Drug Dependence And Addiction Biology Essay

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Drug dependence occurs when a person has physical and/or psychological needs for a particular drug. Physical dependence can result in symptoms of withdrawal when the person stops taking the drug and the withdrawal symptoms ultimately differ on the type of drug. Psychological dependence results in the person taking a drug because it gives pleasure and satisfaction, to cure cravings and to avoid feelings of uneasiness (Battegay et al. 1977). Accordingly, drugs that cause dependence fall into two categories; firstly, the psychomotor stimulants which cause an increase in excitation, brain activity stimulation and increased locomotion and secondly, the CNS depressants; those drugs in which brain activity is depressed which ultimately results in drowsiness and dehydration (Rang et al. 2007). The most common legal drugs that are known to cause dependence are; alcohol, nicotine and caffeine and the illegal drugs; opiates, barbiturates, benzodiazepines, amphetamines and cocaine. Due to drug dependence being a very big field, this essay will cover a few drugs in greater detail and I have chosen to discuss opioids because most people that seek treatment regarding drug use are first and foremost, addicted to opioids (WHO, 2010). This essay will focus on the pharmacological aspects; of how the drug operates, activity dependent on structure, side-effects and pharmacokinetic properties; the way the drug influences its action.

MAIN SECTION

Drug dependence is a condition that usually causes obsessive behaviour and can result in neglecting other needs, and ultimately, the desperation for the 'next hit' overrides any concerns for safety. This can usually result in complications and unfavourable circumstances. A patient's response to a drug is dependent on overall health and aspects such as age, diet, gender, cardiovascular function, GI function and many other factors. Tolerance to a drug occurs when larger doses are needed to produce the same effect of that drug; the patient usually has a reduced response to the drug with time (Berry et al. 2009). According to the World Health Organization, there are approximately 15.3 million people that suffer from drug dependence. Regarding the use of Opiates, the United Nations Office on Drugs and Crime exclaim there has been a worldwide amplification of the production, transportation and consumption of this chemical, primarily with regards to heroin. Internationally speaking, approximately 13.5 million people are said to take opioids and out of this majority, 9.2 million are said to use heroin. Given that heroin is used by the method of injection, health risks like hepatitis and HIV are on the increase (WHO, 2010).

Opioids are the family of opiates which involves the complete endogenous or synthetic substances. Opiates are generally used for non-synthetic opioids and it is an older term. Opioids are mainly used to mean opioids and opiates. Accordingly, the term opium is the extract from the poppy, Papaver somniferum. Some opioids include morphine, heroin (diamorphine), codeine, pethidine and methadone (Rang, H.P, et al. 2007). All opioids produce their effect on the spinal cord and the limbic system, which is associated with emotion. Accordingly, opioids are involved in causing effects on the pathways that send pain from the peripheral nervous system to the central nervous system. This essay will cover morphine, diamorphine, codeine and methadone as these compounds are known to cause the highest tolerance and dependence and they are the uppermost in analgesic potency (Waller, et al. 2010). There are three main types of opioids receptors; the Mu (µ) type receptors, Kappa (k) type receptors and finally, the Delta (δ) type receptors. The Mu (µ) type receptors are involved in the binding of morphine.

Effect

Mu (µ) type receptors

Kappa (k) type receptors

Delta (δ) type receptors

Analgesia

Ã-

Ã-

Ã-

Respiratory

Ã-

-

Ã-

Euphoria

Ã-

-

-

Miosis

Ã-

Ã-

-

Dependence

Ã-

-

-

Sedation

Ã-

Ã-

-

GI motility reduction

Ã-

-

Ã-

Table - This table shows the effects of the three major classes of the opioids receptors (Adapted from Bennett & Brown, 2003).

Morphine

Clinical use of morphine is mostly for severe pain, for example, in cancer patients, patients suffering from a myocardial infarction and in severe life threatening cases like road traffic accidents. It does not generally cause dependence but however, if the consumption is long term like in chronic cases, then dependence may occur (Joint Formulary Committee, 2010).

How morphine works

Morphine is the standard alkaloid that comes from opium. Morphine acts chiefly on the Mu (µ1) type receptors which are located in the CNS; accordingly, the binding of morphine at these receptors gives pain relief and feelings of euphoria; however, particular signs of dependence are significant in these type of receptors. When morphine binds to the Mu (µ2) type receptor, this causes respiratory depression and reduced movement of gut content. Opioid peptide neurotransmitters in the CNS are endorphins, enkephalins and dynorphins. These endogenous opioid receptors attach to the three different types of receptors (Bennett & Brown, 2003). The opioid receptors, which are part of the G protein-coupled receptors (GPCRs) family, inhibit adenylate cyclase which causes a reduction in the cAMP content (Rang, et al. 2007). Accordingly, opioids cause the potassium channels to open and inhibit the voltage-gated calcium channel opening and this subsequently causes a reduction in electrical excitability and inhibition of substance P, which is involved in pain neurotransmission (Bennett & Brown, 2003).

Figure - When the agonist binds to the opioid receptor, which is part of the GPCR family; GTP activation occurs and adenylate cyclase is inhibited by the GTP-bound α subunit, which results in the reduction of cAMP concentration. Accordingly, the β/γ subunits cause the potassium channel activation and inhibition of the voltage activated calcium channels. Note: GIRK stands for G protein-coupled inwardly-rectifying potassium channels (Figure adapted from Kreek & LaForge, 2007).

The unbalancing of the CNS chemistry occurs when the body's homeostasis is disrupted and the CNS strives to preserve the normal status. The CNS becomes disturbed and side effects arise resulting in withdrawal symptoms. Morphine consumption causes inhibition of adenylate cyclase and this causes a lowering of the intracellular messenger, cyclic adenosine monophosphate (cAMP) as shown in figure 1. Homeostasis compensation then tries to increase the cAMP synthesis but this causes adenylate cyclase production. When the person stops taking morphine, there is a larger amount of cAMP produced and this continues until the adenylate cyclase levels return to the normal standard. Regular opioid use causes adenylate cyclase to be amplified and accordingly, the high levels of cAMP production cause the withdrawal effects (Rang, H.P, et al. 2007).

Figure 2- This figure shows that after morphine is consumed, adenylate cyclase is in inhibited which subsequently causes cAMP production to be reduced. The high levels of cAMP production cause withdrawal symptoms and this lasts until the adenylate cyclase expression goes down to a normal level. When adenylate cyclase rises, cAMP production decreases when morphine is consumed and this is a particular cause of tolerance. (Figure adapted from Rang, H.P, et al. 2007).

When withdrawal takes place, adenosine; which is involved as adenosine triphosphate (ATP) used in energy transfer and also a significant mediator of the central nervous system is important in drug dependence. The synthesis of adenosine is amplified when a person goes through drug withdrawal and this is because cAMP, which, is obtained from ATP as well, is produced in excess during withdrawal and is converted to adenosine. Subsequently, adenosine acts on the A1 receptors at the presynaptic nerve terminal and it consequently inhibits the release of the excitatory neurotransmitter; glutamate, in the nervous system. This inhibition of glutamate release results in the offset of neuronal hyperexcitability. There are ongoing tests that may help people suffering from drug abuse; by the use of adenosine agonists as these would help prevent drug withdrawal symptoms (Rang, H.P, et al. 2007).

CNS effects

Pain relief, feelings of euphoria, sedation effects, respiratory depression, hypotension, constriction of pupils, nausea.

Peripheral effects

Contraction of smooth muscle, reduction of gut motility, itch, urine retention.

Table - This table shows the effects of morphine when it binds to the Mu (µ1) receptors, which are located in the CNS and Mu (µ2) receptors which are located in the peripheral tissues (Reid, et al. 2006).

Structure

The structure consists of a phenanthrene skeleton that has two aliphatic rings, which are made up of carbon and hydrogen, it also has two planar rings and its structural formula is C17H19NO3 and has a molecular mass of 285.34g. Other analogues of the morphine structure have different groups at the hydroxyl groups on position 3 and 6 in figure 2 or at the nitrogen part of the molecule on position 17 (Rang, H.P, et al. 2007). The synthetic opioids have alternative functional groups at positions 3, 6 and 17; these may be esters, hydroxyl groups, ketones, methyl groups or extra carbon atoms (Armstrong & Cozza, 2003).

.

Position 3

Position 6

Position 17

Alkene

Amine group

Aromatic ring

Alcohol group

Ether group

Phenol group

Figure 3 -the structure of morphine; displaying the phenol group, ether group, alcohol group, aromatic ring, amine group and the alkene. (Diagram adapted from: Nelson, 2008).

Side-Effects

Side-effects commonly experienced with morphine consumption are respiratory depression; which causes a decreased sensitivity to carbon dioxide and this is the prime cause of death in patients who over dose. Morphine consumption can cause an increase in pCO2 when morphine administration is a bit high; oxygen saturation decreases and occasionally results in hypoxia. Miosis, Nausea and vomiting and constipation are other considered side effects. Constipation occurs due to a decrease in the GI motility. Histamine release is another side effect and thus morphine is not recommended for people that suffer with asthma. Withdrawal and dependence symptoms are not as widespread in morphine as they are in diamorphine (Dale & Haylett, 2009).

Pharmacokinetic Properties

When morphine is taken orally, it is metabolized when it passes from the gut wall to the liver and it is said that 20% of a single dose goes to the system circulation; this is known as the first-pass effect in which the concentration of morphine is much less when it gets to the system circulation. In moments of circulatory shock like in road traffic accidents, morphine is given intravenously because subcutaneous and intramuscular injections would take too long to be absorbed (Bennett & Brown, 2003).

Subsequently, morphine is metabolized by two organs; the liver and the kidney. It is metabolized to morphine-6-glucuronide and morphine-3-glucuronide which are secreted in the urine. A study undertaken on morphine-6-glucuronide shows that is has pain relief effects; however larger amounts of morphine-6-glucuronide are needed to give the same outcome as morphine (Skarke C, et al. 2002). The half-life of morphine is between 3-4 hours (Rang, et al. 2007).

Diamorphine (also known as 3,6-diacetylmorphine and heroin)

Diamorphine is a semisynthetic drug processed from morphine. It is used in medicine for acute and chronic pain. Subsequently, is more effective than morphine with regards to pain relief, due to its solubility. It is a very common drug that causes dependence and for this reason it is banned for medical use in most countries (Bennett & Brown, 2003).

How diamorphine works

Diamorphine is a narcotic analgesic, which is known to have quite a strong dependence liability. Being an analogue of morphine, this substance is similar in structure to morphine and acts by comparable mechanisms. Heroin is the diacetate ester of morphine and subsequently, it is more lipophilic and crosses the blood-brain barrier easier due to the acetyl groups. This causes major increase in euphoria and addictiveness (Rang, et al. 2007). Heroin itself does not have strong CNS effects, which is due to a low affinity binding to the opioid receptors. (Rossi et al.1996). However, diamorphine goes through an intermediate process during metabolism, as shown in figure 3, to produce a compound called 6-acetylmorphine and this metabolite has a much greater affinity for the Mu (µ) type receptors and is able to cross the blood brain barrier where it is later metabolized to morphine when it is penetrated into the CNS (Weitz et al. 1988).

Heroin is commonly injected but it is also snorted and inhaled by smoking. The method of injection causes the greatest feeling of euphoria; consequently, euphoria tends to take much longer when heroin is injected into the muscle or by snorting and smoking normally takes 15 minutes before these feelings occur. Following to the euphoric emotions, drowsiness starts to take place and usually mental function is dulled and this is because the use of opioids causes depression of the CNS. When mental function is dulled, this causes reaction time to decrease as well as cardiac output and respiration have a reduced effect. With prolonged heroin use, the body becomes accustomed to having this drug in its system and larger doses are required to give the euphoric feelings; accordingly, larger doses commonly cause over dose. Withdrawal effects arise when heroin depletes in the system leading to the side effects (Stenter & Mathieson, 2007).

Structure

Figure 4- Diamorphine undergoes a rapid metabolization process (Diagram adapted from Barret et al. 1991).

Diamorphine is deacetylated very rapidly to 6-acetylmorphine which is less lipid soluble than its precursor and accordingly, crosses the blood-brain barrier at a slower rate. Nevertheless, 6-acetylmorphine has a greater affinity to the opioids receptors situated in the brain (Morrison et al. 1991). Morphine is metabolized to morphine-6-glucuronide, morphine-3-glucuronide and normorphine as shown in figure 3, which is another metabolite of morphine; they are all secreted in the urine.

Side-Effects

Side effects of diamorphine are similar to morphine; dizziness, itching, perspiration, nausea and vomiting, constipation, drowsiness, decrease in alertness, miosis and in high doses respiratory depression is liable to occur (Smith & Beecher 1961).

Pharmacokinetic Properties

Diamorphine has a 2-3 minute half life is uncommonly detected in the blood due to its rapid conversion to 6-acetylmorphine (Rang, et al. 2007). The withdrawal symptoms begin after 6-12 hours. Accordingly, the particular withdrawal symptoms experienced consist of feelings of anxiety, insomnia; runny nose, perspiration, fever, diarrhoea, back and muscle pain, muscle spasms, dilation of the pupil and goose bumps (Stenter & Mathieson, 2007).

Codeine (3-methylmorphine)

How Codeine works

Codeine is another morphine analogue that has high affinity for the Mu (µ) type receptors and a considerably lower affinity to the Kappa (k) type receptors and the Delta (δ) type receptors. Codeine is less potent than morphine and is normally taken orally because it has a good absorption. It is quite commonly combined with ibuprofen, paracetamol and aspirin. This drug is useful in mild/moderate pain like headaches, back pain etc. and dependence does occur occasionally but it is not as common as morphine and diamorphine. It has some antitussive activity and is frequently used as a suppressant in cough medication, like codeine linctus (Reid, et al. 2006). People who are generally dependent on codeine have outside problems like depression or anxiety disorders. Codeine is of popular use in chronic pain sufferers and the reason people could become dependent is if their pain treatment is not helping to treat their pain effectively (Sproule, et al. 1999).

Structure

Codeine has a methyl group on position 3 of the hydroxyl group on the morphine structure. It is changed from -OH to -OCH3, as in figure 5 (Armstrong & Cozza, 2003).

Extra methyl group

Position 3

Figure 5- The structure of codeine with the extra methyl group on position 3 (Figure adapated from National Center for Biotechnology Information, 2010).

Side-Effects

Long term use of codeine can cause constipation (Bennett & Brown 2003) and it mainly has similar side effects to the other two opioids mentioned above.

Pharmacokinetic Properties

Codeine is metabolised to morphine and the glucuronides by the CYP3A4 and CYP2D6 enzymes (Nagar & Raffa, 2008) and undergoes first pass metabolism; accordingly, 10% is demethylated to form morphine. The half life of codeine is between 3-4 hours (Bennett & Brown 2003). Codeine is metabolized by the enzyme CYP3A4 to norcodeine and is also glucuroridated to codeine-6-glucuronide in the liver. In addition, codeine is also metabolized to morphine by the enzyme CYP2D6 and the metabolism of morphine occurs, where it is glucuronidated to morphine-3-glucuronide and morphine-6-glucuronide which is involved in the outcome of pain relief and the kidney is in charge of the glucuronide removal as shown in figure 6. However, accumulation of the glucuronides, perhaps in an over dose, could have dire effects on the kidney (Nagar & Raffa 2008).

Figure 6- Diagram showing the metabolism of codeine in the liver by the enzymes CYP3A4 and CYP2D6. The glucuronides are excreted by the kidney (Adapted from Nagar & Raffa 2008).

CONCLUSION

Opioids are very commonly used to treat different types of acute and chronic pain. The production of metabolites from each drug has great importance in the drug efficacy and tolerability in patients. To avoid opioid dependence, drugs that do not have active metabolites may be prescribed for acute and chronic pain cases (Nagar & Raffa 2008). Lots of drugs can cause dependence; however, the family of opioids were explored, three of the drugs were discussed; morphine, diamorphine and codeine, this enabled the similarities, differences and the root of drug addiction on a pharmacological basis to be displayed; consequently, when the body's homeostasis is unbalanced, the CNS tries to alter the body back to a normal level. In drug dependence, withdrawal is common and by using adenosine agonists, these can help with the withdrawal symptoms; accordingly, more research is being undertaken to help those suffering from drug abuse (Rang, H.P, et al. 2007).

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