This document discusses opioids including their classification, mechanism of action, receptors, metabolism, pharmacokinetics, and management of opioid-dependent patients. It covers specific opioids like morphine, diamorphine, fentanyl, alfentanyl, remifentanyl, oxycodone, and codeine. Transdermal delivery systems and concerns using remifentanyl PCA in labor are also mentioned. The final section discusses anesthetic management and concerns for an addict pregnant female undergoing cesarean section.

1. OPIOIDS
DR.IBRAHIM HASSAAN , MBCHB,MSC,EDAIC
14/04/2023

2. CLASSIFICATION OF OPIOIDS
• Traditional: based upon analgesic potency
• Origin of drug: naturally occurring, Semisynthetic & Synthetic
• Function: their action at the opioid receptor

3. CLASSIFICATION OF OPIOIDS

4. MECHANISM OF ACTION

5. G PROTEINS & TYPES OF G PROTEINS?
 G proteins (or GTP-binding proteins) are regulatory proteins, which couple the activation of a surface
receptor to the activation of an intracellular enzyme (e.g. adenylate cyclase) so that a secondary
messenger can be produced (e.g. cAMP), allowing signal transduction and amplification to occur.
 They are heterotrimeric proteins (i.e. they consist of α, β and γ subunits, which join together to form a
trimer).
The main types of G proteins are the ‘stimulatory’ (i.e. Gs and Gq) and the ‘inhibitory’ (i.e. Gi ) proteins.
1-Gs proteins stimulate adenylate cyclase, causing a rise in cAMP (e.g. β adrenoceptors and glucagon
receptor).
2-Gq proteins stimulate phospholipase C, causing a rise in IP3 and DAG (e.g. α1 adrenoceptor and
muscarinic acetylcholine receptor (mAChR)).
3-Gi proteins inhibit adenylate cyclase, causing a fall in cAMP (e.g. α2 adrenoceptors and opioid receptors).

6. OPIOID RECEPTORS
• MOP (mu 1,2 opioid peptide R)------------site brain & sp cord
• KOP (kappa 1,2,3opioid peptide R)--------site brain & sp cord
• DOP (delta 1,2 opioid peptide R) ---------site brain
• NOP (nociceptin FQ orphanin peptide R)----site brain & sp cord

7. METABOLISM
a wide variety of metabolic pathways.
 In general, opioids are metabolized by the hepatic microsomal cytochrome P450 (CYP) system, although
hepatic conjugation and subsequent excretion by the kidney are important for some drugs.
 For certain opioids, the specific metabolic pathway involved has important clinical implications in terms
of active or toxic metabolites (e.g., morphine, meperidine) or an ultrashort duration of action (e.g.,
remifentanil).

9. PHARMACOKINETICS
*Bolus front-end kinetics (the latency to-peak effect after bolus injection)
*Bolus back-end kinetics (the time to offset of effect after bolus injection)
*Infusion front-end kinetics (the time to steady-state after starting a continuous infusion)
*Infusion back-end kinetics (the time to offset of effect after stopping a continuous infusion)

12. (CSHT) DEFINED AS THE TIME REQUIRED TO ACHIEVE A 50% DECREASE IN
PLASMA CONCENTRATION AFTER STOPPING A CONTINUOUS

13. Dependence
A physically dependent patient will need to repeatedly administer the drug to avoid suffering from
withdrawal symptoms
Addiction
is characterised by the patient’s behaviour resulting from their dependence. An addict will:
>Crave and seek out the drug
> Have no control over their drug use
> Use the drug compulsively
> Continue to use the drug even if it is causing them harm

14. HOW WILL YOU MANAGE POST OPERATIVE PAIN CONTROL IN AN
OPIOID-DEPENDENT PATIENT?
 their baseline pre-existing opioid dosage should be continued.
 additional pain relief should be administered as required. The patient will be tolerant to opioids and so
may need more than the ‘average patient’ to achieve pain relief.
 pethidine should be avoided as large doses may cause the proconvulsant metabolite nor-pethidine to
accumulate.
 It is sensible to include simple analgesia and regional techniques where possible.
 If the patient is on a methadone programme, ascertain their daily requirements and continue this
dosage perioperatively

15. MORPHINE
Pharmacokinetic
 Dose &Route of admi : Oral: 5–40 mg/4 hourly • Rectal: 15–30 mg/4 hourly • IV: 0.05–0.1 mg/kg/4
hourly • IM/SC: 0.1–0.2 mg/kg/4 hourly • Intrathecal 0.1–1 mg • Epidural 1–5 mg
 MOA : Agonist at MOP and KOP G-protein coupled opioid receptors
Pharmacokinetic
 Absorption: Oral bioavailability at 15–20% • 20–40%PPB • VD 3.4–4.7 L/kg • Low lipid solubility
 Met: Hepatic metabolism to: • morphine-3- glucuronide (inactive) and • morphine-6- glucuronide
(active)
 Execration :in urine
 intrathecal morphine cause pruritus because of activation of receptor s on mast cells in the skin
mainly face around nose ,tt bt 50-100 mic iv naloxone

16. DIAMORPHINE
 Uses :Analgesia • Sedation on ITU • Palliative care • CCF • Drug of abuse
 MOA : Metabolites act at MOP or KOP receptors • Diamorphine itself has no affinity for opioid receptors
 Dose &Route of admi :2.5–5 mg IV for pulmonary oedema/MI • 0.1–0.4 mg intrathecally • 1–3 mg
epidurally
Pharmacokinetic
 Absorption :Bioavailability low • Protein binding 40%
 Met: Hydrolysed by plasma enzymes and by RBCs, (probably by esterases and pseudocholinesterases) to
6-O-acetylmorphine, the active form of the drug
 Execretion : excreted in urine

17. FENTANYL VS ALFENTANYL

18. TRANSDERMAL DELIVERY SYSTEM
 TDD is a painless method of delivering drugs systemically by applying a drug formulation onto intact
and healthy skin
 There are two designs of transdermal patch :
the reservoir (membrane-controlled system)
A reservoir patch holds the drug in a gel or solution and delivery is determined by a rate-controlling
membrane between the drug reservoir and the skin .
the matrix system.
The matrix patch incorporates the drug into an adhesive polymer matrix, from which the drug is
continuously released into the skin. The dose of drug delivered depends on the amount of drug held in the
matrix and the area of the patch applied to the skin.

19. OPIOID TRANSDERMAL DRUG DELIVERY SYSTEMS
 Ex: Fentanyl & Buprenorphine
 Fentanyl patches are designed to deliver fentanyl at four constant rates: 25, 50, 75, and 100 mic h21 for a
period of 72 h.
 Factors affecting
 Vascular supply
 Thickness of the skin
 Advantages ---decrease SE of opiods
 Disadvantage ---skin irritation,resp depression still occour ,removal of patch will not immediately stop
the effect

20. REMIFENTANIL
 USES: • Analgesia during general anaesthesia • Hypotensive anaesthesia • Sedation on ICU and for
procedures, e.g. awake fibre optic intubation
 MOA :Pure MOP opioid receptor agonist
 Dose & Route of admi : 0.05–2 µg/kg/min
Pharmacokinetic
 Absorption: Only given IV • t½ 2 hours • Effects last only 10 min from termination of infusion • Context
insensitive half-life
 Met: rapid ester hydrolysis by non-specifc plasma/tissue esterases
 Execretion: in urine

21. PRECAUSES OF REMIFENTANIL PCA USING IN LABOUR
 Use O2 supply
 Useful but incomplete analgesia
 No residual analgesia
 Ideal dose not clear
 Feta; and maternal SE
Respiratory depression ,hypotension,bradycardia & hypothermia

22. OXYCODONE
 Oxycodone is available in immediate- and controlled release preparations.
 The drug is available in intravenous use oral use
 Kinetics
 oral bioavailability of oxycodone is 60–87%. The time to
 Distribution The VD of oxycodone is 2.6 l/kg at steady state.
 Approximately 45% of the drug is bound to plasma proteins.
 Metabolism The drug undergoes extensive hepatic metabolism via CYP450 3A to noroxycodone and
CYP450 2D6 to oxymorphone and various other conjugated glucuronides.
 renal elimination.

23. CODEINE
 Codeine is actually a prodrug that is metabolized in part by O-demethylation into morphine, a metabolic
process mediated by the liver P450 isoform CYP 2D6.
 Interestingly, Asians have less CYP 2D6 activity and thus may be an ethnic group particularly resistant to
codeine therapy.
 Conversely, certain ethnic groups (e.g., Ethiopians) are thought to be particularly susceptible to the effects
of codeine because they carry frequently duplicated, functional CYP 2D6 genes, resulting in the ultra rapid
conversion of codeine to morphine.
 In addition to therapeutic failure, Genetic variability occurs with the cytochrome P450 enzyme CYP2D6
which causes conversion to morphine, so ‘fast’ metabolizers produce more morphine
 Functional CYP 2D6 gene duplication has recently been implicated in fatalities among infants breastfed by
mothers who are ultra rapid metabolizers

25. ANESTHETIC MANAGEMENT AND CONCERNS FOR ADDICT
PREGNANT FEMALE UNDERGOING AN ELECTIVE CS
Concerns related to addict female
-history about substance used for addiction,last uses
-Needle related infection (HIV, Hepatits ) maybe asymptomatic
-Preoperative referral to addict center or psychiatric consultation to adjust patient for programmed plan as
methadone to reduce fatal complications
Concern related to fetus
-NAS( neonatal abstinence syndrome)
-NOWS (neonatal opioid withdrawal syndrome)
-Malpresentation, LBW, prematurity, CHD, fetal distress