Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2014 Publisher: Aurum Pharmaceuticals Ltd, Bampton road, Harold hill, Romford, Essex, RM3 8UG
Cocaine has two distinct pharmacological actions:
This drug produces its local anaesthetic effects by inhibiting the permeability of the cell membrane to sodium ions during depolarisation, thus blocking the initiation and conduction of electrical impulses within nerve cells. Its actions on the central nervous system involve the alteration of several neurotransmitters. Cocaine affects the sympathetic nervous system by blocking the re-uptake of noradrenaline and dopamine. This initially causes cortical stimulation and may result in restlessness, excitement, euphoria, garrulousness, and increased motor activity. Confusion, paranoia, hallucinations, altered tactile sensations, and psychosis have also been reported, especially with high doses or repeated use. Seizures can occur, perhaps due to lowering of the seizure threshold, due to cocaine-induced hyperpyrexia, or due to life threatening cardiac arrhythmias. Cocaine directly causes a rise in body temperature by increasing heat production through stimulated muscle activity, and indirectly by causing vasoconstriction that decreases heat loss. A direct pyrogenic effect may be caused by cocaine’s direct effect on thermoregulatory centres in the hypothalamic area.
Cocaine initially stimulates the respiratory centre, resulting in increased respiratory rate. However, the depth of respiration is soon decreased to a rapid and shallow pattern. This may be followed by depression of the medullary centres, causing respiratory failure. Cocaine’s effects on the lungs and respiration can also result in metabolic acidosis or alkalosis. The respiratory effects of Cocaine appear to be dose related. Low doses in humans do not change respiratory rate or depth, but at higher doses a CNS mediated increase in respiratory rate and decrease in tidal volume is described. At very large cocaine doses, Cheyne-Stokes respirations and apnoea occur.
Cocaine can reduce blood flow within the brain. A migraine-like headache may be the result of cocaine induced vascular changes. Other complications include cerebral haemorrhage or infarction, most likely related to sudden intensive hypertension resulting from adrenergic stimulation. In the central nervous system, cocaine suppresses both rapid eye movement (REM), sleep and total sleep. In low doses, cocaine has an anorexic effect.
The initial effect of cocaine on the cardiovascular system is bradycardia, which is short-lived and followed by tachycardia that results from central and peripheral stimulatory effects. The tachycardia and intense peripheral vasoconstriction result in hypertension. Ventricular premature contractions, ventricular tachycardia and fibrillation, asystole, and myocardial infarction have also been reported. In cocaine induced acute myocardial infarction, cocaine increases cardiac activity, which raises oxygen demand within myocardial tissue. Cocaine simultaneously produces vasoconstriction of coronary arteries. Thus when cardiac tissue requires increased oxygenation, cocaine induced vascular changes prevent it. Other signs of adrenergic excess seen with cocaine include mydriasis, diaphoresis, tremor, hyperactive bowel sounds and hyperreflexia. Vasoconstriction due to cocaine may also produce ischaemia in the fingers, toes, spinal cord, kidneys, spleen, and intestines.
On an acute basis, cocaine can prolong the time to reach orgasm in men and women.
Cocaine use by pregnant women can interfere with gestation and produce abnormalities, possibly permanent, in their children. (See Pregnancy And Lactation).
Cocaine is metabolised in humans by two major pathways. The first accounts for over 90% of the transformation and involves various hydrolytic reactions. The second is an oxidative process. The hydrolytic pathway is catalysed by serum and liver pseudocholinesterase which produces ecgonine methyl ester, benzoylecgonine and ecgonine. The minor oxidative route appears to be responsible for the hepatotoxicity. Cocaine is N-demethylated to produce norcocaine which is then rapidly oxidized to N-hydroxynorcocaine, which in turn is further metabolised producing norcocaine nitroxide. The latter is believed to be ultimately responsible for the hepatotoxicity elicited by cocaine.
Absorption from mucous membranes is delayed by vasoconstriction, and peak plasma concentrations of up to 474ng/ml have been obtained 15-120 minutes after application of doses of 1.5-2mg per Kilogram bodyweight to the nasal mucosa as a 10% w/v cocaine hydrochloride solution.
Cocaine applied to the mucous membranes may be detectable for as long as three hours after its application. A true biological half-life for cocaine is difficult to ascertain, as serum concentrations reflect a dynamic balance between the absorption and degradation of cocaine, i.e. the concentration of cholinesterase in the blood can vary between individuals.
It is considered possible that topical application of cocaine to the nose or pharynx, may indeed implicate an unintentional oral administration of cocaine should a small quantity of the solution trickle down the back of the throat. It is thus necessary to consider the effect of an oral dose equivalent to the topical dose.
In a well controlled study after oral ingestion of cocaine, the plasma levels, objective findings and subjective effects all correlated with the levels after intranasal application.
A common misconception is that if taken orally, cocaine is rendered ineffective by gastric acidity.
Cocaine is not completely destroyed by hydrolysis in the stomach. When ingested orally, the gastrointestinal absorption is delayed, but at least 30% is estimated to be absorbed and bioavailable. Oral ingestion results in a lag time of 30 minutes before plasma levels can be detected. Peak plasma concentrations occur 50-90 minutes following ingestion and are similar to those after nasal application.
Absorption of cocaine may be enhanced where the skin is broken or where there is inflammation. In addition, absorption of cocaine from the mucosa varies in different parts of the respiratory tract. It has been found that absorption from the trachea is greater and more rapid than from the pharynx. Also, absorption is greater from the respiratory tract than from other mucous membranes.
The half life of cocaine in serum is dependent on the route of administration, and average values of 0.6 hour for intravenous administration, 0.9 hour for oral use, and 1.3 hours after intranasal have been quoted. However, these values must be interpreted with caution, as there is considerable variability between individuals and within individuals over time, and cocaine applied to the mucous membranes may be detectable in serum for as long as three hours after its application.
When applied to mucous membranes, surface anaesthesia develops rapidly and persists for 30mins or longer depending on the concentration of cocaine solution used, the dose, and on the vascularity of the tissue.
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
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