Analgesia and analgesic drugs

Mohanad AlBayati
Mohanad AbdulSattar Ali Al-Bayati, BVM&S, MS. Physiology, PhD. Assistant Professor of Pharmacology and Toxicology Department of Physiology and Pharmacology College of Veterinary Medicine University of Baghdad Al-Ameria, Baghdad Phone: 0964 7700766550 E. Mail: aumnmumu@covm.uobaghdad.edu.iq aumnmumu@yahoo.com

Three category of these collections

Analgesic Antipyretic Anti-inflammatory (at higher doses)

Analgesia and analgesic drugs

Relief-Relieve of pain
Pain is a direct response to an untoward event associated with tissue damage, such as injury, inflammation or cancer, It can also occur as a consequence of brain or nerve injury (e.g. following a stroke or herpes infection). There are two components, involved in pain states:

1. The peripheral nociceptive afferent neuron, which is activated by noxious stimuli 2. The central mechanisms by which the afferent input generates a pain sensation.

The termination of afferent fibers in the six laminae of the dorsal horn of the spinal cord.

Summary of modulatory mechanisms in the nociceptive pathway. 5-HT, 5-hydroxytryptamine; BK, bradykinin; CGRP, calcitonin gene-related peptide; NA, noradrenaline; NGF, nerve growth factor; NO, nitric oxide; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; SP, substance P.

The descending control system, showing the main sites of action of opioids on pain transmission.

Modulation of pain transmission Transmission in the dorsal horn is subject to various modulatory influences, constituting the 'gate control' mechanism. Descending pathways from the midbrain and brain stem exert a strong inhibitory effect on dorsal horn transmission. Electrical stimulation of the midbrain periaqueductal grey area causes analgesia through this mechanism. The descending inhibition is mediated mainly by enkephalins, 5hydroxytryptamine, noradrenaline and adenosine . Opioids cause analgesia partly by activating these descending pathways, partly by inhibiting transmission in the dorsal horn, and partly by inhibiting excitation of sensory nerve terminals in the periphery. Repetitive C-fibre activity facilitates transmission through the dorsal horn ('wind-up') by mechanisms involving activation of NMDA and substance P receptors.

Mechanisms of pain and nociception

Nociception is the mechanism whereby noxious peripheral stimuli are transmitted to the central nervous system. Pain is a subjective experience not always associated with nociception. Polymodal nociceptors (PMNs) are the main type of peripheral sensory neuron that responds to noxious stimuli. The majority are non-myelinated C fibres whose endings respond to thermal, mechanical and chemical stimuli. Chemical stimuli acting on PMNs to cause pain include bradykinin, protons, ATP and vanilloids (e.g. capsaicin). PMNs are sensitized by prostaglandins, which explains the analgesic effect of aspirin-like drugs, particularly in the presence of inflammation. PMN neurons release glutamate (fast transmitter) and various peptides (especially substance P) that act as slow transmitters. Peptides are also released peripherally and contribute to neurogenic inflammation. Neuropathic pain, associated with damage to neurons of the nociceptive pathway rather than an excessive peripheral stimulus, is frequently a component of chronic pain states and may respond poorly to opioid analgesics.

ANALGESIC DRUGS
Centrally acting drugs
MORPHINE-LIKE DRUGS

Opioid: The term opioid applies to any substance, whether endogenous or synthetic, that produces morphine-like effects that are blocked by antagonists such as naloxone. Opium is an extract of the poppy Papaver somniferum, which has been used for social and medicinal purposes for thousands of years as an agent to produce euphoria, analgesia and sleep, and to prevent diarrhoea. It was introduced in Britain at the end of the 17th century, Opium contains many alkaloids related to morphine

Phenylpiperidine series. Pethidine the first fully synthetic morphinelike drug, was discovered accidentally. It are more potent and shorteracting derivatives, or for chronic pain, to treat severe pain or as an adjunct to anaesthesia. Methadone series. Methadone, It is longer acting than morphine but otherwise very similar to it. Dextropropoxyphene was used clinically for treating mild or moderate pain (no longer recommended on account of cardiotoxicity). Benzomorphan series. pentazocine and cyclazocine. These drugs differ from morphine in their receptor-binding profile, and so have somewhat different actions and side effects. Thebaine derivatives. Etorphine is a highly potent morphine-like drug used mainly in veterinary practice. Buprenorphine resembles morphine but is a partial agonist, its maximal effect is less than that of morphine, and it antagonizes the effect of other opiates.

Analgesic opioid receptor :, ,

PHARMACOLOGICAL ACTIONS

Effects on the central nervous system Analgesia Euphoria

Respiratory depression Depression of cough reflex

Nausea and vomiting Pupillary constriction

Histamine release, causing bronchoconstriction and hypotension

Effects on the gastrointestinal tract Morphine increases tone and reduces motility in many parts of the gastrointestinal system, resulting in constipation

Opioid receptors
-Receptors are thought to be responsible for most of the analgesic effects of opioids, and for some major unwanted effects (e.g. respiratory depression, euphoria, sedation and dependence). Most of the analgesic opioids are -receptor agonists. -Receptors are probably more important in the periphery but may also contribute to analgesia. -Receptors contribute to analgesia at the spinal level and may elicit sedation and dysphoria, but produce relatively few unwanted effects and do not contribute to dependence. Some analgesics are relatively selective. -Receptors are not true opioid receptors but are the site of action of certain psychotomimetic drugs, with which some opioids interact.

All opioid receptors are linked through G-proteins to inhibition of adenylyle cyclase. They also facilitate opening of potassium channels (causing hyperpolarisation) and inhibit opening of Calcium channels (inhibiting transmitter release).

OTHER OPIATE ANALGESICS

Diamorphine (heroin) is the diacetyl derivative of morphine. it crosses the bloodbrain barrier more rapidly than morphine. It is said to be less emetic than morphine, Its only advantage over morphine is its greater solubility, Codeine is more reliably absorbed by mouth than morphine, but has only 20% or less of the analgesic potency. Codeine has marked antitussive activity and is often used in cough mixtures Dihydrocodeine is pharmacologically very similar to morphine Pethidine is very similar to morphine in its pharmacological effects, except that it tends to cause restlessness rather than sedation, and it has an additional antimuscarinic action that may cause dry mouth and blurring of vision. Fentanyl and sufentanil are highly potent phenylpiperidine derivatives, with actions similar to those of morphine but with a more rapid onset and shorter duration of action, particularly sufentanil. Their main use is in anaesthesia. Etorphine is a morphine analogue of remarkable potency, more than 1000 times that of morphine Methadone is also pharmacologically similar to morphine, the main difference being that its duration of action is considerably longer Pentazocine is a mixed agonist-antagonist Tramadol, a metabolite of the antidepressant trazodone (Ch. 39), is widely used as an analgesic for postoperative pain

OPIOID ANTAGONISTS Nalorphine is closely related in structure to morphine, was the first specific antagonist Naloxone was the first pure opioid antagonist, with affinity for all three opioid receptors. It blocks the actions of endogenous opioid peptides as well as those of morphine-like drugs

Naltrexone is very similar to naloxone but with the advantage of a much longer duration of action (half-life about 10 hours)
OTHER ANALGESIC DRUGS Tricyclic antidepressants, particularly imipramine and amitriptyline

Antiepileptic drugs, Carbamazepine, gabapentin and occasionally phenytoin

Ketamine, a dissociative anaesthetic lignocaine , a local anaesthetic drug

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

The NSAIDs, sometimes called the aspirin-like drugs. They provide symptomatic relief from pain and swelling PHARMACOLOGICAL ACTIONS

An anti-inflammatory effect: modification of the inflammatory reaction. The NSAIDs reduce mainly those components of the inflammatory and immune response in which prostaglandins, mainly derived from COX-2, play a significant part. These include: vasodilatation oedema (by an indirect action: the vasodilatation facilitates and potentiates the action of mediators such as histamine that increase the permeability of postcapillary venules) pain, again potentiating other mediators, such as bradykinin

An analgesic effect: reduction of certain types of

(especially inflammatory) pain, The NSAIDs are effective against mild or moderate pain

An antipyretic effect: lowering of body temperature

when this is raised in disease (i.e. fever). Normal body temperature is regulated by a center in the hypothalamus that controls the balance between heat loss and heat production. Fever occurs when there is a disturbance of this hypothalamic 'thermostat', which leads to the set point of body temperature being raised by increase interleukin-1 releases prostaglandins . NSAIDs 'reset' this thermostat. Once there has been a return to the normal set point, the temperature-regulating mechanisms (dilatation of superficial blood vessels, sweating, etc.) then operate to reduce temperature. Normal body temperature in humans is not affected by NSAIDs.

ANALGESIC EFFECT
The NSAIDs are effective against mild or moderate pain, especially that arising from inflammation or tissue damage. Two sites of action have been identified. First, peripherally, they decrease production of the prostaglandins that sensitise nociceptors to inflammatory mediators such as bradykinin and they are therefore effective in arthritis, bursitis, pain of muscular and vascular origin, toothache, the pain of postpartum states and the pain of cancer metastases in bone-all conditions that are associated with increased local prostaglandin synthesis. the peripheral effects, there is a second, less well-characterised central action, possibly in the spinal cord. Inflammatory lesions increase prostaglandin release within the cord, causing facilitation of transmission from afferent pain fibres to relay neurons in the dorsal horn.

MECHANISM OF CYCLO-OXYGENASE INHIBITORY ACTION

the main actions of NSAIDs were bought about through inhibition of arachidonic acid oxidation by the fatty acid COXs

Prostaglandin Biosynthesis, Function, and Pharmacologic Inhibition.

Control of vascular tone and platelet activation by thromboxanes and prostacyclins

Pharmacological Effects (contd)

Diverse group of chemicals, but all inhibit cyclooxygenase. Resultant inhibition of PG synthesis is largely responsible for their therapeutic effects. But, inhibition of PG synthase in gastric mucosa GIT damage (dyspepsia, gastritis).

Common Adverse Effects

Platelet Dysfunction Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects) Acute Renal Failure in susceptible Sodium+ water retention and edema Analgesic nephropathy Prolongation of gestation and inhibition of labor. Hypersenstivity (not immunologic but due to PG inhibition) GIT bleeding and perforation

NSAID
Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils

Leukocyte-Endothelial Interactions

Capillary Obstruction Ischemic Cell Injury

Proteases + Oxygen Radicals

Endo/Epithelial Cell Injury

Mucosal Ulceration

Cyclo-oxygenase (COX)

Exists in the tissue as constitutive isoform (COX-1). At site of inflammation, cytokines stim the induction of the 2nd isoform (COX-2). Inhibition of COX-2 is thought to be due to the antiinflammatory actions of NSAIDs. Inhibition of COX-1 is responsible for their GIT toxicity. Most currently used NSAIDs are somewhat selective for COX-1, but selective COX-2 inhibitors are available.

COX (contd)
Celecoxib, etoricoxib, valdecoxib selective COX-2 inhibitors. Have similar efficacies to that of the non-selective inhibitors, but the GIT side effects are decr by ~50%. But, no cardioprotection and there is actually increased MI.

SOME IMPORTANT NSAIDS

ASPIRIN Aspirin (acetylsalicylic acid) was among the earliest drugs synthesised, and is still one of the most commonly consumed drugs worldwide. It is relatively insoluble, but its sodium and calcium salts are readily soluble. A newer related drug is diflunisal

For analgesia (e.g. headache, dysmenorrhoea, backache, bony metastases, postoperative pain): short-term use: aspirin, paracetamol or ibuprofen chronic pain: more potent, longer lasting drugs (e.g. diflunisal, naproxen, piroxicam) to reduce the requirement for narcotic analgesics (e.g. ketorolac postoperatively). For anti-inflammatory effects (e.g. rheumatoid arthritis and related connective tissue disorders, gout and soft tissue disorders). Note that there is substantial individual variation in clinical response to NSAIDs and considerable unpredictable patient preference for one drug rather than another. To lower temperature (antipyretic): paracetamol

The Salicylates - Aspirin

Effect on Respiration: triphasic 1. Low doses: uncoupling phosphorylation CO2 stimulates respiration. 2. Direct stimulation of respiratory center Hyperventilation resp. alkalosis renal compensation 3. Depression of respiratory center and cardiovascular center BP, respiratory acidosis, no compensation + metabolic acidosis also

PARACETAMOL Paracetamol (called acetaminophen) is one of the most commonly used nonnarcotic analgesic-antipyretic agents, and is a component of many over-the-counter proprietary preparations

Paracetamol has potent analgesic and antipyretic actions but rather weaker antiinflammatory effects than other NSAIDs. It may act through inhibition of a central nervous system-specific cyclo-oxygenase (COX) isoform such as COX-3, although this is not yet conclusive. It is given orally and metabolised in the liver (half-life 2-4 hours). Toxic doses cause nausea and vomiting, then, after 24-48 hours, potentially fatal liver damage by saturating normal conjugating enzymes, causing the drug to be converted by mixed function oxidases to N-acetyl-p-benzoquinone imine. this compound reacts with cell proteins and kills the cell.

Ibuprofen Less anti-inflammatory activity (AIA) than indomethacin, analgesic, antipyretic well absorbed, 99% plasma protein bound, t 1/2=2 hrs. rheumatoid arthritis (RA), osteo-arthrosis, for mild- moderate pain. well tolerated, few GI effects. Indomethacin Potent AIA, anti-pyretic, some analgesic effect. uncouples oxidative - phosphorelation in cartilage and hepatic mitochondria. Readily absorbed, 90% plasma protein bound, t 1/2= 4 -1 2 h r s . For rheumatoid arthritis RA when ASA ineffect , ankylosing, spondylitis, acute gout, patent ductus art. frontal headache, GI and hematopoietic probs. antagonized furosemide Sulindac rheumatoid arthritis RA, osteoarthrosis GI effect, few headaches, (1/2 =7 hr as potent), well absorbed

Naproxen
Slightly Less anti-inflammatory activity , analges, antipyretic , well a b s o r b e d , 98% plasma protine bound t 1/2 = 10 - 17 hrs . Potent anti-inflammatory activity , t1/2 = 1-2 hrs RA, osteoarthritis, ankylosing spondylitis GI effect s c o m m o n Good anti-inflammatory activity, long plasma t 1/2=20 - 40 hrs. RA, osteoarthritis better tolerated than ASA. Some GI problem

Diclofenac

Piroxicam

Oxaproxin
Good anti-inflammatory activity, long plasma t 1/2 = 50 -60 hrs, 1 / day RA, osteoarthritis, ankylosing spondylitis

CELECOXIB AND ETORICOXIB Selective cyclooxygenase 2 (COX - 2) inhibitors Celecoxib and etoricoxib are symptomatic relief in the treatment of osteoarthritis and rheumatoid arthritis Aspirin - irreversibly acetylates cyclooxygenase 1 and 2 Most other NSAIDs - reversibly, competitively inhibit cyclooxygenase 1 and 2

. Know the fatty acid precursor from which the 2 -series of prostaglandins ( PG ) is made . . Know there 4 major enzyme pathways for production of arachidonic acid metabolites . . Understand the actions of the enzymes phospholipase and cyclooxygenase . Understand the difference between cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2).

cyclooxygenase 2 isoforms, cyclooxygenase 1 (COX- 1 ) and cyclooxygenase 2 (COX- 2) . COX- 1 is normally present in most tissues . COX- 2 is normally present in brain and kidney and is induced in most tissues during inflammation and injury Lipoxygenase Pathway Agents which have been tested and found effective at reducing the occurrence of asthmatic symptom and the need for beta-agonists to produce bronchiolar dilation include zileuton, a 5 -lipoxygenase enzyme inhibitor, and zafirlukast and montelukast, competitive leukotriene receptor blockers.

Clinical uses of analgesic drugs

Analgesics are used to treat and prevent pain, for example: o pre- and postoperatively o common painful conditions including headache, labour, trauma, burns o many medical and surgical emergencies (e.g. myocardial infarction and renal colic) o terminal disease (especially metatastic cancer). Opioid analgesics are used in some non-painful conditions, for example acute heart failure (because of their haemodynamic effects) and terminal chronic heart failure (to relieve distress). The choice and route of administration of analgesic drugs depends on the nature and duration of the pain. A progressive approach is often used, starting with non-steroidal anti-inflammatory drugs (NSAIDs), supplemented first by weak opioid analgesics and then by strong opioids. In general, severe acute pain is treated with strong opioids (e.g. morphine, fentanyl) given by injection. Mild inflammatory pain (e.g. sprains, mild arthralgia) is treated with NSAIDs (e.g. ibuprofen) or by paracetamol supplemented by weak opioids (e.g. codeine, dextropropoxyphene). Severe pain (e.g. cancer pain) is treated with strong opioid given orally, intrathecally, epidurally or by subcutaneous injection. Patient-controlled infusion systems are useful postoperatively. Chronic neuropathic pain is often unresponsive to opioids and is treated with tricyclic antidepressants (e.g. amitriptyline) or anticonvulsants (e.g. carbamazepine, gabapentin).

 NSAID including paracetamol are useful for musculoskeletal and dental pain and for uterine origine pain. They reduce opioid requirements in acute and chronic (bone metastasis) pain. Weak opioids (e.g. codeine) combined with paracetamol are useful in moderately severe pain if non-opioids are not sufficient. Tramadol (a weak opioid with additional action on 5hydroxytryptamine and noradrenaline uptake) is an alternative.