PHARMACOLOGY Opioid Analgetics

Nonsteroidal Antiinflammatory and Antipyretic-Analgesics

TOROKHTIN ALEXANDER

professor, doctor of medical science

biochemistry, pharmacology and physical treatment methods chair-chief

Classification of analgetics

Opioid (narcotic/morphine-like analgetics)

Non-opioid (non-narcotic/aspirin-like analgetics)

Opioid (narcotic/morphine-like analgetics)

Natural opium alkaloids

Semisynthetic opiates

Synthetic opiates

Opioid Analgetics. Opioides. Opium

Opium – a dark brown, resinous material obtained from poppy (Papaver somniferum) capsule.

Opioid Analgetics

Opium –contain two types of alkaloidsPhenantren derivatives

Morphin (~10% in opium)Codein (~0.5% in opium)Thebain (~0.2% in opium)

Benzoisiquinolone derivatives (nonanalgetic)Noscapine (~6% in opium)Papaverine (~1% in opium)

Natural opium alkaloids (Phenantren derivatives)

Morphine [R = H]

Codein [R = CH3]

Aethylmorphin [R =С2H5]

R

Opioid receptor transducer mechanisms

AC – adynylyl cyclase; Gi – coupling protein; cAMP – cyclic AMP

μ-receptor – is characterized by its

high affinity for morphin

κ-receptor – is defined by its high affinity for ketocyclazocine and

dynorphin Aδ-receptor – has high

affinity for leu/met enkephalins which are its endogenous ligands

ε-receptor – β-endorphins

σ-receptor – GIT and galucination action

Opioids natural mediatorsIn 1975 John Hughes – pentapeptides - enkephalines

Methionine enkephalin (met-enkepaline)

H3N – TRY – GLY – GLY – PHE – MET – COO–

Leucine enkepaline (leu-enkepaline)

H3N – TRY – GLY – GLY – PHE – LEU – COO–

In 1976 Roger Guillemin – in hypophisis – endorphins,

Met-enkephaline – (25amino acids residues) – GLN – COO–

Complex action Opioids and opioid antagonists

Agonists-antagonists (κ analgetics) –Nalorphin

PentazocineButorphanol

Partial/weak μ-agonist + κ-antagonists –Buprenorphine

Pure antagonists –Naloxone

NaltrexoneNalmefene

Action ascribed to different types of opioid receptors

Nature of interaction of opioid ligands with the tree major types of opioid receptors, along with equvalent

analgetic doses

Morphine1 [Pharmacological action]

CNS-analgesia (interacting primarily μ-opioid receptors)

-sedation-mood and subjective effects

-respiratory centre (depressing respiratory centre; death in morphine poisonong is due to respiratory failure)

-cough centre (morphin depressess cough centre)

-temperature regulating centre (depressed)

-vasomotor centre (depressess in high concentration)

1.chemoreceptor trigger zone2.Edinger Westphal nucleus

3.vagal centre4.central cortical areas and hippocamal

Morphine2 [Pharmacological action]

Neuro-endocrine (FSH, LH, ACTH levels are lowered)

CVS (morphin causes vasodilatation due to: a.histamin release; b.depression of vasomotor centre; c.direct action decrease tone of blood vessels)

GIT (the enteric plexus neurons and GI mucosa are rich in opioid receptors; morphine exerts effect on GI motility as well as on fluid dynamics across GI mucosa:a.direct action on intestines increase tone and segmentation but decreases propulsive

movements; tone of duodenum and colon may be increased to level of spasm; b.spasm of pyloric, ileocaecal and anal sphincters; c.decrease in all DI secretions due to

reduction in movement of water and electrolytes from mucosa to the lumen; d.central action causing inattention to defecation reflex, no tolerance develops to this action:

addicts remain chronically constipated)

Morphine3 [Pharmacological action]

Other smooth muscles-billiary tract (morphin couses spasm of sphincter Oddi, the intrabiliary

pressure is increased several fold)

-urinary bladder (tone of both detrusors and shphincter muscle is increased leads to urinary urgency and difficulty in micturition)

-uterus (action is clinically insignificant, but may slightly prolong labour)

-bronchi (releases histamine; may cause bronchoconstriction in case of asthma – no consequence in normal individuals, but can be dangerous on asthmatics)

ANS (autonomic nerve system) (morphin couses mild hyperglycaemia due to central sympathetiv stimulation; it has weak antichlolinesterase

action)

Opioids precautions and contraindications

Morphin is a drug of emergency, but due care has to be taken in its use

-infants and the elderly are more susceptible to respiratory depressant action;-it is dabgerous in patiets with respiratory insufficiency (); sudden death have occurred;

morphin accentuates sleep apnoea;-bronchial asthma (histamine releasing action)

-head injury; reasons are:a.retaining CO2, it increases intracranial tension, which is add to that caused by injury

b.even therapeutic doses can cause marked respiratory depressionc.vomiting, miosis and altered mentation produced by morphin interfere with

assessment of progress in head injury causes;-hypotensive states and hypovolaemia exaggrate fall in BP due to morphin

-undiagnosed acute abdominal pain – morphine can aggravate certain conditions (but can be given after the diagnosis is established)

-elderly male – chances of urinary retantion-hypothyroidism, liver and kidney disease patients are more sensitive to morphine-unstable personalities – are liable to continue with its use and become addicted

Semisynthetic opiates

Diacetylmorphine (Heroine)

Pholcodine

Ethylmorphine

Synthetic opiates

Pethidine (Meperidine)

Fentanil

Methadone

Dextropropoxyphen

Tramadol

Non-opioid (non-narcotic/aspirin-like analgetics)

Antipyretic-analgetics

Antipyretic-analgetics – are chemically diverse, but most are organic acids

They are also called nonopioid (nonnarcotic)or aspirin like analgetics

Willow bark (Salix alba) had been used for many centuries, due to salicylic acid, which was prepared by hydrolysis of the bitter glycoside obtained from in this plant. Sodium salicylate was used for fever and pain; its great success led to

the introduction of acetylsalicylic acid (aspirin) in 1899 [phenacetin and antipyrine were produced at same time]. The term Nonsteroidal

Antiinflammatory Drug (NSAID) was coined to designate such drugs.A host of compounds heralded by the propionic acid derivative (ibuprofen)

have been added since then and cyclooxygenase (COX) inhibition is recognised to be their most important mechanism of action. Subsequently some selective

COX-2 inhibitors (celocoxib) have been added.

Cyclooxygenase action on arachidonic acis

Eicosanoids ways of synthesis

NSAIDs and prostaglandin (PG) synthesis inhibition

In 1971 Vane and coworkers discovered that aspirin (and some NSAIDs) block PG generation (prostaglandines, prostacyclin [PG I2] and thromboxane A2 [TXA2] are produced from arachidonic acid by the enzyme cyclooxygenase which exists in a constituative [COX-1] and an inducible [COX-2] isoforms; the former serves physiological

‘house keeping’ functions, while the latter [COX-2], normally present in minute quantities, and is induced by cytokines and other signal

molecules at the site of inflammation. However, COX-2 is constitutively present at some sites in brain, in juxtaglomerular cells and in the foetus (it may serve physiological role at these sites. Most NSAIDs inhibit COX-1 and COX-2 nonselectively, but now some

selective COX-2 inhibitors have been produced.

COX inhibition

Aspirin inhibits COX irreversibly by acetylating one of its serine residues

Return of COX activity depends on synthesis of fresh enzyme.Other NASIDs are competitive and reversible inhibitors of COX;Return of activity depends on their dissociation from the enzyme

which in turn is governed by the pharmacokinetic characteristics of the compoud (drug).

NSAIDs selectiveness

COX-1/COX-2

[enzyme] Inhibition Coefficient - IC

IC25 , IC50 , IC75

NSAIDs actions

AnalgesiaAntupyresis

AntiinflammatoryDysmenorrhoea

Antiplatelet aggregatoryDuctus arteriosus closure

ParturionGastric mucosal damage

Renal effectsAnaphylactoid reactions

Classification of Antipyretic-analgetics

A.Nonselective COX inhibitors (traditional NSAIDs)

B.Preferential COX-2 inhibitors

C.Selective COX-2 inhibitors

D.Analgetic-anthipyretics with poor antiinflammatory action

A.Nonselective COX inhibitors1

[Salicilates]

1.SalicilatesAspirin (acethylsalicylic acid)

Aspirin (prototype)1

Aspirin (prototype)(it is rapidly converted in body to salicylic acid which is responsible for most of the

action)

Analgetic, antipyretic, antiinflammatory actionIs a weaker analgetic than morphine type (aspirin 600mg~codeine 60mg). However, it relieves inflammatory, tissiue injury related, connective tissue and integumental pain (mainly due to obtunding of peripheral pain receptors and preventing of PG-mediated sensitization on nerve endings), but is relatively ineffective in severe visceral pain. No

sedation, subjective effects, tolerance or physical dependence. Aspirin resets the hypothalamic thermostat and rapidly reduce fever by promoting heat loss (sweating, cutaneous vasodilatation) but does not decrease heat production. Antiinflammatory action is exerted at high doses (3-6 g/day or 100 mg/kg/day). Signs of inflammation

like pain, tenderness. Sweating, vasodilatation and leucocyte infiltration are suppressed. In addition to COX inhibition, quenching of free radicals may contribute to

its antiinflammatory action

Aspirin (prototype)2

Metabolic effectsThere are significant only at antiinflammatory doses. Cellular metabolism is increased, especially in skeletal muscles. Due to uncoupling of oxidative phosphorilation which increase heat production this leads to increasing utilization of glucose, so blood sugar

may decrease (especially in diabetics) and liver glycogen is depleted. However, hyperglycaemia often occurs at toxic doses: due central sympathetic stimulation which

leades to release of Adrenalin and corticosteroids. Chronic use of large doses cause negativ N2 balance by increasing conversion of protein to carbohydrate. Plasma free

fatty acids and cholesterol levels are reduced.

RespirationThe effects are dose dependent: at antiinflammatory doses, respiration is stimulated by

peripheral (increase CO2 production) as well as central (increased sensivity of respiratory centre to CO2) actions. Hyperventolation is prominen in salicylate

poisonoing. Further rise in salicylate level causes respiratory depression; deth is due to respiratory failure.

Aspirin (prototype)3

Acid-base and electrolyte balanceUsual analgetic dose (0.3-1.0 g) have partically no effect. Antiinflammatory doses

producesignificant changes in the acid-base and elrctrolyte composition of bodu fluids. Initially, respiratory stimulation predomonates and tends to wash out CO2, despite

increasing production leads to respiratory alkalosis, which is compensated by increased renal excretion of HCO3

– (which accompanying Na+ and K + and water). Most adults treated with 4-5 g/day stay in state of compensated respiratory alkalosis. Still higher doses cause respiratory depression with CO2 retension, while excess CO2 production

continues that leads to respiratory acidisis, these cause uncompensated metabolic acidosis since plasma HCO3

– is already low. Dehydration occur in poisoning due to increased water loss in urine (to accompany Na+ and K + and HCO3

–) increased sweating and hyperventilation.

Aspirin (prototype)4

Cardio-vascular SystemThere is no direct action on heart or blood vessels in therapeutic dose. Large dose

increase cardiac output to meet the increased O2 demand, and couse direct vasodilatation. Toxic doses depress vasomotor centre: BP may fall.

Gastro-Intestinal tractAspirin and released salicilic acid irritate gastric mucosa that cause epigastric distress,

nausea and vomiting.Aspirin remains unionized and diffusible in the acid gastric juice, but on entering the mucosal cell (pH7.1) it ionizes and becomes indiffusuble. This ‘ion trapping’ in the gastric mucosal cell enhances gastric toxicity this couse focal necrosis leading to

erosive gastritis and haemorrhages. The occult blood loss in stools is increase by even a single tablet of aspirin. Blood loss average 5ml/day at antiinflammatory doses.

Heamatemesis occurs occasionally: may be idiosyncrastic reaction.Solible aspirin tablets containing calcium carbonate and citric acid and other buffered preparations are less liable to cause gastric irritation, but incidence of ulceration and

bleeding is not significantly lowered.

Aspirin (prototype)5

Urate excretionDose-related effect is seen

< 2 g/day – urate retantion and antagonism of all other uricosuric drugs2-5 g/day – variable effects, often no change

> 5 g/day – increased urate excretionbut Aspirin is not suitable for use in chronic gout

BloodIn small doses irreversibly inhibits tromboxan A2 synthesis by platelets.

Uses of NSAIDs

As analgeticAnalgetic dose 0.3-0.6 – 6-8 hourly.

Analgetic effect (of aspirin) is maximal at 1000 mg (single dose)

As antipyreticAcute rheumatic fever

Dose 4.0-5.0 g or 75-100 mg/kg/day. Serum salicylate concentration 15-30 mg/dl – brings about marked symptomatic relief in 1-3 days. Dose reduction may be started

after 4-7 days and maintenance doses 50 mg/kg/day are continued for 2-3 weeks or till signs of active disease (raised ESR) persist.

Rheumatoid arthritisDose 3.0-5.0 g/day

OsteoarthritisPostmyocardial infarction and poststroke patients

Dose 60-100 mg/day

Adverse effects

Side effectsAnalgetic dose 0.3-1.0 g/day are nausea, vomiting, epigastric distress, increased occult

blood loss on stools.

Hypersensivity and idiosyncrasyReactioninclude rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema, asthma

and anaphylactoid reaction. Profuse gastric bleeding occurs in rare instances.

Acute salicylate poisoningFatal dose in adults is estimated to be 10-30 g, but is considerably lower in children.

Serious toxicity is seen at serum salicilate levels > 50 mg/dl.Treatment: symptomatic and supportive. Blood transfusion and vitamin K should be

given if bleeding occurs.

Choice of nonsteroidal antiinflammatory drug1

Efficacy differences among different NSAIDs are minor.They differ quantitativly among themselves in production different side effects and

there are large inter-individual difference. No single drug is superior to all others for every patient.

Choice of drug is inescapable. Some subjects ‘feel better’ on a particular drug, but not on a closely related one. Some guidelines are:

1.mild-to-moderate pain with little inflammation: paracetamol or low-dose ibuprofen2.postoperative or similar acute but short lasting pain: paracetamol or propionic acid

derivative, diclofenac or nimesulide3.acute musculoskeletal, osteoartritic, injury associated pain: paracetamol or propionic

acid derivative, diclofenac4.exacerbationof rheumatoid artritis, ankylosing spondylitis, acut gout, acute rheumatic

fever: naproxen, piroxicam, indomethacin, high dose aspirin5.gactric intolerance to traditional NSAIDs or predisposed patients: a selective COX-2 inhibitor or paracetamol (patients who are dependent on NSAIDs and have developed

peptic ulcer must receive concurrent proton pump inhibitor)6.patients with history of asthma or anaphylactoid reaction toaspirin/other NSAIDs:

nimesulid, COX-2 inhibitors

Choice of nonsteroidal antiinflammatory drug2

7.patients with hypertension or other risk factor for heart attack/stroke: avoid selective COX-2 inhibitor; a propionic acid derivative or aspirin may be used at the lowest dose

for the shortest period8.paediatric patients: only paracetamol, aspirin, ibuprofen and naproxen have been adequately evaluated in children – should be prefered in them due to risk of Rey’s

syndrome, aspirin should be avoided9.elderly patients: use lower dose of the chosen NSAID

10.fast acting drug formulation is suitable for fever, headache and other short lasting pain, while longer acting drugs/sustained release formulations are appropriate for

chronic arthritic pain11.prednancy: paracetamol is the safest; lowe dose aspirin is probably the second best12.hypertensive, diabetic, ischemic heart disease, epileptic and other patients receiving

long-term regular medication: possibly of drug interaction with NSAIDs should be considered

A.Nonselective COX inhibitors2

[Propionic acid derivatives]

2.Propionic acid derivativesIbuprofen 0,4-0,6 or 5-10mg/kg TDS [3 times a dat\y] (introduced in 1969 as a

better tolerated alternative to aspirin, it is has been rated as a safest traditional NSAID: 0,4 ibuprofen more efficacious than 0,65aspirin+0,06codein)

Naproxen 0,75 start followed by 0,28 each 8 hours

KetoprofenFlurbiprofen

A.Nonselective COX inhibitors3

[Fenamate]

3.Fenamate (Anthranilic acid derivative)Mephenamic acid – t½ = 2-4 hrs 0.2-0.5 g TDS

A.Nonselective COX inhibitors4

[Enoic acid derivatives]

4.Enoic acid derivatives (Oxicams)Piroxicam – long acting t½ nearly 2 days 0.02 g BD (twice daily)

Tenoxicam

A.Nonselective COX inhibitors5

[Acetic acid derivatives]

5.Acetic acid derivativesKetorolac – t½ = 5-7 hrs 0.01-0.02 g every 6 hours

Rated superior than 0.65aspirin~0.6paracetamol~0.4ipuprofen

Indometacin – t½ = 2-5 hrs 0.-025-0.05 g BD- [four times a day] QID

Nabumetone – t½ = 24 hrs 0.5 g OD [once day]

A.Nonselective COX inhibitors6

[Pyrazolone derivatives]

6.Pyrazolone derivativesPhenylbutazone

Metamizolum sodiumOxyphenbutazone

B.Preferential COX-2 inhibitors

Nimesulid – t½ = 2-5 hrs dose: 0.1 g BD

Diclofenac (Ortophen, Voltaren) – t½ ~ 2 hrs dose: 0.05 g TDS, BD oral

Aceclofenac – dose: 0.1 g BD

Meloxicam – plasma t½ = 15-20 hrs dose: 0.0075-0.015 g OD

Etodolac – t½ = 7 hrs dose: 0.2-0.4 g BD-TDS

C.Selective COX-2 inhibitors

Celocoxib – t½ ~ 10 hrs dose: 0.1-0.2 g BD

Etoricoxib – t½ ~ 24 hrs dose: 0.06-0,12 g OD

Parecoxib – dose: 0.04 g oral/i.m./i.v. repeated after 6-12 hours

D.Analgetic-anthipyretics with poor antiinflammatory action

I.Paraaminophenol derivativeParacetamol (Acetaminophen)

II.Pyrazolone derivativesMetamisol (Dipyrone, Analgin)

Propiphenazone

III.Benzoxazocine derivativesNefopam

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