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MEDICINES AND RISK OF LOWERING THE SEIZURE THRESHOLD

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I am on medications for seizures. Recently I was diagnosed with a urinary tract infection and put on Ciprofloxacin. It was changed when my details showed a history of seizures. Kindly shed more light on this issue. Yes, it is true that Ciprofloxacin can lower the seizure threshold and therefore could precipitate a seizure for someone with a history of seizures and taking medications.

A seizure is the clinical manifestation of abnormal, excessive or synchronous neuronal firing in the brain. The clinical features of seizures may include abnormalities of consciousness, movement, sensation, behaviour and autonomic function. Epilepsy is the enduring tendency to experience seizures.  The seizure threshold describes the minimum intensity of a stimulus required to induce a seizure. It is clinically evident in the context of electroconvulsive therapy, but is otherwise primarily an experimental phenomenon, in which seizures are induced by electrical or chemical stimuli.

Seizures occur when there is an excess of excitatory activity relative to inhibitory activity. Glutamate and gamma-aminobutyric acid (GABA) are, respectively, the principle excitatory and inhibitory neurotransmitters in the central nervous system (CNS). Glutamate acts via N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and kainite receptors to cause an influx of sodium and calcium ions, favouring depolarization. GABA acts primarily through GABAA receptors to cause an influx of chloride ions, inducing hyperpolarization. The mechanisms of action of antiepileptic drugs include interference with sodium (e.g. phenytoin, carbamazepine, lamotrigine) and calcium channels (e.g. ethosuximide); enhancing the effects of GABA(e.g. benzodiazepines); antagonizing glutamate at AMPA receptors; and a combination of these effects (e.g. valproate). Drugs with the opposite effects may induce seizures.

Seizure potential is often evaluated during drug development to quantify the extent to which a drug prevents seizures (if this is the intended therapeutic effect) or induces them (as an unwanted effect). As a broader concept, it is useful in clinical practice as a framework to help understand the complex interplay between the patient, their medicines, and their risk of seizures (Hitchings .W. Drugs that lower seizure threshold. St George’s, University of London and St George’s University Hospitals NHS Foundation Trust.  Thundiyil JG, Kearney TE, Olson KR. Evolving epidemiology of drug-induced seizures reported to a Poison Control Center System. Journal of Medical Toxicology 2007;3:15-9).

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The propensity of a drug to induce seizures depends on its effects on neurotransmission and their timecourse (e.g. whether it increases seizure risk during use or on withdrawal), the concentration of drug reaching the brain, and the susceptibility of the individual patient. Susceptibility factors include previous seizures, structural or functional brain abnormalities, and concurrent drug use. In the face of such complexity, it is rare that seizures can be ascribed primarily to the effects of a drug (i.e. ‘drug-induced seizures’). Commonly, however, drugs contribute to a shift in excitatory/inhibitory balance which, in that individual at that time, leads to a seizure. In this respect, it is generally more helpful to regard such drugs as having lowered the seizure threshold, rather than having incited seizures.

Many drugs have indirect effects on the seizure threshold, for example by inducing hypoglycaemia, electrolyte disturbances or respiratory depression, or by interacting with antiepileptic therapy. Drugs with potential to lower the seizure threshold are numerous and diverse. Whether they contribute to clinically overt seizures depends on the dosage in which they are taken, the time-course of their effects, and the susceptibility of the patient. It is important to add that the contribution of medicines to seizure risk is potentially modifiable. For antimicrobials, the beta-lactams (penicillins, cephalosporins and carbapenems), interact with the GABAA receptor to interfere with the inhibitory effects of GABA in a concentration-dependent manner. Correspondingly, they have dose-dependent effects on the seizure threshold. However, the CNS penetration of penicillins and cephalosporins is relatively low. As such, most reports of seizures associated with these agents emerge from their use in high doses (often in the treatment of CNS infections) or in renal failure.  Carbapenems more readily penetrate the CNS and their use is associated with an increased seizure risk compared with non-carbapenem antibiotics. Among the carbapenems, imipenem is generally regarded to have the highest risk. However, this may be because studies conducted on the newer agents (meropenem, ertapenem and doripenem), informed by earlier experience with imipenem, generally excluded patients with a history of seizures.  All cephalosporins have the propensity to lower the seizure threshold but the one often associated with this phenomenon is cefipime. The quinolones are another group with the most common ones being ciprofloxacin and levofloxacin.

The antituberculous agent isoniazid inhibits pyridoxine phosphokinase, the enzyme which converts pyridoxine to its active form, pyridoxal-5-phosphate. Pyridoxal-5-phosphate is an essential cofactor in the synthesis of GABA from glutamate. The resulting fall in inhibitory activity and rise in excitatory activity leads to a dose-dependent reduction in the seizure threshold. Isoniazid toxicity is characterised by a triad of altered mental status, metabolic acidosis and refractory seizures. Treatment with pyridoxine and a benzodiazepine usually results in prompt seizure termination.

The antimalarial agents mefloquine and chloroquine can precipitate seizures in people with epilepsy. This effect has been reported even in healthy individuals.Antipsychotics are another group with the most common ones being chlorpromazine and clozapine. Some antidepressants also have this tendency with the notable ones being Amitriptylline and Venlafaxine..Seizures are common in cases of antidepressant overdose, particularly with venlafaxine and TCAs.

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Narcotics such as Meperidine, Fentanyl and tramadol have also been associated with lowering of the seizure threshold.Many drugs can adversely affect the seizure threshold, although whether this leads to overt seizures depends on the concentration of drug reaching the brain, the susceptibility of the individual to its effects, and how these effects vary over time. In managing patients with epilepsy or other risk factors for seizures, one must be mindful of the potential for medications to lower the seizure threshold, so as not to precipitate avoidable seizures. Likewise, in evaluating patients with seizures, consideration must be given to the seizure-provoking potential of their medications. As noted by Hitchings information on the intended medicine’s risk to lowering the seizure threshold becomes an important factor in the decision to withhold or stop the medication to improve seizure control or prevent it in the first place.

As always use medicines safely. Always consult your pharmacist on safe use of medicines.

DR. EDWARD O. AMPORFUL

CHIEF PHARMACIST

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COCOA CLINIC

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This sanitation issue!

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Some things do not change in this country.  The rains shall fall in May, and June and even July.  That is out of our control.  It is an act of God and he decides how often and the intensity.  Who are we to question God? 

However, there is something man-made that is gradually becoming something that is also not changing and it is worrying.  A week ago the President initiated a national clean up campaign to address the issue of sanitation in the country, especially in Accra. 

Citizens enthusiastically got involved and engaged in cleaning their environment and other places but afterwards, the issue that is becoming a permanent feature resisting change, reared its ugly head again. 

The rubbish and the silt that were dug out of the drains, were heaped on the shoulders of the drains and left there.  Any little rain will render the whole effort futile because the rubbish and silt will be washed right back into the drains. 

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This is what is not changing in the country and the various assemblies must ensure that this issue is dealt with and must become a thing of the past.

There is the need to engage the citizenry across board, in connection with mindset change, as far as sanitation is concerned.  At this juncture, I must acknowledge the thoughtful initiative of the current crop of Abenfo (i.e. students both present and past) of SUTESCO of Suhum, with support of the school administration for decorating the area under the overpass on the Accra Kumasi highway, near the school, with fascinating paintings.  This is an example worthy of emulation and makes me proud as one of the Abenfo. 

An example not worthy of emulation is an eyesore currently existing behind a cemetery along the Atta Mills link as you branch left, off the main Accra-Cape Coast road at Old barrier and head towards the beach through Aplaku, Bortianor, Oshiyie, Korobite through to Tuba and beyond. 

The drain along the walls of the cemetery also lying astride the road, is choked with silt and rubbish.  This has created a problem near the end of the cemetery wall just before you enter Bortianor. 

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Water has accumulated at that point, creating potholes and also gradually creating a channel across the road, creating a nightmare for motorists using that route.  This route is the main link between parts of Kasoa and the Accra – Cape Coast road and whenever it rains and the Atala stretch of the road is blocked, that is the route most motorists from Kasoa uses.

It is also the route used by tourists going to the beaches along the sea of the towns stretching from Bortianor to Kokrobite and so it does not speak well of us, as a nation at all.

A few days ago, I had to pass through Tema Station, the place where a major clean up exercise was conducted just fews days ago and it was very shocking to see the level of wanton littering that had taken place. 

One begins to wonder if this whole exercise initiated by the President was worth it.  People just do not care and are not willing to change their attitude towards sanitation. 

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We cannot continue like this and to win this battle against insanitary conditions in our environment, the NCCE must be resourced to embark on a serious educational drive.  The MMDCEs must also be held accountable for sanitation lapses in their administrative areas, by making sanitation part of their KPIs among other innovative policies.  This is one of the surest ways to overcome this sanitation challenge confronting us. God bless.

By Laud Kissi-Mensah

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Disqualified — Part 1

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THE discussion lasted only ten minutes. Mr Philip Sampson, Eunice’s father, had asked to see him, and he was led to the sitting room for the first time. Mr Sampson indicated that he should sit down.

‘Yes, Kakraba. I know that you have been, er, friends with Eunice for some months now, and naturally, as her father, I thought it would be important to meet you, and to reach an understanding with you on, er, some basic issues. So, I hear you are a graduate in building technology. Now, tell me about what you do’.

‘Okay. I worked with the Electricity Company for two years after National Service. During that time I interacted with some lawyers and land surveyors on our project sites, so I suggested to some of them that we take some dilapidated buildings in some parts of Accra, rehabilitate them and find new owners. Soon after starting that I got a job as Project Manager with a group of development agencies who are executing projects in the Northern Region, so I have been balancing the two positions’.

‘I see. That sounds like a bold step. So is it going well, financially?’

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‘Well, sir, I absolutely enjoy what I’m doing now. Financially, I would only say that I am a work in progress. A lot of what I’m doing now involves some risk taking, as it involves trust issues with land and property owners.

I am partnering with prominent lawyers and land surveyors, so I am not taking any serious risks. So currently I am doing okay financially, but it will take me some time before I reach the level where I can say I am comfortable financially.’

‘Okay. Now tell me about your parents’.

‘My father was an Agricultural Extension Officer, so we spent some time at several locations with him. He is now enjoying his retirement. And my mother is a retired nurse. I have three elder sisters, all married’.

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‘So you live with your parents?’

‘Yes and no. My dad built his home on one acre at Pokuase, so he gave me one plot, and I have done a three-bedroom house, where I live’.

‘Okay, fine. Thanks for the answers. You see, in addition to my position socially, I spent many years in the diplomatic service, so I’m sure you will understand that I need to ensure that my kids, especially my daughters, maintain suitable relationships. For now I think it is fine that you and Eunice are friends. I’m sure you understand what I mean’.

‘Yes sir. I understand perfectly well.’

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‘Great, okay, that would be all.’

Kakraba stood up, bowed and said thank you to Mr Sampson, and walked to the garden where his girlfriend Eunice, her mother Mrs Elaine Sampson and her two elder sisters, Yvonne and Emma, were seated, busily discussing some dresses being offered for sale online.

‘So,’ Mrs Elaine asked him, ‘you and Daddy had a good discussion?’

‘Yes, Ma. We certainly did. I really appreciate Dad for the discussion. It was really good.’

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‘Great. Although he has met you here on quite a number of occasions, I think it is good that you have met for a chat.’

‘Yes indeed, Ma, and I really appreciate it. So Eunice, I will be on my way. I will call.’

Eunice led him to his car, and after driving off he exhaled and shook his head. Although he had long concluded that Eunice’s family were so snobbish that a future relationship with her would be problematic, this discussion, or was it interrogation, had virtually cancelled any likelihood.

Mr Sampson just told him, in no uncertain terms, that the Sampson family was so prominent and socially connected that a union between his daughter and him was undesirable.

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He had a good relationship with Eunice. They shared some beautiful moments together, and often went out to entertainment joints, often with her three friends Marian, Patricia and Amanda. But Kakraba was often uncomfortable with their preferences.

Eunice regularly spoke about her family’s experiences during her father’s postings in Europe and Asia, and her three friends were always discussing the latest fashion trends, always noting the importance of placing themselves among the best-dressed ladies in town.

Eunice, her mother and siblings had indicated in several ways that he did not quite fit into their social standing. They had only said a mild ‘thank you’ when he brought them a goat or sheep and a generous amount of foodstuffs from the north every month.

But Kakraba did not really take it to heart, because they were quite inexpensive up north. Moreover, he always went to the food market and arranged with the truck drivers for a big package which was picked up by his buddy Paa John and delivered to his family and a few others, including the Sampsons.

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By Ekow de Heer

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