analgesics

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1/- Introduction :

Pain is a sensory experience and unpleasant emotional, linked to a real or potential tissue damage.

Pain is both a sensation (feel of a noxious stimulus) and emotional experience (intense feeling of displeasure).

2/- Neurobiology of Pain :

A- The pain pathways :

Ensure the transmission of a stimulus nociceptor peripheral receptors to the cerebral cortex.

Nocicepteurs: sitting in skin tissue and visceral organs.

1- free nerve endings :

  • What are the ramifications of fibers of small fruits, their stimulation can be physical or chemical origin.
  • Tissue damage leads to the accumulation of alien substances: (prostaglandins, bradykinine, serotonin, histamine).
  • Prostaglandins are involved in the genesis of painful symptoms by sensitization of nerve terminal receptors to the action of mediators allogenic.

2- The ascending pathways medullary :

  • The nerve endings are extended by fibers in peripheral nerves and reach the CNS via the dorsal root of the spinal cord.

3- Routes supra medullary :

Nerve fibers transmit the impulses of the cord to the thalamus and the thalamus to the cortex.

The fibers are grouped into bundles:

  • The fibers A large caliber has, Ap they support the discriminative sensibility (tactile fine) more involved in the control of pain in transmission.
  • The fibers of small caliber A 5 AC and supporting non discriminative sensitivity (rough tactile perception, thermal, painful,) were they that transmit pain impulses.

    Fig 01 : the pain pathways

B- Control of pain messages :

1- Gate Control Theory :

Competition between large and small caliber fibers.

Wholesale fiber gauges A has, Ap inhibit the propagation of impulses algetic conveyed by the fibers A and O AC exciting inter neural inhibitory system (closed door).

The intense pain impulses lift this inhibition the role of wholesale fiber sizes become negligible and fibers A 5 transmit influx durable manner to the cerebral structures (open door).

2- Control by neuropeptides :

  • Substance P: Neurotransmitter C fibers that transmit intense pain. The impulses carried by the C fibers release substance P in the synaptic cleft which excites the post synaptic neuron at the marrow or C-fibers are relay.
  • The peptides endogenous opioids

■ substances synthesized by the body that mimic the effects of morphine they gather : endorphins (endogenous morphine).
+ enkephalins (morphine brain).
+ dynorphins.

  • Endogenous opioids bind to opioid receptors sites that also bind the central analgesics.
  • The enkephalin produced in neurons inters inhibits the release of substance P by C fibers.

3- serotonergic and adrenergic downward path :

Third mode of inhibition blocks the transmission of pain signals in the spinal cord.

Fig 02 : medullary enkiphalinérgique system
Fig 03 : Control of pain messages.

3/- Classification of pain :

A- temporal classification :

  • Sharp pain: recent, transient. Can be caused by a burn or sting and persists until healing.
  • Chronic Pain Acute pain can last and become a syndrome. It loses its alert function. We speak of chronic pain when it lasts several weeks.

B- Classification by origin :

  • Pain nociceptive: There are excessive stimulation of peripheral pain receptors and may be due to lesion destruction (trauma, burn, etc.); inflammation; ischemia.
  • Deafferentation pain or neurogenic: She comes from a disruption of ways of nociception which can be due to nervous system damage (phantom limb pain, diabetic peripheral neuropathy).

4/- painkillers :

A- Definition :

Analgesia :

Decreased sensation of pain without loss of consciousness.

Analgesic :

Or analgesics are drugs that suppress or mitigate the painful sensation by peripheral action and / or Central.

Three ways are possible :

  • Inhibit the production of substances algogenic.
  • Strengthen painful afferents control system, at the marrow, brainstem, thalamo the hypothalamic region .
  • Edit the psyche.

B- Classification :

1- WHO classification based on the power of analgesic agents :

– Analgesics Level 1 (peripheral devices)

Analgesics Level 2 (weak opioids)

Analgesics Level 3 (strong opioids)

2- Classification based on the mechanism of action :

a- Binding to opiate receptors :

• Agonists or morphine :

They lead to attachment by intense analgesia receptors are distinguished p :

+ Major morphine : Analgesics bearing 3

  • Morphine, for injection, oral and oral (SKENAN®, MOSCONTIN®).
  • Oxycodone OXYCONTIN®
  • Fentanyl FENTANYL®.
  • Methadone Hydrochloride Methadone®

+ Minors morphine : Analgesics bearing 2

  • codeine CODOLIPRAN®
  • Dihydrocodéine DICODIN LP®
  • Tramadol TOPALGIC®

• Agonists and Antagonists :

  • They are agonists for certain receptor antagonists but for others.
  • They overlooked opioid receptor greater affinity than morphine but their activity is lower.
  • They have an analgesic effect in the absence of morphine but before this they will behave like antagonists.
  • On a : buprenorphine Temgesic® (partial agonist and antagonist p k ).

• antagonists :

  • They bind to receptors p, k, and 6 without activating.
  • They will have an antagonistic action in the presence of morphine.
  • Naloxone NARCAN® et Naltrexone NALOREX®.
substances action

“mu”

action

“kappa”

morphine agonist agonist
pentazocine antagonist agonist
nalbuphine antagonist agonist
buprenorphine agonist

partial

antagonist
fentanyl agonist

+++

agonist
nalorphine antagonist agonist
naloxone antagonist antagonist

C- Mechanism & rsquo; Action :

Central Mechanism of Action: les récepteurs médullaire μ, K, d

In the medulla :

  • Decreases the release of excitatory neurotransmitters (including substance P),
  • Depresses the transmission of nociceptive messages.
  • Strengthen inhibitory control supra-spinal descendant.

D- Opioid analgesics :

1- morphine : (du grec Μορφεύς, twilight sleep, Greek god of sleep and dreams) is an alkaloid of & rsquo; opium (opioid).

/Users / adlane / Downloads / m% C3% A9decine / 3% C3% A8me ann% C3% A9e / Pharmacologie / Constantine / Les cours de 2016:2017/3/media / image4.jpeg—> Opium is extracted from poppy latex (papaver somniferum), it contains two groups of alkaloids : the phenanthrene : morphine, heroin, codeine

Les benzylisoquinolones : papaverine

pharmacological Action :

depressant direct spinal and supra spinal on the transmission of pain signals

Morphine, RI =R2= OH

SNC
  • analgesic action
  • Action psychomotrice: acute stimulation followed by sedation
  • psychodysleptique effect
Respiratory system – respiratory depression
(effect central order) – Indeed powerful antitussive
vomiting center
  • Emetic low dose
  • Anti-emetic in large doses
smooth muscles
  • Decreased intestinal peristalsis
  • Increased tone of the sphincters (anus, bladder)
other effects
  • Myosis
  • Decreased secretion & rsquo; pituitary hormones :LH, FSH, ACTH
  • Increased prolactin and GH
  • Hypothermia high dose

Opiates are used for therapeutic purposes three:

  1. As analgesics
  2. As antitussifs
  3. As anti diarrheal

Indication :

—> Beyond symptomatic pain treatment:

  • acute pain : liver and renal colic (antispasmodic), ID M, O AP.
  • chronic pain : cancerous.
  • per and postoperative pain.
  • addiction treatment: methadone, buprenorphine.

Side effects :

  • respiratory depression.
  • Dependence leading to addiction.
  • possible disappearance of abdominal signs suggestive diagnosis & rsquo; a condition requiring surgery.
  • Effect "spasmogenically" (sr ++ biliary).
  • C onstipation (le + frequent).
  • emetic effect in early treatment.
  • Histamine release, bradycardia, hypotension.
  • Intoxication —> triad : respiratory depression, pinpoint pupils, consciousness disorders up up & rsquo; coma. —> Antidote : naloxone.

2- Major morphine (mornhiniciues pure and agonist-antagonists used as agonists) :

These are drugs

Particular case

  • Methadone painkiller = Very good> could replace morphine but n & rsquo; s not a & rsquo; MA, Marketed only as replacement therapy of major opioid drug dependence,
  • Buprenorphine The n & rsquo; is not a narcotic (product registered in the list 1).

2 indications :
+ The treatment of severe pain and / or refractory to analgesic 2 ° offset
+ Replacement therapy major opioid drug dependence

Indications :

  • intense acute pain (OAP, IDM, colic) and / or analgesics to alleviate the rebels 1 or 2
  • chronic noncancer pain
  • cancer pain
  • Anesthésiologie : induction and maintenance of general anesthesia FENTANYL®.

Side effects :

  • central respiratory depression dose dependent
  • dyspnea
  • depression cough reflex
  • bronchoconstriction (by release of histamine liberators)
  • depression of the vomiting center in high doses (at low doses, c & rsquo; is & rsquo; reverse !) => antiemetic effect
  • constipation (↓, intestinal peristalsis, ↓ digestive secretions)
  • nausea in low doses
  • biliary tract spasm
  • euphoria, dysphorie, hallucination, somnolence, mental confusion, dizziness
  • physical and psychological dependence d & rsquo; rapid onset 1 at 2 weeks with withdrawal syndrome.
  • habit
  • At heart level : cardiovascular depression (bradycardia, hypotension)
  • Metabolism : – ↑ glucose – urinary retention (↑ ADH, blocking sphincters)

Drugs interactions :

Agonist-antagonist opioids are cons-indicated with all the morphine => risk of withdrawal syndrome and inefficiency of morphine.

Alcohol : ↓ alertness by increasing the sedative effect

morphine (even minors and antitussives) : ↑ respiratory depression

psychotropic (HAD, tricyclic, CNS depressant, neuroleptics) : somnolence, confusion, convulsions, HTA

β blockers : hypotension orthostatique

Precautions

Opioids should be used with caution in the following cases :

  • Renal failure : reduced dosage in early treatment and care with morphine : active metabolite excreted renally
  • Respiratory failure
  • frail especially the elderly and children
  • Constipation : ensuring the absence of occlusive syndrome
  • intracranial hypertension
  • Pregnancy and breast feeding

3- Opioid analgesics (weak opioids) :

These structurally related to morphine derivatives have more or less intense analgesic and powerful antitussive activity.

  • Codeine (= methylmorphine) CODOLIPRAN® It is metabolized to a small portion of morphine (about 10 %) which is responsible for its analgesic effect. L & rsquo; antitussive activity is antagonized by naloxone.
  • Opioid analgesic tramadol TOPALGIC® active by :

+ Mounting on the receiver p
+ Inhibition of the capture of norepinephrine and serotonin.

Indications :

Treatment of moderate to severe pain and / or do not meet the painkillers to alleviate 1.

– codeine Codoliprane®
– dihydrocodéine DICODIN LP®
– tramadol TOPALGIC®
■ Symptomatic treatment of non productive cough annoying

Side effects :

– constipation – somnolence – dizziness – nausea – respiratory depression (moderate therapeutic doses) => rare – supra therapeutic doses : risk of dependence and withdrawal syndrome on abrupt.

Drugs interactions :

Agonist-antagonist opioids => risk of withdrawal syndrome and inefficiency of the morphine-selective MAO inhibitors and non-selective type A (dextromethorphan) Alcohol : ↓ alertness by increasing the sedative effect.

Cons-indications :

Child <30 month – respiratory failure – productive cough, asthma – hypersensitivity

4- The opioid antagonists :

  • The pure antagonists act by specific competition at the level of opioid receptors.
  • La Naloxone NARCAN® :

pure antagonist, specific and competitive morphine, n & rsquo; therefore no effects in a subject not treated by morphine. It antagonizes specifically and competitively depressant effects of opioids (respiratory depression, myosis, analgesia).

Indications :

+ differential diagnosis of toxic coma not d & rsquo; morphine poisoning if the & rsquo; n & rsquo clinical condition; unchanged.
+ treatment of acute poisoning by opiates
+ neonatal respiratory depression d & rsquo; origin morphine

4- Non-opioid analgesics :

Their action is mainly but not exclusively device.

classified 3 pharmacological series:

  1. Pure analgesics.
  2. Analgesics antipyretics.
  3. Analgesics antipyretics : AINS

a- Pure Analgesics :

Floctafénine IDARAC® : is hardly used.

pharmacological properties : Inhibiting the action of bradykinin, Serotonin, de la prostaglandin E2, histamine and acetylcholine hence its analgesic effect.

Nefopam Acupan * Inj :

  • Analgesic "central" non morphine, non antiinflammatory, non antipyretic,
  • d & rsquo mechanism; action remains poorly understood.
  • II also has antidepressant properties by inhibition of reuptake of norepinephrine and serotonin.

b- Antipyretic analgesics :

Paracetamol (Perfalgan®):

1- Pharmacological properties of paracetamol :

– Decreased prostaglandin synthesis by reversible inhibition of the COX.
– it practically has no anti-inflammatory properties (peroxides)
– paracetamol preferentially inhibits COX-brain 3, which explains the absence of anti-inflammatory action

2- pharmacokinetics :

– The complete resorption 30 at 60 minutes.
– The half-life is 4 at 6 hours.
– Paracetamol is poorly bound to plasma proteins.
– Metabolism is hepatic (Le cytochrome P450)
– toxic metabolite N-acetyl-p-benzoquinone imine: inactivated by glutathione
– Risk of hepatotoxicity: toxic dose > 8 g
– Eliminated by the kidneys as inactive conjugates.

—> Sudosage :

  • Hepatic necrosis dose-dependent : death from a decision 8 at 10 g
  • Antidote: N-acetylcysteine ​​MUCOMYST® (buts) or FLUIMUCIL® (inj)

—> Side effects :

  • Exceptional therapeutic dose (allergy : skin rash, thrombocytopenia)
  • Hepatorenal toxicity at dose supra-therapeutic

—> Indications :

In first-line fever symptoms and moderate pain but also in case of against-indications to NSAIDs:

+ pregnancy, feeding with milk,
+ peptic ulcers,
+ AVK treatment…

c- Analgesics NSAIDs antipyretics : see course NSAIDs.

5- The Co adjuvant analgesics :

Adjuvant analgesics (sometimes called coantalgiques) are drugs commonly used to d & rsquo; purposes other than pain, but also possess analgesic properties: for some people, they are effective on different types of neuropathic pain.

Two main families of drugs are currently used in the treatment of neuropathic pain :

  • antidepressants
  • antiepileptic

a- antidepressants :

Mechanism & rsquo; Action :

  • independent analgesic activity of antidepressant activity
  • Central Action
  • Inhibit the reuptake of serotonin and / or noradrenaline
  • The increase rate of 5-HT and NA causes an increase in local activity opioid and decreases the transmission of the pain message.

+ Imipraminiques (tricyclic)
+ selective reuptake inhibitors of serotonin and NA (IRSNA)

b- antiepileptic :

* Several mechanisms of action :
■ Blockers voltage dependent Na + channels (carbamazepine, oxcarbazépine)
■ modulation voltage dependent calcium channels (gabapentine, pregabalin)

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