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Opioids

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Carol McLoughlin

Opioids were first derived from the opium plant. Nowadays most opioids are synthetically prepared; however, the structure resembles that of the original plant's alkaloids (Karch, 2003).

Opioids were first derived from the opium plant. Nowadays most opioids are synthetically prepared; however, the structure resembles that of the original plant's alkaloids (Karch, 2003).

Opioids are also known as opiates and narcotics and are used mainly to relieve moderate to severe pain. They also have a sedative effect, inducing sleep, and are used as a preoperative medication and as an analgesia during anaesthesia. Repeated administration may cause physical and psychological dependence hence the stronger formulations are controlled by the Misuse of Drugs Act 1971.

In this article two key areas in understanding the pharmacology of opioids are considered; pharmacokinetics and pharmacodynamics.

- Pharmacokinetics is concerned with the routes of administration and the processes of absorption, distribution, metabolism and excretion of drugs

- Pharmacodynamics looks at how drugs modify the function of body organs through their effects at the level of individual cells.

Pharmacokinetics
Opioids may be administered via the routes described in the box.

Absorption

Absorption refers to the process of getting the drug from the site of administration into the blood circulation. The main principles of drug absorption are:

- The disintegration and dissolution of tablets

- Passive diffusion down a concentration gradient

- The cell membrane and fat-solubility of drugs

- Active transport of ions and water-soluble drugs

- Presystemic metabolism (McGavock, 2003).

Tablets and liquid formations of drugs start to disintegrate and dissolve in the stomach, the rate of breakdown being affected by the stomach contents. Hence, if drugs are taken with or after food they will take longer to pass through the stomach and into the intestine. Enteric-coated drugs prevent early disintegration in the stomach which is useful to prevent gastric irritation and also to prolong the effect of the drug when slow release is preferable.

Most orally administered drugs are absorbed from the small intestine, which has a large surface area. The rate of absorption depends on three factors:

- The concentration gradient

- The surface area for absorption

- Fat-solubility of the drug.

Drugs diffuse from the area of higher concentration in the intestine into the bloodstream. The more lipid soluble the drug the more readily it will pass through the cell membrane of the intestinal wall.

The cell membrane acts as a gateway, allowing only certain molecules to gain entry into the cell. Fat-soluble molecules gain entry easier than water-soluble molecules. Morphine is relatively insoluble in lipid and does not therefore bind well into the easier absorbed molecular form. It has moderate oral efficacy while pethidine is more lipid soluble and hence is more effective orally.

Distribution

Drugs are diluted and transported around the body in the systemic blood circulation. Transport to a certain point depends on perfusion to that area or organ. Organs such as the brain, heart, kidneys and lungs are well perfused and hence drug concentration at these sites is reached quicker. As the concentration of the drug in the plasma is greater than that in the interstitial fluid the drug passes from the capillaries into the interstitial fluid in an effort to establish equilibrium. In the interstitial fluid the drug has access to the tissue cell receptors on which the drug exerts its therapeutic effect.

Drug action also depends on the readiness of the drug to bind with plasma proteins such as albumin. The drug protein combination cannot cross cell membranes and hence affects uptake of the drug by cell receptors. If the drug is tightly bound to the plasma proteins and released slowly it will have a long duration of action.

Metabolism

Once drugs enter the bloodstream they are carried via the portal vein to the liver. Further breakdown of oral drugs occurs in the liver due to the action of a system of enzymes called the cytochrome P450 oxidase system or CYP.

In the liver most drugs are inactivated or rendered less active through oxidation (adding of oxygen ions), reduction or hydroxylation (adding of OH ions). The fraction of the drug reaching the systemic circulation is known as the bioavailability of a drug.

After phase 1 metabolism many drugs are then carried to the kidneys where they are excreted in the urine. However, some drugs are not water soluble enough for excretion and undergo further metabolism in the liver.

In phase 2 metabolism the drug or its partially metabolised form is chemically bound or conjugated to a number of molecules including glucuronide as in the case of morphine which becomes morphine-6-glucuronide. In this form it becomes more active than morphine (McGavock, 2003).

Drugs may react with the enzyme system to either reduce CYP enzyme action (inhibition) or enhance it (induction). This is important if two drugs are metabolised with the same enzymes as the metabolism of one drug may be speeded up as a result of the induction effect x of the other. This will reduce the plasma concentration quicker and may prevent a therapeutic drug level building up. Conversely inhibition of CYP may slow down metabolism allowing toxic levels to build up. The use of opioids, particularly pethidine, should be avoided in patients taking monoamine-oxidase inhibitors (MOAI) antidepressants. Other interactions are listed in the BNF (BNF 47, March 2004).

Half-life of opioids

The half-life of a drug is the time it takes for the plasma concentration level to fall to half of its original value. Half-life is important in producing a therapeutic effect and determining the intervals between doses. The half-life is influenced by absorption, distribution and metabolism and excretion of the drug.

Excretion

Drugs may be removed from the body via the skin, saliva, lungs, bile and urine and faeces. However, most excretion takes place in the kidneys. Twenty per cent of the drug content in blood passing through the kidneys diffuses from the glomerulus into the renal tubules. The remaining 80% exits the glomerulus into the efferent arterioles and is finally reabsorbed in the distal tubules with water and excreted in the urine. Renal function is thus important in eliminating drugs from the body. If renal function is impaired there is a risk of build up of the drug and therefore doses should be amended accordingly by either reducing the dose or prolonging the interval between doses.

Pharmacodynamics
Cellular level

Opioids act as a chemical signal at cell level, binding with specific receptors on the cell membrane. These receptors respond to naturally occurring peptins, the endorphins and the enkephalins. These peptins or neurotransmitters are released in times of stress. Opioid receptors are found in the brain and spinal cord, on peripheral nerves and on cells in the gastrointestinal (GI) tract.

There are four types of opioid receptors: mu (m), kappa (k), beta (b), and sigma (s). The mu receptors are pain-blocking receptors and also are associated with respiratory depression, feelings of euphoria, decreased GI activity, pupil constriction, and the development of physical dependence. The kappa receptors are associated with analgesia and with pupil constriction, sedation and dysphoria. Enkephalins react with beta receptors in the periphery to modulate pain transmission. Sigma receptors cause pupil dilation and have also been associated with hallucinations, dysphoria and psychoses (Karch, 2003).

The effect achieved by different opioids will depend on the type of receptors with which the drug reacts. Effects other than analgesia may therefore result depending on the types of opioid receptors affected by each drug. Choice of opioid will thus depend on the desired effect versus the anticipated side-effects. For example, opioids with a significant sedative effect such as diamorphine may be inappropriate in mobile patients with chronic pain but may be appropriate in late stages of a terminal illness.

Pain perception

Injured cells release chemicals, for example kinins and prostagladins, which stimulate specific sensory nerves which generate impulses producing sensations of pain.

Nerve impulses are carried by small diameter C-fibres from the site of injury to the substantia gelatinosa in the dorsal horn of the spinal cord. From the dorsal horn the impulses are transmitted upwards via the thalamus to the cortex of the brain where the pain registers (gate control theory). Opioids bind with receptors along the spinal cord/substantia gelatinosa and prevent the impulse transmitting upwards to the brain (Hopkins and Kelly, 1999). The transmission of impulses operates in both ascending and descending pathways. Messages relayed from the cortex and limbic system in the brain down the spinal cord have an inhibitory effect and influence the subjective nature of pain.

Side-effects

The most common side-effects include nausea, vomiting, constipation and drowsiness. More serious side-effects include respiratory depression possibly leading to apnoea and cardiac arrest.

The GI effects result from stimulation of the chemoreceptor trigger zone (CTZ). Neurological effects such as light-headedness, dizziness, psychoses, pupil constriction and impaired mental processes may result from stimulation of opioid receptors in the cerebrum, limbic system and hypothalamus (Karch, 2003).

Genitourinary effects including urethral spasm, urinary retention, hesitancy and loss of libido are related to direct receptor stimulation or CNS activation of the sympathetic pathways.

McGavock, H. (2003) How Drugs Work. Abingdon, Oxon: Radcliffe Medical Press.

Karch, A.M. (2003)Focus on Pharmacology (2nd edn). Philadelphia, Pa: Lippincott, Williams and Wilkins.[QQ]

Hopkins, S.J., Kelly, J.C. (1999)Drugs and Pharmacology for Nurses (13th edn). London: Churchill Livingstone.

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