Majorly associated with the brand name, Topamax, Topiramate is an anticonvulsant or antiepileptic drug. They have a wide spectrum (broad-spectrum). Before the year 2012, the drug had been in use but off- label. It was used for weight loss. But in the year 2012, it became approved by the FDA (the United States Food and Drug Administration) as a recipe for weight loss when used in conjunction with phentermine.

The most common route for administration of the drug is orally and it is a prescription drug. It is metabolised in the liver and the majority of it (about 70% to 80%) is excreted via urine. As a prescription drug, it comes in four major forms (all taken orally) which are:

  • Immediate- release sprinkle capsules,
  • Immediate- release tablets,
  • Extended-release sprinkle capsules and
  • Extended-release capsules

Topiramate as a chemical is a member of the sulfamate family. But it is unique as it has been modified by fructose diacetonide. This also gives it a very unique and outstanding chemical structure, especially for a pharmaceutical component. Hence it is a sulfamate-substituted monosaccharide anticonvulsant or more commonly an antiepileptic drug (AED).

During the excretion mentioned earlier, the topiramate is still in an unchanged state. The drug is absorbed fairly quickly. The remaining portion of the topiramate that is not excreted from the body is metabolised extensively through the processes of glucuronidation, hydrolysis and hydroxylation. In humans alone, about six metabolites of the drug have been discovered out of which no one makes up more than 5% of an administered dose. These drugs have been suggested to target a fair number of cells which are responsible for its variety of therapeutic activities. These cellular targets include the high voltage-activated calcium channels; the voltage-gated sodium channels; the AMPA/kainite receptors; the GABA-A receptors; and the carbonic anhydrase isoenzymes. Moreover, instead of using direct action, topiramates have been discovered to alter the actions of their targets through the modification of their phosphorylation states.

But its unique method of activation (especially its effect on sodium channels) has been found to be effective, as the drug is of particular importance in the treatment of seizures. Another interesting fact is that its unique effects on certain specific GABA-A receptor isoforms have been discovered to also make a significant contribution to the antiseizure activities of the drug. The clinical significance of the inhibitory properties of topiramates towards high voltage-activated calcium channels has not yet been discovered. Topiramates also inhibit cytosolic and membrane-associated forms of carbonic anhydrase. But this topiramate interaction with carbonic anhydrase isoenzymes may actually be contributing to the drug` side effects. These mentioned side effects include a tendency to cause calcium phosphate kidney stones and metabolic acidosis.

While a lot of the existing anticonvulsants have been found to induce apoptosis together with their required effect in young animals. Though some anticonvulsants have been discovered that successfully induce their anticonvulsant effect without inducing apoptosis, such as carbamazepine, levetiracetam and even lamotrigine. Now, topiramate has been discovered to be part of the select few that do not induce apoptosis while still inducing its anticonvulsant effect.

Clinically, the broad spectrum nature of topiramates has been proposed due to its inhibitory effect on generalized tonic-clonic seizures in the kindling model (both the partial and secondary generalizations are included). It (topiramate) also serves to inhibit pentylenetetrazol-induced seizures and maximal electroshock. The action of the drug on mitochondrial permeability transition pores has been proposed to be recognised as a mechanism.

So, generally, it is not known exactly how the drug functions but it is a fact that it interacts with some channels, enzymes, receptors and even chemicals in the brain to produce seizure- control effects and also migraine prevention.

Topiramate Uses (Medically)

First and foremost, it serves as an antiepileptic or anticonvulsant either when taken in conjunction with other drugs or taken independently. The seizures that can be treated through independent use of the drug are usually primary generalized tonic-clonic seizures and partial onset seizures. While seizures that require that the drug is taken as part of a combination are those associated with Lennox- Gastaut syndrome, primary generalized tonic-clonic seizures and partial onset seizures.

It is also useful in the treatment of migraine headaches. It is not a “miracle” drug that eliminates the migraine once it is ingested. But it will act to reduce the frequency at which the migraines occur. But it would be advisable to treat the migraine headaches the more traditional way (lying down in a quiet dark room) or as directed by your physician.

When prescribed the drug, it would do you good to consume lots of water or other liquids (unless otherwise directed by your physician) this is to prevent the formation of kidney stones. Also, do not suddenly stop taking the medication. Instead, continue taking the medication at exactly the same time daily (or as directed by your physician) and if the need arises the physician would slowly reduce the dosage intake until termination in due time. Some conditions might actually worsen if the drug is suddenly stopped. But this is not really surprising as it has been discovered that there are a few similar biological and clinical features that exist between epilepsy and migraine headaches. To that end, most of the newer antiepileptic drugs also serve as treatments to reduce the frequency of migraine headaches in a patient. How exactly the topiramate migraine relationship occurs is not currently clear-cut but it seems to have the ability to step down the hyperexcitability that elicits the occurrence of the migraine headaches in individuals (especially the genetically susceptible individuals).

Topiramates have also been successfully used in the treatment of alcoholism. Matter of fact, the 2015 edition of the guideline by VA/DoD, recommended topiramate as a “strong for” in the treatment of alcohol use disorder. It is currently being studied to aid in the treatment of PTSD (post-traumatic stress disorder) and even in the treatment of obesity. Another review in 2010 also listed it as being beneficial in the treatment of borderline personality disorder.

The use of topiramate for weight loss has been discovered to be a success. The extended use of topiramate as the major component in a combination with phentermine (while abiding by the recommended dosage) has been proven to cause an average weight loss of about 8.9% for patients taking the highest dosages. Evidence of the effectiveness of topiramate for weight loss is also observed from the fact that the FDA has approved a drug containing topiramate as one of the two major components as the second weight reduction drug in more than ten years.

Topiramate Interaction

Topiramate interaction can be broken down into about six vital ones.

  1. Topiramate interaction with alcohol will lead to increased drowsiness or hyper sedation. Not to mention the increased risk of having a seizure.
  2. Topiramate interaction, given the right conditions, could lead to increased levels of phenytoin in the plasma.
  3. Carbamazepine or other enzyme inducers could lead to an increment in the rate at which topiramate is eliminated from the body. This interaction could make it necessary to “up” the doses already being administered.
  4. Due to the fact that topiramate produces an inhibitory effect toward carbonic anhydrase, using it together with other carbonic anhydrase inhibitors such as acetazolamide could greatly increase the chances of kidney stones occurrence.
  5.  Topiramate interacts (albeit weakly and as an inhibitor) with CYP2C19 to induce CYP3A4. In association with this topiramate reaction, a reduction in the levels of estrogens and digoxin found in the plasma has been noticed during use of topiramate therapy. This reduction would further decrease the effectiveness of birth control pills or oral contraceptives, hence other birth control methods such as the use of IUDs (intrauterine devices) or Depo-Provera are recommended during this period (as these are not influenced by topiramates).
  6. Topiramate has natural bicarbonate lowering effect. If health conditions or other therapies that have a tendency to cause acidosis are taken within the same period as the topiramate, the bicarbonate lowering effects can be compounded.

Topiramate Dosage

The topiramate dosage varies for various conditions and age grades.

Using topiramate monotherapy:

For adults (18 to 64 years of age) treatment would require the intake of 400 mg daily. This is to be taken twice a day in divided doses. The doctor would usually start the patient off on a lower dosage before increasing to the recommended dose. While for adults aged 65 and above, the doctor would also start them off on low dosages and slowly (very slowly) increase the dosages under careful supervision to rule out the possibility of the build-up of topiramate in the body (since their kidneys are somewhat weaker than in younger adults.

The dosage for children between the ages of 10 and 17 is also 400 mg which is to be taken in two divided portion twice daily. This is taken under the supervision of a physician who will slowly increase the dosage should the need arise. For children between the ages of 2 and 10, it is administered based on the weight of the child.

Using Topiramate as an add- on:

Adults between the ages of 17 and 64 should be given at just about between 200 mg and 400 mg. This is for partial onset seizures. While for primary generalized tonic-clonic seizures, the accepted dose is 400 mg daily to be taken in two divided doses.

While for children, 5 – 9 mg/kg is a typical standard, every child will have a different dosage based on their weight.

In summary, the dosage for topiramate is based on the physician` prescription.

Overdosing could lead to various conditions ranging from asymptomatic to status epilepticus. This refers to someone who previously did not have a seizure history. Hallucinations are also present in cases of topiramate overdose. Other symptoms indicating overdose include depression, troubled thinking, loss of consciousness experienced, speech problems, fainting, seizures and even fainting, not to mention the occurrence of seizures. Be careful not to double- dose. If you miss a dose take it as soon as possible, but if it is inside six hours of the next dose, then forget about it.

Recently, topiramates have been extremely helpful in combatting addiction as they help endure withdrawal symptoms. Their generic form, Topamax, is used. Topamax is prescribed to those suffering addictions to help them add stability to their moods and terminate their cravings. This action inadvertently aids in prolonging abstinence periods from specific drugs or alcohol. It is frequently used in rehabilitation centers to aid those undergoing alcohol and drug detoxification. It helps prevent the occurrence of seizures or convulsions in such individuals. But along the line, some might get a feel for the topiramate high. When eventually some start to plan their whole day around the intake of their medication or if they show signs of slight headaches or discomfort whenever a dose is missed, then they are becoming addicted to topiramate. Some eventually begin to mix the drug with other substances (other drugs or alcohol) to increase the feeling of the topiramate high.

Side Effects of Topiramate

We have more than a few side effects, some more popular or prevalent than the others. For instance, the more prevalent topiramate side effects (occurring in more than 10% of the side effect cases) include:

  • Depression
  • Paraesthesia
  • Diarrhoea
  • Weight loss
  • Nasopharyngitis
  • Fatigue
  • Dizziness
  • Somnolence, etc.

The more uncommon topiramate side effects are more numerous than the common one. But these uncommon side effects take place in as low as 10% (even lower) of the incidence reports. They include:

  • Memory impairment
  • Convulsion
  • Lethargy
  • Mood swings
  • Psychomotor skills impaired
  • Balance disorder
  • Weight gain
  • Anaemia
  • Sedation
  • Vertigo
  • hypersensitivity
  • Intention tremor
  • Blurred vision
  • Vomiting
  • Anger
  • Abdominal discomfort
  • Nasal congestion
  • Rash
  • Anxiety
  • Hair loss (alopecia)
  • Muscle twitching
  • The slowness of thought, etc.

It would be wise for pregnant women to abstain from topiramate intake (especially for treatment of migraine headaches) due to the fact that there is a high risk of the infant developing cleft lip or cleft palate. Moreover, in about 1 in 500 people, there is a possibility that topiramate could increase suicidality, prompting increased suicidal thoughts and in the worst case scenario, suicidal actions.