narcotic analgesics part 2

Question 1

what are EOP receptor natural agonists (opioid analgesics)?

Answer 1

Morphine

- Predominant constituent of opium
- Agonist at mu receptors
- Poorly absorbed after oral administration 
- When given i.v., plasma T1/2 ≈ 2 hours

Codeine

- Also a constituent of opium
- Less potent than morphine at mu receptors
- Good oral absorption, T1/2 ≈ 3 hours
- Converted to morphine by CYP 2D6
- Good cough suppressant

Meperidine

- Synthetic mu agonist
- Moderate oral absorption, T1/2 ≈ 3 hours
- Less respiratory depression than morphine
- May induce psychosis in some elderly people

Methadone

- Synthetic mu agonist,
- Good oral absorption, T1/2 ≈ 35 hours
- Used in addiction treatment programs due to 
	- long T1/2
	- Less euphoria
- Has a good analgesic profile, chronic pain syndrome

Question 2

what is fentanyl?

Answer 2

Very potent opioid

Good for treatment of chronic cancer pain, used frequently for palliative care

Question 3

what are opioid pharmokinetics?

Answer 3

Opioids are metabolized by hepatic glucuronidation

The glucuronides, which are highly polar are then excreted readily by the kidneys

Beware of toxicity in renal failure

The metabolites are readily detected in urine up to one week after consumption (Urine toxicology screen) → shows abuse, toxicity

Question 4

what are the pharmacological actions of opiod analgesics?

Answer 4

• Dose dependent
• Mood changes: usually mellow, pleasant, euphoria, occasionally dysphoria
• Analgesia without sedation:
  
  • The negative emotional overtone of the pain is gone (altered pain perception).
  • The pain sensation is reduced or blocked
    (altered pain sensory transmission).
• Pupillary miosis –> pinpoint pupils
• Constipation: reduced GI propulsive motility
• Nausea and vomiting: chemoreceptive trigger zone
• Increased release of prolactin and growth hormone
• Drowsiness: reduced reticular activating system in the brain
• Respiratory depression: reduced responsiveness of carbon dioxide sensing neurons in brain stem respiratory center. This is the cause of death in overdose

Question 5

what does tolerance have to do with opiod analgesics?

Answer 5

Tolerance is common
Acquired tolerance: repeated administration of a drug shifts the dose-response curve of the drug to the right (larger dose → same effect)
1- Pharmacokinetic tolerance: ↑metabolism/Excretion

Question 6

what does neuronal adaptation have to do with pharmacological tolerance?

Answer 6

2- Pharmacodynamic tolerance: Neuronal adaptation (main mechanism for opioids)
Short-term exposure:
↓ Neurotransmitter release
↑ Neurotransmitter clearance
↓ drug receptors
Long-term exposure:
Change in expression of genes relevant to pharmacologic action of the drug
Same changes in brain involved in learning and adaptation

• Tolerance includes down-regulated of EOP receptors (blue arrows) and up-regulated downstream receptors (red arrow head)

Question 7

what does withdrawl have to do with opioid analgesics?

Answer 7

• Withdrawal is the exact opposite of the direct drug action
• Withdrawal is more severe with short half-life drugs than
  with long half-life drugs: morphine and heroin vs. methadone → good to treat addiction
• EOPs are released by acupuncture
• EOPs are released by physical activity such as long
  distance running: runners high, second wind, addicted joggers, etc.

Question 8

what are the three stage withdrawal symptoms?

Answer 8

Stage I
Anxiety
Drug craving

Stage II
 Anxiety
 Insomnia
 GI disturbance
 Rhinorrhea
 Mydriasis
 Diaphoresis

Stage III
 Tachycardia
 Nausea/ Vomiting
 Hypertension
 Diarrhea
 Fever/ chills
 Tremors
 Seizure
 Muscle spasms

Question 9

what about addiction to opioid analgesics?

Answer 9

Drugs that are potentially addictive in people:

• Have a pleasant, enjoyable direct drug action
  
  • opiates cause euphoria, pain relief
• Have a rapid onset of action
  
  • i.v. injection reaches brain in less than 20 seconds
• Have a short biological half-life
  
  • morphine T1/2 ≈ 2 hours

Once tolerance to morphine has developed, i.e. down-regulated EOP receptors, up-regulated downstream receptors, withdrawal is quick in onset, severe and miserable

Escape from withdrawal syndrome reinforces drug taking behavior

Taking drug to avoid withdrawal is the final step in addiction

Question 10

what are EOP receptor antagonists?

Answer 10

Naloxone

- Blocks all EOP receptors				
- Poor oral absorption				 					
- After i.v. administration T1/2 ≈ 1 hour

- Used in opioid overdose, may need several injections

Naltrexone
- Blocks all EOP receptors
- Good oral absorption but first pass metabolism
- T1/2 ≈ 3 to 4 hours but has an active metabolite with
a T1/2 ≈ 12 hours

- Used in addiction treatment for narcotics 
- Reduces craving for alcohol by alcoholics