Transcript analg_opioide_Engl_2013

ANALGESICS
TYPES OF PAIN
symptom
Pain
disease
physological
pain
acute
Pain
chronic
pathological
PAIN CLASIFICATION
somatic
nociceptive
visceral
pain
neuropatic
nonnociceptive
psyhogenic
R. Kannev, Pain Management Secrets, 1997
TREATMENT OF PAIN
 Local anesthetics
 Infiltration
 Intravenous
 Epidural
 Intrarahidian
 General anesthetics :
 Inhalatory
 Intravenous
 Intrarectal
 Epidural
TREATMENT OF PAIN
 Analgesics
 Opioids



Natural
Semisynthetics
synthetics
 Non-opioids

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

Inhibitors of COX1,2,3
Alfa 2 agonists
5HT agonists
NMDA antagonists
TREATMENT OF PAIN
Class/ Representatives
Coanalgezics:
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Tricyclic antidepressants;
neuroleptics;
anticonvulsantants;
Muscle rrelaxants;
calcitonine;
adenosinee;
metoclopramide;
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Paraanalgessics:
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Corticoids (in inflammatory pain);
nitrite (in pectoris angina);
antacids (ulcer disease);
acetazolamide (in glaucomas).
Calcium channel blockers;
cannabinoidds;
GABA-agonists;
L-dopa;
capsaicine;
anti-arrhythmias;
antivirals.
CHRONOLOGICAL MARKERS
1803
1874
1939
1952
1971-1974
1974 -1975
1976-1986
↓
Morphin isolation from opium
Heroine – semisynthesis
Petidine – synthesis
 total synthesis of morphyn
Isolation of opioid receptors
Isolation of encephalins
Isolation of endorphines

the list goes on….
 Non-opioid analgesics
 Opioid analgesics
 Drugs for neuropathic and functional pain
 Antimigraine drugs
NONOPIOID ANALGESICS
 Acetaminophen (paracetamol)
 NSAIDs – non selective
- Selective Cox 2 inhibitors
ANALGESICS-ANTIPIRETICS-NONSTEROIDAL
ANTIINFLAMMATORY AGENTS
Non selective inhibitors of COX
• Organic acids
• Salicitats – acetic acid, sodium salicilate, diflunisal,
sulfasalazine, olsalasine
• Heteroaril acetic acid deriv – indometacin, sulindac
• Aril propionic deriv – tolmetin, diclofenac, ketorolac
• Arilpropionic deriv – ibuprofen, naproxen, flurbiprofen
• Antranilic deriv (fenamats) – mefenamic acid,
meclofenamic acid
• Enolic acid deriv – piroxicam, meloxicam
• Non acidic compounds
• Pirazolone deriv – metamizol (dipyrone)
• Para-amino-fenol deriv – acetaminofem, fenacetine
• Fenazone deriv – fenazone, propifenazone
ANALGESICS-ANTIPIRETICS-NONSTEROIDAL
ANTIINFLAMMATORY AGENTS
Selective inhibitors of COX2
• Sulfonanilide – nimesulide
• Coxibi (furanone/pirazolone diaril-substitute) – rofecoxib,
celecoxib
• Indol-acetic acids - etodolac
NSAIDs
Classifications
 Mild to moderate anti-inflammatory action
propionic acid derivatives ibuprofen, naproxen
fenamic acids
mefanamic acid
 Marked anti-inflammatory action
-
salicylic acids
pyrazolone derivatives
-
acetic acid derivatives
oxicam derivatives
 Selective COX2 inhibitors
aspirin
azapropazone,
phenylbutazone
diclofenac, indomethacin
piroxicam
celecoxib, rofecoxib
Aspirin (acetyl salicylate)
Actions
 Analgesic - central and peripheral action
 Antipyretic - act in hypothalamus to lower the
set point of temperature control elevated by
fever, also causes sweating
 anti-inflammatory - inhibition of peripheral
prostaglandin synthesis
 respiratory stimulation - direct action on
respiratory centre, indirectly by ↑ CO2 production
Aspirin (acetyl salicylate)
 Metabolic effects
 ↑peripheral




O2 consumption (uncoupled oxidative
phosphorylation) hence ↑CO2 production with ↑
respiration, and direct analeptic action - respiratory
alkalosis
renal loss of bicarbonate with sodium, potassium and
water
Dehydration
metabolic acidosis - effects on Krebs cycle, ↑ ketone
body, salicylic acid in blood, renal insufficiency due to
vascular collapse, dehydration
hypoglycaemia or even hyperglycaemia can occur
Aspirin (acetyl salicylate)
 Uricosuric effects
 reduces renal tubular reabsorption of urate but
treatment of gout requires 5-8g/d,
 < 2g/d may cause retention of urate
 antagonises the uricosuric action of other drugs
 Reduced platelet adhesion –
 irreversible inhibition of COX by acetylation, prolongs
bleeding time, useful in arterial disease
Note: low doses are adequate for this purpose since the
platelet has no biosynthetic capacity and can not
regenerate the enzyme
 Hypothrombinaemia : occurs with large doses ie >5g/day
Aspirin (acetyl salicylate)
OVERDOSAGE
 Ingestion of > 10 g can cause moderate/severe poisoning in
an adult
 Clinical features - ‘salicylism’
 Tremor
 Tinnitus
 Hyperventilation
 Nausea
 Vomiting
 sweating
 Management- mainly supportive
PARACETAMOL
(acetaminophen)
 equivalent analgesic efficacy to aspirin
 no useful anti-inflammatory action
 used for mild to moderate pain, but
aspirin is preferred if due to inflammatory
process
PARACETAMOL
(acetaminophen)
Metabolism
 is conjugated in the liver as the inactive glucuronide and
sulphate
 a number of minor oxidation products
N-acetylbenzoquinoneimine (NABQI) are also formed
 NABQI is highly chemically reactive and is usually
inactivated by conjugation with SH (thiol) groups of
glutathione
 Supply of glutathione is limited and exhausted in overdose
 NABQI then reacts with cellular macromolecules and
causes cell death
PARACETAMOL
(acetaminophen)
Adverse effects
 rare in therapeutic usage
 occasional skin rash and allergy
 overdose can result in fulminant hepatic
necrosis and liver failure
PARACETAMOL
(acetaminophen)
Paracetamol overdose
 Ingestion of >10g of paracetamol may be fatal
 may be lower in chronic alcoholics or subjects with
underlying liver disease.
Clinical features
In severe poisoning
 up to 24 hours – none/nausea and vomiting
 > 24 hours
 nausea and vomiting
 Right upper quadrant pain
 jaundice
 encephalopathy
PARACETAMOL
(acetaminophen)
Management
 Blood for paracetamol at 4 hours post ingestion
 Check treatment curve for N-acetylcysteine infusion ( if
in doubt of severe poisoning, don’t delay)
 Check prothrombin time and plasma creatinine, pH
 acute renal (due to acute tubular necrosis) and hepatic
failure and occur at 36-72 hours after ingestion
 Indications for referral to liver unit are
rapid development of Grade 2 encephalopathy
PTT >45 secs at 48 hours or >50 secs at 72 hours
rising plasma creatinine
Arterial pH <7.3 more than 24 hours after ingestion
NSAIDs
Mechanism of action
 inhibits cyclo-oxygenase (prostaglandin synthase) that is
responsible for conversion of arachidonic acid to cyclic
endoperoxides
 2 isoforms of enzyme
-
COX-1 constitutive, present in platelets,
stomach and kidney
COX-2inducible by cytokines & endotoxins at
sites of inflammation e.g., joints
NSAIDs
Main actions
1.) Analgesic -effective against mild to moderate pain, do
not cause dependence
2.) Anti-inflammatory
3.) Anti-pyretic
4.)Anti-platelet- prevent thromboxane production, derived
from prostaglandins and cause platelet aggregation
Others
5.) Useful in treatment of dysmenorrhea, associated with
increased prostaglandin synthesis and increased uterine
contractility
6.) Used to close the patent ductus arteriosus
NSAIDs
Adverse effects
1.) Gastric or intestinal mucosal damage
- mucosal prostaglandins inhibit acid secretion, promote
mucus
secretion, prevent back diffusion of acid into the gastric
submucosa
- Inhibition thus results in erosions, ulceration, bleeding,
perforation
2.) Disturbances of fluid and electrolyte balance
- inhibition of renal prostaglandin production results in
sodium retention and oedema, possible hyponatraemia,
hyperkalaemia, antagonism of anti-hypertensive agents
NSAIDs
Adverse effects
3.) Analgesic nephropathy
- due to long term ingestion of mixtures of agents
- chronic interstitial nephritis, renal papillary necrosis,
acute renal failure
NSAIDs
Non selective Vs selective COX2 inhibitors
↑ risk of cardiovascular adverse events with COX 2
inhibitors
 Rofecoxib was withdrawn from the market
 Higher BP, incidence of myocardial infarction,
stroke
 Mechanism _ ? Unopposed effect of cox 1 action
- ? Block protective effect of COX2 on
ishaemic
myocardium
or
atherogenesis
OPIOID ANALGESICS
 SOURCE
 Opium is obtained from the opium
poppy by incision of the seed pod after
the petals of the flower have dropped.
The white latex that oozes out turns
brown and hardens on standing.
 This sticky brown gum is opium. It
contains about 20 alkaloids, including
morphine, codeine etc. The principal
alkaloid in opium is morphine, present in
a concentration of about 10%.
OPIOID AGONISTS
 Morphine (strong mu receptor agonist)
 Codeine
 Heroin
 Meperidine (pethidine)
 Fentanyl
 Loperamide (over the counter for diarrhea)
 Diphenoxylate
 Dextromethorphan
OPIOID AGONIST-ANTAGONIST
/PARTIAL AGONIST
 Nalbuphine
 Pentazocine
OPIOID ANTAGONISTS
 Nalorphine
 Naloxone
 Naltrexone
OPIATE ANALGESICS
Routes of administration
 Oral
 Parenteral
 Suppositories
 Transdermal- Patch
 s/c Syringe driver
Opioid Analgesics-Pethidine
 Pethidine/meperidine and fentanyl are the most widely
used agents in this family of synthetic opioids
 The principal effects of pethidine with affinity for mu
receptors are on the central nervous system.
Pharmacological Effects
• the pharmacological effects of Pethidine is similar to
morphine, primarily at the mu receptor
•it has less potent analgesics than morphine and has a shorter
duration of action
•Pethidine dosn`t delay delivery
The Opioid Antagonists
 The opioid antagonist drugs naloxone and naltrexone
are morphine derivatives.
 When given in the absence of an agonist drug these
antagonists are almost inert at doses that produce marked
antagonism of agonist effects.
 When given intravenously to a morphine-treated subject,
the antagonist will completely and dramatically reverse
the opioid effects within 1-3 min.
Mechanism of action

Opioid agonists produce analgesia by
binding to specific receptors,
located primarily in brain and
spinal cord regions involved in the
transmission and modulation of pain.
Mechanism of action
Receptor types: The major classes of
receptors are
µ (mu for morphine)
delta (δ)
Kappa (κ)
All are members of the G-proteincoupled family of receptors.
Mechanism of action
 Analgesia, as well as the euphoriant,
respiratory depressant, and
physiologic dependence properties of
morphine result principally from actions
at mu receptors.
 Most of the currently available opioid
analgesics act primarily at the mu
receptor.
OPIOID RECEPTORS
 Certain opioid receptors are located:
 on primary afferent and spinal cord pain
transmission neurons (ascending pathways)
 in the midbrain and medulla (descending pathways)
that function in pain modulation
 All 3 receptors appear to be involved in anti
nociceptive and analgesics mechanisms
OPIOID RECEPTORS
 Presynaptically:
 Opioid receptor activation can close voltage –
gated calcium ion channels to inhibit
neurotransmitter release (serotonin, glutamate and
substance P)
OPIOID RECEPTORS
 Postsynaptically:
 Activation of these receptors can open potassium ion
channels to cause membrane hyperpolarization
(inhibitory post synaptic potential).
 Direct inhibition of neurons in ascending pathways
PHARMACOLOGICAL EFFECTS
CNS:
 Analgesia: most powerful drug available for relief of
pain
 Euphoria: addict experiences a pleasant floating
sensation and freedom from anxiety and distress.
 Sedation
 Respiratory depression: main cause of death from
opioid overdose due to reduced responsiveness of
respiratory centre in brainstem to blood levels of
CO2
PHARMACOLOGICAL EFFECTS
 Increase arterial CO2 retention causes cerebral
vasodilation resulting in increase intracranial pressure
 Cough suppression: suppression of cough centre in
nucleus of tractus solitarius
 Miosis: results from stimulation of Edinger- Westphal
nucleus
causing
pin-point
pupils
except
meperidine.
 Emesis: due to stimulation of brainstem
chemoreceptor trigger zone results in nause and
vomiting
MIOSIS
PHARMACOLOGICAL EFFECTS
 CVS: No significant direct effect on CVS
 Hypotension may occur if CVS is already stressed.
Due to the peripheral arterial and venous dilation
resulting from histamine release.
 GIT: Decrease intestinal propulsive peristalsis and
stomach motility leads to constipation
 Biliary tract: Constriction of biliary smooth muscles
leads to biliary colic except meperidine
 Constriction of sphincter of oddi leads to increase
biliary pressure, reflux of biliary and pancreatic
secretions and elevated plasma and lipase levels
PHARMACOLOGICAL EFFECTS
 Renal functions: depressed due to decrease renal
plasma flow.
 Also has antidiuretic effect. Mechanism involve both
CNS and peripheral site
 Ureteral and bladder tone is increased
 Increased sphincter tone….urinary retention
 Occasionally, ureteral colic caused by renal calculus
is made worse by opioid induced increase in ureteral
tone
PHARMACOLOGICAL EFFECTS
 Uterus: decrease uterine tone lead to prolong labor
 Skin: flushing and warming, sweating, itching due to
histamine release
CLINICAL USES
 Analgesia for
 MI
 terminal illness
 surgery
 obstetrical procedures
 cancer
 Cough
 Diarrhea
CLINICAL USES
 Acute pulmonary edema: decrease dyspnea
 Proposed mechanism:
 Reduced anxiety (perception of shortness of breath)
 Reduced cardiac preload (reduced venous tone)
 Reduced afterload (decreased peripheral resistance)
 If respiratory depression is there then use furosemide
Clincal Use
 The major application of naloxone is in the
treatment of acute opioid overdose
 In individuals who are acutely depressed by an
overdose of an opioid, the antagonist will effectively
normalize respiration, level of consciousness, pupil
size
 More recently, considerable interest has been aroused
by reports that naltrexone decreases craving for
alcohol in chronic alcoholics, and it has been approved
by the FDA for this purpose.
ADVERSE EFFECTS
OPIOID ANALGESICS
 Morphine
 Morphin 6 glucuronid


-
3.7 s.c.
45  i.c.v. Foley 1993
Dosage form with slow release
Bashford 2001
Roxanol SR (8 ore)
MS Contin (12 ore)
MST
Heroine – metabolit:
Morphine im 2 
- 6 acetil morphine
(link to opioid receptors)
OPIOID ANALGESICS
 Hydromorphon 5  - benefits the elderly (t1/2 1.5-2 ore)
- excellent analgesia
- minimal side effects (Brose 1991)
 Levorphanol 2  - in chronic pain who can not tolerate
morphyne
- affinity for  receptor
 Codeine – for stage II– in combinations DH codeina
 Oxycodone 10  codeine – moderate and severe pain

- present in combination
OPIOID ANALGESICS
 Meperidine – 75 mg = 10 mg morphine i.m.
- normepteridine: activ metabolit – convulsant 2
- analgezic ½
 Metadone - 10mg = 10mg morphine
- analges stage II
- addiction therapy
Propoxifen – moderate pain 1/2 – 1/3 from codeine
-metabolit: norpropoxifen (convulsant)
 Fentanyl – 1:20, 1:30 from morphine
- intra and post operative pain
- various routes of administration
- inactive metabolites
AGONISTS /ANTAGONISTS
 Pentazocine 35 mg = 10 mg morphine. Receptors , 
 BP – disphoria, psyhotic effects
 Nalbufina – equivalent to morphine
- for postoperative pain
effects)
-
substitute
for
morphine
(fewer
side
- lower potential for abuse as morphine
- Potential low psyhotic edffect
 Butorfanol – 2 mg i.m. = 10 mg morphine
- low physical dependence potential
- useful for acute pain in patients who
have not received opioids
TOLERANCE
TOLERANCE
 Tolerance occur due to receptor uncoupling.
 Physical dependence:
 It results in withdrawal (abstinence) syndrome if there
is failure to continue administer drug. Sudden withdrawal
(abstinence syndrome) has following signs/symptoms:
 lacrimation
 yawning
 chills
 hyperventilation
 hyperthermia
 diarrhea,vomiting
 anxiety
SYMPTOMS OF WITHDRAWAL
TOLERANCE
 Psychological dependence:
 euphoria
 indifference to stimuli
 sedation
 Morphine poisoning….antidote is naloxone
Toxicity
Acute morphine poisoning:
 Coma
 Severe respiratory depression
 Miosis
 with blood pressure decreased
 Urinary retention.
Respiratory paralysis often is the mainly lethal reason.
Treatment:
 respiratory support
 intravenous injection of naloxone.