Analgesics2009

Pharmacology of

Analgesia

Opium is a narcotic formed from the latex(juice) released by lacerating the immature seed pods (fruits) of Papaver Papaver somniferum.somniferum.

Opium contains up to 12% morphine, an opiate alkaloid, which is most frequently processed chemically to produce heroin for the illegal drug trade.

Opioid AnalgesicsOpioid AnalgesicsOpioid AnalgesicsOpioid Analgesics

Opioid AnalgesicsOpioid AnalgesicsOpioid AnalgesicsOpioid Analgesics

µ- receptors are most important

CNS contains opioid peptides – enkephalins, endorphins, dynorphins, orphanin/nociceptin

Four receptors subtypes – µ, κ, ∂, N/OFQ

(Gi-coupled - AC inhibition - decrease cAMP)

Presynaptic and postsynaptic inhibition

OpioidOpioidss

pharmpharmacologyacology

AnalgesiaAnalgesia An analgesicanalgesic (also known as a painkiller) is any drug used to relieve pain (achieve analgesia)

Tissue injury lead to activation of nociceptors (pain receptors) by differrent substances released by injured tissues.

Thermal Chemical

MechanicalElectrical

Activated pain receptors generate impulses that go into spinal cord through primary afferent neurons.

Opioid ReceptorsOpioid Receptors

Opioid agonists inhibit the release of excitatory transmitters from these primary afferents, and they directly inhibit the dorsal horn pain transmission neuron. Thus, opioids exert a powerful analgesic effect directly on the spinal cord.

It is well established that the analgesic effects of opioids arise from their ability to directly inhibit the ascending transmission of nociceptive information from the spinal cord dorsal horn and to activate pain control circuits that descend from the midbrain to the spinal cord dorsal horn.

Morphine inhibits the release of:gonadotropin-releasing hormone (GnRH)corticotropin-releasing hormone (CRH) thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and b-endorphin; As a result plasma concentrations of testosterone and cortisol decline.

Convulsions• With most opioids, convulsions occur only at doses

far in excess of those required to produce profound analgesia.

• High doses of morphine and related opioids produce convulsions

SedationDrowsiness and clouding of mentation are common effects of opioids. There is little or no amnesia. Sleep is induced by opioids more frequently in the elderly than in young, healthy individuals. Ordinarily, the patient can be easily aroused from this sleep.

Respiratory depressionAll of the opioid

analgesics can produce significant respiratory

depression by inhibiting brainstem respiratory mechanisms acting on

receptors. The respiratory depression is

dose-related. Opioid-induced respiratory

depression remains one of the most difficult

clinical challenges in the treatment of severe pain.

Cardiovascular system

Most opioids have no significant direct effects on the heart

and, other than bradycardia, no major effects on cardiac rhythm.

Smooth muscles• Longitudinal relaxes• Circular constricts:- GI: peristalsis, constipation, cramping- GU: urinary retention- Bile duct : pressure(OA contraindicated - in biliary colic)- Pupils: miosis

Morphine and related opioids also depress the cough reflex at least in part by a direct effect on a cough center in the medulla.

When we use OA for cough suppression?

Cough is due to foreign body in the lungs

Cough is due to lung cancer Cough is due to pleura

irritation by broken ribs parts after trauma

The opioid analgesics can activate the brainstem chemoreceptor trigger zone to produce nausea and vomiting(action on dopamine receptors)

Histamine releaseMorphine and some other opioids provoke release of histamine, which sometimes plays a large role in the hypotension.

Morphine pharmacokinetics• Glucoronidation• Morphine-6-glucuronide is highly active• Caution in renal dysfunction

Type Drug name PropertiesFull agonist Mepiridine

Methadone

MorphineFentanyl subgroupLevorphanol

Antimuscarinic action(atropine-like action), no miosis, tachycardia, no spasm of smooth muscles.

Long half-life, use for maintenance of opiate addicts

Partial agonists

Codeine

PropoxypheneHydrocodone

AntitussiveAnalgesic in combination with NSAIDsand other drugs (Solpadeine)

Type Drug name PropertiesMixed opioid agonist-antagonists

Nalbuphine k-agonist – spinal analgesia, dysphoriam – antagonist – precipitation of withdrawal

Antagonists Naltrexone

NaloxoneNalmefene

IV, reversal of respiratory depression, used in opiate addiction

Problems with opioid therapyProblems with opioid therapy1.1. Acute toxicity(classic triad):Acute toxicity(classic triad):- ComaComa- Pinpoint pupilsPinpoint pupils- Respiratory depressionRespiratory depressionManagement of acute toxicity:Management of acute toxicity:- SupportiveSupportive- IV naloxoneIV naloxone2.Tolerance(pharmakodynamic)2.Tolerance(pharmakodynamic) – decrease of drug efficiency over time with

multiple administrations. This is due to increased cAMP production in cells. Tolerance can be overcome by dose increasing . Marked tolerance may develop to the analgesic, sedating, and respiratory depressant effects, but not to the miotic, convulsant, and constipating actions.

3.Dependence3.Dependence(psychological and physical symptoms on withdrawal)

4.Withdrawal: 4.Withdrawal: sweating, lacrimation, rhinorrhea, anxiety, restlessness, insomnia, dilated pupils, tachycardia, hypertension, nausea/vomiting, abdominal pain, diarrhea,muscle aches. Opioid withdrawal is not life threatening. Emergence of withdrawal symptoms varies with half-life of the particular opioid; within 6-12 hours after the last dose of morphine/hydromorphone/oxycodone or 72-96 hours following methadone. Duration and intensity of withdrawal symptoms can be variable and are related to clearance of the drug; withdrawal from morphine is short (5-10 days) but more protracted with methadone.

Management of withdrawal

•Supportive•Clonidine•Methadone

Drug with specific action

Loperamide (Imodium) – antidiarrheal agentDextromethorphan – antitussive agentBoth are over-the-counter (OTC) drugs

NSAIDs• Non-steroidal anti-inflammatory drugs• NAIDs have analgesic, antipyretic and, in higher doses, anti-

inflammatory effects• Term "non-steroidal" is used to distinguish these drugs from

steroids, which have a similar anti-inflammatory action• NSAIDs are non-narcotic analgesics

BurnsChemical irritantsFrostbiteToxinsInfection by pathogensPhysical injuryImmune reactionsIonizing radiationForeign bodies

Tissue Injury

Activation of the arachidonic acid cascade

through membrane bound phospholipase A2 (PA2).

o Arachidonic acid is a polyunsaturated fatty acid that is present in the phospholipids of membranes of the body's cells.

o Enzyme phospholipase A2 (PLA2) release arachidonic acid from a phospholipid molecule

PLA2

Arachidonic

acid

NSAIDsInhibition

-vasoconstrictor - platelet aggregation.

- inhibit platelet aggregation-vasodilation

-↓ gastric acid secretion- ↑ gastric mucus secretion- hyperalgesia- pyrogenic

COX-1 is expressed in most tissues including platelets and GICOX-2 is inducible; is expressed in brain, kidney and in sites of inflamation.COX-1 generates prostanoids for "housekeeping" such as gastric epithelial cytoprotection, COX-2 is the major source of prostanoids in inflammation and cancer.

This distinction is overly simplistic, however; there are both physiologic and pathophysiologic processes in which each enzyme is uniquely involved and others in which they function coordinately. For example, endothelial COX-2 is the primary source of vascular prostacyclin (PGI2), whereas renal COX-2-derived prostanoids are important for normal renal development and maintenance of function.

COX-1- selective Non-selective COX-1,2

COX-2- selective

- Low-dose aspirin

- (up to 325 mg per day),

- 75 mg as therapeutic agent for MI prevention

All other:-Indomethacin-Ibuprophen-Naproxen-Diclofenac-Ketorolac-Piroxicam-Meloxicam

COXIBs:-rofecoxib-celecoxib-lumaricoxib-parecoxib-valdecoxib-etoricoxib

Nimesulide

1)Antipyretic2)Analgesic3)Anti-inflammatory

All NSAIDs, including selective COX-2 inhibitors, are antipyretic, analgesic, and antiinflammatory, with the exception of acetaminophen(paracetamol), which is antipyretic and analgesic but is largely devoid of antiinflammatory activity.

• Alleviate pain of low-to-moderate activity• Have no opioid-like effects on CNS• Pain arising from inflammation is controlled particularly well by

NSAIDs• Effective for menstrual pain• Lower body temperature by inhibiting PGE2 synthesis in

hypothalamic thermo regulating centers• Do not lower normal body temperature

Antiplatelet action Most notable for aspirin.Unlike other agents Aspirin is

irreversible inhibitor of COX(COX should be resynthesized)

No nucleus – no new COX synthesis – no new TXA2- no platelet activation- no thrombus formation

Acetaminophen(Tylenol, Panadol)• No inhibition of COX in peripheral tissues• Lack of significant anti-inflammatory action• Analgesic and antipyretic activity due to COX inhibition in CNS• No antiplatelet action• Not increase bleeding• Not cause Reye syndrime• Minimal GI distress

Adverse effectsHepatotoxicity in high dose

Adverse effects are generally quite similar for all of the NSAIDs:Central nervous system: Headaches, tinnitus(aspirin), and dizziness.

Cardiovascular: Fluid retention hypertension, edema, and rarely, congestive heart failure.

Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and ulcers or bleeding.(2,5% incidence in clinical trials)

Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia.

Hepatic: Abnormal liver function tests and rare liver failure.Pulmonary: Asthma.Rashes: All types, pruritus.Renal: Renal insufficiency, renal failure, hyperkalemia, and

proteinuria.

Coxibs controversy• Rofecoxib and valdecoxib was withdrawn from the

market because of increased cardiovascular mortality in chronic drug users• Overall mortality was higher in patients on coxibs in

clinical trials

NSAIDs cannot be used (are contraindicated) in the following cases: • Allergy to aspirin or any NSAID • Aspirin should not be used under the age of 16 years (associated

with Reye syndrome)• During pregnancy • During breast feeding • On blood thinning agents (anticoagulants) • Suffering from a defect of the blood clotting system (coagulation) • Active peptic ulcer

1)Salicylates Salicylic acidAspirin(ASA)Methyl salicylateSalsalateDiflunisalOlsalazineSulfasalazine.

5)Heteroayl acetic acid derivatives

TolmetinKetorolacDiclofenac

2)Para-aminophenol derivatives

Acetaminophen(paracetamol)

6)Propionic acid derivatives

IbuprofenNaproxenFenoprofenFlurbiprofenKetoprofen

3)Acetic acid derivates

IndomethacinSulindacEtodolac

6)Enolic acid derivates(oxicams)

PiroxicamMeloxicamLornoxicamothers

4)Fenamates Mefenamic acidFlufanamic acidMeclofenamic acid

7)Pyrazolon derivatives AnalgineAntipyrine Phenybutazone