CREATINE Pharmacodynamics Creatine is a essential, non-proteinaceous amino acid derivative found in all animals. It is synthesized in the kidney, liver, and pancreas from L-arginine, glycine and Lmethionine. Following its biosynthesis, creatine is transported to the skeletal muscle, heart, brain and other tissues. Most of the creatine is metabolized in these tissues to phosphocreatine (creatine phosphate). Phosphocreatine is a major energy storage form in the body. Supplemental creatine may have an energygenerating action during anaerobic exercise and may also have neuroprotective and cardioprotective actions. Mechanism of action In the muscles, a fraction of the total creatine binds to phosphate - forming creatine phosphate. The reaction is catalysed by creatine kinase, and the result is phosphocreatine (PCr). Phosphocreatine binds with adenosine diphosphate to convert it back to ATP (adenosine triphosphate), an important cellular energy source for short term ATP needs prior to oxidative phosphorylation. L carnitine Levocarnitine is a carrier molecule in the transport of long chain fatty acids across the inner mitochondrial membrane. It also exports acyl groups from subcellular organelles and from cells to urine before they accumulate to toxic concentrations. Lack of carnitine can lead to liver, heart, and muscle problems. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. Only the L isomer of carnitine (sometimes called vitamin BT) affects lipid metabolism. The "vitamin BT" form actually contains D,L-carnitine, which competitively inhibits levocarnitine and can cause deficiency. Levocarnitine can be used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. Mechanism of action Levocarnitine can be synthesised within the body from the amino acids lysine or methionine. Vitamin C (ascorbic acid) is essential to the synthesis of carnitine. Levocarnitine is a carrier molecule in the transport of long chain fatty acids across the inner mitochondrial membrane. The carnitine-mediated entry process is a rate-limiting factor for fatty acid oxidation and is an important point of regulation.[11] Inhibition[edit] The liver starts actively making triglycerides from excess glucose when it is supplied with glucose that cannot be oxidized or stored as glycogen. This increases the concentration of malonyl-CoA, the first intermediate in fatty acid synthesis, leading to the inhibition of carnitine acyltransferase 1, thereby preventing fatty acid entry into the mitochondrial matrix for β oxidation. This inhibition prevents fatty acid breakdown while synthesis occurs.[11] Activation[edit] Carnitine shuttle activation occurs due to a need for fatty acid oxidation which is required for energy production. During vigorous muscle contraction or during fasting, ATP concentration decreases and AMP concentration increases leading to the activation of AMP-activated protein kinase (AMPK). AMPK phosphorylates acetyl-CoA carboxylase, which normally catalyzes malonyl-CoA synthesis. This phosphorylation inhibits acetyl-CoA carboxylase, which in turn lowers the concentration of malonyl-CoA. Lower levels of malonyl-CoA disinhibits carnitine acyltransferase 1, allowing fatty acid import to the mitochondria, ultimately replenishing the supply of ATP.[11] Drug interactions and adverse effects[edit] Carnitine interacts with pivalate-conjugated antibiotics such as pivampicillin. Chronic administration of these antibiotics increases the excretion of pivaloyl-carnitine, which can lead to carnitine depletion.[1] Treatment with the anticonvulsants valproic acid, phenobarbital, phenytoin, or carbamazepine significantly reduces blood levels of carnitine.[4] When taken in the amount of roughly 3 grams (0.11 oz) per day, carnitine may cause nausea, vomiting, abdominal cramps, diarrhea, and body odor smelling like fish.[1][4] Other possible adverse effects include skin rash, muscle weakness, or seizures in people with epilepsy.[4] Drug Interaction – Mechanism of action Many of supplemental L-arginine's activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to nitric oxide or NO. NO is produced by all tissues of the body and plays very important roles in the cardiovascular system, immune system and nervous system. Figure 1. L-Arg, L-Cit and their role in vasodilation. Step 1. Citrulline in systemic circulation is metabolized in the kidneys by ARGs to form L-arginine. Step 2. L-arginine is released systemically into blood vessels. Step 3. Larginine is transported into endothelial cells via CAT transporters and eNOS to produce nitric oxide (NO). Step 4. NO diffuses from endothelial cells into skeletal cells. Step 5. NO presence and activation of GC and GTP produces cGMP causing cellular calcium efflux, leading to vasodilation. Abbreviations;ARGs = arginosuccinate synthase; CAT = cationic amino acid transporter; eNOS = extracellular nitric oxide synthase; NO = nitric oxide; GTP = guanosine triphosphate; GC = guanylyl cyclase; cGMP = cyclic guanosine monophosphate. Figure 1 was provided as a courtesy by Mr. Jackson Williams. HMB Exogenous HMB-FA administration has shown to increase intramuscular anabolic signaling, stimulate muscle protein synthe- sis, and attenuate muscle protein breakdown in humans [2]. Therefore, the anabolic and anticatabolic properties of HMB-FA offer an appealing nutritional supplement for athletes participating in high-intensity, muscle-damaging exercise. Recently, several studies investigated the efficacy of HMB-FA supplementation in conjunction with resistance training. Pathways of Testosterone Action. In men, most (>95%) testosterone is produced under LH stimulation through its specific receptor, a heptahelical G-protein coupled receptor located on the surface membrane of the steroidogenic Leydig cells. The daily production of testosterone (5-7 mg) is disposed along one of four major pathways. The direct pathway of testosterone action is characteristic of skeletal muscle in which testosterone itself binds to and activates the androgen receptor. In such tissues there is little metabolism of testosterone to biologically active metabolites. The amplification pathway is characteristic of the prostate and hair follicle in which testosterone is converted by the type 2 5α reductase enzyme into the more potent androgen, dihydrotestosterone. This pathway produces local tissuebased enhancement of androgen action in specific tissues according to where this pathway is operative. The local amplification mechanism was the basis for the development of prostate-selective inhibitors of androgen action via 5α reductase inhibition, the forerunner being finasteride. The diversification pathway of testosterone action allows testosterone to modulate its biological effects via estrogenic effects that often differ from androgen receptor mediated effects. The diversification pathway, characteristic of bone and brain, involves the conversion of testosterone to estradiol by the enzyme aromatase which then interacts with the ERs α and/or β. Finally, the inactivation pathway occurs mainly in the liver with oxidation and conjugation to biologically inactive metabolites that are excreted by the liver into the bile and by the kidney into the urine. ginseng Panax (Chinese or Korean) ginseng is often proposed to increase maximal exercise capacity (VO2peak) and enhance performance [5–7]. In contrast, other research has failed to find an ergogenic effect following ginseng supplementation [10– 11]. The absence of compelling research demonstrating the ability of ginseng to consistently enhance physical performance in humans may be due to the variability in the quality of the supplement [1] and/or different methods of study. Interestingly, there is a lack of information regarding the effects of ginseng supplementation on young healthy adults. Such research is necessary given that much of the ginseng advertising campaign is directed at this demographic group. In fact, approxi- mately 40% of the 5 to 6 million Americans who are currently taking this supplement would be considered healthy young adults. Glutamine and improved muscle growth – Many studies have suggested that glutamine stimulates protein synthesis and inhibits protein breakdown in muscles. One of the mechanisms by which glutamine appears to exert its effects is by increasing cell volume. Glutamine taken up by the muscle cells acts to draw fluid into cells through an increase in intracellular osmolality. This may then promote muscle fiber growth via the stimulation of an enzyme called nitric-oxide synthase (in a similar way that a mechanical stretch influences gene expression). Shabert et al (1999) reported that glutamine supplementation was successfully able to reverse muscle mass loss in non-exercising HIV patients(10), while Rennie et al (1996) found evidence that the glutamine pool size may affect an osmotic signalling mechanism that regulates the whole body protein metabolism(11). Glutamine and improved glycogen synthesis – Replenishing muscle glycogen stores after training is another crucial factor in recovery and adaptation to exercise, and glutamine seems enhance this process. Perriello et al (1997) found that not only can glutamine itself be used as a substrate to synthesise glycogen (which is normally synthesised from glucose units contained in dietary carbohydrates) but also that glutamine can increase the process of gluceogenesis in the body (where glucose and therefore glycogen can be made from carbon fragments other than those derived from glucose)(12). Put simply, glutamine seems to both provide a source of glycogen and tell other cells in the body to make glycogen from fragments of other molecules – thus adding to the normal glycogen replenishment that occurs when post-exercise carbohydrate is consumed. Glutamine may do even more; Wagenmakers (1998) reported that glutamine may act to modify the ‘citric acid cycle’ (the main energy producing pathway or furnace in muscle mitochondria) in glycogen depleted muscle, by supplying fragments to the cycle, which in turn may enhance fatty acid oxidation(13)Anything that increases fatty acid burning should in theory at least help an athlete produce more energy and act to spare precious muscle glycogen.
