pharmacology of CNS Flashcards

Question

What is the PK of morphine?

Answer 1

 Oral absorption  Low bioavailability (~ 25%) due to first-pass metabolism  Metabolism  Conjugation with glucuronic acid  М6G: analgesic potency > parent compound  M3G: excitatory effects on CNS (allodynia, myoclonus, seizures)  Renal and biliary excretion of metabolites  Dose reduction in renal failure (М6G and M3G tend to accumulate in renal failure)  Plasma half-life ~ 3 h  Routes of administration  Parenteral: SC, IV  Oral – in cancer patients, in prolonged release drug forms  Epidural (in OG); spinal (in surgery)

Answer 2

 Central effects: ```  Analgesia  Increased pain threshold for moderate to severe pain  Reduced emotional (affective) response to pain  Euphoria (DA pathway)  Respiratory paralysis  Sedation (“Morpheus” – the god of dreams)  Cough suppression  Miosis  Nausea and vomiting  Neuroendocrine effects  ↑ АDH, prolactin  ↓ FSH, LH; CRF ```  Peripheral effects: ```  Constipation, biliary spasm  Urine retention  Bronchoconstriction (histamine release)  Cardiovascular – at high doses  Hypotension  Venodilation  Immunosuppression (with long-term administration) ```

Answer 3

 Analgesia – simulation of opioid receptors at:  Supra-spinal level  Descending pain inhibitory pathways (enkephalin, NA, 5-HT) ```  Spinal cord:  Presynaptic inhibition of glutamate and SP release from nociceptive afferents  Inhibition of the secondary afferent neuron  Gate control: opioid interneuron ```  Periphery:  Reduced excitability of nociceptors by opioids secreted by immune cells during tissue inflammation  Euphoria  Stimulation of the DA reward pathway (VTA to NAcc)  Abstinence  LC activation (NA)

Answer 4

 Side/toxic drug reactions: ```  Constipation  Requires treatment with laxatives or methylnaltrexone  Nausea and vomiting  Sedation  Bronchospasm, itching, urticaria, (histamine release)  Respiratory depression  ↑ intracranial pressure (ICP)  Urine retention  Tolerance and dependence ```  Contraindications: ```  Cranial trauma  ↑ CO2, vasodilation, ↑ ICP  “Acute abdomen” (morphine obscures the clinical picture)  Bronchial asthma ```  Acute intoxication: ```  Symptoms:  Respiratory paralysis  Pin-point pupils (NB!)  Coma and death  Treatment: Naloxone ```

Answer 5

 Tolerance:  Develops rapidly (days) but becomes clinically manifest after 2-3 weeks  Dose escalation up to 30-50 times possible  No tolerance to:  Miosis  Constipation Opioid dependence:  Psychological dependence – prominent (in addicts):  Due to euphoria  Compulsive drug seeking behavior  Upon discontinuation – long lasting (months) craving for the drug, leading eventually to relapse  Physical dependence – prominent:  Clear-cut abstinence syndrome upon withdrawal following chronic administration (piloerection, yawning, lacrimation, chills, hyperventillation, hyperthermia, mydriasis, diarrhea, anxiety, hostility)  Precipitated by opioid antagonists and/or partial agonists

Answer 6

``` Codeine  Better absorbed by mouth and easier access to brain  Partly converted to morphine (CYP2D6)  Weaker agonist  Cough suppression at lower doses  Weaker dependence and respiratory depression  Contraindicated in children under 12/18 ```

Answer 7

``` Tramadol  Weaker analgesic  Mode of action  Agonist at opioid receptors  Inhibitor of 5-HT and NE reuptake  Suitable for post-operative and other moderate pains  Lower addiction liability and respiratory toxicity ```

Answer 8

``` Oxycodone  More potent than morphine  Oral use; CYP-dependent metabolism  Abusable ```

Answer 9

Meperidine (pethidine): ```  Good oral bioavailability and shorter half-life  Antimuscarinic (spasmolytic) effects  Preferred for labor analgesia, renal colic or biliary spasm  Local anesthetic activity  Hypothermia (a kappa effect)  Used to treat post-operative shivering  Excitation up to seizures (convulsive metabolite)  Drug interactions with МАОIs (hyperpyrexia, convulsions) and SSRIs (serotonin syndrome) ```

Answer 10

Fentanyl ```  More potent (50-100 x) and shorter acting agonist  Routes of administration  Parenteral (acute)  Transdermal (chronic)  Intrathecal (in anesthesiology) ``` ```  Indications  Malignant pain  Labor  Neuroleptanalgesia (in combination with droperidol) – in surgery, cardiology ```  Similar drugs:  Remifentanil, sufentanil

Answer 11

Methadone:  Potent and longer-acting µ agonist  Also blocks NMDA receptors and monoamine transporters  Indications  Substitution therapy in opioid dependence  ADR  Abusable; QT prolongation

Answer 12

Buprenorphine  Potent and long-acting partial µ agonist and kappa antagonist  Useful in opioid dependence as a substitution  Prevents euphoric action of full agonists  Sublingual administration, CYP3A4 substrate  Buprenorphine/naloxone combination  ADR  Similar to other opioids  Less sensitive to naloxone

Answer 13

 Pain (moderate to severe) in:  Cancer patients (morphine, fentanyl, etc.)  Post-operative (tramadol, meperidine) ```  Other pain syndromes  Trauma, burns  Delivery (meperidine, fentanil, remifentanil)  Renal/biliary colic (meperidine)  Myocardial infarction (fentanyl) ```  Other indications: ```  Cough suppression (codeine)  Cardiac asthma (morphine, IV)  Soothing the irritated respiratory center (?)  Venodilation  Diarrhea – peripheral agonists (loperamide) ```

Answer 14

Acute intoxication: ```  Cause of death  Respiratory depression: the patient “forgets” to breathe (“Cheyne-Stokes” breathing) ```  Therapy  Naloxone IV  Clinical criterion:  Dilation of the pupils

Answer 15

Chronic intoxication = dependence  Methadone, buprenorphine  Substitution therapy  Milder abstinence syndrome  Naltrexone  Oral antagonist  Blocks the effect of morphine “high” in “detoxicated” users  Clonidine  Inhibits stress and reduces the severity of the abstinence symptoms (LC)

pharmacology of CNS Flashcards

(39 cards)