory Depression
- Impairing Cognitive and Motor Performance
- Hepatitis
- Hypotension
- **Overdose Coma Death
What is GABA converted to in astrocyte?
- Succinic Semialdehyde

What does Vigabatrin have little clinical use?

- It causes Visual Field Defect, Sedation and Mood Change

What are the drugs used to treat All Types of Seizures (Inc. Absence Seizure)?
- Clonazepam: a BZD with Type-T Ca2+ Channel blocking activity
- Valproate: (Multiple actions) GABA Transaminase Inhibitor, Voltage-gated Na+ Channel Blocker
- Lamotrigine: Voltage-gated Na+ Channel Blocker, Type-T Ca2+ Channel blocker,
**Inhibit Glutamate Release** (NOT Glutamate Receptor Agonist- SEVERE SIDE EFFECTS)

What are the side effects of Clonazepam?

- Just like ordinary BZD: Sedation and Withdrawal Symptoms

What are the side effects of Valproate?

- Hepatotoxicity
- Teratogenicity
(Both very Serious)

What is an advantage specific to Valproate?

- It’s the only GABA targeting drug that has NO Sedation effect.

What are the drugs used to treat Absence Seizure ONLY?

- Type-T Ca2+ Channel blocker: Ethosuximide

What are the side effects of Ethosuximide?

- May Worsen Tonic-clonic Seizure (Generalized)
- Nausea
- Drowsiness
- Epigastric pain
- Anorexia

What drugs do you prefer if treating Partial Seizures ONLY?

- Gabapentin, Pregabalin (Newer drugs with GABA-Mimetics Actions) (Less Severe Side Effects)
What are the drugs used to treat Status Epilepticus?
- IV injection of Diazepam, Lorazepam, Phenytoin, Carbamazepine
- Buccal and Rectal Route should be used in Children

What are the common Drug Interactions of Antiepileptics?

- CYP450 Inducer: Carbamazepine, Phenytoin, Phenobarbital

- CYP450 Inhibitor: Valproate

- Highly Protein-bound: Phenytoin, Valproate  High free drug level when get displaced
 Anti- Parkinsonian Drugs
What is the difference between Parkinson’s Disease and Parkinsonism?
- Parkinson’s Disease: Motor+ Non- motor Syomtoms
- Parkinsonism: ONLY Motor Symptoms

What are the symptoms of Parkinson’s Disease?

- Motor: Bradykinesia, Rigidity, Resting Tremor
- Non- Motor: Dementia, Mood Disorders, Unexplained Pain, Constipation, Speech and
Swallowing problems

What are the drugs used to treat Parkinson’s Disease?

- Central DA-R Agonists:
 Ergoline Derivative: Bromocriptine, Carbergoline
 Non-ergoline derivatives: Apomorphine, Ropinirole

- DA Synthesis Stimulator: Amantadine

- Anti-Muscarinic Agents: Benzatropine

- Levodopa & its Enhancers:

 Peripheral DOPA decarboxylase Inhibitor: Carbidopa, Benserazide
 Selective Irreversible MAO-BI: Selegiline, Rasagiline
(Rmb Reversible MAO-AI in Antidepressant)
 COMT Inhibitors: Tolcapone, Entacapone

How can we use the Short-Acting & Rapid Onset of Apomorphine?

- As a Rescue Treatment for profound “Off- state” from Levodopa

Which Parkinsonism Symptom is NOT well-treated by Anti-Muscarinic R Agents?

- Bradykinesia
(*Rmb combined use of Benzatropine and Typical Antipsychotics for reducing EPS)

What are the undesirable side effects of Anti-muscarinic Agents?

- Typical PNS suppression symptoms (Dry mouth, constipation, Urinary retention)
- Dementia Because worsen the situation of Cholinergic Neuron Degeneration in the brain
Why is Rasagiline more preferred than Selegiline?
- Selegiline, but not Rasagiline is metabolized into Methamphetamine Adverse effect on CVS
and causes Psychosis
(* Research also shows Neuroprotective effect of MAO-B I through BCl2 Induction)

What is the difference between Tolcapone and Entacapone?

- Tolcapone inhibit both Central and Peripheral COMT
- Entacapone can’t cross BBB

What is the undesirable effect of Tolcapone?

- Hepatotoxicity

What are the undesirable side effects of Levodopa?

- Activation of Chemoreceptor Trigger Zone (CTZ) and Vomiting Centre: Nausea and Vomiting
- Peripheral accumulation: Arrhythmia and Hypotension
- Central accumulation (=Schizophrenia): Psychosis, Hallucination, confusion
- Sedation

Why is Levodopa not used in early onset of Parkinson’s Disease?

- Tolerance with time
- On-Off Effect: “Peak-dose Dyskinesia” & “End-dose Akinesia” in severe case