section 3 Flashcards
pharmacokinetic tolerance
REDUCED PLASMA CONCENTRATION OF THE
DRUG BECAUSE OF ENHANCED ENZYME
ACTIVITY & METABOLISM OF THE DRUG
pharmacodynamic tolerance
REDUCED RECEPTORS, RECEPTOR “DOWN
REGULATION”, OR ACTIVITY.
DESENSITIZATION.
- a phenomenon in which the body becomes less responsive to the effects of a drug over time. This occurs due to changes in the sensitivity of the receptors or signaling pathways targeted by the drug. As a result, higher doses of the drug may be required to achieve the same level of therapeutic effect that was initially obtained with lower doses.
- normally used receptors are recycled
- system is constantly turning over the receptors if drug intake is high and continuous
- receptor resynthesis will decrease
tolerance problems?
- more drugs needed (not so simple)
- toxicity and/or side effects risks increased
cross tolerance
tolerance to one drug may produce tolerance to similar drugs
- a phenomenon in which tolerance to one drug results in a reduced response to another drug, even if the second drug has a different chemical structure or mechanism of action. This occurs because the two drugs target the same receptors or signaling pathways in the body, leading to a shared tolerance.
- in order to see effect
- may cycle off drug
- take drug with different pharmacodynamics (different receptor), but same effect
history of drug testing
THE MOST COMMON METHODS OF DETECTING “DOPING” IN SPORT WAS
TO TEST A BIOLOGICAL FLUID FOR THE SPECIFIC (PRIMARILY ARTIFICIAL)
COMPOUND
* BUT WHAT HAPPENS WHEN THOSE COMPOUNDS LOOK LIKE (OR ARE)
BIOLOGICAL COMPOUNDS (E.G. RH-EPO, RH-HGH), OR PRODUCE EFFECTS
THAT LAST AFTER ELIMINATION OR DETECTION OF THE COMPOUND IS
POSSIBLE?
* WHAT HAPPENS TO THOSE ATHLETES WHO ARE GENETICALLY GIFTED?
* PROPOSED AND CREATED “LONGITUDINAL” TRACKING OF BIOMARKERS
ASSOCIATED WITH DOPING.
- In order to adapt to the ever-changing cold war/arms race of doping vs doping control, the
biological passport was developed.
“The fundamental principle of the Athlete Biological Passport (ABP) is to monitor selected
variables (`biomarkers of doping ́) over time that indirectly reveal the effect of doping, as
opposed to the traditional direct detection of doping by analytical doping controls.”
- WADA
haematological module
The haematological module refers to a set of tests and evaluations that are used to assess the blood and blood-forming tissues in the body. These tests can provide important information about a person’s overall health, as well as help diagnose and monitor certain medical conditions.
The haematological module typically includes a complete blood count (CBC), which measures the levels of various blood components, including red blood cells, white blood cells, and platelets.
steroidal module
The steroidal module refers to a set of tests and evaluations that are used to assess the levels of hormones in the body that are related to steroid metabolism. Steroid hormones are a class of hormones that are produced by the body’s adrenal glands and gonads and play important roles in a variety of physiological processes, including growth and development, metabolism, and immune function.
The steroidal module typically includes tests to measure the levels of hormones such as testosterone, estrogen, progesterone, cortisol, and aldosterone. These hormones can be measured in blood, urine, or saliva samples.
ABP versus normal doping control
ONE DOES NOT REPLACE THE OTHER
* NORMAL DOPING CONTROL AIMS TO DETECT PROHIBITED SUBSTANCES, METABOLITES, AND METHODS BUT IS LIMITED BY NEW SUBSTANCES, INTERMITTENT USE, AND LOW-DOSES.
- Remember, the aim of taking any drug is to elicit an EFFECT.
Normal Doping Control:
Looks for the drug and what the body does to the drug
Athlete Biologic Passport:
Looks for what the drug does to the
body
The world anti-doping agency (WADA)
“doping” originated from `dop’ refers to a stimulant drink used in tribal
ceremonies in South Africa during the eighteenth century
* 1968: The International Olympic Committee (IOC) publishes first banned list
of drugs for the 1968 Summer Olympics.
* 1999: WADA was established, after The First World Conference on Doping
in Sport held in Lausanne, Switzerland on February 2-4, 1999 to promote
and coordinate the fight against doping in sport internationally.
- the prohibited list
a mandatory International Standard as part of the World Anti-Doping Program.
* updated annually following an extensive consultation process facilitated by WADA.
* The effective date of the List is 01 January 2021.
the prohibited list
at all times :
S1 ANABOLIC AGENTS
S2 PEPTIDE HORMONES, GROWTH FACTORS, RELATED SUBSTANCES,
MIMETICS
S3 BETA-2 AGONISTS
S4 HORMONE AND METABOLIC MODULATORS
S5 DIURETICS AND MASKING AGENTS
M1/M2/M3 PROHIBITED METHODS** (BLOOD DOPING, GENE DOPING)
in competition:
S6 STIMULANTS
S7 NARCOTICS** (FENTANYL, HEROIN, ETC.)
S8 CANNABINOIDS
S9 GLUCOCORTICOIDS
P1 BETA-BLOCKERS
S2 peptide hormones, growth factors, related substances
major drugs: EPO, HGH (human growth hormone), IGF-1
-These substances are typically used to stimulate muscle growth, increase endurance, and improve recovery time.
- Substances that increase red blood cell count, blood oxygenation, or oxygen-carrying
capacity, and other drugs to treat anemia.
* Pituitary gland hormones, and many growth hormones, growth factors, and
hormone-releasing factors (sometimes called “secretagogues”) and any “other
growth factor or growth factor modulators affecting muscle, tendon, or ligament
protein synthesis/degradation, vascularization, energy utilization, regenerative
capacity or fiber type switching.
ERYTHROPOEITIN (EPO)
A protein hormone produced and released by the kidneys
*Binds to membrane spanning EPO receptor (EpoR), a
tyrosine kinase receptor
Major Roles:
* stimulates RBC formation – called secondary polycythemia
* can increase hematocrit and Hb by 4-11%, thereby
enhance ability to carry oxygen
- Exogenous Source:
* recombinant bioengineered agents EPOETIN ALFA
(epogen, procit): identical to endogenous EPO
* Or could use Epo mimetic peptides
T ½ = 6-140 h
(dependent on drug
brand)
Effects last ~2 weeks
EPO and Anemia
-treatment of anemia with EPO
due to inadequate kidney EPO
production = significant
hematocrit improvement
how does exercise effect epoetin alfa?
Exercise can stimulate the body’s production of erythropoietin (EPO), a hormone that regulates red blood cell production. When EPO levels increase, the bone marrow is stimulated to produce more red blood cells, which can improve oxygen delivery to the muscles during exercise.
In the context of using epoetin alfa, a synthetic form of EPO, in combination with exercise, the effects can be more pronounced than with exercise alone. Epoetin alfa can stimulate the production of red blood cells directly, bypassing the normal regulatory mechanisms that limit EPO production in response to exercise alone. This can lead to significant increases in red blood cell production and improved oxygen transport, resulting in improved endurance and athletic performance.
However, the use of epoetin alfa in this way is considered doping and is prohibited by anti-doping agencies due to the potential health risks associated with its use.
what effects does epoetin alfa have on normal EPO production?
Epoetin alfa is a synthetic form of erythropoietin (EPO) that is used to treat anemia in patients with kidney disease, cancer, or HIV. However, when used as a performance-enhancing drug, epoetin alfa can lead to abnormally high levels of red blood cells in the body, known as polycythemia. This can increase the risk of blood clots, stroke, and heart attack, and also suppress the body’s natural production of EPO, which can have long-term effects on the body’s ability to regulate red blood cell production. Therefore, the use of epoetin alfa is considered doping and is prohibited by anti-doping agencies.
EPO side effects
Primary unwanted effect is an increase in BP
Why?
* Raises blood viscosity (blood get thicker)
* Blood volume increases
* Reversal of hypoxia induced vasodilation
* Resistance to blood to flow increases that may
result in poorer perfusion
* Potential for thrombolytic effects (blood clots
because of thicker blood)
* Potential carcinogen (EPO is a cell proliferator and
may increase angiogenesis), but little data
growth hormone (somatotropin)
Human growth hormone (HGH) is a protein hormone that is naturally produced by the pituitary gland in the human body. It plays an important role in the growth and development of the body, particularly during childhood and adolescence
- multi-isoform protein
- regulating body growth
- enhances amino acid incorporation
- peripheral fat metabolism
- somatomedins
normal growth hormone isoform secretion over a day
Human growth hormone (GH) is secreted by the pituitary gland in short pulses throughout the day and night, with the majority of secretion occurring during deep sleep. The secretion of GH is regulated by a complex feedback loop that involves the hypothalamus and the pituitary gland.
The secretion pattern of GH follows a circadian rhythm, with the highest levels of GH being secreted during the first few hours of sleep. GH secretion is also influenced by other factors, such as exercise, stress, and nutrition.
