Riccardo Raffaldi
Lisa Marie Rorato
Opiates and opioids
Opiates, sometimes referred to as narcotics, are a group of drugs which are used medically to relieve pain, but also have a high potential for abuse. Some opiates come from a resin taken from the seed pod of the Asian poppy, papaver somniferum.
Opiate drugs can be grouped in:
- Morphine similar. These drugs summarized from morphine include its agonists (heroin and codeine), partial agonists (nalorphine and levallorphan), antagonists(naloxone and naltrexone).
Other opiates, such as meperidine (Demerol), are synthesized or manufactured.
- Thebaine similar (buprenorphine and etorphine)
- Fenilpiperidine (fentanil and pethidine)
- Series of methadone (methadone and destropropoxifene)
- Benzomorphan (pentazocine and cyclazocine).
The last three groups are chemical compounds with a structure not correlate to morphine.
The term opiate refers only to the alkaloids found naturally in opium, but is often uncorrectly used to describe all drugs with opium- or morphine-like pharmacological action, which are more properly classified under the broader term opioid.
Heroin
Diacetylmorphine (Heroin) was first synthesized in 1874 by C. R. Alder Wright, an English chemist working at St. Mary's Hospital Medical School in London. He had been experimenting with combining morphine with various acids. He boiled anhydrous morphine alkaloid with acetic anhydride for several hours and produced a more potent, acetylated form of morphine, now called diacetylmorphine or morphine diacetate.
In 1895, the German drug company Bayer marketed diacetylmorphine as an over-the-counter drug under the trademark name Heroin. The name was derived from the Greek word "Heros" because of its perceived "heroic" effects upon a user. It was developed chiefly as a morphine substitute for cough suppressants that did not have morphine's addictive side-effects. Morphine at the time was a popular recreational drug, and Bayer wished to find a similar but non-addictive substitute to put on the market. However, contrary to Bayer's advertising as a "non-addictive morphine substitute," heroin would soon have one of the highest rates of dependence among its users.
Pharmacology
Opioid receptors were classified into three types, identified by Greek letters δ, µ and κ. All these receptors are part of the group of G protein-coupled receptors.
Heroin, part III: the pharmacology of heroin. 2003
Through G proteins are coupled in the sense inhibitory to the cascade of signal transduction Adenylate cyclase-cAMP-PKA. Opioids tend to inhibit the transmission of nociceptive stimuli. In fact, the stimulation of presynaptic mu receptors causes inhibition of N-type calcium channels to and therefore a reduction of the production of Neurotransmitters while stimulation of postsynaptic µ receptors produces hyperpolarization by activating the potassium channels and those inhibiting the L-type Calcium. Opiate receptors are distributed widely in the brain, and are found in the spinal cord and digestive tract.
Opioid Receptors. 2010
Intake, metabolism and effects
When taken orally, heroin undergoes extensive first-pass metabolism via deacetylation, making it a prodrug for the systemic delivery of morphine. When the drug is injected, however, it avoids this first-pass effect, very rapidly crossing the blood–brain barrier because of the presence of the acetyl groups, which render it much more fat soluble than morphine itself. Once in the brain, it then is deacetylated variously into the inactive 3-monoacetylmorphine and the active 6-monoacetylmorphine (*6-MAM*), and then to morphine, which bind to μ-opioid receptors, resulting in the drug's euphoric, analgesic (pain relief), and anxiolytic (anti-anxiety) effects; heroin itself exhibits relatively low affinity for the μ receptor. Unlike hydromorphone and oxymorphone, however, administered intravenously, heroin creates a larger histamine release, similar to morphine, resulting in the feeling of a greater subjective "body high" to some, but also instances of pruritus (itching) when they first start using.
Dependence
Both morphine and 6-MAM are μ-opioid agonists that bind to receptors present throughout the brain, spinal cord, and gut of all mammals. The μ-opioid receptor also binds endogenous opioid peptides such as β-endorphin, Leu-enkephalin, and Met-enkephalin. Repeated use of heroin results in a number of physiological changes, including an increase in the production of μ-opioid receptors (upregulation). These physiological alterations lead to tolerance and dependence, so that cessation of heroin use results in a set of remarkably uncomfortable symptoms including pain, anxiety, muscle spasms, and insomnia called the opioid withdrawal syndrome. Depending on usage it has an onset four to 24 hours after the last dose of heroin. Morphine also binds to δ- and κ-opioid receptors.
Other types of receptors
There is also evidence that 6-MAM binds to a subtype of μ-opioid receptors that are also activated by the morphine metabolite morphine-6β-glucuronide but not morphine itself. The third substype of third opioid type is the mu-3 receptor, which may be a commonality to other six-position monoesters of morphine. The contribution of these receptors to the overall pharmacology of heroin remains unknown.
Effects of heroin on neurotransmitters
Heroin is an addictive drug that occurs because of the drugs negative and diminishing effect on the brain. Opiates bind to the same receptors as endogenous opioids which the body naturally produces and uses as neurotransmitters. The receptors that heroin binds to influence if ion channels will open, which in some cases reduce neurons excitability and cause the euphoric effects. This effect also involves the GABA-inhibitory interneurons of the ventral tegmental area. When the heroin binds to the receptors, the amount of GABA released is reduced. GABA usually reduces the amount of dopamine released in the nucleus accumbens but opiates like heroin increase the amount of dopamine produced and feeling of pleasure being felt. Continual consumption of heroin inhibits the production of cAMP. When heroin is not
being taken by a user, the increased cAMP results in neural hyperactivity and a craving for the drug.
The Pharmacological Effects of Diacetylmorphine (Heroin) After Diffusion Through the Blood-Brain Barrier. 2009
Short-Term Effects
Heroin’s short-term effects will last over a period of three to six hours.
Effects on the eyes
One of the most easily noticeable abnormal conditions is mitotic pupils. Heroin stimulates the central nervous system by exciting the oculomotorius nuclei and affecting the sphincter muscle of the iris which cause the narrowing of pupils. These mitotic pupils are referred to as pinpoint pupils and react poorly to light.
Effects on the gastrointestinal region
Other affects users of the drugs face are problems in the gastrointestinal region, which is the reason for nausea, vomiting, and constipation. Nausea and vomiting occur because heroin and morphine stimulate the area postrema equaling chemoreceptor trigger zone in the medulla and affects gastrointestinal receptors.
Long-Term Effects
Besides the addiction and instant results that come with the use of heroin, it has other long-term effects.
Systemic effects
Users who continually use heroin experience long-term effects such as collapsed veins, liver disease, pulmonary complications, kidney disease, and respiratory problems. Some chemicals do not completely dissolve in heroin and if entered intravenously can lead to blood vessels being blocked. These vessels, the majority of the time, lead to the lungs, liver, kidney, or brain. In current research done to get a bettering understand of heroin, fifteen mice were injected with heroin. Fifteen minutes after the time of injection, scientists from the University of California looked at the carcasses. They noted that in various organs, a few molecules of heroin, morphine,and 6-monacetylmorphine (MAM)were present. The making of these two after subcutaneous injection were seen to happen the quickest in the liver, explaining why one
side effects of heroin is liver failure and damage. The human liver catalyzes the hydrolysis of deacetylation of heroin into 6-acetylmorphine. Heroin has a half-life time of two and a half minutes which is a quick half-life. Heroin also rapidly penetrates the blood-brain barrier and due to these two factors, the pharmacologists sawless heroin and more MAM and morphine in the mice’s brain, as well.
Immunosuppressive effects
Like most opioids, unadulterated heroin does not cause many long-term complications other than dependence and constipation. Due to increased vulnerability to infectious agents, particularly viruses and intracellular bacteria resulting from the suppression of various cell-mediated immune pathways, the use of heroin and other opioids, even at normal therapeutic levels, may lead to opportunistic infections, which carry their own lasting effects.
Medical use
Diacetylmorphine continues to be widely used in palliative care in the United Kingdom, where it is commonly given by the subcutaneous route, often via a syringe driver, if patients cannot easily swallow oral morphine solution. The advantage of diacetylmorphine over morphine is that diacetylmorphine is more fat soluble and therefore more potent (by injection only), so smaller doses of it are needed for the same analgesic effect. Both of these factors are advantageous if giving high doses of opioids via the subcutaneous route, which is often necessary in palliative care. Its use includes treatment for acute pain, such as in severe physical trauma, myocardial infarction, post-surgical pain, and chronic pain, including end-stage cancer and other terminal illnesses. In other countries it is more common to use morphine or other strong opioids in these situations.
Heroin Tolerance, Addiction, and Withdrawal
With regular heroin use, tolerance develops. This means the abuser must use more heroin to achieve the same intensity or effect. As higher doses are used over time, physical dependence and addiction develop. With physical dependence, the body has adapted to the presence of the drug and withdrawal symptoms may occur if use is reduced or stopped.
Withdrawal, which in regular abusers may occur as early as a few hours after the last administration, produces drug craving, restlessness, muscle and bone pain, insomnia, diarrhea and vomiting, cold sweats with goose bumps ("cold turkey"), kicking movements ("kicking the habit"), and other symptoms. Major withdrawal symptoms peak between 48 and 72 hours after the last dose and subside after about a week. Sudden withdrawal by heavily dependent users who are in poor health is occasionally fatal, although heroin withdrawal is considered much less dangerous than alcohol or barbiturate withdrawal.
What are the symptoms of heroin withdrawal?
Regardless of dosage, these reactions may appear during heroin withdrawal:
- Convulsions
- Increased heart rate
- Abnormal heartbeat
- Heart attack
- Sudden, sharp blood pressure increase
- Stroke
- Extreme depression
- Suicidal behavior
As withdrawal progresses, elevations in blood pressure, pulse, respiratory rate and temperature occur. Symptoms of heroin overdose -- which may result in death -- include shallow breathing, clammy skin, convulsions and coma. Heroin can cause feelings of depression, which may last for weeks. Attempts to stop using heroin can fail simply because the withdrawal can be overwhelming, causing the addict to use more heroin in an attempt to overcome these symptoms. This overpowering addiction can cause the addict to do anything to get heroin.
Opioid receptors and opioid pharmacodynamics. 2009
Conclusions
Opioid pharmacodynamics are both unique and complex. Advances in molecular medicine have unravelled many of the mysteries behind the wide diversity of opioid responses among individuals. Heroin is considered a dangerous drug but probably its modification can create in the future a new medicine with less side effects and more benefits.
In a new research program, scientists were able to develop the first crystal structure of the protein human carboxylesterase 1 also known as hCE1. These protein enzymes are found in the liver, kidney, small intestines, and lungs locations effected when heroin binds to µ-receptors. The researches found that if they are able to engineer a more active form of the enzyme, by changing the amino acid sequence, the new enzyme would metabolize heroin before it became toxic in the body.
This could save the lives of opioid users, however long term effects will still be breaking down the body. Research must be done to stop or even reverse the effects heroin has had on the body especially in the brain and spinal cord where most opioid-receptors experience severe contact with the products of the drug.
