Running head: CARDIOVASCULAR EFFECTS OF DRUG

Cardiovascular Effects of Drug Use: Focusing on Recreational and Illicit Drugs Daniel Jones Skagit Valley College

CARDIOVASCULAR EFFECTS OF DRUG Abstract

Statistics show that 1 in 4 myocardial infarctions (MI), also known as heart attacks, in people between the ages of 18 and 45 can be linked to cocaine use (Qureshi, A., Suri, F., Guterman, L., & Hopkins, N., 2001). Cocaine is not the only illicit and recreational drug to have adverse affects on the cardiovascular system. The primary sources of data used for this study will be reports and studies completed in the health care field. The secondary source of data will be statistical data from local hospitals regarding cardiac complications in patients with documented drug use and history. This study should pull the various pieces together of the many non-associated studies into the subject. The selection of specific participants used in this study and the other studies examined are random. The control group for the study will be the statistical information regarding cardiac complications in individuals with no history of recreational drug use. The age group of the study is individuals between the ages of 18 and 45. The individuals examined come from all ethnic and socioeconomic groups. There is no disclosure of personal health care information and all patient information is held at the highest confidentiality.

CARDIOVASCULAR EFFECTS OF DRUG Cardiovascular Effects of Drug Use: Focusing on Recreational and Illicit Drugs I. Introduction According to the National Survey on Drug Use and Health (NSDUH),

approximately 21.8 million Americans, ages 12 or older, in 2009 consumed illicit drugs (Health, United States, 2010.) Of the 21.8 million illicit drug users, approximately 5.1 million in total used drugs other than marijuana (Health, United States, 2010). Statistics show that 1 in 4 myocardial infarctions (MI), also known as heart attacks, in people between the ages of 18 and 45 can be linked to cocaine use (Qureshi, A., Suri, F., Guterman, L., & Hopkins, N., 2001). Recreational and illicit drug use has a profound effect on the central nervous system but studies also show acute effects to the heart and circulation system. Drug-related morbidity has a strong link to their cardiovascular effects due to their significant and profound changes to the cardiovascular system. According to Paramedic Kelly Grayson (2011), most, if not all, emergency medical technicians (EMT), paramedics, nurses and physicians will likely encounter patients with cardiovascular complications related to illicit and recreational drug use. Medical professionals are required to have an awareness of the pathophysiological and pharmacological effects of these substances in order to diagnose the complications that are originated form their use. The purpose of the study is to show and educate the present and forthcoming facts and evidence of the link between recreational drug use and their effects on the cardiovascular system. The more that recreational drugs are used; therefore, recreational drugs will be linked to cardiovascular complications and disease.

CARDIOVASCULAR EFFECTS OF DRUG II. Methods

I carefully searched the MEDLINE, EMBASE, PROQUEST and EBSCOHOST databases for all relevant articles, published until July 2011, using the following keywords: marijuana, atrial fibrillation, arrhythmias, tachycardia, pcp, narcotic, inhalant, volatile substance, hallucinogen, palpitations, 'recreational drug', 'cocaine', 'khat', 'MDMA', 'stimulants', 'barbiturates', 'illicit drug', 'myocardial infarction', heart and cardiovascular. A manual search of reference lists from identified reports, to find additional sources, was also performed. Finally, I identified all relevant articles dealing with the cardiovascular effects and complications of recreational and illicit use. III. Medical Effects The majority of cardiovascular complications from drug use are from their sympathetic nervous system activation (Ghuran, A., Nolan, J., 2000). Sympathetic nervous system activation can cause vasoconstriction, tachycardia, arrhythmias and erratic and unpredictable blood pressure changes (Ghuran et al., 2000). Due to spiking catecholamine levels and sympathetic nervous system activation hypertension is very common, but hypotension is also possible (Delvin, R., Henry, J., 2008). Amphetamines are primarily responsible for myocardial infarction and ischemia, which is a result of increased oxygen requirement, thrombus formation and platelet aggregation from elevated catecholamine concentrations. Recreational and illicit drugs interact with various central nervous system neurotransmitters. A general understand of these neurotransmitters is required to understand how each drug effects the body and can have an effect on the cardiovascular system. The primary neurotransmitters are GABA, Glycine, Glutamate, Aspartate,

CARDIOVASCULAR EFFECTS OF DRUG 5 Acetylcholine, Catecholamines (Dopamine, Norepinephrine and Epinephrine) Serotonin, Histamine, Vasopressin, Oxytocin, Tachykinins, CCK, NPY, Neurotensin, Opiod peptides, Somatostatin and Purines (Goodman, L., Brunton, L., Chabner, B., Knollmann, B., 2008). GABA (-amino butyric acid) is the primary and major neurotransmitter with an inhibitory effect in the central nervous system (Goodman et al., 2008). GABA facilitates inhibitory actions of interneurons in the brain and presynaptic inhibition within the spinal cord (Goodman et al., 2008). GABA receptors are divided into 3 types, A, B and C. GABAA being the most important to this study as it is the most prominent subtype (Goodman et al., 2008). GABAA is a ligand gated Cl- ion channel, which is an inotropic receptor that opens after release of GABA by presynaptic neurons (Goodman et al., 2008). GABAA is the binding site of neuroactive drugs such as barbiturates, benzodiazepines, ethanol (alcohol), volatile anesthetics and anesthetic steroids (Goodman et al., 2008). Catecholamines are fight or flight hormones that are released by the adrenal glands (Goodman et al., 2008). There are three different hormones released by the adrenal glands (Goodman et al., 2008). Norepinephrine, sometimes called Noradrenaline, Epinephrine, also known as adrenaline, and dopamine all have strong links to stimulant use and have great effect on the cardiovascular system (Goodman et al., 2008). Dopamine is the most predominant catecholamine hormone constituting for over half its content. Within the CNS Dopamine plays a large part in the limbic zones of the cerebral cortex, which is responsible for controlling the autonomic nervous system and gives the high associated with many recreational drugs (Goodman et al., 2008). Dopamine

CARDIOVASCULAR EFFECTS OF DRUG 6 receptors have been linked to the pathophysiology of schizophrenia and Parkinsons disease (Goodman et al., 2008). Norepinephrine is mostly located in the hypothalamus and in specific zones of the limbic system, which include the central nucleus of the amygdala and dentate gyrus of the hippocampus. Norepinephrine has three different androgenic receptors (1, 2 and ) characterized by their pharmacologic properties and distribution (Goodman et al., 2008). adrenergic receptors are coupled to stimulation of adenylyl cyclase activity. 1 is primarily associated with neurons, where 2 are more characterized with vascular and glial elements and functions (Goodman et al., 2008). Epinephrine is found in the medullary reticular formation. Epinephrine makes connections on a restricted level to a few pontine and diencephalic nuclei. The physiological properties have yet to be identified for epinephrine. Serotonin (5-Hydroxytryptamine, 5-HT, 3-[-aminoethyl]-5-hydroxyindole) is found in enterochromaffin cells in the gastrointestinal (GI) tract, broadly throughout the central nervous system and in storage granules in platelets (Goodman et al., 2008). Serotonin, or 5-HT, is synthesized from tryptophan by a two-step process, which is then actively transported to the brain (Goodman et al., 2008). Serotonins cardiovascular system response is blood vessel contraction (Goodman et al., 2008). The blood vessel contraction is primarily in the pulmonary, renal, splanchnic and cerebral vasculatures (Goodman et al., 2008). Serotonin in increased levels can cause notable bradycardia and hypotension (Goodman et al., 2008).

CARDIOVASCULAR EFFECTS OF DRUG

Gilman Manual of Pharmacology and Therapeutics (2008) (p. 193)

Aggregation triggers the release of 5-HT stored in platelets. Local actions of 5-HT include feedback actions on platelets (shape change and accelerated aggregation) mediated by 5-HT2A receptors, stimulation of Nitric Oxide production mediated by 5-HT1-like receptors on vascular endothelium, and contraction of vascular smooth muscle mediated by 5-HT2A receptors. These influences act in concert with many other mediators (not shown) to promote thrombus formation and hemostasis (Goodman et al., 2008). IV. Recreational and Illicit Drugs The majority of recreational and illicit drugs have an effect on the cardiovascular system (Ghuran et al., 2000). Sedatives (Benzodiazepines, benzodiazepine agonists, barbiturates, alcohol, gammahydroxybutyrate, GBL, 1,4-butandiol), Stimulants (Amphetamines and cocaine), Narcotics (Full opiod agonists, partial, selective or mixed opiod agonists), Cannabis (delta-4-tetrahydrocannabinol and cannabidiol), Psychedelics (Phenethylamines, tryptamine and ergolines), Dissociative anesthetics (Phencyclidine (PCP), dextromethorphan and ketamine), Inhalants (Diethyl ether (starter fluid), chloroform, toluene, gasoline, glue, paint, xenon, cyclopropane, Freon, halothane,

CARDIOVASCULAR EFFECTS OF DRUG 8 sevoflurane, nitrous oxide, nitrites, isoamyl nitrite, isobutyl nitrite and Other (Salvinorin A (salvia divinorum), muscimol, nicotine, caffeine, methaqualone, khat, thalidomide, meprobamate, carisoprodol, glutethimide, chloral hydrate, ethchlorvynol, methyprylon and primidone) substances have direct (primary) and indirect (secondary) adverse effects on the cardiovascular system (Fallows, Z., 2009). i. Sedatives Sedative abuse is very common among recreational drug users. Medically, sedatives are normally prescribed and used to treat anxiety, insomnia, muscle tension, drug and alcohol withdraw, seizures and sometimes hypertension (high blood pressure) (Goodman et al., 2008). Sedatives, such as benzodiazepines and
Ashton, H., from http://www.benzo.org.uk/manual/bzcha01.htm

barbiturates, act at benzodiazepine receptors that are located closely to -aminobutyric acid (GABA1) receptors (Goodman et al., 2008). When benzodiazepines bind to the receptors (GABAA, GABAB and GABAC) are located on chloride ion channels at the inhibitory synapses within the central nervous system (CNS), which includes the reticular activating system (RAS).
1 GABA

CARDIOVASCULAR EFFECTS OF DRUG 9 receptors and the chloride channels open the chloride ions flow inward causing the neuronal membrane to hyperpolarize (Goodman et al., 2008). This causes a reduction in anxiety and wakefulness because benzodiazepines enhance the effects of GABA at their receptors (Goodman et al., 2008). Benzodiazepines primarily target the CNS and only have two effects that act on the peripheral nervous system (PNS) (Goodman et al., 2008). Coronary vasodilation, causing hypotension, observed after intravenous use and blockade of neuromuscular receptors, only seen in very high doses, are the only two PNS actions known of benzodiazepines (Goodman et al., 2008). Benzodiazepine, along with other narcotic analgesic and sedative, intoxication and withdraw can cause hypotension and bradycardia (Goodman et al., 2008). Adverse cardiovascular effects due to histamine release from mast cell degranulation can also induce cardiac arrhythmias including premature ventricular and atrial ectopic activity, idioventricular rhythms, atrial fibrillation and ventricular tachyarrhythmias (Ghuran, A., Nolan, J., 2000). Many of the sedatives are commonly taken intravenously which is known to cause cardiac complications such as bacterial endocarditis, which is sometimes associated with pulmonary abscesses (Goodman et al., 2008). Barbiturates, derivatives of 2,4,6-trioxohexahydropyrimidine, reversibly reduce the activity of all excitable tissues (Goodman et al., 2008). The action of barbiturates takes place by decreasing nerve impulses traveling to the cerebral cortex by potentiating gamma-aminobutyric acid (Lisanti, P., 1998). The mechanisms in which barbiturates act on GABAA receptors are markedly distinct from GABA or benzodiazepines (Goodman et al., 2008). Barbiturates promote with the binding of

CARDIOVASCULAR EFFECTS OF DRUG 10 benzodiazepines to GABAA receptors and potentiate GABA induced chloride by lengthening periods where bursts of channel opening occur instead of making bursts more frequent as of benzodiazepines (Goodman et al., 2008). Also, and subunits of the channel are required for barbiturate action unlike benzodiazepines (Goodman et al., 2008). Because of these actions, barbiturates produce depression of the CNS varying from mild sedation to anesthesia clinically (Goodman et al., 2008). Barbiturates normally cause bradycardia and hypotension due to their depression of the CNS (Goodman et al., 2008). In cases of barbiturate abuse and intoxication, mixed with alcohol, and overdose have caused cardiovascular collapse from extreme CNS depression (Goodman et al., 2008). Intravenous use of barbiturates has an increased incidence of ventricular arrhythmias, particularly, but not required, when epinephrine and halothane2 are present (Goodman et al., 2008). Serious and sometimes-extreme deficits in cardiovascular functions occur after acute barbiturate intoxication, which is why barbiturates have mostly been replaced by somewhat safer benzodiazepines (Goodman et al., 2008). ii. Stimulants Stimulant use is among the top of the list in recreational and illicit drug users. Most stimulants commonly abused have analogous adverse effects on the cardiovascular system (Ghuran et al., 2000). The majority of adverse effects of stimulants are related to sympathetic nervous system activation (Ghuran et al., 2000). Cocaine inhibits reuptake of norepinephrine and dopamine at sympathetic nervous 2 Volatile liquid anaesthetic that has growing levels of abuse as many barbiturates and benzodiazepines are increasing more difficult to obtain due to tighter drug control regulations.

CARDIOVASCULAR EFFECTS OF DRUG 11 system terminals as well as stimulating release of norepinephrine from the adrenal medulla oblongata (Goodman et al., 2008). Amphetamines, including methylenedioxymethamphetamine (MDMA), cause indirect activation of the sympathetic nervous system by releasing dopamine, norepinephrine and serotonin from central and autonomic nervous system (ANS) terminals (Goodman et al., 2008). The toxicity of amphetamines is exemplified when administered with alcohol (Ghuran et al., 2000). The sympathetic activation by both cocaine and amphetamines causes vasoconstriction, tachycardia, hypertension, hypotension and cardiac arrhythmias (Ghuran et al., 2000). Cocaine is also commonly known for causing myocardial infarction (Aslibekyan, S., Levitan, E., Mittleman, M., 2008). Cocaine can raise catecholamine levels as high as five times their normal level (Ghuran et al., 2000). At extremely high doses, cocaine impairs myocyte electrical activity as well as blocking fast sodium and potassium channels and inhibiting the entry of calcium into myocytes (Goodman et al., 2008). The serum halflife of cocaine is relatively short, being approximately 30-80 minutes (Goodman et al., 2008). Ninety percent of cocaine is metabolized and excreted in urine within two weeks (Goodman et al., 2008). The period of excretion provides a means of diagnosing recent ingestion in the hospital environment (Goodman et al., 2008). When cocaine is consumed alongside alcohol, a metabolite is formed called cocaethylene (Goodman et al., 2008). Cocaethylene is an extremely cardiotoxic metabolite that is much more toxic than its parent, cocaine (Goodman et al., 2008). A study also revealed that marijuana use with cocaine increases plasma cocaine levels and concentrations of the drug (Goodman et al., 2008).

CARDIOVASCULAR EFFECTS OF DRUG 12 Amphetamine and MDMA both produce indirect sympathetic activation by releasing norepinephrine, serotonin and dopamine from CNS and ANS terminals (Ghuran et al., 2000). Compared to cocaine, amphetamine inhibits monoamine oxidase and does not contain a local anaesthetic effect (Goodman et al., 2008). Alcohol potentiates amphetamine when taken concurrently with each other (Goodman et al., 2008). Ecstasy and amphetamine plasma half-life are similar, as ecstasy is a derivative of amphetamine (Goodman et al., 2008). iii. Narcotics (Opioid Analgesics) Opiod is a term that refers to all compounds that have a relation to opium, which is a derivative of the poppy (Goodman et al., 2008). The drugs that are derived from opium are opiates that include morphine, thebaine, codeine and a large amount of semi- and synthetic derivatives (Goodman et al., 2008). Opiates work by mimicking endogenous opiod peptides, also known as endorphins that are the naturally occurring ligands for opiod receptors (Goodman et al., 2008). Opiod receptors, or endogenous opiod receptors, have the known sensory role, which is inhibiting painful response from painful stimuli (Goodman et al., 2008). Opioids primarily act through three different receptor types. The three receptor types are the , and , which have been studied thoroughly (Goodman et al., 2008). Similar to morphine, the majority of clinical used opioids select receptors (Goodman et al., 2008). High doses possibly change the pharmacological profile of the opioid taken and become especially true when doses are increased to overcome tolerance, which is very common with recreational opioid use (Goodman et al., 2008).

CARDIOVASCULAR EFFECTS OF DRUG 13 Tolerance occurs when a decrease in effectiveness of a drug due to repeated administration (Goodman et al., 2008). Clinically used opiates exert themselves through the receptors affecting numerous systems (Goodman et al., 2008). The effects most commonly seen are alterations of respiratory, gastrointestinal, neuroendocrine and cardiovascular system function (Goodman et al., 2008). Morphine-like opioids produce many CNS effects as well (Goodman et al., 2008). The effects most likely encountered are drowsiness, analgesia, mental clouding and mood changes (Goodman et al., 2008). In addition to these effects, euphoria is commonly reported which is one of the factors that make opioids a commonly abused recreational and illicit drug (Goodman et al., 2008). As doses increase the effects of the drugs increase including respiratory and cardiovascular depression (Goodman et al., 2008). The specific cardiovascular effects of opioids vary according to the dose taken. When a patient or user is supine, the majority of cardiovascular effects of opioids are negligible (Rea, R., Thames, M., 1993). Orthostatic hypotension and fainting generally occur when a supine patient assumes the upright position (Rea et al., 1993). Much of these effects are provoked by the concurrent release of histamine when taking opioids (Rea et al., 1993). Goodman & Gilmans Manual of Pharmacology and Therapeutics (2008) shows that: Effects on the myocardium are not significant in normal individuals. In patients with coronary artery disease but no acute medical problems, 815 mg morphine administered intravenously produces a decrease in oxygen consumption, left ventricular end-diastolic pressure, and cardiac work; effects on cardiac index

CARDIOVASCULAR EFFECTS OF DRUG usually are slight. In patients with acute myocardial infarction, the

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cardiovascular responses to morphine may be more variable than in normal subjects, and hypotension may be more pronounced. Morphine may exert its well-known therapeutic effect in the treatment of angina pectoris and acute myocardial infarction by decreasing preload, inotropy, and chronotropy, thus favorably altering determinants of myocardial O2 consumption and helping to relieve ischemia. Morphine can mimic the phenomenon of ischemic preconditioning, where a short ischemic episode paradoxically protects the heart against further ischemia. This effect appears to be mediated by d receptor modulation of a mitochondrial ATP-sensitive K+ channel in cardiac myocytes. Morphine-like opioids should be used with caution in patients who have a decreased blood volume because the drugs can aggravate hypovolemic shock. Morphine should be used with great care in patients with cor pulmonale because deaths after ordinary therapeutic doses have been reported. The concurrent use of certain phenothiazines may increase the risk of morphine-induced hypotension. (p. 355) iv. Ethanol (Alcohol) Ethanol is a sedative and CNS depressant but has a different structure and action than the pharmacological sedatives listed earlier (Goodman et al., 2008). Ethanol is the only legal, non-prescription recreational drug that is as widely accepted and as much of a societal problem as it is. The disturbance between the inhibitory and excitatory influences in the brain causing disinhibition, sedation and ataxia are some of

CARDIOVASCULAR EFFECTS OF DRUG 15 the adverse effects of ethanol (Goodman et al., 2008). Unlike most drugs, exceedingly large amounts of ethanol are required to cause physiological effects (Goodman et al., 2008). Studies regarding the epidemiology of alcohol consumption show that 20-30 grams ethanol/day confers a cardioprotective effect (Goodman et al., 2008). Paradoxically consumption of larger amounts of alcohol daily infer a much greater and increased risk of cardiovascular failure including, cardiomyopathy, arrhythmias and stroke (hemorrhagic) (Whicker, S., Sayer, G., Saltman, D., 2006). Large amounts of alcohol use can cause hypertension by raising diastolic and systolic blood pressure (Goodman et al., 2008). Ethanol causes numerous effects pharmacologically on cardiac conduction, which includes sympathetic stimulation and ventricular repolarization (Goodman et al., 2008). The ventricular repolarization is indicated by a prolonged QT interval (Goodman et al., 2008). Goodman & Gilmans Manual of Pharmacology and Therapeutics (2008) shows that: Atrial arrhythmias associated with chronic alcohol use include supraventricular tachycardia, atrial fibrillation, and atrial flutter. Some 1520% of idiopathic cases of atrial fibrillation may be induced by chronic ethanol use. Ventricular tachycardia may be responsible for the increased risk of unexplained sudden death that has been observed in persons who are alcohol-dependent. During continued alcohol use, treatment of these arrhythmias may be more resistant to cardioversion, digoxin, or Ca2+-channel blocking agents. (p. 376)

CARDIOVASCULAR EFFECTS OF DRUG 16 Alcohol is known to cause cardiomyopathy by having a toxic dose-related effect on cardiac and skeletal muscles (Goodman et al., 2008). Various studies show the depression of cardiac contractility by alcohol, which leads to cardiomyopathy (Goodman et al., 2008). Statistics show that half or more of patients with idiopathic cardiomyopathy are alcohol dependent (Goodman et al., 2008). 40-50% of all patients with cardiomyopathy that is ethanol/alcohol induced will die within 3-5 years as an effect of their alcohol dependence (Goodman et al., 2008). v. Cannabis and Khat Cannabis, also known as Marijuana, is the 2nd most used drug in America right behind ethanol (Health, United States, CDC, 2010). -9-tetrahydrocannabinol (THC) is the primary psychoactive chemical in cannabis. (Ghuran et al., 2000) THC is only one of 61 cannabinoids and approximately 340 other chemical compounds in cannabis not including the same carbon monoxide, tars, carcinogens and irritants found in tobacco smoke (Hall, W., Solowij, N., 1998). The action of THC is on at least two types of cannabinoid receptors, CB1 and CB2. CB1 receptors are primarily present in the cognitive, memory, reward, anxiety, pain, endocrine function, sensory perception and motor co-ordination regions of the brain (Goodman et al., 2008). CB2 can be found in the spleen and other tissues and can possibly but culprit for the immunosuppressive activities of cannabis (Goodman et al., 2008). Outside of the psychoactive effects of cannabis it also has cardiovascular and respiratory effects that can be notable (Hall, W., Solowij, N., 1998). The cardiovascular effects of cannabis have a biphasic effect based off of dose taken (Ghuran et al., 2000). Cannabis in acute doses is responsible for tachycardia and

CARDIOVASCULAR EFFECTS OF DRUG 17 vasodilation resulting in hypotension and increased core temperature (Ghuran et al., 2000). The cardiac output due to the effects of cannabis has been noted to increase as high as 30%, which is normally accompanied by and increased cardiac work and O2 demand (Goodman et al., 2008). At higher doses the actions of cannabis reverse commonly causing bradycardia and hypotension (Caldicott, D., Holmes, J., RobertsThompson, K., Mahar, L., 2005). Along with these higher dose effects there have been ECG abnormalities affecting the P & T waves as well as the ST segment (Goodman et al., 2008). The onset of the physiological effects of cannabis is seen very shortly after absorption (Hall, W., Solowij, N., 1998). The plasma half-life of cannabis is between 20-30 hours (Goodman et al., 2008). Catha edulis, also known more commonly as khat, is one of the more common and popular drugs in the Arabian Peninsula and horn of Africa (Al-Motarreb, A., Al-Kebsi, M., Al-Adhi, B., Broadley, K., 2002). It is estimated that there are between 5-10 million khat users in the world (Al-Motarreb et al., 2002). Khat has various pharmacologically active constituents but S-(-)-Cathinone [S-(-)-aminopropiophenone] is the most significant (Widler, P., Mathys, K., Brenneisen, R., Kalix, P., Fisch, H., 1994). Cathinone is an alkaloid that is closely related to amphetamines, which raises concern for cardiovascular complications (Wilder et al., 1994). Much of these complications are caused by marked hypertension due to cathinone metabolizing into norephedrine and norpseudoephedrine (Apps, A., Matloob, S., Dahdal, M., Dubrey, S., 2011). There have been reported cases of khat use linked with myocardial infarction and ischemia (Al-Motarreb et al., 2002). vi. Psychedelics

CARDIOVASCULAR EFFECTS OF DRUG 18 Lysergic acid diethylamide (LSD) and psilocybin (Shrooms) are the primary recreationally used psychedelics (Ghuran et al., 2000). Both LSD and psilocybin chemically resemble serotonin so their actions are similar (Ghuran et al., 2000). LSD is an ergot alkaloid that is a nonselective 5-HT agonist (Goodman et al., 2008). LSD primarily acts through the 5-HT2 receptors inhibiting the firing of raphe neurons (5-HT) (Goodman et al., 2008). The cardiovascular effects of LSD can include increased pulse and hypertension (Ghuran et al., 2000). Serotonin abnormalities may result in atypical clotting and reduced clot retraction (Goodman et al., 2008). Although rare, myocardial infarction and supraventricular tachyarrhythmias have occurred as a result of LSD use (Ghuran et al., 2000). vii. Dissociative anesthetics Phencyclidine (PCP) and Ketamine and are the primary dissociate anesthetics abused (Goodman et al., 2008). Ketamine clinically is used for conscious sedation and anesthesia and has some very unique properties (Goodman et al., 2008). Ketamine is in the same drug class as phencyclidine (PCP) and is water-soluble (Goodman et al., 2008). Administration and induction of ketamine normally causes hypertension, tachycardia and an increase in cardiac output (Goodman et al., 2008). These cardiovascular effects are most likely due to the inhibition of central and peripheral catecholamine reuptake making this an indirect effect (Goodman et al., 2008). Ketamine does have direct adverse cardiovascular effects including inotropic and vasodilation activity (Goodman et al., 2008). Ketamine also increases myocardial O2 consumption that can cause severe cardiac complications in users with myocardial ischemia (Goodman et al., 2008).

CARDIOVASCULAR EFFECTS OF DRUG viii. Inhalants or Volatile Substances

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Recreationally used inhaled substances are common among adolescents and non-selective drug seekers (Ghuran et al., 2000). These volatile substances are normally cheap, legal and can easily be obtained which make this very concerning and hard to control (Ghuran et al., 2000). Varied and extremely detrimental cardiovascular effects can occur from inhalant use, including sudden death (Ghuran et al., 2000). Tachyarrhythmias from sympathetic nervous system activation are a common occurrence from volatile substance use (Ghuran et al., 2000). Myocardial sensitivity to circulating catecholamines may also cause lethal tachyarrhythmias (Ghuran et al., 2000). Some of the notable cardiovascular complications from volatile substances include bradyarrhythmias, supraventricular arrhythmias, ventricular arrhythmias, hypotension, cardiac ischemia and cardiomyopathy (Ghuran et al., 2000). ix. Synthetics and Analogues Spice, K2 and bath salts are among the top of the list of the most popular legal drugs available on the street (HDAP, 2011; Office of, 2011). Spice and K2 are synthetic cannabinoids, which belong in the same drug class as cannabis (HDAP, 2011). Bath Salts are a stimulant being sold as a legal cocaine and ecstasy substitute that contains Methylenedioxypyrovalerone (MPDV), which is also known as mephedrone (Wehman, J., 2011; OMalley, P., 2011). MPDV has no known clinical medical value therefore information is extremely limited on its pharmacodynamic, pharmokinetic and pharmacological properties (OMalley, P., 2011). Spice being like cannabis has many similar effects. One frightening difference between spice and cannabis is that the potency has been found to be upwards

CARDIOVASCULAR EFFECTS OF DRUG 20 of 5 times more potent than the strongest marijuana (HDAP, 2011). The effects of the synthetic cannabinoids have not been fully tested yet but many adverse effects have been seen. Spice has been associated with adverse effects such as heart palpitations, respiratory complications, paranoia and aggression (HDAP, 2011). V. Statistics Drug use and abuse is growing in massive proportions from year to year and is causing an overwhelming and increasing workload on emergency rooms and prehospital providers around the globe. The Drug Abuse Warning Network (DAWN) monitors drug-related emergency room/department visits and deaths as a public health surveillance system in order to track the impact of drug use in the United States. Each year data is compiled from hospitals across the country about drug-related emergency department visits and death and made available to the public.

DAWN Drug Related ED Visits

2,500,000 Annual Estimated Visits 2,000,000 1,500,000 1,000,000 500,000 0 Total ED Visits Estimates 2004 Estimates 2005 Estimates 2006 Estimates 2007 Estimates 2008 Estimates 2009 1,619,054 1,616,311 1,742,887 1,883,272 1,999,861 2,070,439

According to the National Survey on Drug Use and Health (NSDUH), approximately 21.8 million Americans, ages 12 or older, in 2009 consumed illicit drugs (Health, United

CARDIOVASCULAR EFFECTS OF DRUG 21 States, 2010.) Of the 21.8 million illicit drug users, approximately 5.1 million in total used drugs other than marijuana (Health, United States, 2010). Between 2004 and 2009 there have been a staggering 10,931,824 drug-related ED visits (DAWN, 2009). Not all of these drugrelated have cardiovascular complications associated with them. Of these 10.9 million visits 3.7 million can alone be contributed to alcohol consumption, which is commonly in combination with other recreational drugs (DAWN, 2009). Statistics show that 1 in 4 myocardial infarctions (MI), also known as heart attacks, in people between the ages of 18 and 45 can be linked to cocaine use (Qureshi, A., Suri, F., Guterman, L., & Hopkins, N., 2001). A total of 2.966,511 visits can be attributed to cocaine use that means nearly 741,627 of those cocaine related visits had a non-fatal myocardial infarction (DAWN, 2009). Dependence of the various recreational and illicit drugs is a contributing factor to cardiovascular complications (DAWN, 2009).

Goodman and Gilmans 2008 VI. Conclusion

CARDIOVASCULAR EFFECTS OF DRUG 22 Recreational and illicit drug use across the board has some varying effect on the cardiovascular system. More information and studies are required to find definitive links to some drugs and their cardiovascular effects, such as marijuana, but evidence does exist that even the drugs viewed as harmless are far from it. Every year there is an increasing number of prehospital and emergency room cases showing and linking cardiovascular complications to drug use. Cardiovascular effects are not the only concern of recreational and illicit drugs but ranks high on the list.

CARDIOVASCULAR EFFECTS OF DRUG References

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Al-Motarreb, A., Al-Kebsi, M., Al-Adhi, B., Broadley, K. (2002). Khat Chewing and Acute Myocardial Infarction. Heart. 87(3). 279-280. Aryana, A., Williams, M. (2007). Marijuana as a Trigger of Cardiovascular Events: Speculation or Scientific Certainty?. International Journal of Cardiology. 118(2). 141-144. Ashton, C. (1999). Adverse effects of cannabis and cannabinoids. British Journal of Anaesthesia. 83. 637-649. Ashton, H. (n.d.). benzo.org.uk : Benzodiazepines: How They Work & How to Withdraw, Prof C H Ashton DM, FRCP, 2002. Welcome to benzo.org.uk. Retrieved August 25, 2011, from http://www.benzo.org.uk/manual/bzcha01.htm Aslibekyan, S., Levitan, E. B., Mittleman, M. A. (2008). Prevalent Cocaine Use and Myocardial Infarction. American Journal of Cardiology, 102(8), 966-969. Butt, A., Xiaoqiang, W., Budoff, M., Leaf, D., Kuller, L., Justice, A. (2009). Hepatitis C Virus Infection and the Risk of Coronary Disease. Clinical Infectious Diseases. 49(2). 225-232. Caffeine/ephedrine :Fatal cardiovascular disorder: case report. (2010). Reactions Weekly. 1315. 16. Caldicott, D., Holmes, J., Roberts-Thompson, K., Mahar, L. (2005). Keep Off the Grass: Marijuana Use and Acute Cardiovascular Events. European Journal of Emergency Medicine. 12(5). 236-244. Charles, R., Holt, S., Kirkham, N. (1979). Myocardial Infarction and Marijuana. Clinical Toxicology. 14. 433-438. Collins, J., Higginson, J., Boyle, D., Webb, S. (1985). Myocardial Infarction During Marijuana Smoking in a Young Female. European Heart Journal. 6. 637-638.

CARDIOVASCULAR EFFECTS OF DRUG 24 Comolli, J. (2000). Facts About Drug Abuse and Hepatitis C. NIDA Notes, 15(1). Retrieved July 13, 2011, from http://archives.drugabuse.gov/nida_notes/nnvol15n1/tearoff.html Delvin, R. J., & Henry, J. A. (n.d.). Clinical review: Major consequences of illicit drug consumption. Critical Care. 202. European Society of Cardiology. (2010). Sudden death in cocaine abusers: Study reveals the role played by the illegal drug. Cardiovascular Week. 384. Fallows, Z. (2009). Drug Misuse Chart. MedLinks: Students Promoting Health at MIT. 1, 1-6. Ghuran, A. (2000). The cardiac complications of recreational drug use. Western Journal of Medicine. 173. 412-415. Ghuran, A., Nolan, J. (2000). Recreational drug misuse: issues for the cardiologist. Heart. 83. 627-633. Ghuran, A., Nolan, J., & der Wicken, L. v. (2001). Cardiovascular Complications of Recreational Drugs. BMJ, 323, 464-466. Goodman, L. S., Gilman, A., Hardman, J. G., Gilman, A. G., & Limbird, L. E. (2008). Goodman & Gilman's Manual of Pharmacology and Theraputics (11th ed.). New York: McGraw- Hill, Health Professions Division. Gotway, M. B., Marder, S. R., Hanks, D. K., Leung, J. W. T., Da wn, S. K., Gean, A. D., Reddy, G. P., Araoz, P. A., Webb, R. W. (2002). Thoracic Complications of Illicit Drug Use: An Organ System Approach. RadioGraphics. 22. S119-S135. Hagan, I. G., Burney, K. (2007). Radiology of Recreational Drug Abuse. RadioGraphics. 27. 919-940. Hall, W., & Degenhardt, L.. (2009). Adverse health effects of non-medical cannabis use. The Lancet. 374(9698), 1383-1391.

CARDIOVASCULAR EFFECTS OF DRUG 25 HDAP - Comprehensive Drug Information on Spice and K2 (Synthetic Cannabinoids). (n.d.). Hunterdon Drug Awareness Program - Substance Abuse Counseling and Prevention Education. Retrieved August 8, 2011, from http://www.hdap.org/spice.html Higgins, J., Tuttle, T., & Higgins, C.. (2010). Energy Beverages: Content and Safety. Mayo Clinic Proceedings, 85(11), 1033-1041. Irvine, R. J., Toop, N. P., Phillis, B. D., Lewanowitsch, T. (2001). The acute cardiovascular effects of 3,4-methylenedioxymethamphetamine (MDMA) and p-methoxyamphetamine (PMA). Addiction Biology. 6. 45-54. Kaiser Permanente. (2010). Coffee Drinking and Caffeine Associated With Reduced Risk of Hospitalization for Heart Rhythm Disturbances. Cardiovascular Week. 119. Korantzopoulus, P., Liu, T., Papaioannides, D., Goudevenos, J. (2007). Atrial Fibrillation and Marijuana Smoking. Institutional Journal of Clinical Practice. 62(2). 308-313. Lidder, S., Dargan, P., Sexton, M., Button, J., Ramsey, J., Holt, D., & Wood, D.. (2008). Cardiovascular Toxicity Associated with Recreational Use of Diphenylprolinol (diphenyl-2-pyrrolidinemethanol [D2PM]). Journal of Medical Toxicology. 4(3). 167169. Minor, R. L., Scott B. D., Brown D. D., et al. (1991). Cocaine-induced myocardial infarction in patients with normal coronary arteries. Annual of Internal Medicine. 107. 13-18. Office of National Drug Control Policy -- Press Release -- February 1, 2011. (n.d.). Office of National Drug Control Policy. Retrieved August 7, 2011, from http://www.whitehousedrugpolicy.gov/news/press11/020111.html

CARDIOVASCULAR EFFECTS OF DRUG 26 Puddey, I. B., Rakic, V., Dimmitt, S. B., Beilin, L. J. (1999). Influence of pattern of drinking on cardiovascular disease and cardiovascular risk factors--a review. Addiction. 94(5). 649663. OMalley, P. (2011). The Worldwide Designer Drug Craze: Bath Salts Behind the Counter to Get High: Update for the Clinical Nurse Specialist. Clinical Nurse Specialist. 224-225. Qureshi, A., Suri, F., Guterman, L., & Hopkins, N. (2001). Cocaine Use and the Likelihood of Nonfatal Myocardial Infarction and Stroke: Data From the Third National Health and Nutrition Examination Survey. Circulation, 1, 1-6. Restrepo, C., Rojas, C., Martinez, S., Riascos, R., Marmol-velez, A., Carrillo, J., & Vargas, D.. (2009). Cardiovascular complications of cocaine: Imaging findings. Emergency Radiology. 16(1), 11-9. Rezkalla, S., Sharma, P., Kloner, R. (2003). Coronary No-Flow and Ventricular Tachycardia Associated with Habitual Marijuana Use. Annals of Emergency Medicine. 42(3). 365369. Rodondi, N., Pletcher, M. J., Liu, K., Hulley, S. B., Sidney, S. (2006). Marijuana Use, Diet, Body Mass Index, and Cardiovascular Risk Factors (from the CARDIA Study). The American Journal of Cardiology. 98(4). 478-484. Saudi, J. (2005). Blood Pressure; Beta-1 Adrenoreceptor Blockade Mediates the Cardiovascular Effects of Khat Chewing. Cardiovascular Week. July 25, 2005. 51. Shechter, M., Shalmon, G., Scheinowitz, M., Koren-Morag, N., Feinberg, M., Harats, D., Sela, B., Sharabi, Y., & Chouraqui, P.. (2011). Impact of Acute Caffeine Ingestion on Endothelial Function in Subjects With and Without Coronary Artery Disease. The American Journal of Cardiology, 107(9), 1255-1261.

CARDIOVASCULAR EFFECTS OF DRUG 27 Thapa, P. B., Walton, M. R., Cunningham, R., Maio, R. F., Savary, P. E., Booth, B. M. (2008). Longitudinal Substance Use Following An Emergency Department Visit For CocaineAssociated Chest Pain. The Journal of Drug Issues. 38(4). 929-956. Hall, W., Degenhardt, L. (2009). Adverse health effects of non-medical cannabis use. The Lancet. 374. 1383-1391. Hall, W., Solowij, N. (1998). Adverse effects of cannabis. The Lancet. 352. 1611-1616. Whicker, S., Sayer, G., Saltman, D. (2006). Substance abuse and other comorbidities management in Australian general practice. Australian Family Physician. 35(3). 169-71. Widler, P., Mathys, K., Brenneisen, R., Kalix, P., Fisch, H. (1993). Pharmacodynamics and pharmacokinetics of khat: A controlled study. Clinical Pharmacology & Therapeutics. 55(5). 556-562.