UNIVERSITY Contest Prep PEDs Fat Loss Agents: Part Clenbuterol Lesson Overview Contest Prep Fat Loss Agents PART THYROID HORMONES • PED deployment overview • Mechanism of action • How are thyroid hormones regulated • Symptoms of hypothyroidism and lab interpretation • Safety of use • Contest prep effects on thyroid • Thyroid protocols for contest prep PART CLENBUTEROL • Mechanism of action • Skeletal muscle anabolism • Clenbuterol as a fat loss agent • Managing clenbuterol side effects and safety • Clenbuterol protocol for contest prep PART YOHIMBINE HCl • Mechanism of action • Yohimbine impact on adipose and skeletal muscle • Caffeine synergy • Gender differences • Side effects and safety • Yohimbine protocol for contest prep • Summary of Fat loss Agent in Contest Prep • Timing of Compounds for Contest Prep Clenbuterol General Overview Anti-asthma medication, sympathomimetic Sympathetic nervous system contains main chemical signalers (epinephrine and norepinephrine) Increased during high stress Adrenal gland secretion increases cardiac output and glucose production Adrenergic Receptors Action mediated via adrenergic receptors (9 different types present) Alpha (1A, 1B, 1C), Alpha (2A, 2B, 2C), Beta (1,2,3) Beta (1) related to cardiovascular function and lipolysis Beta (2) actions in skeletal muscle anabolism (highest content in relation to other subunits) and adipose tissue lipolysis Beta (3) primarily in adipose tissue and stimulation increase lipolysis Clenbuterol Receptor Action Primary action of Clen is selective to the Beta receptors with some action on the B3 receptor Little beta activity making it favorable to reduce airway obstruction with lessen cardiac effects making it an effective bronchodilator Long half like of 34 hours, single daily dosing is effective Beta receptor stimulation directly on adipose tissue and liberalize fatty acids via increased in adenylyl cyclase leading to an increase in cyclic adenosine monophosphate and protein kinase A(PKA) This action is turning on the cell’s energy status pathway PPAR alpha activation and UCP1 increasing fatty acid oxidation Beta activation in decrease protein degradation and potential increase in protein synthesis Downregulation occurs quickly in skeletal muscle, but this does not mean a decrease in fatty acid oxidation Clenbuterol Skeletal Muscle Action mTOR activation mechanism Fasted administration of 80mcg of clenbuterol healthy men 21% increase in Resting energy expenditure and 39% increase in fat oxidation Phosphorylation of mTOR increased by 121% and PKA increased by 35% (Jessen 2020) Muscle/Fat Mass in Surrogate studies In protein deficient animals, clenbuterol treatment may help conserve body protein at the expense of fat In rats fed a normal (22% protein) diet, injection of clenbuterol (1 mg/kg/d for 21 d) (Rothwell 1987) resulted in a smaller but leaner body mass Strength in Humans Study in 20 healthy male patients Patients were treated with 40mcg of Clenbuterol drug or placebo for weeks postoperatively Muscle strength and cross-sectional area were determined before and after surgery (medial meniscectomy), Clenbuterol associated more rapid recovery in strength in knee extensor muscles (Maltin, 1993) Clenbuterol Skeletal Muscle Action Muscle Mass Humans Other agents in same class as clenbuterol have shown hypertrophy in humans Inhaled Terbutaline, 76 participants, weeks, (8x0.5mg) or placebo treatment w/o concurrent training, with resistance training, or with endurance training 3x per week Terbutaline increased lean body mass by 1.03kg and 1.04kg compared to the placebo in concurrent and resistance training group but not in the endurance group (Jessen, 2018) 71 patients, brachial plexus injuries given 60mcg Clen 2x per day or placebo months Effect on attenuating muscle atrophy Clen mitigated the decrease in cross sectional area of muscle fiber (Jiang 2011) Receptor Down Regulation After 18 days administration there was 50% downregulation in Beta-2 receptors and 80% decrease in blood flow in skeletal muscle However, a 5-fold increase in white and brown adipose tissue blood flow is seen Indicative chronic usage continues to increase lipolytic and thermogenic activity despite effects on skeletal muscle dissipating (Rothswell, 1987) Clenbuterol in Clinical Setting Clenbuterol is not approved for usage in the USA Clenbuterol is approved in Europe and Latin America world and has undergone human safety trials 20mcg tablets most common In asthma 20mcg twice per day is common (40mcg) , up to 40mcg twice per day (80mcg) Clenbuterol Side Effects CNS stimulation induced: Tremors • Increase is natural tremor of body and awareness occurs • Overstimulation of Beta receptor • Hypokalemia • Muscle Cramps associated with Clenbuterol via K depletion and cell volume shrinkage (Moratinos 1993) • B2 desensitization occurs rapidly and tremors resolve with normal usage • Clenbuterol for 18 days there was a 50% reduction in Beta2 density in muscle, explaining development of tolerance to tremors(Rothwell 1987) Insomnia Sweating Increased blood pressure Nausea Clenbuterol Side Effects Clen and the Heart Taurine depletion in heart, liver, and lung increase in muscle (rat studies with extreme doses 63-500mccg/kg) Taurine needed via antiarrhythmic, regulates ion flow, cardiotoxicity at lethal doses (Doheny 1998) Used in Congestive Heart Failure patients, 80mcg per day of Clen for 12 weeks, no effects on arrhythmia, increased lean/fat mass ratio, 27% increase in maximal strength, decrease in endurance “well tolerated in patients with CHF” 25x therapeutic dose has been shown cardiac recovery in left ventricular assist device support (Birks) Cardiac support at therapeutic doses, not reaching levels to support Taurine supplementation Deaths have occurred from high dosages of clenbuterol • Bodybuilder hospital admission cases studies have seen myocardial injury, tachycardia and death with dosages ranging up to 300 to 4500mcg per day (Spiller, 2013) Clenbuterol Protocol Consideration Timeline • Caloric restriction and expenditure is a first means to fat loss • Managing fatigue is high priority increased Stimulant fat agents can impeded sleep, which will impede recovery, muscle retention, and fat loss • Implement agents later stage of prep once cardio is high and food is low and need another tool to play Clenbuterol Dosing and Timing • 34-hour half life, stable levels with daily administration • Preferably first thing AM • Initiate 20mcg day, titrate dosage up as needed to 80mcg/day Discontinuing Usage • No taper is needed • days out remove to allow for fatigue management and enhanced sleep References: Clenbuterol Jiang GL, Gu YD, Zhang LY, Shen LY, Yu C, Xu JG Randomized, double-blind, and placebo-controlled trial of clenbuterol in denervated muscle atrophy ISRN Pharm 2011;2011:981254 doi: 10.5402/2011/981254 Epub 2011 Aug 15 PMID: 22389867; PMCID: PMC3263717 Spiller, Henry A.; James, Kyla J.; Scholzen, Steven; Borys, Douglas J (2013) A Descriptive Study of Adverse Events from Clenbuterol Misuse and Abuse for Weight Loss and Bodybuilding Substance Abuse, 34(3), 306–312.doi:10.1080/08897077.2013.772083 Rothwell NJ, Stock MJ Effect of a selective beta 2-adrenergic agonist (clenbuterol) on energy balance and body composition in normal and protein deficient rats Biosci Rep 1987 Dec;7(12):933-40 doi: 10.1007/BF01122126 PMID: 3453750 Rothwell NJ, Stock MJ, Sudera DK Changes in tissue blood flow and beta-receptor density of skeletal muscle in rats treated with the beta2-adrenoceptor agonist clenbuterol Br J Pharmacol 1987 Mar;90(3):601-7 doi: 10.1111/j.1476-5381.1987.tb11211.x PMID: 3032321; PMCID: PMC1917183 Jessen S, Solheim SA, Jacobson GA, Eibye K, Bangsbo J, Nordsborg NB, Hostrup M Beta2 -adrenergic agonist clenbuterol increases energy expenditure and fat oxidation, and induces mTOR phosphorylation in skeletal muscle of young healthy men Drug Test Anal 2020 May;12(5):610-618 doi: 10.1002/dta.2755 Epub 2020 Jan 19 PMID: 31887249 Maltin CA, Delday MI, Watson JS, Heys SD, Nevison IM, Ritchie IK, Gibson PH Clenbuterol, a betaadrenoceptor agonist, increases relative muscle strength in orthopaedic patients Clin Sci (Lond) 1993 Jun;84(6):651-4 doi: 10.1042/cs0840651 PMID: 8334811 Jessen S, Onslev J, Lemminger A, Backer V, Bangsbo J, Hostrup M Hypertrophic effect of inhaled beta2 -agonist with and without concurrent exercise training: A randomized controlled trial Scand J Med Sci Sports 2018 Oct;28(10):2114-2122 doi: 10.1111/sms.13221 Epub 2018 Jun PMID: 29777633 Moratinos J, Reverte M Effects of catecholamines on plasma potassium: the role of alpha- and betaadrenoceptors Fundam Clin Pharmacol 1993;7(3-4):143-53 doi: 10.1111/j.14728206.1993.tb00228.x PMID: 8388847 Doheny MH, Waterfield CJ, Timbrell JA The effects of the beta 2-agonist drug clenbuterol on taurine levels in heart and other tissues in the rat Amino Acids 1998;15(1-2):13-25 doi: 10.1007/BF01345277 PMID: 9871484 Kamalakkannan G, Petrilli CM, George I, LaManca J, McLaughlin BT, Shane E, Mancini DM, Maybaum S Clenbuterol increases lean muscle mass but not endurance in patients with chronic heart failure J Heart Lung Transplant 2008 Apr;27(4):457-61 doi: 10.1016/j.healun.2008.01.013 PMID: 18374884  ... atrophy ISRN Pharm 20 11 ;20 11:98 125 4 doi: 10.54 02/ 2011/98 125 4 Epub 20 11 Aug 15 PMID: 22 389867; PMCID: PMC 326 3717 Spiller, Henry A.; James, Kyla J.; Scholzen, Steven; Borys, Douglas J (20 13) A Descriptive... use • Contest prep effects on thyroid • Thyroid protocols for contest prep PART CLENBUTEROL • Mechanism of action • Skeletal muscle anabolism • Clenbuterol as a fat loss agent • Managing clenbuterol. .. training: A randomized controlled trial Scand J Med Sci Sports 20 18 Oct ;28 (10) :21 14 -21 22 doi: 10.1111/sms.1 322 1 Epub 20 18 Jun PMID: 29 777633 Moratinos J, Reverte M Effects of catecholamines on