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MEDICINES AND RISK OF LOWERING THE SEIZURE THRESHOLD

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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The Prophet part 3

In anticipation of a sizeable offer­ing, he had brought a big silver bowl and placed it close to the ‘pulpit’. He kept glancing at it in the course of the service and noted with satisfac­tion that it was ‘doing very well’.

By the close of the service it was full. Immediately the final ‘Amen’ was said, he grabbed it and placed it close to his new desk. He managed to extricate himself from the people who wanted to thank him or shake his hands, and sat down to attend to the people who had lined up to consult him.

He gave them the required ‘direc­tions’, taking appropriate fees after invoking special prayers. The last person to consult him was Mr. Kwame Dofu, who had specifically asked to be the last.

‘Osofo’, he started, ‘I wanted to discuss a special business with you, that is why I asked to see you last. I am in the gold business. There is big money in it, but there is also com­petition, so many of the people in it are using all kinds of powers. I came to ask for your special assistance. I want to win the confidence with the foreigners who come to buy gold, and the foreign big men at the mines who are able to give us big business. If you are able to help me, I will give you a very big reward. I have two friends who will also need your help. I will bring them too’.

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‘Don’t worry, Mr. Dofu. I can help you. Give me two days to prepare, and come back for the necessary directions. You will certainly do big business’.

‘I knew you will help, Osofo. I am very glad I came to see you. Now, here is five hundred cedis for your petrol. When I come in three days’ time I will prepare fully’.

Now, Papa Antubam told himself, why did I wait so long to start this business. Only a few days, and things couldn’t be better. Wow!

He remembered that there was money to be counted. He moved to pick the big bowl, but two young smiling ladies stepped forward.

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‘Osofo, we wanted to ask your permission to count it. I am Mary, and she is Suzzie’.

‘That’s very kind of you’, he said. ‘Please go ahead, but before that, please go to the lady at the kiosk over there and ask her to give you the cold box I left with her’. They brought it, and as they counted the money, Papa Antubam sipped two bottles of beer, which he had re-labeled as Sprite Or­ange Drink, just in case some inquisi­tive busybody asked stupid questions.

‘They finished, presented the neat­ly packed notes and coins to him’.

‘Osofo, it adds up to three thou­sand, three hundred and two cedis’.

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‘Thank you very much, beautiful ladies’. Take a hundred cedis each for your kind effort. They gratefully accepted the offer, and were moving away when Antubam called them back.

‘Now, Mary and Suzzie, which one of you is married?’

‘We are both unmarried’, Suzzie said.

‘In that case, there is something you must do for me. You know this is a new church. You already know what miracles have started happening here. Bigger things are about to hap­pen. Now, I want you two to be with me. I will give you senior positions in the church. And I will take care of all your needs. Fortunately, you are both very good looking. From today, you belong to me. What do you say to what I have just said?

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The two ladies looked at each other for a minute, and smiled.

‘We agree, Osofo’.

‘Fantastic! Now take the money to my place, and since we are all hungry and tired, buy something nice for us to eat, and let’s see what interesting things the afternoon will do for us’.

The girls picked up the money bowl and followed him to his house. They dropped the items, collected money and left to buy the take-away food.

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‘Now Suzzie’, Mary said to her friend, ‘what have we led ourselves into? We only wanted to pinch a few cedis, now we have agreed to be his wives, or is it concubines?’

‘You surprise me, Mary. This is the nicest thing that ever happened to us. How much did you pinch, by the way?’

‘250 cedis. Not bad at all for an hour’s work? But how can the two of us be his wives? Suzzie, what will peo­ple think? Did we go to the church for God’s help or to practice polygamy?’

‘You don’t get the point, Mary. Lis­ten, this is no church. Any pastor who drinks alcohol disguised as orange juice and proposes to two congre­gants on the first day is no pastor. He is doing business with the church, thanks to some village jujuman. And as you clearly saw, he is overwhelmed by the money flowing. So we will help him. And I can assure you, he will not get even a kiss from either of us.’

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‘How will we do that? He is a man, and we have agreed to be his wives’.

‘Give me just one hour. I’ll show you’.

They bought the food, and Mary also bought a bottle of Zap Whisky Medium. They laid the table.

‘Osofo, I brought a nice appetiz­er for you. You know your work is tedious, and you need to save some energy for tomorrow.’

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‘Er, er, normally I stay away from alcohol, but you have a point, let me try just a little. Mary dropped small amounts into his glass, and by the time they finished eating, half of the drink was gone.

‘Osofo, I suggest we get a solid briefcase with a lock to keep your money. You should open a bank account. We’ll make payments into it, and you can sign cheques anytime you need money. For now we’ll record the denominations and the amount, then I’ll wrap it up – you can keep it under your mattress. Let me top your drink’.

‘You are so thoughtful, Mary. How can I thank you?’

As the girls pretended to be doing some serious calculations, Papa Antu­bam eased himself on the bed, hoping that the girls would soon join him for some fun. Within a short while, he was fast asleep, snoring rhythmically. The girls tucked the money under his bed, closed the door and went out of the house.

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‘And how long are we going to keep this up, Suzzie?’

‘Not for very long. Very soon all kinds of women, single and married, would be fighting over him. The mon­ey and spiritual power will attract them. When he realizes that we do not want to have sex with him he will throw us out. By then I would have al­ready set up my shop, and you would have opened your salon’.

‘You have worked it all out have you? You are a real thief’.

‘Me, a thief? Then what do you call Osofo Antobam? Let me tell you, Suzzie. Those people who are using the name of God to make money and use people are real criminals, and I will enjoy everything I do to Anto­bam. And I know your next question. Am I not afraid of his powers? What powers? I don’t fear his fake powers. Let’s go home and get some rest. Tomorrow, we’ll fleece him of a few more cedis’.

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By Ekow de Heer

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Beyond Big English

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Any minister-designate who is about to be vetted by a parliamentary vetting committee must prepare for the worst.

 He must understand that the vetting process is not a test for mere eloquence and bombast, alliteration and poetic delivery. It goes beyond the parapet of diction and usage, semantics and grandiloquence.

The aspiring minister may, therefore, speak big English, but it doesn’t really matter.

There is always a dictionary around to be consulted anyway. What matters is his (or her) ability to prove beyond every reasonable doubt that he can handle the job based on his academic, professional and moral track record.

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The minister must be seen to be qualified for the job in all facets. If so, every question may be relevant no matter how frivolous. It has always been the case.

For example, if someone is a homosexual, that is his own palaver. But if he vies for public office, his homosexual activities must be well-examined and although he may be the best suited for the job, his unnatural desires may well disqualify him for obvious reasons. Of course, who wants a minister who will be sodomising his driver, garden boy and the tall security guard?

The case of Canaan Banana, one time Vice President of Zimbabwe, is fresh in memory. He was recently released from jail for sodomy, a conduct completely unbefitting of a nation’s vice-presidency.

It is also useful for questioners enquire about marital status, number of previous and current wives, number of children and the like.

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Someone might have two wives for very good reasons. May be, one woman is not enough for him due to his extraordinary sexual appetite. And to avoid being adulterous, he takes another wife. It is a legitimate reason and polygamy is not a crime in Sikaman.

However, parliament must know whether he’d have time for the job as a minister when he is always thinking about sex and how to satisfy two wives while fathering and catering for kids on both sides.

A minister may have 13 children. It is a matter of choice, and some people naturally like large families so his talent in procreation might probably not be to his sexual vitality, but to fulfil biblical principles of being fruitful and proving it by multiplying to gratify a desire for a jumbo size family.

However, such a family size may attract queries bordering on population control and family planning.  “Mr So-and-so, Assuming every man had 13 children, can you estimate what the population of Sikaman will be? And will your government be able to provide jobs and schools for all?

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But of course, that is, according to the questioner, a mere assumption and can, therefore never be the case. However, the question is relevant.

RIDICULE

The reason why all ministers-designate should be prepared for the worst is that some questioners may also be prepared to ridicule them. However, in the process, the aspiring minister’s patience is tested.

Is the man going to be a minister who easily flares up and starts misbehaving? And how would anyone know if he is not that type unless his annoyance gauge is not tested in public?

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We may have a mister who would be slapping his staff left and right, occasionally throwing karate kicks when foreign dignitaries are around.

I hear that to be chosen as a minister is easier than preparing for the vetting. The problem that you wouldn’t know which skeleton in your cupboard will be exposed and which dirty linen will be advertised for all to see.  So some ministers designate have had sleepless nights and others have to be forced to do some fasting.

After fasting and praying, the aspiring minister must prepare his (or her) wardrobe for the occasion. How do ministers dress? Are they simple or flamboyant like peacocks?  Anyhow the minister-designate must start looking-like a minister, talking and acting like one.

He must wear a three-piece suit and get a stylish tailor. The suit in his wardrobe isn’t quite good. It would be okay for a poor aristocrat, not a newly nominated candidate who just learnt to cough and sneeze like a minister. He has even proven to his wife that he snores like a minister.

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And when the day comes, must he merely walk or rather dance to take his seat to be vetted?  Should he smile broadly showing all his teeth or only some? He isn’t quite sure.       

One thing Parliament has forgotten is something called “Lie Detector Test”. It could be used only if candidates are answering questions about their past deeds. Everybody has cupboard skeletons, but that of some are too many. Fraudulence, immorality with teenage girls, exaggerated CVs, sexual harassment, whatever.

A Lie Detector may not be very accurate, but at least it can make ten children, but they declare only four.  The Lie Detector can be useful here.

But what is the relevance of all these when people argue that the more wayward the candidate the more efficient he is? They cite Bill Clinton. But his is an exception? Isn’t it?

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This article was first published was on Saturday, February 10, 2001

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