Diamorphine (heroin) is a narcotic analgesic that may be habit-forming. It is a controlled substance (opium derivative) listed in the U.S. Code of Federal Regulations, Title 21 Parts 329.1, 1308.11 (1987). Sale is forbidden in the United States by Federal statute. (Merck Index, 11th ed) Internationally, diamorphine is controlled under Schedules I and IV of the Single Convention on Narcotic Drugs. As heroin, it is illegal to manufacture, possess, or sell in the United States and the UK. However, under the name diamorphine, heroin is a legal prescription drug in the United Kingdom.

Indication

Diamorphine, as a prescription medication in the United Kingdom, is indicated for use in the treatment of severe pain associated with surgical procedures, myocardial infarction or pain in the terminally ill and for the relief of dyspnoea in acute pulmonary edema 6.

Contraindications & Blackbox Warnings

Pharmacodynamics

The onset of heroin's effects is dependent on the method of administration. Taken orally, heroin is totally metabolized in vivo via extensive first-pass metabolism into morphine before crossing the blood-brain barrier; so the effects are the same as orally administered morphine 5,6. Take by injection, diamorphine's acetyl groups facilitate rapid crossing into the brain 5,6. Once in the brain, heroin is rapidly metabolized into morphine by removal of the acetyl groups, therefore making it a prodrug for the delivery of morphine 5,6. Subsequently, whether eliciting actions peripherally (on smooth muscle, skeletal muscle, kidney, lung, liver, or spleen tissue 5, for example) or on the central nervous system, it is ultimately the morphine metabolite of heroin that then binds with opioid receptors and produces the narcotic opioid effects commonly associated with the substance 5,6.

Mechanism of action

When administered orally, diamorphine experiences extensive first-pass metabolism by way of deacetylation to generate the active metabolites 6-monoacetylmorphine (6-MAM) and morphine 5,6. Alternatively, when given as an injection the acetyl groups present in the diamorphine/diacetylmorphine compound confer the substance lipophilicity that facilitates diamorphine's rapid crossing of the blood-brain-barrier 5,6. Once in the brain, diamorphine is metabolised via deacetylation to the active 6-MAM and morphine metabolites as well 5,6. Despite diamorphine possessing little to no opioid agonist activity itself, its rapid transit across the blood-brain-barrier elicits a far faster onset of activity in comparison to the extensive first-pass metabolism of oral administration 5,6. Regardless, the metabolism of diamorphine to morphine makes heroin a prodrug for the delivery of morphine 5,6. Morphine is subsequently a mu-opioid agonist. It acts on endogenous mu-opioid receptors that are spread in discrete packets throughout the brain, spinal cord and gut in almost all mammals 1. Morphine, along with other opioids, are agonists to four endogenous neurotransmitters 1. They are beta-endorphin, dynorphin, leu-enkephalin, and met-enkephalin 1. The body responds to morphine in the brain by reducing (and sometimes stopping) production of the endogenous opioids when morphine is present 1. Endorphins are regularly released in the brain and nerves, attenuating pain. Their other functions are still obscure, but are probably related to the effects produced by morphine besides analgesia (antitussin, anti-diarrheal) 1. Nevertheless, morphine ultimately elicits the majority of its analgesic activity by binding to mu opioid receptors in both the central and peripheral nervous systems 7. The overall effect of morphine is activation of descending inhibitory pathways of the central nervous system as well as inhibition of nociceptive afferent neurons of the peripheral nervous system, which results in an overall reduction of the nociceptive pain transmission 7. Target Actions Organism A Mu-type opioid receptor agonist Humans U Kappa-type opioid receptor agonist Humans U Delta-type opioid receptor agonist Humans U Liver carboxylesterase 1 Not Available Humans

Absorption

Bioavailability is less than 35% when orally administered 2. In particular, some studies have determined that the bioavailability of orally administered diamorphine could be as low as 22.9% (16.4-29.4%) on average in opioid-naive subjects 3. Nevertheless, diamorphine administered by any many medically indicated routes of administration leads to a rapid absorption 5. Peak serum levels are achieved five to ten minutes subcutaneously, three to five minutes intranasally and intramuscularly, and less than one minute intravenously 5.

Volume of distribution

Data regarding the volume of distribution specific to diamorphine is not readily accessible or available. However, considering diamorphine is considered a prodrug for morphine, the volume of distribution of morphine has been determined to be approximately 1 to 6 L/kg 8.

Protein binding

Diamorphine does not bind to plasma protein 6. However, considering diamorphine is considered a prodrug for morphine, morphine itself is about 20 to 35% reversibly bound to human plasma proteins 6,8.

Metabolism

Once administered into the body, diamorphine undergoes deacetylation via various esterase enzymes to generate active metabolites like 6-monoacetylmorphine and morphine 5,6. In particular, when administered orally, diamorphine undergoes extensive first pass metabolism 5,6. Hover over products below to view reaction partners Diamorphine 6-Monoacetylmorphine morphine morphine



Route of elimination

The majority of the drug is excreted via the kidney as glucuronides and to a much lesser extent as morphine 6. About 7-10 % is eliminated via the biliary system into the faeces 6.

Half-life

In humans, administered diamorphine has a half-life of approximately two to three minutes 6.

Clearance

Some studies have determined a relatively high systemic diacetylmorphine clearance of about 8.7 +/- 2.6 L/min, suggesting that the intestine, liver, and blood might all collectively take part in the first pass metabolism of diacetylmorphine to morphine 3, although such clearance observations were made only in opioid-addicted individuals 4. However, considering diamorphine is considered a prodrug for morphine, the mean adult plasma clearance of morphine is approximately 20 to 30 mL/min/kg 8.

Adverse Effects

Toxicity

Overdosage with diamorphine well characterised by a number of symptoms including respiratory depression, pulmonary oedema, muscle flaccidity, coma or stupor, constricted pupils, cold, clammy skin and occasionally bradycardia and hypotension 5,6. The antidote for heroin overdose or poisoning is naloxone 5.

Affected organisms

Humans and other mammals

Pathways

Pathway Category Heroin Action Pathway Drug action Heroin Metabolism Pathway Drug metabolism

Pharmacogenomic Effects/ADRs