History, Pharmacodynamics, Pharmacokinetics, and the Effects of Cocaine
Cocaine is a stimulant and psychoactive agent that users usually abuse for recreational purposes. According to Zyoud et al. (2017), the substance is commonly presented in its hydrochloride form as a white, water-soluble powder. It may be used orally, intravenously, or intranasally. The relatively pure formulations without hydrochloride portions are in crystalline form, called ‘crack’ or ‘freebase’ cocaine (Zyoud et al., 2017). There are also pharmaceutical preparations in countries that permit medicinal use, as a local anesthetic agent or for managing nosebleeds. Since cocaine is a highly addictive stimulant that contributes to a major global public health problem, it is important to understand its history and the pharmacodynamics and pharmacokinetics profile.
History
Although cocaine carries a dangerous and illicit drug connotation, its history indicates a substance that was commonly available to everyday users. Villa (2019) asserts that cocaine and products containing it were regularly sold at pharmacy stores at the turn of the twentieth century. The substance was a normal ingredient of medications, tonics, and health products. Biondich and Joslin (2016) assert that coca is an indigenous South American plant with numerous alkaloid properties. The most well-known psychoactive component is cocaine. Coca leaf products have been integral to the Andean people’s lives for thousands of years, from a cultural and traditional medicine viewpoint (Biondich & Joslin, 2016). The indigenous populations in the Andes Mountains’ highlands used cocaine for traditional purposes. Hence, the substance was not always recognized with its addictive and damaging drug profile as it is in modern America. Vila (2019) notes that Colombia, Peru, and Bolivia are the world’s biggest producers of coca because they primarily grow a viable variety of the plant.
Furthermore, Dr. Albert Nieman first isolated cocaine from leaves of cultivated coca in 1860 (Biondich & Joslin, 2016). Scientific literature indicates that E. coca var. coca, the most widely cultivated plant, contains approximately 0.6 percent cocaine in its dried leaves (Biondich & Joslin, 2016). An important point to note is that not all coca plant species contain enough of the alkaloid chemical component. Havakuk et al. (2017) add that the cocaine history in medicine traces back to the summer of 1884 when dissolved cocaine powder was applied to a frog’s cornea, which marked the birth of anesthesia. Chewed coca leaves were also used as a powerful stimulant or a spiritual communication instrument with the Gods, through the goddess of health and joy, Incan Kuka Moma, dating back to 2500 BC. Although there was delayed cocaine acceptance in European culture, the substance became popular once well-known physicians like Sigmund Freud admitted to its use and recommended it (Havakuk et al., 2017). However, the misconception on the non-prescription use culminated in the cocaine abuse that faces the world today.
Pharmacokinetics
Orally administered cocaine is absorbed well from the gastrointestinal tract (Coe et al., 2018). Besides, the substance is detectable within 30 minutes of administration and reaches peak plasma concentrations within 50 to 90 minutes. Coe et al.’s (2018) within-subject study to characterize the pharmacokinetics of oral cocaine also indicated that the concentration-time plots for the substance showed an absorption phase and a subsequent elimination stage. Hence, cocaine behaves as a high-extracting drug that undergoes first-pass intestinal and liver metabolism. The substance is absorbed from the gut and metabolized before reaching systemic circulation (Coe et al., 2018). Besides, the primary metabolites detected in plasma following administration were benzoylecgonine (BZE) and ecgonine methyl ester (EME). However, the study also showed the detection of minor metabolites like benzoylecgonine (BNE), p-hyrdoxybenzoylecgonine (p-HOBZE), and norcocaine (NCOC) in lower concentrations. The exposure to greater cocaine concentrations is likely to have saturated hepatic/intestinal metabolism, which allows a more unchanged substance to reach systemic circulation with increased administration exceeding 200 mg (Coe et al., 2018).
Additionally, the altered metabolism of cocaine can change its behavioral and toxic effects. Schindler and Goldberg (2012) assert that plasma butyrylcholinesterase (BChE) metabolizes cocaine to EME. Besides, tissue esterases and spontaneous conversion metabolize the substance to BZE. The CYP450 in the liver also minimally metabolizes norcocaine. Consequently, researchers believe any alteration in BChE activity might change the levels of cocaine in the body. The BChE enzyme occurs naturally in humans and can be used as the most direct approach to treating cocaine abuse. For instance, administering additional BChE potentially speeds the metabolism of the substance sufficiently to reduce its amount in the body and limit its entry into the brain (Schindler & Goldberg, 2012). Consequently, the added enzyme may decrease the behavioral and toxic effects of cocaine.
Pharmacodynamics
Increased extracellular dopamine levels in the forebrain mediate cocaine reinforcement (Goertz et al., 2014). Hence, the neurochemical effect represents a pharmacodynamics property of the substance and requires dopamine reuptake inhibition. Cocaine elicits motor activity and rapid elevation in dopamine levels, involving alpha-1 receptor activation in the ventral midbrain (Goertz et al., 2014). The a-1 activation entails decreased calcium-activated potassium channel current (SK) that heightens dopaminergic neuron burst firing. Besides, the modulation of SK and the hyperpolarization-activated cation currents also elevates dopaminergic neuron pacemaker firing. The increased background firing rate rose from a mean of 2.67 Hz+-0.24 to 3.75 Hz+-0.54, after pressure injection of the a-1 adrenergic receptors (Goertz et al., 2014). Hence, cocaine both blocks dopamine reuptake and increases dopamine levels and locomotor activity by activating the ventral midbrain a-1 adrenergic receptors. Genetic and pharmacological noradrenergic system manipulations show evidence of adrenergic signaling involvement in mediating psychostimulant behavioral effects.
Besides, cocaine is a local anesthetic (LA) agent that produces direct effects on cell membranes. According to Tikhonov ad Zhorov (2017), the LA mechanism involves blocking the voltage-gated sodium channels. Modulators often target the sodium channels by binding to distinct sites and act by different mechanisms. The LAs are flexible molecules containing a protonatable amino group at one end, an aromatic moiety at the opposite end, and polar groups in the middle (Tikhonov & Zhorov, 2017). The tonic and use-dependent block of sodium channels result from drug interaction with a receptor site that has diffusion pathways guarded by the position of channel activation and inactivation gates (Crumb & Clarkson, 1990). Therefore, the closure of activation gates prevents drugs from binding to the channel receptor because the gates prevent access to the receptor site through the hydrophilic and hydrophobic pathways. Thus, cocaine reduces cardiac sodium current like other LAs.
Effects
Havakuk et al. (2017) note that cocaine potentially causes acute sympathetic effects on the cardiovascular system. For instance, it might increase inotropic and chronotropic effects and cause increased peripheral vasoconstriction. Increased endothelin-1 levels and blockade of nitric oxide (NO) synthase affect the vasoconstrictive response (Havakuk et al., 2017). Besides, the sodium-channel-blocking effect of cocaine induces the vasoconstriction of specific arterial beds. Hence, the intake of the substance induces chronic hypertension among abusers of the drug. Furthermore, cocaine causes chest pain by inducing myocardial ischemia, including increased myocardial oxygen demand due to the heightened inotropic and chronotropic effect. The drug has a deleterious effect on the oxygen supply/demand balance, which explains the chest pain (Havakuk et al., 2017). Additionally, cocaine causes cardiac arrhythmias linked to heightened sympathetic tone. The induction of myocardial ischemia and prolonged cardiac repolarization enhances the sympathetic tone that induces ventricular ectopies and ventricular fibrillation. Cocaine inhibition of voltage-gated sodium channels reduces the rapid upstroke of the cardiac action potential (Havakuk et al., 2017). The drug also has sought-after effects like euphoria and sustained elevation of mood. Hence, abuse of the substance has multiple deleterious effects on the wellbeing of the abusers.
References
Biondich, A. S., & Joslin, J. D. (2016). Coca: the history and medical significance of an ancient Andean tradition. Emergency Medicine International, 2016.
Coe, M. A., Jufer Phipps, R. A., Cone, E. J., & Walsh, S. L. (2018). Bioavailability and pharmacokinetics of oral cocaine in humans. Journal of Analytical Toxicology, 42(5), 285-292.
Goertz, R. B., Wanat, M. J., Gomez, J. A., Brown, Z. J., Phillips, P. E., & Paladini, C. A. (2015). Cocaine Increases Dopaminergic Neuron and Motor Activity via Midbrain α 1 Adrenergic Signaling. Neuropsychopharmacology, 40(5), 1151-1162.
Havakuk, O., Rezkalla, S. H., & Kloner, R. A. (2017). The cardiovascular effects of cocaine. Journal of the American College of Cardiology, 70(1), 101-113.
Schindler, C. W., & Goldberg, S. R. (2012). Accelerating cocaine metabolism as an approach to the treatment of cocaine abuse and toxicity. Future Medicinal Chemistry, 4(2), 163-175.
Tikhonov, D. B., & Zhorov, B. S. (2017). Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants. Journal of General Physiology, 149(4), 465-481.
Villa, L. (2019, Nov. 1). The history of cocaine around the world and in the US. Recovery.org. https://www.recovery.org/cocaines/history/
Zyoud, S. E. H., Waring, W. S., Al-Jabi, S. W., & Sweileh, W. M. (2017). Global cocaine intoxication research trends during 1975-2015: a bibliometric analysis of Web of Science publications. Substance Abuse Treatment, Prevention, and Policy, 12(1), 6-6.