Psych, Parkinson drugs Flashcards
MAOI SE’s
- Isocarboxazid
- Phenelzine
- Tranylcypromine
- Selegiline
- Drowsiness
- Orthostatic hypotension
- Blurred vision
- Dry mouth
- Dysuria
- Constipation
Serotonin syndrome
• MAO inhibitor + serotonergic agent such as SSRIs, SNRIs or TCAs or meperidine, may result in a life-threatening serotonin syndrome (hyperthermia, muscle rigidity and myoclonus)
• Serotonin syndrome results from overstimulation of 5-HT1A and 5-HT2 receptors.
• An irreversible MAO inhibitor with a serotonergic agent is the most toxic reported combination.
THE CHEESE REACTION
• Tyramine is contained in certain foods, such as aged cheeses, chicken liver, soy products, pickled fish and red wines.
• Tyramine is normally inactivated by MAO in the gut.
• Patients on an MAO inhibitor cannot degrade tyramine.
• Tyramine causes release of catecholamines resulting in tachycardia, hypertension, arrhythmias, seizures, and possibly, stroke.
• Sympathomimetic drugs may also cause significant hypertension when combined with an MAO inhibitor.
• OTC cold preparations that contain pseudoephedrine and phenylpropanolamine are contraindicated in patients taking MAO inhibitors.
TCAs
• Amitriptyline, Clomipramine, Desipramine, Imipramine, Nortriptyline
- There is variability in affinity for SERT versus NET.
- For example, clomipramine has very little affinity for NET but potently binds SERT.
- On the other hand, desipramine and nortriptyline are more selective for NET.
- Additionally,TCAs block α-adrenergic, muscarinic, histamine and 5-HT receptors.
- Blockade of these receptors are responsible for many of the adverse effects of the TCAs.
SE’s
• TCAs slow cardiac conduction similarly to quinidine, which may precipitate arrhythmias.
• Blockade of α1-adrenoceptors causes orthostatic hypotension and reflex tachycardia. Most serious problem in the elderly.
• H1 blockade causes sedation and weight gain.
• Sexual effects are common, particularly with highly serotonergic agents such as clomipramine.
• The TCAs have a narrow therapeutic index.
• Depressed patients who are suicidal should be given only limited quantities of these drugs and be monitored closely.
- Overdose of TCAs can induce lethal arrhythmias.
- Treatment includes cardiac monitoring, airway support and gastric lavage.
- Sodium bicarbonate is useful in reversing conduction block.
SSRI’s
• Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline
- SSRIs have little blocking activity at muscarinic, α-adrenergic, and histaminic H1 receptors.
- Adverse effects associated with TCAs, such as orthostatic hypotension, sedation, dry mouth, and blurred vision, are not seen with the SSRIs.
USES
• SSRIs are the drugs of choice in treating depression.
• OCD, PD, GAD, PTSD, SAD, PMDD, bulimia
SEs
• Increased serotonergic activity in the gut is associated with nausea, GI upset and diarrhea.
• Increased serotonergic tone at the level of the spinal cord and above is associated with diminished sexual function and interest.
• Some patients gain weight when taking SSRIs, particularly paroxetine.
• Fatality rate is low. Overdoses may cause seizures.
DRUG INTERACTIONS
• Fluoxetine and paroxetine inhibit CYP2D6: high potential for drug interactions.
• Fluvoxamine inhibits CYP1A2, CYP2C19 and CYP3A4: high potential for drug interactions.
• Citalopram, escitalopram and sertraline have low potential for interactions.
• All SSR Is have the potential to cause a serotonin syndrome when used in the presence of a MAO inhibitor or another serotonergic drug.
SNRI’s
- Venlafaxine, Duloxetine
- Differ from TCAs by their lack of blockade of H1, muscarinic and α1 receptors.
- May be effective in treating depression in patients in whom SSRIs are ineffective.
Venlafaxine
• Potent inhibitor of 5HT uptake.
• At higher doses inhibits norepinephrine uptake.
• Also inhibits reuptake of dopamine very weakly.
Duloxetine
• Inhibits serotonin and norepinephrine reuptake at all doses.
DRUG INTERACTIONS
• SNRIs have relatively fewer CYP450 interactions than the SSRIs.
NDRI’s
Bupropion
• Inhibits norepinephrine and dopamine uptake.
• Increases norepinephrine and dopamine release.
• Not associated with sexual dysfunction problems which occur with SSRIs because it lacks the serotonergic component.
• Bupropion is associated with seizures in overdose.
SARI’s
- Nefazodone, Trazodone
- When 5HT reuptake is blocked by SSRIs, all 5HT receptors are stimulated by increase in 5HT.
- Stimulation of 5HT1A receptors in raphe may help depression.
- But stimulation of 5HT2 receptors in forebrain may cause agitation or anxiety, and stimulation of 5HT2 receptors in spinal cord may cause sexual dysfunction.
- SARIs combine 5HT reuptake blockade with 5HT2 antagonism
- This decreases undesired actions of stimulation of 5HT2 receptors.
- The main action of both nefazodone and trazodone is blockade of the 5-HT2A receptor.
- Inhibition of this receptor is associated with antianxiety, antipsychotic, and antidepressant effects.
Nefazadone
• Nefazodone is a weak inhibitor of SERT and NET and a potent antagonist of 5-HT2A.
• Nefazodone has been associated with
hepatotoxicity.
• Nefazodone is no longer commonly prescribed.
Trazodone
- Trazodone is a weak inhibitor of SERT.
- Primary metabolite is a potent 5-HT2 antagonist.
- Trazodone also blocks α1 and H1 receptors.
- Extremely sedating.
- Excellent hypnotic.
- The main use of trazodone is as hypnotic.
- Rare but troublesome side-effect: priapism.
Mirtazapine
- NASSA. Antagonist of central presynaptic α2 receptors: enhances release of norepinephrine and 5-HT.
- Antagonist at 5-HT2 and 5-HT3 receptors.
- H1 antagonist, which is associated with sedation and weight gain.
Lithium
- Used prophylactically in treating manic- depressive patients and in treatment of manic episodes.
- Also effective in 60-80% patients with mania and hypomania
- The inositol depletion theory is the most widely accepted explanation for the actions of lithium.
- G protein-linked receptors coupled to Gq activate PLC, which cleaves PIP2 to yield DAG and IP3.
- IP3 signaling is terminated by conversion to IP2.
- IP2 is converted to IP1 by inositol polyphosphatase.
- IP1 is converted to inositol by inositol monophosphatase.
- Lithium inhibits inositol polyphosphatase and monophosphatase, thus blocking the regeneration of inositol.
- Free inositol is essential for the synthesis of PIP2, therefore lithium blocks the phosphatidylinositol signaling cascade in the brain.
- Inositol circulates freely in blood, but it cannot cross the blood-brain barrier.
- The two mechanisms of inositol synthesis in CNS neurons: regeneration from IP3 and de novo synthesis from glucose-6-phosphate, are inhibited by lithium.
- By blocking the regeneration of PIP2, lithium inhibits central adrenergic, muscarinic, and serotonergic neurotransmission.
- Inhibition by lithium is uncompetitive.
- This means that only neurons with active receptors will be affected by lithium.
SEs
• Lithium has a narrow therapeutic window.
• Acute lithium toxicity results in neurological effects, progressing from confusion and motor impairment, to coma, convulsions and death if the plasma concentration reaches 3 – 5 mM.
• Adverse neurologic effects of lithium include tremor, sedation, ataxia, and aphasia.
• The use of lithium during pregnancy may increase the incidence of congenital cardiac anomalies. Category D.
• Contraindicated in nursing mothers.
Alternatives to lithium
• The antiepileptics valproate and carbamazepine are widely used.
Other alternatives:
• Atypical antipsychotics: olanzapine, aripiprazole, quetiapine, risperidone & ziprasidone.
• Antiepileptics: lamotrigine.
- Chlorpromazine
- Haloperidol
- Fluphenazine
- Thioridazine
- Classical antipsychotics are subclassified according to their potency:
- High-potency drugs: Fluphenazine and haloperidol. More likely to produce EPRs.
- Low-potency drugs: Chlorpromazine and thioridazine. Less likely to produce EPRs and more likely to produce sedation and postural hypotension.
• The efficacy of the traditional neuroleptic drugs correlates closely with their ability to block D2 receptors in the mesolimbic pathway.
- Clozapine
- Risperidone
- Olanzapine
- Quetiapine
- Ziprasidone
- Aripiprazole
- Paliperidone
ATYPICAL ANTIPSYCHOTIC DRUGS
• Atypical antipsychotic drugs have higher affinities for other receptors than for the D2 receptor. For example:
• Clozapine has high affinity for D1, D4, 5HT2, muscarinic and a-adrenergic receptor, but it is also a D2 blocker.
• Risperidone blocks 5HT2 to a greater extent than it does D2.
- Dual antagonism at 5-HT2A and D2 receptors.
- Part of their action is due to 5HT receptor blockade.
- Less likely to cause EPRs than classical agents.
- Less likely to cause tardive dyskinesia
- Less likely to cause increases in prolactin
- More effective at treating negative symptoms.
- Effective in refractory populations.
ACTIONS OF ANTIPSYCHOTIC DRUGS
- ANTIPSYCHOTIC
- ANTIEMETIC
ANTIPSYCHOTIC ACTIONS • Reduce hallucinations and agitation. • Have a calming effect. • Do not depress intellectual function. • Motor incoordination is minimal. • Onset of antipsychotic action is ≤24h.
- With the exception of aripiprazole and thioridazine, most neuroleptics have antiemetic effects.
- Mediated by blockade of D2 receptors of the chemoreceptor trigger zone of the medulla.
- Most antipsychotic drugs are almost completely metabolized, mainly by CYP2D6, CYP1A2 and CYP3A4.
- Antipsychotics do not interfere with the metabolism of other drugs.
Flumazenil
- Flumazenil: blocks actions of benzodiazepines.
- Only benzodiazepine receptor antagonist available for clinical use.
- Approved for reversing the CNS depressant effects of benzodiazepine overdose and to hasten recovery following use of these drugs in anesthetic and diagnostic procedures.
- Rapid onset.
- Short duration: half-life about 1 hour, due to rapid hepatic clearance.
- Frequent administration may be necessary to maintain reversal of long-acting benzodiazepines.
- May precipitate withdrawal in physiologically dependent patients or may cause seizures if a benzodiazepine is used to control seizures.
Barbituates
- Barbiturates induce tolerance, drug-metabolizing enzymes, physical dependence and cause very severe withdrawal symptoms.
- They can cause coma in high doses.
- Barbiturates also act on GABAA receptors, and enhance GABAergic transmission.
- The binding site of barbiturates is different from that of the benzodiazepines.
- Barbiturates increase the duration of the GABA- gated chloride channel openings.
- Barbiturates can also block glutamate receptors and sodium channels.
- The multiplicity of sites of action of barbiturates may explain their ability to induce full surgical anesthesia and their more pronounced central depressant effects.
Respiratory depression
• Barbiturates suppress the hypoxic and chemoreceptor response to CO2. Overdosage causes respiratory depression and death.
Enzyme induction
• Barbiturates induce liver cytochrome P450 enzymes.
Anesthesia
• Ultra short acting barbiturates, such as thiopental are used IV to induce anesthesia.
Anticonvulsant
• Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus and eclampsia.
Anxiety
• Replaced by benzodiazepines.
Hepatic Metabolic Uses
• Phenobarbital has been used to treat hyperbilirubinemia and kernicterus in the neonate.
• The nondepressant barbiturate N-phenylbarbital works equally well.
- CNS: drowsiness, impaired concentration, mental and physical sluggishness.
- Paradoxical excitement
- Hypersensitivity
- Hangover
- Barbiturates increase porphyrin synthesis: contraindicated in patients with porphyria.
- In the presence of pulmonary insufficiency they may cause serious respiratory depression.
- Rapid IV injection of a barbiturate may cause cardiovascular collapse.
- Pain: May worsen perception of pain.
- Addiction: severe withdrawal syndrome.
- Poisoning: severe respiratory depression and central CV depression.
NON-BENZODIAZEPINE BENZODIAZEPINE RECEPTOR AGONISTS
• These drugs act only on the BZ1 subtype of benzodiazepine receptors.
Zolpidem
- Hypnotic. Short duration of action.
- Short half life = 1.5 - 3.5 h.
- Indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
- Minimal muscle relaxing and anticonvulsant effects.
- Little or no tolerance.
- Low incidence of adverse effects.
Zaleplon
- Rapid onset and very short duration of action.
- Elimination half life = 1 h.
- Indicated for the short-term treatment of insomnia.
Eszopiclone
- (S)-Entantiomer of zopiclone.
- Pharmacologically active enantiomer of zopiclone.
- Approved for treatment of insomnia.
- Decreases sleep latency and improves sleep maintenance.
- Half-life = 6 hours.
BUSPIRONE
• No hypnotic, anticonvulsant or muscle relaxant properties.
• Only anxiolytic.
• Indicated for management of anxiety
disorders.
• Onset: 2 - 3 weeks.
• Mechanism of action may be analogous to antidepressants.
Advantages:
• Less psychomotor impairment than BZ.
• No drug interactions with EtOH
• No drug interactions with benzodiazepines and other sedative-hypnotics
• No rebound anxiety or withdrawal signs on abrupt discontinuance
• No dependence
Ramelteon
- Agonist at MT1 & MT2 melatonin receptors.
* Indicated for the treatment of insomnia characterized by difficulty with sleep onset.
Hydroxyzine
- Antihistamine with antiemetic activity.
- Approved for symptomatic relief of anxiety.
- Nonprescription antihistamines with sedating properties, such as diphenhydramine and doxylamine, are effective in treating mild types of insomnia.
- However, these drugs are usually ineffective for all but the milder forms of situational insomnia.
