Pharm II Final
Glutamate receptors
3 ionotropic NMDA: N-methyl D-aspartate, ionotropic, linked to Ca++ channels AMPA: α- amino-3-hydroxy 5-methyl-4-isoxazole propionic acid, ionotropic, linked to Na+, K+, Ca++ channels Kainate: ionotropic, linked to Na+, K+ channels
Phenobarbital
A barbiturate First efficacious antiepileptic drug introduced in 1912 Use GTCS generalized tonic-clonic seizures, simple partial seizures, complex partial seizures Status epilepticus
Antidepressants
A class of psychotropic medications used for the treatment of depression
Primidone
A deoxybarbiturate, converted by liver to phenobarbitone and phenylethyl malonamide (PEMA). Dose to dose less potent but antiepileptic efficacy and side effects are similar to phenobarbitone.
Fomepizole
A potent alcohol dehydrogenase inhibitor, used as an antidote in methanol poisoning. Metabolic acidosis is resolved within three hours of initiating therapy.
Hypertensive crisis with MAOIs
'Beer, Wine & Cheese' Reaction MAO-A isoenzyme metabolizes serotonin, norepinephrine, dopamine, & also tyramine. Thereby, MAO restricts the uptake of tyramine into the circulatory system during digestion. If high levels of tyramine enter the bloodstream as a result of oral MAO use, there is an accompanying dramatic, rapid displacement of norepinephrine from neurons, which can cause a rapid increase in blood pressure. Diet: Limit tyramine exposure when taking an MAO inhibitor - avoid aged cheeses; cured or aged meats; meats, fish, broad bean pods (such as fava bean pods); concentrated yeast extract; sauerkraut; tofu; soy bean condiments including soy sauce; and tap beer, wine. Use of MAOIs with certain other medications— amphetamines, sympathomimetic vasoconstrictors, and over-the-counter decongestants—is also believed to increase the risk of hypertensive crisis.
Novel GABAergic
(Sedative/Hypnotic) Zolpidem Zaleplon Eszopiclone Chemically distinct from benzodiazepines. Zolpidem, zaleplon, & eszopiclone bind & interact only with GABAA-receptor isoforms that contain alpha-1 subunits. Selective agonist at BZ1 type GABAA receptor No tolerance or withdrawal Are less likely than benzodiazepines to disrupt sleep patterns Do not cause muscle relaxation or anticonvulsive effects
Flumazenil
Antagonist of BZD binding-site of GABAA receptor. Competitively inhibits BZD, NOT ethanol NOT barbiturates. Useful for reversing BZD drug overdose NOT barbiturates, ethanol. Indications for Flumazenil Use ..to minimize need for intubation Accidental pediatric poisoning or intentional overdose with compromised airway & breathing where intubation and/or ventilation are not available Confirming diagnosis of benzodiazepine overdose Reversal of benzodiazepine (e.g. midazolam) conscious sedation (iatrogenic overdose).
Phenytoin
Anticonvulsant activity was tested in 1938 Major antiepileptic drug. Fosphenytoin- I.V. preparation Mechanism of action: Na+ channel inactivation ('use' or 'state' or 'rate' dependent blockade- please see the next slide) At high dose also inhibits Na+ / Ca++ influx & glutamate levels Pharmacokinetics: Slow oral absorption; Variations in preparations 97-98% bound to plasma proteins; Metabolized in liver; Low Therapeutic Index Elimination kinetics: Changes from first order to zero order (t1/2= 12-24 h to 60 h) TDM- therapeutic drug monitoring- is required
Selective Serotonin Re-Uptake Inhibitors (SSRI)
Antidepressants Clinical indications: Major depression, anxiety disorder, panic disorder, obsessive compulsive disorder, post-traumatic stress disorder, bulimia t ½ ~ 15 -20 hrs Citalopram Escitalopram Fluoxetine Paroxetine Sertraline
Tricyclic Antidepressants (TCAs)
Antidepressants that have been relegated to the status of 2nd line agents because non-specific interactions with adrenergic and muscarinic receptors confer undesirable / intolerable side effects MOA Inhibit re-uptake of NE & 5HT Antagonize post-synaptic α1 adrenergic receptors Their main role in contemporary medicine is in depressed patients with sleep disturbances, weight loss, poor appetite ....in these patients the nonspecific actions on histamine or Alpha-1 receptors are acceptable / potentially beneficial. Also approved for treatment of bipolar disorder, chronic pain states
'Use' or 'State' or 'Rate' Na+ blockade
Antiepileptic drugs inhibit sodium channels by binding to inactivation gate during inactivated state and increase the recovery time of channels which increases refractory period Higher the firing rate of neurons (higher the rate of stimulation), more effective is the blockade by Na+ channel blockers
Newer Antiepileptic drugs (post-1990)
Are not first line antiepileptic drugs Less efficacious Are used in adjunctive therapy Less drug-drug interactions (no/minimal effect on CYP 450 enzyme system) Usually narrow spectrum Exceptions: Broad spectrum Lamotrigine Topiramate Zonisamide Levetiracetam Narrow: Gabapentin Vigabatrin Lacosamide Perampanel Ezogabine Felbamate Tiagabine Rufinamide
Adverse Effects of Phenytoin
At therapeutic levels -Gum hypertrophy (very common, 20%) -Hirsutism -Megaloblastic anemia (due to antifolate effect) -Osteoporosis (induction of CYP 450 ↑metabolism of Vit D) -Pregnancy- 'fetal hydantoin syndrome' (arene-oxide metabolite- features are microcephaly, hypoplastic phalanges, cleft lip and palate) Hyperglycemia Dose related toxicity (CNS toxicity) Ataxia, vertigo, diplopia, nystagmus Confusion/hallucinations
Benzodiazepine withdrawal
Avoid prolonged use and abrupt discontinuation of benzodiazepines. Abrupt discontinuation or reduction in benzodiazepine dose among chronic users can produce withdrawal - a potentially life-threatening problem. Signs and symptoms include tremors, anxiety, perceptual disturbances, dysphoria, psychosis, and seizures. Prompt recognition and treatment of benzodiazepine withdrawal is essential. Withdrawal symptoms can be managed or avoided by using (substituting) benzodiazepines with a long half-life, such as diazepam or chlordiazepoxide, and a gradual tapering of the patient's BZD dose over several months, depending upon the dosage and degree of dependency. Onset of withdrawal varies. Withdrawal symptoms may be delayed for 2-3 weeks with benzodiazepines with long half-lives. Conversely symptoms may appear within 1-2 days after discontinuation of benzodiazepines with short half-lives. The severity and duration of withdrawal is determined by the duration of benzodiazepine use, how rapidly drug was discontinued or tapered, the pharmacokinetics of the particular drug. Symptoms typically last from 1 to 2 weeks.
Benzodiazepines and panic attacks
Benzodiazepines are 2nd line therapy for treatment of panic disorder. Antidepressants are 1st line therapy. Nevertheless, benzodiazepines are often used in combination with anti-depressants during first 2-4 weeks of treatment to achieve a more rapid response. Rapid relief limits clinical deterioration in severely affected patients. All benzodiazepines appear to be equally effective; however, alprazolam (rapid onset, intermediate duration of action) has FDA approval for this indication. Because of its quick onset, Clonazepam is also FDA approved for panic disorder. Clonazepam has less intensive symptoms on discontinuation than alprazolam. Benzodiazepines reduce panic attack frequency, anticipatory anxiety, and phobic avoidance.
Sodium Valproate
Broad spectrum antiepileptic Mechanism of action: Multiple mechanisms: Na+ channel inactivation, attenuation of T Ca ++ current, augmentation of GABA Use: Absence seizures GTCS/partial seizures Myoclonus/ atonic seizures Manic depressive illness (to control maniac phase) ADR: Alopecia, curling of hair Hepatotoxicity Hepatitis in children (contraindicated below 3 years) In pregnancy: neural tube defects (spina bifida) Monitor blood levels (Therapeutic drug monitoring)
Topiramate
Broad spectrum antiepileptic drug Mechanism of action: Na+ channel inactivation; also, antagonizes glutamate receptors (kainate receptors) Use: All refractory seizures ADR: Sedation, ataxia, psychiatric symptoms, weight loss, paresthesia, renal stones
Monoamine Oxidase Inhibitors
By inhibiting MAO-A/B these drugs enrich the monoamine content of neuronal vesicles, enhancing amounts released by vesicles fusion to membrane. Clinical indications - 3rd, 4th line for patients unresponsive to other drugs. Due to concerns over safety, the most serious of which are Hypertensive Crisis and Serotonin Syndrome. Phenelzine Selegiline Tranylcypromine
Serotonin - Norepinephrine Re-Uptake Inhibitors (SNRIs)
By inhibiting both SERT and NET - the reuptake pumps for serotonin and norepinephrine - the SNRIs enhance and prolong the levels of these neurotransmitters in the synaptic cleft. Inhibit NE & 5HT reuptake & thereby augment enkephalin release & signaling Clinical indications: Major depression, * Duloxetine: used for chronic pain, fibromyalgia, diabetic neuropathy Duloxetine Venlafaxine t ½ ~ 10-15 hrs
Parkinson Disease
Cardinal Features: -Bradykinesia (slowness & lack of movement) -Muscular rigidity -Resting tremor -Impairment of postural balance leading to disturbances of gait and falling
Benezodiazepine clinical uses
Cause sedation, hypnotic effects, muscle relaxation, and anxiolytic and anticonvulsant effects. Have high anxiolytic potency in relation to their depression of CNS function. Because of their lower potential to produce fatal CNS depression in overdose situations they are safer, compared to barbiturates, in accidental overdoses.
Mirtazapine
Central acting α2 receptor antagonist (pre-synaptic !) Negates 'feedback' inhibition mediated by pre-synaptic α2 receptors thereby enhancing & prolonging NE levels in synapse Indication - major depressive disorder. Also a non-specific histamine H1 receptor antagonist sometimes used for the treatment of insomnia. Can be useful in depressed patients with insomnia, but shouldn't be used as primary treatment for insomnia without depression.
Anticholinergic Drugs For Parkinson's Disease
Centrally acting mAChR antagonists are available to treat patients with PD. mAChR antagonistAgents include benztropine, orphenadrine, procyclidine, trihexyphenidyl. Patients are given a low dose of drug, which is titrated upwards in amount until benefit occurs or adverse effects limit use. If one agent is unsuccessful, trial with a different agent is warranted and may be successful. Adverse effects include common peripheral anticholinergic effects (sedation, mental confusion, constipation, urinary retention, blurred vision)...similar to atropine. May improve tremor and rigidity but have little effect on bradykinesia. Are most helpful in early onset Parkinson disease patients < 50 years old with tremor-dominant PD. Side effects may limit their usefulness... Side Effects Confusion Hallucinations Decreased short-term memory Dry mouth Blurry vision Urinary retention ....like atropine
ADRs of barbiturates
Clinical consequences of direct actions at GABAA receptor Powerful, drug mediated non-specific CNS depression, independent of the neurotransmitter GABA, can cause significant sedation & lethal respiratory depression. Barbiturates have significant abuse & addiction potential.
Bupropion
Clinical use: Major depression. Smoking cessation. Mechanism unclear Complications - Drug-drug interactions (CYP2D6 inhibitor)
GABAa receptor
Consists of five subunits (alpha, beta, & gamma) arranged in various combinations. The composition of subunits determines the affinity of the various drugs/agents that bind to the GABAA receptor. The subunits of the GABAA receptor form a ligand-gated Cl- channel. GABAA receptor pentamer 2 α, 2 β, 1 γ subunits In addition to containing sites for binding the neurotransmitter GABA, also contain sites for binding other agents (drugs) e.g. benzodiazepines, barbiturates, ethanol, etc. that modulate GABAergic activity & promote inhibitory neurotransmission. Clinically this causes CNS depression, which confers utility as anxiolytic / sedative / hypnotic drugs.
Considerations in the treatment of epilepsy
Control of seizures: 50%; partial control: 20-30%; rest (20-30%): refractory Start the drug as early as possible (preferably with single drug at low dose, titrate upward, carry out therapeutic drug monitoring before dosage modification) If monotherapy with maximum tolerable dose fails, start combination therapy (combine drugs with different mechanisms) Patients/relatives should be asked to maintain a seizure diary Treatment may be life long or at least 3 years from the last seizure onset, drug withdrawal should be gradual (otherwise 'status epilepticus' may be precipitated). Factors that are favorable for withdrawal are; childhood epilepsy, negative family history, primary generalized tonic-clonic seizure, recent onset at the start of treatment, absence of cerebral disorder (even with these features, the relapse rate is 12-40%)
Benzodiazepine Tolerance
Develops from Chronic Use (Overuse) Chronic use of BZDs leads to conformational changes in the GABAA receptor. Conformational changes lower GABAA receptor affinity for BZD. Reduced BZD affinity corresponds with reduced GABAergic activity (tolerance to BZD). When 'Tolerance' develops the reduced GABAA receptor activity provides less inhibition of excitatory neurotransmitters, which shifts the balance toward a pro-excitatory state when BZDs are discontinued. If BZDs are discontinued abruptly it can be dangerous, due to convulsions
Benzodiazepine anticonvulsants
Diazepam Rapid tolerance to anticonvulsant action (antiseizure effect ↓ses after 20 mins) Diazepam: Rectal route in febrile convulsions Emergency control of seizures (in status epilepticus): -Diazepam: 0.2-0.5 mg/kg slow I.V. -Lorazepam: 0.1mg/kg not exceeding 2mg/min I.V., less lipid soluble than diazepam has less re-distribution, anticonvulsant effect 6-12 h; Drug of choice) -Fosphenytoin, Phenobarbitone, General Anesthesia Clonazepam Absence seizures Myoclonic seizures As adjuvant in infantile spasm/ akinetic seizures Clobazam Used as an adjuvant drug in refractory epilepsy
Treatment of Insomnia
Diazepam is generally not used to treat insomnia because it has a long duration of action and can lead to the accumulation of active metabolites There is little role today for long-acting benzodiazepines in the management of insomnia, unless a coexisting anxiety disorder is present then
Nigrostriatal Pathway
Dopamine and dopamine receptors in the brain enable the smoothly coordinated movements of the body's muscles. Degeneration and loss of dopamine-producing neurons in the substantia nigra, eventually, leads to symptoms of Parkinson's disease − tremors, slowness of movement (bradykinesia), rigidity, & difficulty with balance. Parkinson's disease can also induce small, cramped handwriting, stiff facial expressions, shuffling when walking, muffled speech, and depression. Most Parkinson's patients (80%) are over the age of 65. Because loss of dopaminergic neurons is progressive and relentless the treatments that offer relief in earlier stages of disease eventually fail.
Monoamine Hypothesis of Depression
Drugs that augment NE & 5HT levels include: 1) Inhibitors of transporter for reuptake of NE or 5HT 2) Inhibitors of metabolic degradation of NE & 5HT in neurons 3) Antagonists of pre-synaptic autoreceptors or post-synaptic receptors Major depression originates from insufficient NE or 5HT in synaptic cleft. Augmenting synaptic levels of these neurotransmitters will alleviate depression. Paradox: Beneficial effect can take weeks to develop and placebo responses are often very robust.
TCAs side effects
Dry mouth, urinary retention, confusion, (dementia - particularly geriatric patients) Sedation, fatigue, dizziness Orthostatic hypotension, tachycardia, cardiac dysrhythmias In overdose: coma-convulsions-cardiotoxicity
Ethosuximide
Effective only in absence seizures Mechanism of action: Suppresses T type Ca++ currents in thalamic neurons Use: Only in Absence Seizure ADR: GI upset (nausea, vomiting, abdominal pain) Relatively safer than valproic acid (sodium valproate). Non-sedating. Monitor blood levels (Therapeutic drug monitoring)
Anti-epileptic drugs ADRs
Enzyme induction Osteoporosis Valproic acid is the most dangerous in pregnancy Lamotrigine is associated with Stevens-Johnson syndrome Ethosuximide is the best for absence/ petit mal seizure
Benzodiazepines for Anxiety
For treatment of generalized anxiety disorders and certain phobias, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are now considered by many authorities to be drugs of first choice . However, SSRI and SNRI agents have a slow onset of action and thus minimal effectiveness in acute anxiety states.
Benzodiazepines
GABAa Receptor Agonists Potentiate (enhance) GABA activity at post-synaptic GABAA receptor Cl- channels... thus, they are GABA neurotransmitter dependent. Do not stimulate the receptor directly. Instead, benzodiazepines INCREASE the FREQUENCY of Cl- channel opening when GABA binds to this receptor. The accompanying rise in the concentration of Cl- ions in the post-synaptic neuron hyperpolarizes this neuron, making it less excitable.
Therapeutic indications of CBZ
GTC seizures Partial seizures Trigeminal neuralgia Manic depressive illness (to control mania)
Therapeutic Indications of Phenytoin
Generalized tonic-clonic seizure, partial seizures Status epilepticus Trigeminal neuralgia (carbamazepine & gabapentin are preferred) Digoxin induced ventricular arrhythmia (lidocaine is first preference)
SSRI drug interactions
Have a high risk of drug-drug interactions due to their inhibition of CYP 450 isoenzymes: 'Worse' is fluoxetine (broad & strong inhibitor of CYP2D6 and CYP3A4 ) 'Better' is citalopram and sertraline (mild inhibitor)
Tiagabine
Inhibits GABA uptake Use: adjunct in partial seizures
Ethanol
Initial Symptoms CNS Depression Confusion, Ataxia, Hallucinations, Slurred speech Zero order elimination
Oxazepam
Intermediate Acting Benzodiazepine Anxiety disorders Alcohol withdrawal
Temazepam
Intermediate Acting Benzodiazepine Insomnia - short term treatment
Carbamazepine (CBZ)
Introduction: Was introduced in the 1960 for trigeminal neuralgia Now an established antiepileptic drug Pharmacological actions resemble phenytoin Mechanism of action: Na+ channel inactivation ('state' or 'use- dependent' blockade) It has additional Anti diuretic action (water retention and hyponitremia may occur) Monitor blood levels (Therapeutic drug monitoring)
Oxcarbazepine
Is closely related to carbamazepine and has improved toxicity profile. However, hyponitremia may occur more commonly with oxacarbazepine than with carbamazepine Is less likely to be involved in drug interactions than carbamazepine
Felbamate
It inhibits NMDA receptors (glutamate receptors) Also has barbiturate like GABA potentiating effect at GABAA receptors Use: Partial seizures Toxicity: Severe hepatitis and aplastic anemia
Perampanel
It is an AMPA (one of the glutamate ionotropic receptors, please see the box below for details) antagonist Use: adjunct in partial-onset seizures
Ezogabine
K+ channel facilitator Use: adjunct in partial-onset seizures Toxicity: risk of retinal damage (possible vision loss)
ADME of Benzodiazepines
Lipophilic Readily absorbed 90% bioavailability 1-2 hr plasma peak Readily distributed into CNS (* readily re-distributed out of CNS) Hepatic metabolism Low induction of CYP450 Grouped as: short-acting (t1/2 < 12 hours), intermediate-acting (t1/2 12 - 24 hours), and long-acting (t1/2 > 24 hours).
Flurazepam
Long acting benzodiazepine with active metabolites Clinical Uses: Insomnia (with anxiety) Trouble staying asleep Goal: Sleep through night. No rebound insomnia after discontinuation. Gain ~ 1 hr of sleep
Lewy bodies
Loss of dopaminergic neurons of substantia nigra is associated with appearance of alpha-synuclein deposits Normally, dopaminergic neurons originating in the substantia nigra inhibit the GABAergic output from the striatum (caudate & putamen) while cholinergic inter-neurons stimulate GABAergic neurons. In PD, the disinhibition of GABAergic neurons impairs movement (bradykinesia). This model implies that PD symptoms may be ameliorated with dopamine agonists and/or anticholinergic agents.
Insomnia
Low-dose sedating antidepressants are being used increasingly for the management of insomnia. Specifically trazodone, and secondarily doxepin, mirtazapine, and amitriptyline, are being used for the treatment of insomnia even in the absence of a depressive disorder - their use for treatment of depression, is declining due to safety-toxicity concerns. The mechanism of action of the low-dose sedating antidepressants is not fully understood. For the tricyclic antidepressants, their antihistaminergic (H1) activity is critical. The role of their anticholinergic activity in the modulation of sleep has not been made clear. Trazodone is a mild inhibitor of serotonin reuptake, and also has antagonistic action at the alpha-1 and alpha-2 adrenoreceptors.
Benzodiazepine Abuse
May alter the effects of other drugs. e.g. some benzodiazepines have a "boosting" effect when used (abused) by methadone-maintained patients. Methadone and various benzodiazepines (alprazolam, diazepam, midazolam, triazolam) are substrates of the 3A4 CYP450 enzyme. Use of a benzodiazepine that competes with methadone for oxidative pathways in the liver produces higher peak levels of methadone in the blood (and brain) shortly after methadone is administered.
Lamotrigine
Mechanism of action: Prolongation of Na+ channel inactivation Also, inhibition of synaptic release of glutamate Use: Add on in partial, tonic-clonic seizures Seizures in Lennox- Gastaut syndrome Monotherapy in akinetic, myoclonus ADR: Dizziness, diplopia, ataxia, vomiting, skin rashes and life-threatening Stevens-Johnson syndrome or toxic epidermal necrolysis.
Gabapentin
Mechanism of action: GABA derivative that ↑ synthesis/release of GABA; also ↓ glutamate release (by binding to α2δ-1 subunit of voltage sensitive N-type Ca++ channels) Use: Refractory partial seizures Neuropathic pain (diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia) Migraine Manic depressive illness (to control mania) ADR: Mild sedation, dizziness, unsteadiness No drug interactions, well tolerated
Vigabatrin
Mechanism of action: Inhibits GABA transaminase Use: Adjuvant in refractory partial seizures ADR: Behavioral changes, depression, psychosis, visual field defects
Lacosamide
Mechanism of action: It inhibits Na+ channels (enhances slow inactivation of voltage gated Na+ channels, in contrast, other antiepileptic drugs prolong the fast inactivation of Na+ channels) Use: Partial seizures
Zonisamide
Mechanism of action: It inhibits Na+ channels; also inhibits T-type voltage gated Ca++ channels Use: Partial and generalized tonic-clonic seizures; Infantile spasms ADR: Severe skin rashes (Stevens-Johnson syndrome)
Levetiracetam
Mechanism of action: It modifies the synaptic release of glutamate and GABA by binding to synaptic vesicular protein (SV2A) Use: As an add-on therapy in partial seizures, generalized tonic-clonic seizures and myoclonic seizures
Ramelteon
Melatonin receptor agonist Recapitulates the role of melatonin and its receptors in the suprachiasmatic nucleus of the hypothalamus, which is responsible for establishing & maintaining circadian rhythm MT1 /MT2 receptor agonist Not a controlled substance No dependence, rebound insomnia Insomnia - trouble falling asleep Goal: "no" hangover
Parkinson's Drugs
Note: Pergolide and bromocriptine are no longer available in the U.S. as treatment for PD.
Buspirone
Novel Anxiolytic Agent a partial agonist at 5HT1A serotonin receptor sub-types Mechanism: '5-HT1A Receptor Partial Agonist (Anxiolytic)' NOT GABAergic No interaction with ethanol; no dependence, no tolerance, no withdrawal. Anxiolytic ONLY - NOT sedative / hypnotic Anxiolytic effect has slow onset ( 2 weeks). Useful for long term therapy Useful in elderly (less interference with motor function compared to alprazolam) Useful in patients with substance abuse issues. Side effects: dizziness, nausea, headache. Buspirone is a category B drug in terms of use in pregnancy
Complications of L-DOPA Administration
Over 95% of L-DOPA administered orally is decarboxylated to dopamine in the gastrointestinal tract and blood vessels - only a small proportion, 1-3%, reaches the brain. This peripheral metabolism of L-DOPA and its conversion by dopa decarboxylase (DDC) accounts for the high incidence of side-effects when L-DOPA(Levodopa) is used alone.... Side-effects: postural hypotension, nausea, vomiting. Other dose-related side-effects are involuntary movements, e.g. orofacial dyskinesias, limb and axial dystonias, & occasionally depression, hallucinations & delusions
Contraindications for Flumazenil
Patient with known seizure disorder • Patient with known or suspected co-ingestions of drugs with convulsant properties • Patient with known benzodiazepine dependence Because death is rare with oral benzodiazepine overdose, the risks of flumazenil treatment often outweigh its benefits. The purported benefit of flumazenil is to avoid the need for procedures, such as endotracheal intubation
Disulfiram
Patients wishing to stop their alcohol abuse are often prescribed a drug that inhibits aldehyde dehydrogenase. If a patient taking the drug drinks any ethanol s/he will experience disagreeable sensations (flushing, a throbbing headache, nausea, vomiting) due to accumulation of acetaldehyde
'Must Know' anti-seizure drugs
Phenytoin Carbamazepine Lamotrigine Ethosuximide Valproate Phenobarbital Gabapentin Topiramate Focus on: mechanism of action, indications (types of seizure), side effects, drug-drug interactions (due to enzyme induction/inhibition)
Osteoporosis
Phenytoin, phenobarbital, carbamazepine: induction of CYP 450 ↑metabolism of Vit D
Methanol Toxicity
Poisoning involves toxic metabolites formed by dehydrogenase enzymes. Inhibition of alcohol dehydrogenase will limit the formation of toxic metabolites Tx: Fomepizole
Drug interactions of CBZ
Potent enzyme inducer (CYP 450) Metabolism is induced by phenobarbital, phenytoin Erythromycin, fluoxetine, isoniazid inhibit metabolism of carbamazepine Failure of Oral Contraceptives Pills Failure of warfarin therapy
Drug Interactions of Phenytoin
Potent microsomal enzyme inducer (CYP 450) Failure of Oral Contraceptive Pills; failure of warfarin therapy Isoniazid, cimetidine inhibit phenytoin metabolism- ↑ toxicity Valproate Valproic acid is enzyme inhibitor, sulfonamides, carbamazepine displace phenytoin- increasing its blood levels which ↑ toxicity of phenytoin
Rufinamide
Prolongs the inactive state of Na+ channel Use: for the treatment of all types of seizures associated (especially tonic-clonic) with Lennox-Gastaut syndrome (first line drug; another drug: lamotrigine)
Novel Sedatives
Ramelteon-Melatonin receptor agonist Suvorexant-Orexin receptor antagonist
Serotonin syndrome
Rare but potentially fatal syndrome can occur as the result of an interaction between drugs that have strong serotonergic effects, for example, other antidepressants, synthetic opioids, and some triptan migraine medications. To avoid serotonin syndrome, contraindicated medications should not be taken for 1 to 2 weeks before initiating therapy with the MAO inhibitor or for 2 weeks after stopping MAO inhibitor therapy. The SSRI fluoxetine, because of its long half-life, requires a 5-week washout period or longer, prior to initiating treatment with an MAO inhibitor.
GABAa alpha sub-units
Recent data suggest that α1 GABAA receptors are the "sedative" and α2- and/or α3-containing receptors are the "anxiolytic" subtype(s).
Suvorexant
Represents the first in a new class of orexin receptor antagonists. Orexin receptors (OX1, -2) in the brain regulate various aspects of arousal and motivation. Trials with suvorexant have not reported adverse effects like those seen with benzodiazepines. ] Has a unique mechanism of action - orexin receptor 1, -2 antagonism. It also appears to be suitable as a chronic therapy for insomnia, because of minimal physical dependence. The availability of this new drug as an effective and safe alternative is an important and welcome development in insomnia management.
SSRI Mechanism of Action
SSRI selectively inhibit the pre-synaptic reuptake of serotonin by SERT - serotonin transporter, leading to enhanced serotonin levels in synaptic cleft and enhanced neurotransmission via post-synaptic 5-HT receptors. As a class, SSRI have few non-specific effects on histamine, muscarinic and adrenergic receptors... fewer autonomic side effects compared to other classes of antidepressants. Most common side effects are sexual dysfunction, nausea, vomiting, dyspepsia), sedation or insomnia/agitation), weight gain. QT prolongation varies among individuals (citalopram is most notable)
Pathogenesis of seizure
Seizure- paroxysmal abnormal discharge at high frequency from an aggregate of neurons in cerebral cortex. Epilepsy- recurrent episodes of such seizures with or without loss of consciousness Most of the cases are primary (idiopathic) and some may be secondary (see the box) Prevalence of epilepsy- 1% of world population Molecular mechanisms of seizure onset: ↑ firing of neurons due to ↑activation of Na+ channels ↓ inhibition i.e. ↓activity of GABA ↑ concentration of excitatory amino acids: glutamate, aspartate ↑ entry of T type Ca++ currents in thalamic neurons (absence seizure)
Sleep maintenance insomnia
Select a longer-acting medication for initial trial to prevent middle of night awakening. These medications may increase the risk for hangover sedation.
Sleep onset insomnia
Select a short-acting medication for initial trial to improve insomnia with no 'hangover' the following morning.
Triazolam
Short acting benzodiazepine Insomnia - trouble falling asleep Goal: "no" hangover Fall asleep ~ 10 minutes sooner
Alprazolam
Short acting benzodiazepine Panic attack General Anxiety disorders Reduce panic attack frequency, anticipatory anxiety, and phobic avoidance. Has a fast onset of action, due to greater lipid solubility & brain penetration. These properties, combined with its short half-life can lead to more 'inter-dose anxiety', reinforce 'pill-taking' to alleviate anxiety, and enhance potential for abuse and overuse in some patients. Used alone - has been associated with respiratory depression.
Midazolam
Short acting benzodiazepine Pre-/peri-operative procedural sedation Has a very rapid onset and a shorter duration of action, which favors its use in procedural sedation. However, in this particular setting, if administered repeatedly, at short intervals during a lengthy procedure, successive doses can lead to accumulation of its alpha hydroxy-metabolites and may prolong the drug's sedative effects .
Levodopa (L-DOPA)
Supplements dopaminergic neurotransmission by providing the brain with a precursor for dopamine synthesis Therapeutic Mechanism: Dopamine-releasing nerve terminals in the striatum decline in Parkinson's disease. However, remaining neurons can produce and store more dopamine by administering its precursor L-DOPA. Does not protect the dopaminergic neurons in the substantia nigra, nor does it halt their degeneration and loss. It simply provides the biosynthetic precursor for dopamine to the remaining, intact neurons.
Serotonin Syndrome
Sweating Hyperreflexia Akathisia-a movement disorder that makes it hard for you to stay still Myoclonus-spasmodic jerky contraction of groups of muscles. Shivering/Tremors Symptoms are similar to Neuroleptic Malignant Syndrome. History of drug exposure is important to manage the patient.
Imipramine
TCA for Enuresis nocturnal bed wetting Mechanism of action is unclear
Clomipramine
TCA used in obsessive compulsive disorder (OCD), most significant of TCA's for risk of seizure, weight gain, and neuropsychiatric signs and symptoms
Absence seizures
The EEG shows characteristic bilaterally synchronous 3 Hz spike and wave rhythm generated by reciprocal activation and oscillation of impulses between thalamus and neocortex through reverberatory synaptic connections. Thalamic neurons exhibit prominent 'T' (transient) current which is low threshold Ca2+ current (due to inward flow of Ca2+ through T type Ca2+ channels) that acts as the pacemaker and amplifies repetitive spikes.
Antagonists of 5HT2 Receptors
Trazodone Nefazodone 'Selectively' block: Pre-synaptic 5-HT2A receptors α1 post-synaptic adrenergic receptors Serotonin reuptake (SERT inhibitors)
Benzodiazepine toxicity
Typically presents with CNS depression with normal vital signs. Patients may have slurred speech, ataxia, & depressed mental status. Respiratory depression is rare* with isolated* benzodiazepine overdose. The low incidence of respiratory depression with orally ingested benzodiazepines appears related to the low density of binding sites in the brainstem respiratory center. * e.g. respiratory depression can occur, and have grave consequences, in patients with sleep apnea, or when taking BZDs together with other CNS depressant drugs - e.g. alcohol Treatment: Flumazenil
Neuronal Dopamine Biosynthesis & Metabolism
Tyrosine ---> Tyrosine Hydroxylase becomes LDOPA---> DOPA Decarboxylase becomes DA
Diazepam
Undergoes biotransformation to active metabolites, which are conjugated & excreted. The main active metabolite is nordiazepam. Other active metabolites are temazepam & oxazepam Uses: Anxiety disorder Skeletal muscle relaxant Managing ethanol withdrawal
GABA mediated Cl- channel opening
Used as Anticonvulsants Barbiturates Benzodiazepines Vigabatrin Valproate Gabapentin Tiagabine Pregabalin
Inhibition of T type Ca++ current
Used as Anticonvulsants Ethosuximide Valproate Zonisamide
Prolongation of Na+ Channel Inactivation
Used as Anticonvulsants Phenytion Carbamazepine Valproate Lamotrigine Topiramate Zonisamide Lacosamide
ADRs of SSRIs
Weight gain Loss of libido, Sexual dysfunction Suicidal thoughts Nervousness , agitation Insomnia Black-box warning During the transition phase from severe depression to relief, anti-depressants provide enough improvement to allow a depressed patient to act upon their suicidal ideas
Barbiturates
e.g. phenobarbital, bind to a distinct site on the GABA-A receptor. Binding to the GABA-A receptor causes the opening of the Cl- channel directly and independently of the GABA neurotransmitter. Increase duration of opening of GABA-A receptor Cl- channel
Short and Intermediate acting benzodiazepines
t1/2 < 12 hours e.g. triazolam & oxazepam & lorazepam - have few active metabolites, don't accumulate with repeated doses (if administered at proper intervals) and their clearance is less affected by age or liver disease. Oxazepam, temazepam, lorazepam are directly conjugated to an inactive glucuronide metabolite excreted by the kidney. These agents do not have cytochrome p450 related drug interactions. Triazolam, alprazolam, midazolam are converted to hydroxylated intermediates that are rapidly conjugated and do not contribute to the drug's overall effect.
Long-acting benzodiazepines
t1/2 > 24 hours Diazepam, flurazepam, and chlordiazepoxide - have active metabolites, can accumulate after multiple doses, and clearance slows with aging & liver disease. t½ of parent drug does not correlate with duration Takes into account the activity of parent drug, plus any active metabolites
