Section 37 Analgesic Drugs

K.E. Lewis OPIOIDS

ORPHANIN-FQ SYSTEM

NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)

OTHER ANALGESIC AGENTS

Paracetamol Meptazinol Tramadol Clonidine FUTURE DEVELOPMENTS Cannabinoids

Nicotinic acetylcholine receptor agonists Other centrally mediated contenders Peripherally mediated contenders

SPECIFIC PHARMACOLOGY Alfentanil Codeine Fentanyl Morphine Remifentanil Naloxone Diclofenac Ibuprofen Ketorolac

Opioids

'Opiate' is a specific term to describe drugs derived from the opium poppy (Papaver somniferum). 'Opioid' describes naturally occurring, semisynthetic and synthetic compounds that produce analgesic effects by combining with opioid receptors and that are, therefore, antagonized by naloxone.

Structure

The opioids have a variety of structural bases. Morphine is a phenanthrene derivative having four rings (Figure AN.1). Rings A and B are coplanar; rings C and D are perpendicular to the A-B plane. Many opioids are analogues of morphine either occurring naturally or synthesized from them.

The other opioid structures are based on phenylpiperidine, methadone, benzomorphan and thebaine. Examples of these are shown in Figure AN.2.

STRUCTURAL CLASSIFICATION OF OPIOID DRUGS

Naturally occurring

Morphine analogues morphine codeine

Semisynthetic

Morphine analogues diamorphine dihydrocodeine naloxone

Synthetic

Phenylpiperidines pethidine n-ch

Figure AN.1 Chemical structure of morphine

Figure AN.1 Chemical structure of morphine phenoperidine fentanyl alfentanil sufentanil remifentanil

Diphenylheptanes methadone dextropropoxyphene

Benzomorphan derivatives pentazocine levorphanol

Thebaine derivatives buprenorphine

Figure AN.2

Opioids may also be classified by their activity, affinity and efficacy at different receptors (Figure AN.3).

FUNCTIONAL CLASSIFICATION OF OPIOID DRUGS

Classification

Example

Affinity

Efficacy

Pure agonists

Morphine

High

100%

Partial agonists

Buprenorphine

Medium

Medium

Mixed agonist-antagonists

Pentazocine

Medium

Predominantly agonist

Nalbuphine

Medium

Predominantly agonist

Nalorphine

Medium

Predominantly antagonist

Pure antagonists

Naloxone

High

Mechanism of Action

Opioids act at opioid receptors in the central nervous system (CNS), which are stereo-specific for the laevorotatory isomer. Opioid receptors exist throughout the CNS, with particularly high concentrations in the peri-aqueductal grey area and the substantia gelatinosa of the spinal cord. They are also present outside the CNS and this may account for some of the other opioid effects such as gastro-intestinal effects. There are three distinct opioid receptors identified by their prototype agonists—OP3 |i, OP2 k and OP1 5. All three receptors have now been successfully cloned and their amino acid sequence defined. The OP classification is the most recent classification scheme for opioid receptors.

A fourth variant, a, was originally classified as an opioid receptor. The selective agonist, N-allyl nometazocine (SKF 10047) produces mydriasis, tachypnoea, tachycardia and delirium. The a receptor is no longer classified as an opioid receptor as it does not meet the full criteria notably:

• It has a high affinity binding for phencyclidine and related compounds

• The a mediated effects are not reversed by naloxone

• a receptors are stereo-specific for dextro-rotatory isomers

In common with many receptors, a number of subtypes of opioid receptors (two OP3 three OP2 (k) and two OP1 (5)) have been identified. Initially it appeared that was responsible for supraspinal analgesia, and |i2 for spinal analgesia, respiratory depression and constipation, but this distinction is now in doubt. The clinical effects attributed to the receptors are shown in Figure AN.4.

Opioid analgesics act at both supraspinal and spinal levels. Supraspinal action may activate descending inhibitory pathways. In the spinal cord, the primary site for nociceptive input is the dorsal horn. The greatest abundance of opioid receptors is in the substantia gelatinosa, where they are on the pre-synaptic terminals of primary afferent sensory neurones and on the dendrites of the post synaptic inter-neurones that modulate spinothalamic transmission. These pre synaptic receptors inhibit the release of substance P, glutamate and other neurotransmitters and post synaptic receptors decrease the evoked excitatory post synaptic potential (EPSP).

Opioid receptors are all G-protein coupled receptors. |i and 5 opioid receptors open potassium ion channels causing hyper-polarization and decreased neuronal firing. At the nerve terminal the action potential plateau will shorten and so reduce calcium ion influx and neurotransmitter release. In contrast, k receptors close calcium channels.

Natural ligands for the opioid receptors include neuropeptides such as enkephalins, endorphins and dynorphins. These exist in the CNS, and in peripheral sites such as the gastro-intestinal tract.

Pharmacokinetics

Figure AN.5 shows pharmacokinetic data for some opioids.

DISTRIBUTION AND ACTIONS AT OPIOID RECEPTORS

Actions

Receptors

OP3 (mu)

OP1 (delta)

OP2 (kappa)

Analgesia

Supraspinal

+ +

+ +

+ +

Spinal

+ +

+ +

+ +

Respiratory depression

+ +

+ +

+

Miosis

+ +

+ +

+ +

Gastro-intestinal motility decreased

+ +

+ +

0

Smooth muscle

+ +

+ +

0

Behaviour

Euphoria

Euphoria

Dysphoria

Sedation

+ +

+ +

+

Physical dependence

+ +

+ +

+

Other

Diuresis

Figure AN.4

PHARMACOKINETIC DATA FOR OPIOIDS

Bio-availability (%)

Protein binding (%)

pKa

Vd (l/kg)

(ml/kg/min)

t1/2ß (min)

Alfentanil

N/A

92

6.5

0.8

6

100

Codeine

60-70

7

5.4

11

168

Fentanyl

NA

85

8.4

4

13

96

Morphine

15-50

35

7.9

3.5

15

180

Remifentanil

N/A

70

0.35

50

15

Naloxone

2

45

2

25

Figure AN.5

Opioids are generally well absorbed from the gastro-intestinal tract. The majority are weak bases (pKa 6.5-9.3). They are highly ionized in the acid environment of the stomach and, therefore, poorly absorbed. Conversely, in the alkaline small intestine they are predominantly unionized and readily absorbed. Following absorption, many opioids undergo considerable first-pass metabolism in the intestinal wall and liver, resulting in low bioavailability. Alternative routes of administration may be used to improve bio-availability.

Distribution depends on lipid solubility, the degree of ionization and plasma protein binding. The lipid solubility is the main determinant of the speed of onset of action, because it determines the rate of entry into the CNS. Fentanyl is highly lipophilic and has a faster onset of action than the less lipophilic morphine. The degree of ionization depends on plasma pH and affects lipid solubility, plasma protein binding and distribution in tissue compartments. Most opioids have a volume of distribution several times greater than total body water and a total clearance similar to hepatic blood flow.

Opioids are predominantly inactivated in the liver, by conjugation to active or inactive metabolites. The metabolites are excreted in urine and bile. Morphine glucuronide is hydrolysed in the gastro-intestinal tract and most is reabsorbed (entero-hepatic circulation). Caution is required in patients with poor renal function as active metabolites, such as morphine 6-glucuronide, may accumulate and cause respiratory depression. Accumulation of norpethidine, a metabolite of pethidine with a half life five times that of the parent drug, causes agitation and convulsions. Diamorphine and codeine are also metabolized to morphine, which accounts for some of their pharmacological effects.

Clinical Effects

Central Nervous System

Opioids cause: • Analgesia

• Euphoria and dysphoria

• Nausea and vomiting

Opioids act against continuous, dull, poorly localized pain resulting from stimulation of supraspinal and spinal pathways. Morphine and other potent opioids cause a sense of contentment and well-being (euphoria) and allay anxiety. This is mediated by stimulation of OP3 receptors. Occasionally dysphoria may occur and this is due to stimulation of OP2 (k) receptors. If there is no pain morphine may cause dysphoria, manifest as restlessness and agitation. These, and nausea, are potential problems if given alone as a pre medicant. Nausea and vomiting are associated with dopamine and 5HT3 receptor stimulation in the chemo-receptor trigger zone of the area postrema. Nausea is dose-dependent but tolerance soon develops with repeated doses. Stimulation of OP3 and OP2 (k) receptors in the Edinger-Westphal nucleus causes miosis (pupillary constriction with pinpoint pupils).

Respiratory System Opioids cause:

• Respiratory depression

• Suppression of protective reflexes

Dose-related respiratory depression is mediated via OP3 receptors. Opioids reduce both the rate and the depth of breathing. Rate is most affected resulting in irregular, gasping respiration and apnoea with increasing opioid levels. The respiratory depression is the result of a decreased sensitivity of the respiratory centre to CO2 and this results in hyper-capnia. The hypoxic drive mediated through peripheral chemo-receptors may still be effective but cannot be relied upon. The stimulatory effect of the nociceptive input and the degree of respiratory depression can be balanced and, therefore, the safest way to give opioids is to titrate them against effect. Partial agonists may produce less respiratory depression if the ceiling effect for respiratory depression is lower than its analgesic effect. Drugs that are OP3 antagonists but OP2 (k) agonists may reverse the respiratory depressant effects while still producing analgesia via the OP2 (k) receptors. The suggestion that |ii receptors produce analgesia and |i2 respiratory depression has led to a suggestion that meptazinol produces less respiratory depression due to its higher affinity for ^ receptors. Opioids have an anti-tussive effect and codeine is used in various cough mixtures.

Was this article helpful?

0 0
Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

Get My Free Ebook


Post a comment