Opiods Flashcards
morphine
Pharmacokinetcs:
Absorbs well sc., im.
significant first pass when given orally
Fast distribution into the brain, lungs, liver, kidneys and spleen
Main reservoirs are skeletal muscles and fat tissue
Easily penetrates the placenta – contraindicated in pregnant woman
Elimantes via glucoronid conjugation
Morfin-3-glucoronid – neuroexcitatory effect
Morfin-6-glucoronid – 4-6x more potent analgesic
Polar metabolites eliminates via the kidneys
In case of renal failure – accumulation -> sedation/respiratory depression
indications:
Pain – acute or chronic
Acute heart failure
In strong states of anxiety (shock, trauma, infarct)
Severe diarrhea induced by tumor or surgery
Preoperative medication
Analgesia – therapeutic effect
Sedation
Euphoria – reason of abuse
Dysphoria – mainly with kappa agonists
Respiratory depression – toxic effect - decreased sensitivity to CO2 in the brainstem
Pain is the „physiologic antagonist” of respiratory depression. When a strongly painfull stimuli (that have prevented the depressive effect) are relieved, respiratory depression may suddenly manifest.
Anti-tussive effect
Nausea/Emetic – triggers the chemosensitive triggerzone – phenotiazins and/or setrons may be effective
Miosis (+constipation) – NO TOLERANCE – reliable symptom of overdose
When the patient becomes hyopoxic, then mydriasis manifest.
Increased truncal rigidity – chest tightness
Epileptogenic – inhibition of GABA release
Neuroendocrine effects: decrease GnRH, decrease CRF release → ACTH decrease, LH decrease, FSH decrease → decrease tesztoszteron, cortisol; PRL increase, GH increase, ADH increase
The peripheral effects of morphine: Decrease of BP Decrease of HR Inhibition of GI motility – constipation – NO TOLERANCE Increase of biliary and urogenital tone (kidney stone, gall stone!) Uterus relaxation Bronchoconstriction (histamine release) Pruritus (histamine release) Immunsuppressive
Miosis Orthostatic hypotension Respiratory depression Pain supression Histamine release/ Hormonal alterations Increased ICT Nausea Euphoria Sedation
Contraindications: COPD (pl. asthma, emphysema) Cor pulmonale Cranial injury Intracranial pressure increases, because during respiratory depression CO2 elimination decrease causing a CO2 accumulation, which wil cause cranial vasodilation Mydriasis can interfere with the proper diagnosis Severe liver function deficits Alcohol intoxication, withdrawal Epilepsy Urogenital stones, biliary stone
Drug interactions:
Sedatohipnotics ↑ CNS (and respiratory) depression
α2 agonists ↑ its effect
Antipsychotics ↑ sedative effect
TCA, antihistamines ↑ its effect
Amphetamine ↑ its analgesic and euphoric effect, while ↓ szedative effect
Probenecid ↑ the penetreation of M6G into the CNS
Preparations of morphine and their use:
Injection (morphine-chloride 10-30 mg sc., iv. 1-10 mg)
Very strong acute pain (infarct!)
Pulmonary edema (with furosemid, decreases dyspnoe)
Retard capsule (morphine-sulphate 10-100mg, 2x/day)
Very strong rheumatic pain which is refractory to other analgesics
Pain associated with tumor
PCA (patient controlled analgesia).
The pain relief is controlled by the patient by pressing a button to deliver a preprogrammed dose of morphine.
A programmable lockout interval prevents admin. Of another dose within this „lockout” time period.
codeine
Weaker painkillers (1/6 of morphine)
Potent antitussive effects
Weak euphoria – no dependence
PD: weak µ-agonist Anti-tussive, weak analgesic/respiratory depressant Ind: Dry cough Adjuvant in angina With aspirin it has an additive analgesic effect PK: A - first pass less pronounced M – demethylation by CYP2D6 (genetic polimorfism!!) SE: Constipation, sedation
hydromorphone
8x more potent µ-agonista than morphine
Its pharmacologic effects is similar to morphine
Available in fast absorbing tablets, retard preparation
dihydrocodeine
Weaker painkillers (1/6 of morphine)
Potent antitussive effects
Weak euphoria – no dependence
Weak analgesic and anti-tussive
oxycodone
Morphine equivalent – with strong abuse potentail
Used in cancer associated pain, and chronic musculoskeletal pain
buprenorphine
Chemistry: phenantrene PD: partial agonist, antagonist 20x more potent than morphine Dissociates slowly from the R -> resistent against naloxon In high doses it will have antagonistic effect PK: D – protein binding 96% M – in the liver via CYP3A4 Ind: Analgesia Detoxification Respiratory depression SE: Precipitates withdrawal symptoms in morphine addicts, dysphoric Adm: Im., sublingual, transdermal Dependence capacity is low
nalbuphine
Chemistry: phenantrene
PD: mixed agonist/ antagonist (equipotent with morphine)
It has distinctive „ceiling effect” in its respiratory depressant effect
fewer cardiovascular effects
Doesn’t relaxes the uterus and for this reason it can be given after cesarean section
SE: sedation, dysphoria, sweating, headache, orientation disturbences,
It has a high receptorial affinity and because of this it is harder to antagonize its effect with naloxone.
meperidine (=pethidine)
PD: full agonist weaker sedative and miotic effect Doesn’t supress coughing Doesn’t cause constipation, less frequently causes urinary retention Weaker uterus relaxant Weaker biliary effect (although closes the Oddi sphincter) Anti-muscarinic effect Duration of action is shorter
PK:
M – in the liver, its metabolite - normeperidine – has convulsive effect (when it was used higer doses and/or in renal failure)
Ind:
Used before truncal – and in heart surgery as preoperative medication
Drug interactions:
↑ incident of respiratory depression and convulsions when it is co-administered with MAO-inhibitors
↑ incident respiratory depression with concomitant use with TCA
Serotonine syndrome
Side effects: low BP, nausea, vomiting, tremor, seizures
fentanyl
PD: similar to morphine (100x more potent), short acting
PK:
D – fast redistribution -> fast acting
M – CYP3A4 (first pass)
SE:
Less frequent constipation, however more prominent truncal rigidity and respiratory depression
Administration possibilities:
In neurolept analgesia with droperidol, neurolept anesthesia with droperidol and nitrous oxide (N2O)
Iv. injection: general anesthesia
Transdermal patch (very lipophilic) - oncology
Sublingual tablet
Sufentanyl 5-7x more potent than fentanyl Alfentanyl: Short acting, but less potent than fentanyl Remifentanyl: Esther derivative, very short acting Carfentanil The most potent opioid It is used in veterinary medicine to sedate large mammals e.g. elephants
mathadone
Chemistry: phenylheptylamine
PD: besides full mü-agonism, it’s NMDA R and monoamine reuptake inhibitor -> efficient in neuropathic pain and in pain associated with cancer (equipotent with morphine)
Duration of action is longer than morphine (24-72 hours)
PK: orally, iv., im., sc., intrathecally and rectally
D – protein binding 85-90%
M – CYP2B6, 3A4 (drug interactions)
Ind: in opiate addiction (mild withdrawal symptoms, but lasting)
SE: morphine + QT prolongation
tramadol
Chemistry: it is trazodon’s metabolite
PD:
weak -agonist (low affinity), NET and SERT inhibitor, acts also on 5-HT R
PK:
CYP2D6, CYP3A4 met.
Ind: weak/moderate pain, Neuropathic pain
SE:
Convulsions, (it is relatively CI with history ofepilepsy and with medications that lowers the convulsion threshold)
Serotonine syndrome
Nausea, dizzines
It can be partially antagonized with naloxon, but its analgesic effect can be block with ondansetrone
Duration of action: 6 h
Low dependence potential – but still used for this purpose
diphenoxylate
Ind:
In combination with atropine for diarrhea
PK:
M – it is metabolizing into difenoxin
Because it is not soluble in water, parenteral abusive potential is low
loperamide
PD:
Slows GI motility and decreases GI secretions
PK:
Penetrates the BBB with difficulty
Significant first pass
Ind:
Diarrhea
SE:
Abdominal spasms
naloxone
Chemistry: phenantrene
PD:
antagonist on all opioid R (highest affinity to μ R)
PK:
Short acting, it can be given via iv., im.
Ind:
In the therapy of opioid overdose, but after anesthesia as well
It is important to consider the short duration of action of naloxone, because an opioid overdosed patient can relapse into come when the naloxone’s effect ceased.
It can be carefully titrated with a very low dose to block some of the potential side effects of an iv. opioid without interfering with its analgesic effect.
methyl-naltrexone (bromide?)
PD:
Peripherally acting antagonist (quaterner)
PK:
Sc.
Ind:
For the treatment of opioid induced constipation – if other laxative were ineffective
Opioid
all compounds that work at opioid receptors.
