Thursday, 15 May 2014

What's the best diet?

Note: Any diet that's as risky as the classic ketogenic diet should only be used under the supervision of a trained and accredited dietitian (make sure when you go into their office you see some sort of degree in dietetics/nutrition on the wall somewhere, I am yet to see a health professional that doesn't have at least one of their degrees on at least one wall in their office). Plus, I don't care how obese somebody is, treat them with the same degree of respect you'd expect somebody to treat you with, or you're the one in need of a shrink, not them. I also italicise notes, brand names, Latin terms and other things that, by convention, should be italicised (like cis and trans) and bold important terms, in-text. 


What's the best diet? Well that's a good question that many of us encounter in our day-to-day lives. The ideal diet for weight loss would have to be one that's more easily sustainable, as if you hate your diet you're going to cheat on it a little at first, then a little more, then a little more, until you're no longer keeping to the diet at all. Despite this the best diet for long-term weight loss that's been proven effective in well-designed clinical trials is the ketogenic diet (KD) and perhaps one of its modern equivalents.1 Another benefit for this diet over other diets is that it's safe for diabetics and is associated with improved diabetes control and reduced risk of strokes and heart attacks.1 It's also associated with improved blood pressure control, compared to other weight-loss measures.2 But, this diet is NOT exactly palatable (i.e. tasty or for that matter, even tolerable-tasting, basically think an extremist version of the Atkins' diet) or risk-free. Unfortunately, it's well-known to cause constipation (mostly due to the lack of fibre), abdominal pain, diarrhoea, headache, weakness and malnutrition (don't worry, if you do use this diet vitamin/mineral supplements will work fine to replace prevent these deficiencies), amongst other problems.3 There's also a tremendous danger associated with the diet in certain people with genetic disorders such as acute porphyria, that might go undiagnosed all of somebody's life, provided they keep to the usual Australian/US diet. Talking to a shrink (psychologist) can also help you loose weight.4


Background on the ketogenic diet

Figure 1: Ketone bodies
The diet was originally developed circa 1920 for kids with epilepsy. The diet works by forcing the body to go into a state called ketosis, which is basically when the body burns fats for energy and a consequence of this is that you'll have an abnormally high amount of small molecules called ketone bodies (hence the "keto" prefix; my fellow students of the health professions might wish to note I'm not just calling them "ketones" because technically speaking one of them isn't one), floating around in your bloodstream. Ketone bodies are basically the fat equivalent to glucose, the body's preferred energy source that's derived from breaking down carbohydrates. See like glucose, ketone bodies are much more readily catabolised (broken down) to make energy than fatty acids as they're far simpler, chemically, and hence it's far simpler to turn them into the end products of fat catabolism in the body  energy, carbon dioxide and water.5,6

Most ketogenic diets do not pay attention to the specific types of fats being consumed. Different fatty acids have differing effects on cardiovascular (risk of strokes and heart attacks) and metabolic (i.e. relating to diabetes risk or control) risk. Diets high in saturated fats (any animal-derived fat will be high in saturated fat, except those found in fish) are associated with perhaps a slight (albeit so slight that most clinical trials have failed to demonstrate any clear effects as most trials aren't large enough to detect this slight difference) increase of cardiovascular and metabolic complications and an increased risk of prostate, breast and pancreatic cancers. Monounsaturated fats seem to reduce cardiovascular risk, ω-6 fats may increase cardiovascular risk and ω-3 fats reduce your risk of cardiovascular disease and cancer. 
ω-3/6s seem to have minimal effect on metabolic risk. Transunsaturated fats increase your risk of cardiovascular and metabolic events like strokes/heart attacks and diabetes mellitus ("sugar diabetes").7-24



Background

Figure 2: Cis-double bond
Fats are composed to three fatty acids chemically (covalently) bonded to glycerol, this conformation is also called a triglyceride. Fatty acids can be classified as saturated, polyunsaturated or monounsaturated, based on their chemistry. See saturated fatty acids, have no double bonds, which means they have as many hydrogen atoms to them as chemically possible, hence the adjective "saturated" as they're saturated with hydrogensMonounsaturated fatty acids have one double bond, which means they have two less hydrogen atoms as chemically possible for them to have. Hence, they are one (hence the "mono" prefix) carbon bond less saturated with hydrogens than the corresponding saturated fatty acid. Polyunsaturated fatty acids, have more than one (hence the "poly" prefix) double bond and are hence, significantly, less saturated than saturated fatty acids.


Figure 3: Trans-double bond
Another subset of fatty acids are the transunsaturated fatty acids (TSFAs) which are unsaturated fatty acids that are in the "trans" configuration. See all unsaturated fatty acids that occur in nature are in the "cis" configuration like in figure 2. But some TSFAs are produced, inadvertently, in the process of cooking (such as the vegetable oils used in fast foods). 
Figure 4: A diagram explaining the omega nomenclature

The omega (ω) nomenclature is basically where one lists how many carbons from the end (or "tail") of a fatty acid the first double bond appears; omega-3 fatty acids are ones in which the first double-bond occurs 3 carbons from the end of the fatty acid.



Some common natural fatty acids Note: ω is a Greek letter that's pronounced: "oh-m-eh-g-ah" and transliterated into English as "omega"
Essential fatty acids
α-linolenic acid (ALA; an ω-3 fatty
 acid). Found predominantly in plant
 oils. 
Linoleic acid (LLA; an ω-6 fatty acid). Found predominantly
in plant oils.
Conditionally essential fatty acids*
Docosahexaenoic acid (DHA; an
ω-3 fatty acid). Found
predominantly in fish oils. The body
is able to derive all of its requireme-
nts from ALA, except in cases of
severe deficiency. 
γ-linolenic acid (GLA; an
ω-6 fatty acid). Found
predominantly in plant oils.
Our GLA requirements can all be
synthesised from our dietary intake
of LLA.
ω-3 polyunsaturated fatty acids
Eicosapentaenoic acid (EPA). Found
predominantly in fish oils.  It can be
synthesised by our bodies from DHA.
ω-6 polyunsaturated fatty acids
Arachidonic acid (AA). Found predominantly in animal fats (not so much fish oils, red meat like pork is highest in arachidonic acid). Although even in animal fats its only found in traces (<5%). 
Dihomo‐γ‐linolenic acid. Found predominantly in vegetable oils
Omega-9 (monounsaturated) fatty acids
Oleic acid. Found predominantly in plant oils, especially, olive oil (the prefix, "ole" actually comes from the Latin name for olives - olea europaea).
Saturated fatty acids
Short-chain fatty acids (SCFAs). Acetic acid is found in small quantities (like 1%, weight-by-weight) in vinegars, butyric acid is present in small quantities in butter, the rest are usually synthesised as a by product of dietary fibre metabolism, by bacterial species living in one's large intestine. Only a small amount of fibre gets converted to SCFAs and unlike LCSFAs they're actually generally good for you. 
Long-chain saturated fatty acids (LCFAs). Found in most meats, especially red meat and chicken's skin, but also palm oil, butter, milk, cream and cheese. 

* These are ones that are essential in certain conditions, such as during infancy.



It was discovered when doctors desperate to control their patient's epilepsy that had resisted all the current drug treatment (which was a class of a really toxic anti-seizure drugs called the bromides, that were deadly even in slight overdoses. There was a then "modern" development called phenobarbital, but it's also toxic in even the slightest overdose and only had efficacy in one subtype of epilepsy) tried an old treatment discovered by Greek physicians thousands of years ago (circa 500 BC); fasting. They noticed a significant improvement in their patients' seizure control within a week. They, of course, realised the fact that they couldn't go on indefinitely starving their patients so they gradually re-introduced individual parts of the kids' diets, as a controlled experiment to determine what, specifically, they needed to deprive the kids of in order to produce seizure control and they found that carbohydrates were, indeed, the answer.26,27


Nowadays, this treatment is reserved as a last resort treatment for epilepsy that hasn't responded to drugs and surgery and quite frankly do you blame the doctors for reserving it this position? This diet is so unnatural for the body that you in effect have to feed the person a diet that's so nutritionally deficient that it's not only unpalatable but that causes severe constipation in a number of kids and vitamin/mineral deficiencies if not taken with vitamin/mineral supplements.27


Part of the reason for this is the fact that dietary fibre, is a form of carbohydrate and fibre's primary job in the human body is to provide some "roughage" for your digestive tract, giving your stools greater volume. Without it you basically having little to defecate, hence the constipation seen in those on low-fibre diets like cKD. Those of you that read the entry in my table above about SCFAs, produced in the large intestine from fibre might be thinking, "Well then fibre must be conducive to the ketogenic diet." Well it isn't, thanks to a little bit of human physiology called gluconeogenesis (GNG).26


Gluconeogenesis, is a term you can actually figure out the meaning of, simply by breaking up the parts of its name. It means the production (hence "genesis") of glucose (hence the "gluco") from small molecules other than carbohydrates (which are basically glucose or other sugar molecules chemically bound together in a very large structure, usually. Hence the "neo" as in "neo-nazi" which means "new" or "from scratch"). One of those small molecules is propionic acid, one of the chief SCFAs produced in response to dietary fibre. Gluconeogenesis is also important in those with type II diabetes mellitus (T2DM), as they have like three times as much GNG occurring in their livers than most people. This is actually why the drug metformin is usually the best first-line treatment for people with T2DM, as it reduces GNG, amongst other more recently discovered actions.27


Glycaemic indices (GIs) are basically a way of objectively measuring how much of a rise in blood sugar ("glucose") occurs immediate after eating the food for which the GI is assigned. It's usually given as a decimal number, between 0 and 1, although it can also be represented as a percentage out of 100. Whereas 50% (or 0.5) indicates, that if you eat the food for which this GI is assigned it'll produce half the increase in blood sugar that eating an equivalent mass of pure glucose would cause. By the way, the refined sugar we generally call "sugar" has a GI of 55%, as it's 50% fructose, 50% glucose (as it's sucrose, which is these two sugars chemically bonded together) and fructose is very slowly converted to glucose in the body (which is why foods loaded in fructose, like fruit and yoghurt, have a low GI, despite being loaded with sugar).28



Modern equivalents

The classic ketogenic diet (cKD) is, by definition (as this is the only way to induce ketosis, as the body will relentlessly favour glucose as an on-demand energy source over ketone bodies), an incredibly low carbohydrate diet, low-moderate protein and high-fat diet and what this means for patients is that the diet consists almost solely of high-fat, low/medium-protein foods like butter and cream. As this diet is so restrictive a few modern equivalents (only really equivalent in their ability to prevent seizures in people with epilepsy and even that equivalence is fairly scratchy) have been thought up (abbreviated mKDs; like the modified Atkins', medium chain triglyceride [MCT] and low glycaemic index [LGI] diets), although their efficacy in achieving weight loss is significantly different from that of the KD.

The evidence supporting the Atkins' diet for weight loss is mixed  some clinical trials, show efficacy (usually modest), whereas others show no efficacy, or intolerable side effects (like clogged arteries which put you at an increased risk of heart attacks/strokes). Usually Atkins or similarly low-carbohydrate diets (like the cKD) produce the most profound weight loss in the short-term (by short-term I mean <6 months), in the long-term most weight loss diets are usually about equal, although there might be small tendencies favouring extremely low carbohydrate diets like cKD. The MCT diet, is significantly more relaxed than the other mKDs, as the use of MCTs is more efficient in causing the body to undergo ketosis, the evidence supporting its use in people with obesity is pretty much non-existent as it's really just used to treat epilepsy. It also has some unpleasant side effects such as diarrhoea and abdominal pain. The LGI diet is effective for weight loss, according to a number of different studies and is pretty much the only mKD that's proven itself effective for weight loss in well-designed trials.29



Alternatives

Alternative weight loss diets for which the evidence to support is good quality and strong include:29
  • Low fat diets (tend to be less effective than low carbohydrate diets)
  • High-protein diets, this is one I want to make it very clear, see a dietitian before starting it as it can kill you if you have poor kidney function, which can be asymptomatic (i.e. without symptoms) in some people. There's also a few genetic disorders that can make this very dangerous. These diets also increase your risk of kidney stones. 
  • High-fibre diets. Might also reduce your risk colorectal cancer as fibre has positive effects on the bowels. This is probably why Vegetarians have a low risk of colorectal cancer. If you have chronic constipation problems this is probably preferable for previously mentioned reasons.30
Exercising is always a good idea, if you want to exercise to loose weight as well as diet I'd advise high-protein diets (after taking the necessary precautions, though) or low glycaemic index diets, as many of the other weight loss diets have the side effect of making you feel more tired than usual, especially when you're just starting on them. Exercise also reduces your risk of complications of obesity like heart disease or diabetes mellitus. There's also some evidence (albeit weak), that it might improve mood. I say weak as it's impossible to perform a controlled experiment with exercise, as it's impossible to give somebody a placebo walk, run, jog or lifting weights. Another thing that it's impossible to control for when it comes to clinical trials is the fact that loosing weight also improves your self-esteem and body-image, so it's possible these people just felt better because they looked better.31,32

Medication, can also help. I personally think they're pretty useless, that is, medications, for weight loss. While they can increase weight loss a little bit (like a couple of kilos), if used in conjunction to exercise and dietary changes, they tend to cause pretty minimal benefit. Mostly, because many weight loss drugs are latter taken off the market due to their unacceptable safety issues (like sibutramine (Reductil; caused heart attacks/strokes), fenfluramine (in "Fen-phen"; caused heart problems), rimonabant (Acomplia; caused suicidal thoughts)) and their efficacy is limited at best. Usually, in clinical trials, they cause like at most (and this is exceptionally rare as far as this sort of extent of weight loss) 3 kilogram reductions, on average, in the long-term. Currently available medications include:

  • Orlistat (Xenical, Zurical); this one is the safest one so far. It's been used for like a decade or so and still no major safety issues have popped up. It works by inhibiting the uptake of fats by the body. Basically meaning you defecate the fat in your food. I should mention it only works on fats, not carbohydrates, and even there it isn't perfect. In a study comparing the cKD with low-fat & orlistat-assisted diet, they found there was no difference in weight loss between the groups but the cKD was associated with better blood pressure control. It is available over-the-counter. I should mention here and now, because I've heard of pharmacists not having the stomach to mention one of its less glamorous side effects, it can cause anal leakage, oily stools, headaches, fatigue and diarrhoea and these are just the common side effects!27

  • Lorcaserin (Belviq); this one is only available in the U.S. so far. It's one I think is more dangerous than its predecessors because it works by activating the 5-HT2C receptors, which are serotonin receptors found in the brain and their roles include regulating body temperature, blood pressure, mood and other essential house-keeping functions in the body. It works by suppressing appetite. Studies so far have shown a lower incidence of side effects, with fewer patients discontinuing due to side effects, but lorcaserin has caused a few cases of serotonin syndrome which is a potentially fatal side effect caused by excessive stimulation of the 5-HT2C receptors (or other serotonin receptors) that's characterised by disturbed house-keeping functions in the body, like raised body temperature, changes in mood, hallucinations, diarrhoea, excessive sweating (disproportionate to surrounding temperature, or activity [like exercise]), dizziness, nausea, shivering, high blood pressure, high heart rate, headache, shivering, coma and tremor. I should mention, try to not self-diagnose where possible, if you do take this medication and fear you might have it, see a doctor. See you can't be objective about your own body, a doctor can be objective about your body. In the U.S. lorcaserin and orlistat are the only drugs that are approved for long-term use as treatments for obesity.33-36

    Another problem I think might pop up with this drug is that it might cause heart problems as a closely related receptor to 5-HT2C, like it's next-door neighbour in effect, 5-HT2B, is weakly bound by the drug and this receptor is implicated in the heart problems fenfluramine can cause.33-36

  • Phentermine (Duromine, Metermine); this one has also been used for decades so its safety record is pretty positive (it was in "fen-phen" but it was the fenfluramine component that caused the heart problems). It also works by suppressing appetite and increasing the expenditure, by the body, on energy-consuming processes in the body. More specifically, it works by causing a cascading release of noradrenaline in the body, one of the "fight or flight" hormones. Common side effects include:27
    • Sleeplessness
    • Restlessness
    • Nervousness
    • Feeling "high"
    • Agitation
    • Irregular heart rhythm
    • High heart rate
    • High blood pressure
    • Diarrhoea




  • Vomiting



  • Headache



  • Rash



  • Urinating a lot



  • Swelling of the face



  • Unpleasant taste



  • Hives



  • Impotence
  • Certain antidepressants (note many of these drugs can be used for a heap of other things besides relieving depression) like venlafaxine (Effexor, Efexor), duloxetine (Cymbalta), milnacipran (Ixel, Savella, Joncia), fluoxetine (Prozac), sertraline (Lustral, Zoloft) and bupropion (Prexatan, Zyban; normally used to help people quit smoking in Australia and the U.K.) can produce weight loss. Fluoxetine and sertraline-induced weight loss is usually temporary and modest (like less than a kilogram is the average). Plus some people have the opposite reaction to fluoxetine and sertraline and gain weight, especially with fluoxetine. Bupropion is actually being developed, in combination with naltrexone (an anti-addictive drug used traditionally to treat heroin addicts), as a stand-alone (i.e. this being this combination's only medical use) treatment for obesity. Their most common side effects are insomnia, headache, dizziness and digestive complaints (like nausea, vomiting, diarrhoea, etc.).27 

  • Certain anticonvulsants (anti-seizure medications) can induce weight loss (although most do the reverse), especially topiramate (Epiramax, Tamate, Topamaxand zonisamide (Zonegran), both of which are currently being developed, in combination with other drugs (phentermine and bupropion, respectively) as a stand-alone treatment for obesity. They have significant safety issues, they both cause short-term impairment in memory and concentration, psychiatric problems (like depression, suicidal thoughts, anxiety, hallucinations, etc.) and they both can (albeit rarely) cause blood cell abnormalities which can be fatal if not caught early, they can both cause digestive complaints (their most common side effects), headaches, dizziness, etc. They can also cause metabolic acidosis (which is when your blood becomes too acidic; which can be fatal) and with long-term use, brittle bones (more prone to breaks) and kidney stones.27 


The supplement acetyl-L-carnitine (ALC), may improve the efficiency of cKD in causing ketosis. As it ALC is like a supercharger of fat metabolism.37

References:

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  11. Azrad, M; Turgeon, C; Demark-Wahnefried, W (2013). "Current Evidence Linking Polyunsaturated Fatty Acids with Cancer Risk and Progression". Frontiers in oncology 3: 224. doi:10.3389/fonc.2013.00224. PMID 24027672. PMC 3761560
  12. Goff, LM; Cowland, DE; Hooper, L; Frost, GS (January 2013). "Low glycaemic index diets and blood lipids: a systematic review and meta-analysis of randomised controlled trials". Nutrition, Metabolism, and Cardiovascular Diseases 23 (1): 1–10. doi:10.1016/j.numecd.2012.06.002. PMID 22841185
  13. Jeppesen, C; Schiller, K; Schulze, MB (April 2013). "Omega-3 and omega-6 fatty acids and type 2 diabetes". Current Diabetes Reports 13 (2): 279–288. doi:10.1007/s11892-012-0362-8. PMID 23325534
  14. Kelly, OJ; Gilman, JC; Kim, Y; Ilich, JZ (July 2013). "Long-chain polyunsaturated fatty acids may mutually benefit both obesity and osteoporosis". Nutrition Research 33 (7): 521–533. doi:10.1016/j.nutres.2013.04.012. PMID 23827126
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  37. US Government. (14 May 2014). "Carnitine Fact Sheet for Health Professionals". Office of Dietary Supplements. National Institutes of Health. Retrieved 10 May 2013. 

Sunday, 11 May 2014

New Zealand

Figure 1: New Zealand (courtesy of Wikipedia)
New Zealand (NZ) is a country that I sometimes think of as miniature Australia, but I realise that this is a vast simplification as they do have a few significant points of difference from Australia, some of which I envy them for. They have a population of approximately 4.4 million people (compared to 22.5 million for Australia, 318.9 million for the U.S. and 63.7 million for the U.K.),  which funnily enough is roughly the population of the Australian city of Sydney, 1.36 million of which are found in Auckland (which is roughly the population of Adelaide and is found in the North Island), 400,000 of which are found in the country's capital, Wellington (which is roughly the population of Canberra and is also found in the North Island), 370,000 of which are found in Christchurch (found in the South Island) and 130,000 are found in Dunedin (Note: there are cities with a population greater than Dunedin but less than Christchurch that I omitted).1-6
Figure 2: New Zealand (courtesy of the CIA Factbook)








































1. History

Figure 3: The Haast's eagle and
 its prey, the Moa
(courtesy of Wikipedia)
Similarly to Australia, NZ, in its current form, at least, started off as a British colony, although, also, similarly to Australia, it also had its own indigenous people that lived on the Islands for hundreds of years prior to the British settlement (or rather invasion as it wasn't exactly a peaceful settlement). The indigenous people of NZ are the Maori people and they are believed to have settled in the NZ circa 800 AD (compared to ~39,000 BC for when the Aboriginal Australians are believed to have settled in Australia). They also housed two of the largest birds of the modern era — the Moa (believed to have gone extinct ca. 1400 AD) and Haast's eagle (also went extent ca. 1400 AD as it fed on the Moa).1,2


2. Demographics

2.1 Ethnicity

About 71% of the New Zealand population is white (compared to 92% for Australia, 80% for the U.S., 87% for the U.K.), 14.1% is Maori (compared to <1% of the Australian population being Aboriginal), 11.3% is Asian (compared to 7% in Australia) and 7.6% is Pacific Islander.1-4

2.2 Religion

Figure 4: Symbols
 of Judaism,
Christianity
and Islam
Approximately, 45.6% of their population is Christian (compared to 61.2% for Australia, 78.5% for the U.S. and 59.5% for the U.K.), 38.5% of the population is irreligious (compared to 22.3% for Australia, 12.1% for the U.S. and 25.7% for the U.K.), 2.1% of the population is Hindu (compared to 1.3% for both Australia and the U.K.), 1.4% is Buddhist (compared to 2.5% for Australia and 0.7% for the U.S.), 1.1% is Muslim (compared to 2.2% for Australia, 0.6% for the U.S. and 4.4% for the U.K.) and 1.4% of the population identifies as another religion (such as Jewish, for instance).1-4







2.3 Health

Figure 5: Medsafe's logo
The standard medical degree that Medical Schools in NZ (which number two — the University of Otago which is in Dunedin and the University of Auckland) give out is the M.B.Ch.B., which is pretty much the same as the M.B.B.S. (stands for: Medicinae Baccalaureus, Baccalaureus Chirurgiae in Latin) degree given by most Australian and British Medical Schools and takes about the same amount of time to complete (6 years). Healthcare in NZ is free, as in Australia and is funded via taxation. Their mean life expectancy is 80.93 years (compared to 82.07 years for Australia, 79.56 years for the U.S. and 80.42 years for the U.K.). Their rate of quacks per 1000 population is 2.74, compared to 3.85 for Australia, 2.42 for the U.S. and 2.77 for the U.K. Their prevalence of HIV/AIDS in adults (i.e. the percentage of adults with HIV/AIDS at the current time) is about 0.1%, which is about the same for Australia and less than said rate for the U.K. (0.2%) and U.S. (0.6%). Their rate of obesity, amongst adults, is 28.3%, compared to 26.8% for Australia, 33% for the U.S. and 26.9% for the U.K. Medsafe is the Government institution responsible for drug regulation in NZ. In NZ pharmacists are amongst the health professionals permitted to prescribe medications (as opposed to their sole role of dispensing in Australia), which is also true in the U.K. and U.S.1-4,7

The names they use for drugs are usually the International Nonproprietary Names (INNs), which are generic names set forth by the World Health Organization (WHO). Australia uses Australian Approved Names (AANs), the U.K. uses British Approved Names (BANs). AANs are what BANs used to be in 1999, mostly, because of the fact that they were last systematically updated in 1999.8,9


2.4 Education

Figure 6: The University of Otago, 
NZ's oldest university (courtesy of Wikipedia)
Their adult literacy rate is 99% (which is pretty much the same for Australia, the U.K. and U.S.), their average years of schooling (including university/TAFE training) is 12.5 years (compared to 12 years for Australia, 13.3 years for the U.S. and 9.4 years for the U.K.).











3. Miscellaneous other facts

Figure 7: Mt. Cook
(courtesy of Wikipedia)
NZ has the sixth highest human development index (HDI) of any country (compared to 2nd for Australia, 3rd for the U.S. and 26th for the U.K.), their highest mountain is Mt. Cook at 3,724 metres, compared to 2,228 for Mt. Kosciuszko, Australia's highest mountain. The combined land area of NZ is 267,710 km2, compared to Australia's 7,741,220 km2, the U.S.'s 9,826,675 km2 and the U.K.'s 243,610 km2.1-4,10












Figure 8: Metamfetamine

The chief class of drugs used illicitly there are amfetamines (most probably metamfetamine), according to the CIA Factbook (for Australia it is mostly cocaine and amfetamines, for the U.S. it's pretty much every illicit drug and for the U.K. it's a major consumer of heroin (especially from South East Asia), cocaine and producer of some synthetic drugs).1-4
Figure 9: Heroin
Figure 10: Cocaine










4. Therapeutic drugs

There's three drugs that make me jealous of New Zealanders as they're not marketed in Australia, or the U.S. for that matter; nefopam (Acupan), nabiximols (Sativex) and levomepromazine (Nozinan). They're also available in the U.K., amongst other countries.

4.1 Nefopam


Figure 11: Nefopam
Nefopam is a serotonin-noradrenaline-dopamine reuptake inhibitor (SNDRI), that's primarily used as a painkiller.11 SNDRIs are a class of drugs that increase the levels of serotonin, noradrenaline and dopamine in the body, especially in the brain and spinal cord. They most often achieve this by inhibiting three types of proteins
Figure 12: The Leucine Transporter, a type of SERT
 the serotonin transporters (SERTs), the noradrenaline transporters (NATs) and the dopamine transporters (DATs). Although exceptions do exist, such as hyperforin, the chief active ingredient in St. John's wort, which achieves its SNDRI effects by activating a receptor called TRPC6.12 Serotonin and noradrenaline are both implicated in the processing of pain in the brain and the transmission of pain signals through the spinal cord. SNDRIs also include cocaine; in the case of cocaine its action on dopamine levels in the brain is believed to be responsible for its addicting and euphoria-invoking effects. Despite this theoretical potential for abuse, nefopam abuse is actually pretty rare and it seldom ever causes patients to feel "high".11 Which is particularly impressive given the fact it's used as a painkiller, which are a class of drugs that are notorious for their ability to be abused, recreationally. My fellow pharm students might be interested to know it appears in schedule 4 of the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP).13 For the rest of you this is basically a legal document about the accessibility of drugs in Australia; schedule 4 is prescription-only medications, but unlike schedule 8 medications, possessing schedule 4 drugs without authority [like a prescription or because of your profession] isn't a criminal offence. If you're bored and want a look the most recent version of the SUSMP can be found here. It also seems to block the muscarinic acetylcholine receptors (mAChRs) which probably account for some of nefopam's side effects (such as constipation, dry mouth, blurred vision, dizziness, etc.).11 Nefopam may also interact with calcium and/or sodium channels in the spinal cord (which is an action it likely shares with the anti-seizure medications gabapentin and pregabalin), hence interfering with the transmission of pain signals down the spinal cord.14

Figure 13: Muscarinic acetylcholine receptor, M3

Nefopam has been in clinical use since the 1960s and produces pain relief that's said to be similar to that of intermediate-strength opioids (narcotic painkillers) like tramadol (when it's by itself it goes by the brand names: Durotram, Tradonal, Tramahexal, Tramal, Tramedo, Zydol; when in combination with paracetamol it's called Zaldiar in Australia), pentazocine (Talwin; not used in Australia) and hydrocodone (called Zohydro when it's by itself; Anexsia, Hycet, Lorcet, Norco, Vicodin, Xodol, Zamicet in combination with paracetamol, only available in North America), although some studies suggest it's significantly weaker and more akin to aspirin in strength.15 Nefopam is also used to treat shivering and intractable hiccups after surgery.16-18 It seems like as though it mediates its action on shivering by means of its effects on serotonin.16 It has also been used, successfully two I might mention, to treat chronic, persistent hiccups (which is a rare condition, but it can be quite distressing as it can make it difficult to sleep and hold a conversation).19

4.2 Nabiximols

Figure 14: Nabiximol's chief active constituents
Nabiximols is an alcoholic extract of the cannabis sativa (marijuana) plant that is sprayed into the mouth for the relief of treatment-resistant multiple sclerosis (MS)-related spasticity (muscle stiffness) and pain and severe treatment-resistant cancer pain. It contains cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), in roughly equal portions. It works by activating the CB1 receptor, which is the single most abundant receptor in the human brain and is also found in the spinal cord and areas of the brain involved in pain processing. Unfortunately the evidence for the effectiveness of nabiximols is weak at best.20-21


4.3 Levomepromazine

Figure 15: Levomepromazine
Levomepromazine (called methotrimeprazine in Canada and older texts) is a drug that's quite popular in palliative care (like in people with terminal cancer) as it possesses painkilling, anti-emetic (nausea/vomiting-relieving), anxiolytic (anxiety-relieving), antidiarrhoeal (diarrhoea-treating) and sleep-inducing effects.22-26 Despite this the evidence behind these uses is weak at best.27 It was, originally, and still is sometimes, used as an antipsychotic. As an antipsychotic it is unremarkable, although it was once potentially the head of the pack for efficacy, prior to the introduction to clozapine and other atypical or second-generation antipsychotics.28


References

  1. "NEW ZEALAND". The World Factbook. The Central Intelligence Agency. 15 April 2014. Retrieved 12 May 2014.
  2. ^ "AUSTRALIA". The World Factbook. The Central Intelligence Agency. 15 April 2014. Retrieved 12 May 2014.
  3. ^ "UNITED STATES". The World Factbook. The Central Intelligence Agency. 15 April 2014. Retrieved 12 May 2014.
  4. ^ "UNITED KINGDOM". The World Factbook. The Central Intelligence Agency. 15 April 2014. Retrieved 12 May 2014.
  5. "2013 Census Usually Resident Population Counts". Statistics New Zealand. New Zealand Government. Retrieved 12 May 2014.
  6. "Subnational Population Estimates: At 30 June 2013 (provisional)" (PDF). Statistics New Zealand. New Zealand Government. 22 October 2013. Retrieved 12 May 2014.
  7. "Pharmacist Prescribing – Protocol Driven" (PDF). Pharmacy Guild of Australia. Retrieved 12 May 2014.
  8. Therapeutic Goods Administration (July 1999). "TGA Approved Terminology for Medicines – July 1999" (PDF). Department of Health and Ageing. Commonwealth of Australia. Retrieved 12 May 2014.
  9. Medsafe (3 May 2013). "International Non-proprietary Names (INN)". The Ministry of Health. Commonwealth of New Zealand. Retrieved 12 May 2014.
  10. "Table 1: Human Development Index and its components"United Nations Development Programme. The United Nations. 2012. Retrieved 12 May 2014.
  11. Heel, RC; Brogden, RN; Pakes, GE; Speight, TM; Avery, GS (April 1980). "Nefopam: a review of its pharmacological properties and therapeutic efficacy.". Drugs 19 (4): 249–67. doi:10.2165/00003495-198019040-00001. PMID 6991238.
  12. Leuner, K; Kazanski, V; Müller, M; Essin, K; Henke, B; Gollasch, M; Harteneck, C; Müller, WE (December 2007). "Hyperforin--a key constituent of St. John's wort specifically activates TRPC6 channels.". FASEB Journal 21 (14): 4101–11. doi:10.1096/fj.07-8110com. PMID 17666455.
  13. Therapeutic Goods Administration (July 2013). "POISONS STANDARD 2013". Department of Health and Ageing. Commonwealth of Australia. Retrieved 12 May 2014.
  14. Kim, KH; Abdi, S (April 2014). "Rediscovery of Nefopam for the Treatment of Neuropathic Pain." (PDF). The Korean Journal of Pain 27 (2): 103–111. PMC 3990817. PMID 24748937.
  15. Evans, MS; Lysakowski, C; Tramèr, MR (November 2008). "Nefopam for the prevention of postoperative pain: quantitative systematic review." (PDF). British Journal of Anaesthesia 101 (5): 610–7.  doi:10.1093/bja/aen267. PMID 18796441.
  16. Alfonsi, P (2001). "Postanaesthetic shivering: epidemiology, pathophysiology, and approaches to prevention and management.". Drugs 61 (15): 2193–205. doi:10.2165/00003495-200161150-00004. PMID 11772130.
  17. Park, SM; Mangat, HS; Berger, K; Rosengart, AJ (November 2012). "Efficacy spectrum of antishivering medications: meta-analysis of randomized controlled trials.". Critical Care Medicine 40 (11): 3070–82. doi:10.1097/CCM.0b013e31825b931e. PMID 22890247.
  18. Bilotta, F; Pietropaoli, P; Rosa, G (November 2001). "Nefopam for refractory postoperative hiccups.". Anesthesia and Analgesia 93 (5): 1358–60. doi:10.1097/00000539-200111000-00066. PMID 11682430.
  19. Bilotta, F (24 February 2007). "Nefopam for chronic persistent hiccups". British Medical Journal. BMJ Publishing Group Ltd. Retrieved 12 May 2014.
  20. Tanasescu, R; Constantinescu, CS (September 2013). "Pharmacokinetic evaluation of nabiximols for the treatment of multiple sclerosis pain.". Expert Opinion on Drug Metabolism & Toxicology 9 (9): 1219–28. doi:10.1517/17425255.2013.795542. PMID 23621668.
  21. Slof, J; Gras, A (August 2012). "Sativex® in multiple sclerosis spasticity: a cost-effectiveness model." (PDF). Expert Review of Pharmacoeconomics & Outcomes Research 12 (4): 439–41. doi:10.1586/erp.12.40. PMID 22681512.
  22. Guidelines & Protocols Advisory Committee (30 September 2011). "Palliative Care for the Patient with Incurable Cancer or Advanced Disease Part 2: Pain and Symptom Management" (PDF). British Columbia Ministry of Health. BRITISH COLUMBIA MEDICAL ASSOCIATION. Retrieved 12 May 2014.
  23. "Control of pain in adults with cancer A national clinical guideline" (PDF). Scottish Intercollegiate Guidelines Network. National Health Service. November 2008. pp. 64–67. Retrieved 12 May 2014.
  24. "Guidelines on Pain Management & Palliative Care" (PDF). UroWeb. European Association of Urology. 2013. p. 88. Retrieved 12 May 2014.
  25. "Levomepromazine in Palliative Care" (PDF). Palliative Care Guidelines. National Health Service. August 2013. Retrieved 12 May 2014.
  26. Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. pp. 23–24,230. ISBN 978-0-85711-084-8.
  27. Darvill, E; Dorman, S; Perkins, P (April 2013). "Levomepromazine for nausea and vomiting in palliative care." (PDF). The Cochrane Database of Systematic Reviews 4: CD009420. doi:10.1002/14651858.CD009420.pub2. PMID 23633372.
  28. Sivaraman, P; Rattehalli, RD; Jayaram, MB (October 2010). "Levomepromazine for schizophrenia." (PDF). The Cochrane Database of Systematic Reviews (10): CD007779. doi:10.1002/14651858.CD007779.pub2. PMID 20927765.

Friday, 9 May 2014

Anticonvulsants, epilepsy and other therapeutic uses of anticonvulsant medications

The anticonvulsants are an interesting little class of medications that are amongst the oldest of synthetic medications currently employed in modern medicine. Their primary use in medicine (and this is where their class name originates from) is in the treatment of epilepsy and other seizure-related disorders. Seizures have plagued mankind since Biblical times and the first effective treatment for epilepsy emerged as early as 500 BC.1 Epilepsy, which is a disorder characterised by repeated seizures, affects about 0.5-1% of people worldwide.2,3

Fasting and dietary changes

Figure 1: Ketone bodies
This effective treatment was fasting; it might seem odd but fasting was proven an effective treatment for epilepsy, in well-designed clinical trials in the 1910s, although its use to relieve the symptoms of epilepsy can be dated back to Ancient Greece. Despite its success it's clearly not ideal to just keep starving people indefinitely so as to control their epilepsy, as they'll eventually develop nutritional deficiencies and die and hence a modern equivalent has been developed and is used in cases of treatment-resistant (refractory) epilepsy, or in kids whom's parents refuse pharmacologic (drug) treatments. This modern equivalent is called the ketogenic diet and it basically consists of a very low-carbohydrate and high fat diet. Its purpose is to force the body to start burning fats for energy (instead of the usual carbohydrates like glucose) and, in so doing, produce a group of compounds called ketones from the body's fat reserves or dietary fats. Ketones, in turn, lower the pH of one's blood and it is believed that it is this action that improves seizure control in people with epilepsy. Despite its efficacy the ketogenic diet has its limitations, especially compliance issues, as many people with refractory epilepsy are kids and kids tend to be picky when it comes to food and most food allowed in the ketogenic diet is very oily and hence not especially palatable. The ketogenic diet can also cause nutritional deficiencies and constipation (due to a lack of fibre in this diet). Plus some people just don't respond to the ketogenic diet. There's also some evidence to suggest that the ketogenic diet might help people with cancer, obesity and diabetes mellitus.1, 4-6

Drugs

Figure 2: GABA

History and background

The first anticonvulsant drugs were incredibly toxic in cases of even slight overdoses and were the bromides (potassium and sodium salts; first introduced in the late 19th century) which are now largely replaced by safer and more reliable anticonvulsants. Later came phenobarbital (Luminal; first introduced in 1912) and phenytoin (Dilantin; first discovered to have anticonvulsant activity in 1938), which are still widely used to treat epilepsy. Later between 1965 and 1990 other drugs such as other barbiturates (like primidone [Mysoline]) carbamazepine (Tegretol), acetazolamide (Diamox), valproate (Depakote, Epilim, Valpro) and the benzodiazepines (such as clobazam [Frisium], clonazepam [Klonopin, Paxam, Rivotril], diazepam [Valium], midazolam [Hypnovel], nitrazepam [Alodorm, Mogadon]) were introduced as anticonvulsants. Many of these agents work by increasing the activity of a neurotransmitter called γ-aminobutyric acid (GABA), which acts by two receptors  GABAA  and GABAB; both of these receptors suppress the activity of the brain cells on which they're expressed.7 Some act on sodium channels, which are involved in the propagation of action potentials (see this link for an introduction to action potentials that's written for kids so it should be easier for ya to follow).8 Acetazolamide inhibits carbonic anhydrase, which is an enzyme involved in the production of carbonic acid in the blood which regulates blood pH. Hence, by inhibiting this enzyme, it decreases blood pH and this seems to confuse the ion channels found in one's brain; hence interfering with their activity.2,3,8-11
Figure 3: Human Carbonic Anhydrase


Figure 4: Glutamate
Later in the 1990s and 2000s a few extra drugs were introduced as anticonvulsants, such as ethosuximide (Zarontin), felbamate (not marketed in Australia; Felbata, Taloxa), gabapentin (Gabatine, Gantin, Neurontin, Nupentin), lacosamide (Vimpat), lamotrigine (Lamictal, Lamidus, LamogineReedos), levetiracetam (Kepcet, Keppra, Kerron, Levecetam), oxcarbazepine (Trileptal), perampanel (not marketed in Australia; Fycompa), pregabalin (Lyrica), retigabine (not currently marketed in Australia; Potiga, Trobalt), sultiame (Ospolot), topiramate (Epiramax, Tamate, Topamax), vigabatrin (Sabril) and zonisamide (Zonegran). Some of these block calcium channels, which are also involved in signal propagation in the brain; others open potassium channels; while others work on GABA signalling; others work on the neurotransmitter, glutamate, which is basically the opposite to GABA in its actions; the remaining work by inhibiting carbonic anhydrase.2,3,8-12

Table 1: Comparison of anticonvulsants2,3
Drug Pharmacology Intro. Medical uses Structure
Acetazolamide Carbonic anhydrase inhibitor. 1953 Glaucoma and epilepsy.11
BZDs GABAA potentiators. 1960s Anxiety, insomnia and epilepsy.
Carbamazepine Stabilises the inactive form of sodium channels.  1965 Trigeminal neuralgia,13-15 bipolar disorder16-22 and epilepsy.
Ethosuximide Blocks calcium currents in the thalamus. 1960 Epilepsy. 
Felbamate NMDA antagonist/GABAA potentiator 1993 Epilepsy.
Gabapentin α2δ calcium channel blocker 1993 Epilepsy; migraine prevention;23,24 restless legs syndrome;25 anxiety;26,27 hiccups;28 neuropathic pain.13,15
Lacosamide Slowing the inactivation of sodium channels. Also affects collapsin response mediator protein-2, which is involved in neuronal survival. 2008 Epilepsy.
Lamotrigine Sodium channel inactivation delayer; glutamate release inhibitor. 1994 Epilepsy, bipolar depression16,18,29-32 and treatment-resistant schizophrenia.31,33
Levetiracetam Has an action on SV2A, a protein involved in regulating neurotransmitter release.  1999. Epilepsy.
Oxcarbazepine Sodium channel inactivation stabiliser. 2000 Epilepsy.
Perampanel AMPA receptor blocker. 2012 Epilepsy.
Phenobarbital GABAA potentiator. 1912 Epilepsy.
Phenytoin Sodium channel blocker. 1938 Epilepsy.
Pregabalin α2δ calcium channel blocker. 2004 Epilepsy; neuropathic pain; migraine prevention; fibromyalgia; anxiety.34
Primidone GABAA potentiator. 1954 Epilepsy.
Retigabine Potassium channel opener. 2010 Epilepsy.
Sultiame Carbonic anhydrase inhibitor. 1991 Epilepsy
Tiagabine GABA potentiator. 1997 Epilepsy.
Topiramate Blocks voltage-dependent sodium channels; potentiates GABA transmission and glutamate signalling. Carbonic anhydrase inhibitor.  1996 Epilepsy; bipolar disorder (although the evidence is against this use);35 addiction;36-39 obesity;40 migraine prevention;23 Lennox-Gastaut syndrome.
Valproate Voltage-dependent sodium channel blocker. 1978 Epilepsy, bipolar disorder19-22 and migraine prevention.23 May have cancer-fighting effects.42
Vigabatrin Inhibits the breakdown of GABA.  2009 Epilepsy.
Zonisamide Carbonic anhydrase inhibitor; sodium and calcium channel blocker; modulates GABA release; reduces glutamate release.  1989 (Japan) Epilepsy; obesity.40

Additional uses

It's interesting how topiramate and zonisamide can be used to treat obesity; topiramate can also be used to treat drug addictions. It can also be used to treat migraines. Valproate and carbamazepine can be used to treat bipolar disorder as can lamotrigine, although lamotrigine is most effective at treating bipolar depression whereas carbamazepine and valproate are best at treating/preventing mania. Valproate can be used (usually as a last resort) to prevent migraines and has also shown some anticancer activity. Pregabalin and gabapentin can be used to treat neuropathic (nerve injury-related) pain and anxiety disorders. Lamotrigine may also be used to treat schizophrenia in treatment-resistant cases.

Adverse effects/drug interactions

All of these drugs do have their disadvantages, of course, carbamazepine, oxcarbazepine, phenytoin and the barbiturates are notorious for their ability to interact with other drugs and even with themselves (which necessitates regulate monitoring for these medications). These drugs can also precipitate acute attacks in people with porphyria. Most anticonvulsants can cause sedation, drowsiness, memory problems and mood changes, especially early on in treatment. Carbamazepine (especially common with this drug), ethosuximide, lamotrigine, oxcarbazepine, phenytoin, pregabalin, topiramate, valproate and zonisamide can all cause potentially fatal blood disorders, although rarely for most. Some, including carbamazepine, ethosuximide, lamotrigine (especially problematic with this one, which necessitates slow dose increases early on in treatment), levetiracetam, oxcarbazepine, phenytoin, sultiame and zonisamide can cause potentially fatal skin reactions, although rare. These skin effects are more common in those of Asian ancestry. Most other side effects are digestive in nature (like nausea, vomiting, constipation, diarrhoea, loss of appetite, etc.) or psychiatric/neurologic (e.g. headache, dizziness, depression, etc.) in nature. Some can even induce hallucinations or suicidal thoughts. Vigabatrin can also cause visual disturbances which are often irreversible. Many can provoke allergic reactions in some people. Carbonic anhydrase inhibitors can also cause dangerously low blood pH which can cause coma or death; long-term consequences of this action can include brittle bones and kidney stones. Valproate, after long-term use, can also cause brittle bones; it can also cause liver damage (sometimes requiring transplant; which topiramate, carbamazepine and oxcarbazepine can also do) or pancreatitis (swelling of the pancreas). Valproate, vigabatrin, pregabalin, gabapentin and ethosuximide are known to cause weight gain in a number of patients whereas topiramate and zonisamide tend to cause weight loss

Reference list:

  1. Wheless, JW (November 2008). "History of the ketogenic diet.". Epilepsia. 49 Suppl 8: 3–5. doi:10.1111/j.1528-1167.2008.01821.x. PMID 19049574.
  2. Rang, HP; Dale, MM; Flower, RJ; Henderson, G (2011). Rang & Dale's Pharmacology (7th ed.). Edinburgh, UK: Churchill Livingstone. ISBN 978-0-70-203471-8.
  3. Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8
  4. Maroon, J; Bost, J; Amos, A; Zuccoli, G (August 2013). "Restricted calorie ketogenic diet for the treatment of glioblastoma multiforme.". Journal of Child Neurology 28 (8): 1002–8. doi:10.1177/0883073813488670. PMID 23670248.
  5. Mobbs, CV; Mastaitis, J; Isoda, F; Poplawski, M (August 2013). "Treatment of diabetes and diabetic complications with a ketogenic diet.". Journal of Child Neurology 28 (8): 1009–14. doi:10.1177/088307381348759. PMID 23680948.
  6. Bueno, NB; de Melo, IS; de Oliveira, SL; da Rocha Ataide, T (October 2013). "Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials.". The British Journal of Nutrition 110 (7): 1178–87. doi:10.1017/S0007114513000548. PMID 23651522.
  7. Kaila, K; Ruusuvuori, E; Seja, P; Voipio, J; Puskarjov, M (November 2013). "GABA actions and ionic plasticity in epilepsy.". Current Opinion in Neurobiology 26C: 34–41. doi:10.1016/j.conb.2013.11.004. PMID 24650502.
  8. Moreau, A; Gosselin-Badaroudine, P; Chahine, M (April 2014). "Biophysics, pathophysiology, and pharmacology of ion channel gating pores." (PDF). Frontiers in Pharmacology 5: 53. doi:10.3389/fphar.2014.00053. PMC 3982104. PMID 24772081.
  9. Winum, JY; Poulsen, SA; Supuran, CT (May 2009). "Therapeutic applications of glycosidic carbonic anhydrase inhibitors.". Medicinal Research Reviews 29 (3): 419–35. doi:10.1002/med.20141. PMID 19058143.
  10. Hübner, CA; Holthoff, K (October 2013). "Anion transport and GABA signaling." (PDF). Frontiers in Cellular Neuroscience 7: 177. doi:10.3389/fncel.2013.00177. PMC 3807543. PMID 24187533.
  11. Aggarwal, M; Kondeti, B; McKenna, R (2013). "Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review.". Expert Opinion on Therapeutic Patents 23 (6): 717–24. doi:10.1517/13543776.2013.782394. PMID 23514045.
  12. Parsons, MP; Raymond, LA (April 2014). "Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders.". Neuron 82 (2): 279–293. doi:10.1016/j.neuron.2014.03.030. PMID 24742457.
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