Mechanism of Action
Name one class of drugs that enhances the effects of GABA
(there are 3+ correct options)
1. Barbiturates
2. Benzodiazepines
3. Z-drugs (non-benzodiazepine hypnotics)
Aromatic antiepileptics (AEDs) such as phenytoin, carbamazepine, and phenobarbital all have a similar effect on CYP450. Describe this effect and its results.
Name the drug that is described as a metabolic "mixed bag" because it only begins to mildly induce CYP3A4 at high doses (greater than 200mg).
Topiramate exhibits complex, dose-dependent interactions with the cytochrome P450 (CYP) enzyme system.
Because it induces CYP3A4 at these higher doses, it can significantly decrease the effectiveness of combined oral contraceptives (COCs).
It simultaneously acts as a mild inhibitor of CYP2C19.
PMHx: 28-year-old female with a history of irregular menstrual bleeding and focal seizures takes 200mg Lamotrigine daily. She presents for a neurology follow-up, noting a sudden increase in "breakthrough" seizure activity over the last month. She was recently diagnosed with PCOS and started a combined oral contraceptive to help with her symptoms.
Identify the medical error.
Estrogen increases the metabolism of lamotrigine by stimulating the liver enzyme uridine-diphosphate glucuronosyltransferase (UGT1A4).
By inducing this enzyme, estrogen boosts the glucuronidation process, converting lamotrigine into an inactive compound faster
These ions/neurotransmitters/hormones are mainly excitatory: (1)
1. Glutamate
2. Acetylcholine
3. GABA
4. Aspartate
5. Na2+
GABA is the main inhibitory neurotransmitter in the human brain.
All of the other options usually result in EPSPs.
Lamotrigine (Lamictal) is a mood-stabilizing drug and antiepileptic that works by inhibiting a channel. Name that channel type.
Lamotrigine is a Na+ Channel blocker.
This prevents the rapid influx of sodium ions necessary for action potentials, limiting high-frequency neuronal firing and reducing hyperexcitability in the brain.
Triptans are synthetic serotonin receptor agonists designed to mimic serotonin's action by binding to specific receptors in the brain.
As a result, there is a serious risk of serotonin syndrome, especially if taken concurrently with a specific drug class often used as an antidepressant. Name that drug class.
MAO inhibitors block the activity of the enzyme monoamine oxidase, which breaks down neurotransmitters such as serotonin.
Thus, they should be avoided in patients taking 5-HT1 receptor agonists (triptans) because when combined, they severely increase the risk of serotonin syndrome, which can be fatal.
Identify the antidote for benzodiazepine and Z-drug overdoses. Does this antidote also reverse barbiturate toxicity?
Flumazenil is a highly effective antidote for benzodiazepine and Z-drug overdoses but is completely ineffective for reversing barbiturate toxicity.
PMHx: 8-year-old girl with no significant history other than deteriorating school performance. Presentation: Her mother describes 10-second episodes where the girl "blanks out" and stares into space without twitching or falling. A local clinic started her on Phenytoin.
Identify the medical error.
Phenytoin is used to treat focal impaired awareness seizures. The presentation above describes an absence seizure, which would be treated with ethosuximide (a T-type calcium channel blocker). Phenytoin is a sodium channel blocker and would not help; it may even exacerbate the absence seizures.
These drugs act on presynaptic receptors: (2)
1. Benzodiazepines
2. Carbamazepine
3. Levetiracetam
4. Gabapentin
5. Ketamine
6. Phenytoin
Carbamazepine and Phenytoin act on presynaptic Na2+ channels.
Leviteracetam acts on SV2A receptors to regulate presynaptic vesicles.
Gabapentin acts on presynaptic Ca2+ channels.
Benzodiazepines and Ketamine are both drugs that act on postsynaptic receptors, GABA and NMDA, respectively.
5-HT 1B/1D receptor agonists aka "-triptans" have a mechanism of action that involves reducing peripheral nociception by inhibiting the release of Calcitonin Gene-Related Peptide (CGRP) in a specific cranial nerve. Name that nerve.
Benzodiazepines are used in the acute treatment of status epilepticus and general seizure management. Name another common use for them. (There are many possible correct answers.)
Some possible correct uses for benzodiazepines include:
1. Sedation
2. Insomnia
3. Night terrors
4. Preoperative anesthesia
5. Alcohol detoxification
6. Muscle relaxation
Name at least 2 drugs for seizures or migraines that do not directly affect CYP450 enzymes at any dose.
I have listed a few of the "CYP-Neutral" medications below. The first 4 especially, are considered to be good safe havens to avoid drug interactions.
1. Leviteracetam
2. Lamotrigine
3. Gabapentin
4. Pregabalin
5. Oxazepam
6. Lorazempam
7. Temazepam
PMHx: 50-year-old male with generalized tonic-clonic seizures and high cholesterol (Hyperlipidemia). Presentation: He is taking Phenytoin for seizures and Atorvastatin for his cholesterol. Despite high doses of the statin, his LDL remains dangerously elevated.
Identify the medical error.
Phenytoin is a strong inducer of the P450 system (specifically CYP3A4). This increases the metabolism of Atorvastatin, significantly decreasing its concentration and effectiveness
The following drugs can be used safely in pregnancy: (2)
1. Lamotrigine
2. Folic Acid
3. Levetiracetam
4. Topiramate
5. Valproic Acid
Lamotrigine and Levetiracetam can be used safely in pregnancy.
Folic acid supplementation is strongly recommended for pregnant women.
Topiramate and Valproic Acid (Valproate) are both strongly contraindicated in pregnancy due to the high risk of major congenital malformations.
Benzodiazepines and barbiturates, though not listed here, are also generally not recommended during pregnancy.
Which dermatologic condition is at increased risk in patients who are prescribed lamotrigine, carbamazepine, and phenytoin?
Stevens-Johnson Syndrome (which can lead to toxic epidermal necrolysis)
These drugs often trigger severe, rapid-onset T-cell-mediated keratinocyte apoptosis within the first 8 weeks. This is a delayed-type (Type IV) hypersensitivity immune response that detaches the epidermis from the dermis and causes blisters.
Dopamine receptor (D2) antagonists are used for acute migraine with nausea/vomiting. Describe their main side effect.
Extrapyramidal symptoms (with other D2 blockers). This includes facial tics, dystonia, Parkinsonism, and akathisia.
Describe the relationship between CGRP receptor antagonists, also known as "Gpants" and CYP450
They are metabolized by CYP450 isoform CYP3A4 but they do not specifically induce or inhibit the enzyme.
PMHx: 55-year-old female with chronic migraines, Hyperlipidemia, and Peripheral Artery Disease (PAD), which causes pain in her calves when she walks. Presentation: She presents with a severe, throbbing unilateral headache with photophobia. The resident physician, noting her blood pressure is currently stable at 130/85, prescribes Sumatriptan.
Triptans work by causing vasoconstriction in the basilar artery and dura mater. They are strictly contraindicated in patients with CVD (Cardiovascular Disease), a history of stroke, or PAD (Peripheral Artery Disease).
A "ditan" such as lasmiditan would be a safer choice because it has a similar target receptor, but no effect on blood vessels.
The following drugs are preventative options against migraines: (1)
1. Metoprolol
2. Amitriptyline
3. SNRIs
4. Botox
5. Sumatriptan
Sumatriptan cannot be used to prevent migraines.
5-HT 1 Receptor Agonists including -triptans and -ditans can only be used to stop active migraines. They are not taken daily.
Ethosuximide reduces low-threshold Ca2+ currents (T-type currents) in thalamic neurons. The thalamus plays a major role in "spike-and-wave" rhythms.
Name the type of seizures this EEG pattern is commonly found in, and which age group is commonly associated with the onset.
Ethosuximide is first line treatment for pediatric absence seizures.
Neurons in the thalamus exhibit large-amplitude T-type currents that underlie bursts of action potentials and likely play an important role in thalamic oscillatory activity such as 3-Hz spike-and-wave activity.
Calcium phosphate kidney stones are a possible side effect of a medication that prevents both seizures and migraines. What is the medication, and what metabolic risk does it pose?
Taking topiramate may result in metabolic acidosis, which can cause kidney stones.
Although commonly prescribed, it has many side effects. This includes but is not limited to paresthesias, weight loss, fatigue, cognitive impairment, CYP40 induction (CYP3A4) AND inhibition (CYP2C19), and metabolic acidosis.
It is also teratogenic.
The "Out ThE Liver" Trio: Oxazepam, Temazepam, and Lorazepam are the three benzodiazepines that undergo direct conjugation for elimination without active metabolites. With this in mind, identify the two patient populations for whom these drugs would be the safest choice when a benzodiazepine is indicated.
1. Elderly patients
2. Those with liver insfficiency
PMHx: 34-year-old female with a history of episodic migraines (averaging 2 attacks per month). She has no history of cardiovascular disease but finds NSAIDs ineffective. Presentation: She presents to the clinic with an acute, severe, throbbing unilateral headache that started two hours ago. She tells the physician she wants a prescription to "stop this pain immediately" before it gets worse. The doctor prescribes her Erenumab (Aimovig). The pain persists 24 hours later.
Identify the medical error
Erenumab (Aimovig) is a CGRP monoclonal antibody drug used specifically for long-term migraine prevention, not for stopping an active attack.
For acute treatment at the onset of pain, a CGRP receptor antagonist (a "-gpant") like Ubrogepant or Rimegepant would be appropriate instead.
The following medications can also be used to HTN: (2)
1. ubrogepant
2. metoprolol
3. lisinopril
4. verapamil
5. amitriptyline
Metoprolol, Lisinopril, and Verapamil can be used to treat HTN in addition to migraines.
Ubrogepant and Amitriptyline cannot be used to treat hypertension or migraines in patients with a history of hypertension. In fact, they may make it worse.