Cocaine - Substances of Dependence and Abuse

Cocaine

Source

Cocaine (“coke” or “snow”) is a natural alkaloid present in the leaves of the coca plant, i.e., Erythroxylon coca (Fig 34.7), a shrub that grows well in South America, Mexico, Indonesia, and West Indies. Chemically, cocaine is benzoylmethylecgo-nine, and belongs to the tropane family of natural alkaloids, other members of which include atropine and scopolamine. It occurs as colourless to white crystals, or white crystalline powder (Fig 34.8).

Mode of Intake

Cocaine is usually abused by either chewing coca leaves, smoking coca paste, or “snorting” cocaine hydrochloride. The last mentioned is the most popular form of cocaine intake, i.e. the drug is inhaled in powder form through the nostrils. Occasionally, cocaine hydrochloride is injected intravenously. Today, a smokable form of cocaine (“crack” or “rock”) has virtually become a rage in the West. Pure alkaloidal cocaine (“free-base” or “baseball”) can also be smoked. Occasionally coca paste or cocaine sulfate (cocaine base, “pasta”, “bazooka”) is smoked. Cocaine freebase is prepared from cocaine hydro-chloride by extracting the cocaine with an alkaline solution (buffered ammonia) and adding a solvent such as ether or acetone. The mixture separates into two layers, the top solvent layer containing the dissolved cocaine. The solvent is then evaporated leaving almost pure cocaine crystals. “Free-base” is a colourless, odourless, transparent, crystalline substance that makes a popping or cracking sound when heated (hence the term “crack”). Both free-base and crack are more stable to pyrolysis than the hydrochloride salt, and therefore can be smoked either using a “coke pipe” or mixed into a cigarette (“joint”). A solution of cocaine hydrochloride can also be heated in a pan with baking soda added until a solid “rock” is formed, pieces of which can be smoked directly.

Street cocaine is often impure. The content of pure cocaine ranges from 10 to 50 per cent (most commonly 15 to 20 per cent). Cocaine which is available on the street is often adul-terated with one or more of the following compounds: talc, lactose, sucrose, glucose, mannitol, inositol, caffeine, procaine, phencyclidine, lignocaine, strychnine, amphetamine, or heroin (“speed ball”). Crack cocaine adulterated with phenytoin (in order to lower cost or increase potency) has resulted in pheny-toin toxicity in some patients.

Uses

■■   Topical anaesthetic (4 to 10% solution) for intranasal and bronchoscopic procedures.

■■   Ophthalmologic anaesthesia.

■■   Relief of severe (oncologic) pain: Cocaine is one compo-nent of Brompton’s cocktail, (the others being morphine, chlorpromazine, and alcohol), which is popular in Europe for the control of intractable pain associated with some forms of cancer.

■■   Cocaine is one of the components of TAC (the others being tetracaine and adrenaline) which is sometimes used as a topical anaesthetic in children with scalp and facial lacerations.

Mode of Action

CNS:

o     Cocaine is the most powerful naturally derived CNS stimulant known to man. Stimulation of the brain occurs in a rostral-to-caudal fashion. The cortex is stimulated first resulting in excitement, restlessness, and increased motor activity. Subsequent stimulation of lower motor centres produces tonic-clonic convulsions. The medulla is at first stimulated resulting in an initial increased respiratory rate, followed by depression with resultant respiratory failure.

o     The CNS stimulant effects of cocaine are mediated through inhibition of dopamine reuptake in the nucleus accumbens. A recent study affirms the central importance of the dopamine-reuptake transporter in the behavioural and biochemical action of cocaine and defines it as a site on which efforts to develop an anti-cocaine medication should be focused. The dopamine-reuptake transporter controls the levels of dopamine in the synapse by rapidly carrying the neurotransmitter back into nerve terminals after its release. Cocaine, which binds strongly to the dopamine-reuptake transporter, is a classic blocker of such reuptake after normal neuronal activity. Because of this blocking effect, dopamine remains at high concentrations in the synapse and continues to affect adjacent neurons producing the characteristic cocaine “high”.

o     Cocaine also increases the concentrations of the excitatory amino acids, aspartate and glutamate in the nucleus accumbens. These excitatory amino acids increase the extracellular concentrations of dopamine. Excitatory amino acid antagonists attenuate the effects of cocaine induced convulsions and death. Dopamine₂ (D₂) receptor agonists accentuate cocaine craving, while dopmanie₁ (D₁) agonists diminish such craving.

o     Cocaine also inhibits reuptake of noradrenaline and serotonin. Increase in the concentrations of the former plays an important role in the toxic effects of cocaine.

Peripheral nerves: Through direct blockade of fast sodium channels, cocaine stabilises the axonal membrane, producing a local anaesthetic effect. Cocaine is the only local anaesthetic that interferes with the uptake of neuro-transmitter by the nerve terminals and simultaneously functions as a vasoconstrictor.

CVS:

o     Initial effect of cocaine on the CVS is bradycardia, secondary to stimulation of vagal nuclei. However, the bradycardia is too transient to be clinically evident, and tachycardia becomes the prominent effect resulting from central sympathetic stimulation.

o     Cocaine produces blockade of fast sodium channels on myocardial tissue, imparting type I antiarrhythmic properties. The cardiostimulatory effect of cocaine is due in large part to sensitisation to adrenaline and noradrenaline, preventing neuronal reuptake of these catecholamines, as well as due to increased release of noradrenaline from adrenergic nerve terminals. The increased concentrations and persistence of catechola-mines near the receptors of the effector organ lead to exaggerated sympathetic effects.

o     Studies have revealed that the peak vasopressor effects of cocaine are mediated by noradrenaline of sympa-thetic neural origin, while the peak tachycardic effects are mediated by direct release of adrenaline of adrenal medullary origin.

o     The sympathomimetic effects of cocaine increase myocardial oxygen demand and the alpha-adrenergic mediated coronary vasoconstriction limits coronary artery blood flow. Cocaine inhibits endogenous fibrinol-ysis, increases thrombogenicity, and enhances platelet aggregation.

Toxicokinetics

Absorption—

·              Ingestion and insufflation: Cocaine is well absorbed from oral, nasal, and pulmonary routes. Onset of action on insufflation is within 1 to 3 minutes, and peak effects are seen in 20 to 30 minutes.

·              Intravenous injection: Onset of action is within seconds, and peak action occurs in 3 to 5 minutes.

·              Inhalation: Smoking produces effects as rapidly as IV injection. 

Metabolism—

·              Cocaine is metabolised by liver esterases and plasma cholinesterase to ecgonine methylester (EME), one of the major metabolites, while non-enzymatic hydrolysis results in the formation of the other major metabolite, benzoylecgonine (BE). Minor metabolites include norcocaine ecgonine, ecgonidine, norecgonidine methylester, norecgonine methylester, and m-hydroxy- benzoylecgonine.

Excretion—

·              The biologic half-life of cocaine is ½ to 1½ hours.

·              Benzoylecgonine and ecgonine methylester possess half lives of 5 to 8, and 3½ to 6 hours respectively. Excretion is mainly through urine. Due to the long elimination half-life of BE, assays for its detection in urine may be successful up to 2 to 3 days following cocaine use. In rare cases, it has been detected even after 22 days.

Clinical Features

Acute Poisoning

a. Hyperthermia—This results from

–– Augmentation of heat production due to increased psychomotor activity.

–– Diminution of heat dissipation due to vasoconstric-tion.

–– Direct pyrogenic effect due to action on thermoreg-ulatory centres in the hypothalamus.

––  Stimulation of calorigenic activity of liver.

b. Body temperature often soars to 108° to 112°F, and does not respond to conventional antipyretics. It is often associated with rhabdomyolysis, seizures, and renal failure.

––  CNS effects— --  Headache:

»» Pattern 1—Develops within minutes, andlasts for 2 to 48 hours. The headache is usually occipital or bilateral, with associ-ated throbbing, photophobia, nausea, and vomiting.

»» Pattern 2—Occurs during a cocaine “binge”,(4 to 14 days of abuse, 1 to 3 g/day), with onset after a few days, which increases in severity progressively. It is mostly frontal, with associated throbbing, nausea and some-times diplopia and dizziness.

»» Pattern 3—Occurs 1 to 4 days after the lastdose of cocaine, and worsens over the next 1 week with continued abstinence. It is also frontal, with associated throbbing, nausea, vomiting, photophobia, and occasionally neck stiffness.

––  Anxiety, agitation.

–– Hyperactivity, restlessness. –– Tremor, hyperreflexia.

–– Convulsions: Generalised tonic-clonic, partial motor, and partial complex seizure have all been reported. Seizures may be recurrent and status epilepticus has been reported, particularly in chil-dren. Sometimes there is lethargy and decreased level of consciousness which can persist up to 24 hours (“cocaine washed out syndrome”).

–– Cerebrovascular accidents are not uncommon, and include subarachnoid haemorrhage, intrac-erebral haemorrhage, cerebral infarction, tran-sient ischaemic attacks, migraine-type headache syndrome, cerebral vasculitis, and anterior spinal artery syndrome. Infarction of the brainstem/spinal cord has occurred.

c. Psychiatric effects—

–– Paranoid state with suspiciousness, hypervigilance, anxiety.

––  Stereotypy.

–– Hallucinations. –– Toxic delirium.

d. Ophthalmologic effects—

–– Mydriasis and/or loss of eyebrow and eyelash hair from smoking crack cocaine may occur.

–– Corneal abrasions/ulcerations due to particulate matter in smoke (“crack eye”).

–– Central retinal artery occlusion and bilateral blind-ness due to diffuse vasospasm. Retinal foreign body granuloma may occur with IV abuse.

e. CVS effects— –– Tachycardia.

––  Systemic arterial hypertension.

–– Coronary artery vasoconstriction with myocardial ischaemia and infarction. Coronary artery disease, heavy smoking, and hypertension are predisposing factors. Myocardial infarction may occur even in young patients without risk factors or pre-existing cardiac pathology.

–– Tachyarrhythmias of all types can occur, including sinus tachycardia, atrial fibrillation or flutter, other supraventricular tachycardias, ventricular premature contractions, ventricular tachycardia, torsades de pointes, and ventricular fibrillation. Sinus tachy-cardia is the most common finding. If hypertension is significant, a reflex bradycardia may occur. Cocaine-induced syncope and bradyarrhythmia have been reported in some cases.

–– Chronic dilated cardiomyopathy can occur.

–– Aortic dissection and rupture.

f. Pulmonary effects—

–– Thermal injuries to the upper airway leading to epiglottitis, laryngeal injury, and mucosal necrosis have been reported after smoking “crack” or free base cocaine.

––Exacerbation of asthma.

––  Noncardiogenic pulmonary oedema is a common finding at autopsy.

–– Pneumothorax, pneumomediastinum.

––Diffuse alveolar haemorrhage.

––  Bronchiolitis obliterans with organising pneumonia.

g. Musculoskeletal effects—Rhabdomyolysis with hyper- thermia, massive elevation of creatine phosphokinase, and acute renal failure. Although the mechanism of cocaine-associated rhabdomyolysis is unclear, it is postulated that it may result from ischaemia due to vaso- constriction, direct toxicity, hyperpyrexia, and increased muscle activity from agitation or seizure activity.

h. GI effects—

––Acute mucosal ischaemia.

––Colitis.

––  Intestinal perforation: It is postulated that cocaine blocks the reuptake of noradrenaline leading to mesenteric vasoconstriction and focal tissue ischaemia and perforation.

––  Pneumoperitoneum has been reported after smoking crack cocaine.

––   Hepatic necrosis (centrilobular, midzonal, and panlobar) has been reported in overdose. R

i. enal effects—Renal failure, usually secondary to myoglobinuria and rhabdomyolysis, has been reported after intravenous or intranasal cocaine use. Renal infarc- tion has occurred following intravenous cocaine use.

j. Uteroplacental effects—

––  Increased incidence of spontaneous abortion, low birthweight, and abruptio placentae. Neonatal intoxi- cation may also occur. Infants exposed to cocaine in utero may display tremulousness, impaired orienta- tion, increased startle response, irritability, muscular rigidity, arousal deficits, impaired motor ability, and lower scores on the Brazelton Neonatal Behavioural Assessment Scale (measuring interactive behaviour and response to environmental stimuli).

––  There are indications that cocaine may be terato- genic.

––   Cocaine toxicity has been reported in breastfed infants of cocaine abusing mothers.

k. Miscellaneous effects—

––  Priapism has been observed after topical applicationof cocaine to the glans penis.

––  Severe metabolic acidosis has been reported due to seizures, agitation, and hypotension.

l. Drug combination effects—

–– Cocaine is often combined with other drugs such as ethanol and heroin. Concurrent use of cocaine and ethanol produces additive effects on the brain. It results in the formation of the metabolite, cocaeth-ylene which is more cardiotoxic, and is associated with enhanced mortality.

––Combination of cocaine with heroin is referred to as “speed ball” and is reputed to produce a double effect of initial high “kick” of cocaine, followed by subsequent euphoric “rush” of heroin. “Speed ball” is usually injected.

Chronic Poisoning

a. Cocaine dependence

–– Cocaine dependence is defined in DSM-IV as a cluster of physiological, behavioural, and cognitive symptoms that, taken together, indicate that the person continues to use cocaine despite significant problems related to such use.

–– Some cocaine users can use cocaine intermittently without becoming dependant, though it is not clear how long such intermittent, non-dependant use can continue. Intermittent use consists of episodes or binges of use, often starting on weekends and paydays, and lasting until the drug supply is exhausted or toxicity develops. Such binges, during which the drug may be used every 15 to 30 minutes, can last 7 or more consecutive days (though usually this extends to only 3 or 4 days). When the binge comes to an end, a “cocaine crash” occurs.

b. Cocaine abuse

–– Some cocaine abusers develop problems or adverse effects related to their drug use (i.e. their use is mala-daptive). Examples of such recurrent maladaptive patterns include use that leads to multiple legal prob-lems, failure to meet major social, school, or work-related obligations, and continued use despite social or vocational difficulties caused by, or aggravated by cocaine use. When one or more such substance-related problems occur in a 12-month period, the diagnosis of cocaine abuse is made.

–– Chronic use of cocaine leads to CNS dopamine depletion and increases in the number and sensi-tivity of dopamine receptors. The dysphoric state associated with cocaine withdrawal (vide infra) and craving for cocaine appears to be a result of the dopamine-depleted condition.

–– Features of chronic cocaine use: -- Anorexia, emaciation.

--  Mydriasis.

-- Agitation, restlessness: A cocaine-associated agitated delirium syndrome has been identified,comprising the following in sequence: hyper-thermia, delirium with agitation, respiratory arrest and death.

-- Hallucinations, especially tactile, characterised by a crawling sensation under the skin (“cocainebugs”) with resultant excoriation, leading toirregular scratches and ulcers (Magnan’s sign). Perceptual disturbances or pseudo-hallucinations involving vision (“snow lights”, geometric patterns), smell, hearing and taste have also been reported.

--  Tremor.

-- Recurrent chest pain. -- Cardiomyopathy.

--  Psychiatric changes: depression, psychosis, panic disorders, attention deficit disorders, and eating disorders.

--Decreased libido, impotence, gynaecomastia, galactorrhoea, amenorrhoea, and sexual dysfunction are common with chronic cocaine abuse.

--Cocaine abuse may be associated with cerebral atrophy.

--“Crack hands”: A syndrome of multiple, black-ened, hyperkeratotic lesions (linear or circular), of the fingers and palms has been described in crack cocaine smokers. These lesions probably result from the heat of the glass cocaine pipe. 

--Maternal chronic cocaine use during preg-nancy has been suggested as a possible factor in Sudden Infant Death Syndrome. Cocaine readily passes into breast milk and can cause adverse effects in the nursing infant.

--Evidence of medical complications (Table34.9).

c. Cocaine withdrawal

–– Conventionally, cocaine withdrawal is said to occur in 3 phases:

Phase I (“Crash”): The total duration of this phaselasts for anywhere between 9 hours and 4 days, and is subdivided further into the following stages—

»»Early: Agitation depression, anorexia, intense craving for cocaine.

»»Intermediate: Fatigue, tendency to sleep, decreased craving.

»»Late: Exhaustion, hypersomnia, hyperphagia, absence of craving.

Phase II: Normalised sleep, improved mood, followedsubsequently by return of anergia, anhedonia, anxiety, and increased craving.

Phase III: (“Extinction”): Increased tendency to relapse.The extinction phase may be prolonged and consists of brief, episodically evoked cravings that occur months to years after withdrawal.

––  Additional points of importance:

-- Impaired colour vision (blue-yellow), which may persist for up to 2 months or more, has been reported in some patients with cocaine with-drawal. A dysregulation of blue cone function has been suggested, since significantly reduced blue cone electroretinogram responses have been observed in recently withdrawn cocaine-dependant patients.

-- Silent ischaemia has occurred upon cocaine withdrawal, and acute myocardial infarction may occur up to 2 weeks after the last cocaine use.

-- ECG changes: Increased PR intervals have been found to correlate with length of abstinence, which is thought to reflect the remediation of a depolarisation variant. Chronic cocaine users may be subject to rapid cardiac depolarisation (decreased PR intervals) that gradually returns to normal over 20–30 days.

--  EEG changes: Evaluation of quantitative EEGs in cocaine-dependant persons after a 10-day drug free interval revealed increased power in the beta-2 band that correlated with the frequency of cocaine use during the last 30 days before hospital admission. Elevated power of EEG beta (fast EEG activity) could be a neurophysiological cocaine withdrawal sign.

--Persistently elevated serum creatine kinase (CPK) levels (>374 Units/L) have been demon-strated in abstinent cocaine abusers, with evidence of impaired spatial motor perfor-mance, and tendency to coarse motor control and impulsive movements.

--Withdrawal from cocaine sometimes results in hyperprolactinaemia during the first month, which may be due to its effect on serotonergic function. Bromocriptine (0.625 mg orally, twice daily) may be of value for treating cocaine withdrawal-induced hyperprolactinaemia.

--Cocaine readily crosses the placental barrier, causing an alteration of the central neurotrans-mitter state, and increasing peripheral catechola-mines in the foetal circulation. In utero cocaine exposure in a foetus nearing term could result in altered behaviour after delivery, consistent with drug abstinence, and in decreased flow velocity in the anterior cerebral artery consistent with the vasoconstrictive effects of cocaine. Abstinence symptoms are seen in the first and second postnatal days, and may last for several weeks. Cocaine-exposed infants may be at an increased risk for sudden infant death syndrome (SIDS). Symptoms of neonatal cocaine abstinence syndrome include irritability, hypertonia/poor muscle tone, tremor, hyperactive Moro reflex, loose stools, sleep disturbances, poor feeding/ excessive sucking, nasal stuffiness, tachypnoea, visual function disturbance.

Usual Fatal Dose

■■   About 500 mg (oral).

■■   About 100 mg (mucosal contact).

■■   Lethal blood level: 0.2 mg/100 ml.

Chronic users of cocaine can tolerate much higher doses.