Pharm Lecture 5 Opioids

all exogenous substances both natural & synthetic binding to opioid receptors producing “morphine-like” effects

Opioids produce analgesia without loss of touch (which make it different than local anesthetics), proprioception, or consciousness (except in large doses)

*operate on different receptors than local anesthetics

• Agonists
• Agonist-antagonists
• Antagonists

naloxone most used and most familiar with

• FALSE! we don’t generally give an agonist
• thinking we can reverse it w/antagonist
• *Much more likely to reintubate if apnic in PACU than to give opioid antagonist.If we were to give it we’d dilute it down significantly.

can cause SNS stimulations as result of reversal of analgesia, get HTN, tachycardia, arrhythmias (VF) and pulmonary edema.

Morphine

Fentanyl and Meperidine

benzylisoquinoline

i.e. Codeine = methylmorphine

TRUE! (ex: fentanyl family)

• Mu 1, Mu 2
• Kappa
• Delta
• Sigma (probably not an opioid receptor)

• CNS, mostly brainstem & spinal cord
• (pre and post synaptic areas in CNS)
• Periphery

• Enkephalins
• Endorphins
• Dynorphins

come from ability to directly inhibit the ascending transmission of info from spinal cord, interrupting the pain circuits

Hemming's says they inhibit release of substance P from primary sensory neurons in the dorsal horn. This mitigates the transfer of painful sensations to the brain. Change the affective response to pain, they don’t complete block the pain but make the patient care less about the pain.

• Part of the guanine (G) protein-coupled receptors (like muscarinic Ach, GABA, adrenergic, etc)
• Inhibition via adenyl cyclase decreasing conductance of voltage-gated calcium channels or opening outward flowing potassium channels
• Receptor activation causes:
• --↓ neurotransmission 2° presynaptic inhibition of neurotransmitters including Ach,dopamine, norepi, substance P
• --Postsynaptic inhibition of evoked activity
• --↑ potassium conductance → hyperpolarization, calcium channel inactivation, or both → mediate ↓ in neurotransmitter release

Mu₂ and Delta

• Mu₂
• *They all cause spinal analgesia

• Mu₁
• Kappa

Kappa

Kappa

Mu₁

• Mu₁
• Kappa

• Mu₂
• Delta

• Mu₂
• Delta

Mu₁

• Mu₁
• Delta

Mu₁ and Mu₂

Mu₁ and Mu₂

Mu₁ and Mu₂

• All of them!
• Mu₁
• Mu₂
• Delta
• Kappa

• Effects:
• Supraspinal analgesia
• Respiratory depression
• Physical dependence
• Muscle Rigidity

• Agonists:
• Morphine
• Fentanyl
• Met-enkephalin (endogenous)
• Beta-endorphin (endogenous)

• Effects:
• sedation
• spinal analgesia

• Agonists:
• Morphine
• Nalbuphine
• Butorphanol
• Dynorphin (endogenous)
• Oxycodone

• Effects:
• analgesia
• behavioral
• epiletogenic

• Agonists:
• Leu-enkephalin (endogenous)
• Beta-endorphin (endogenous)

• Effects:
• Dysphoria
• Hallucinations
• Respiratory stimulation

• Agonists:
• Pentazocine
• Nalorphine
• ?Ketamine

• Alfentanil (6.5)
• Remifentanil (7.1)
• Morphine (7.9/9.4)
• Sufentanil (8.0)
• Fentanyl (8.4)
• Meperidine (8.5)

• Alfentanil (6.5)
• Remifentanil (7.1)
• --this means the % ionized is lower than the rest, (they are basic drugs) so these drugs have a quick onset!

• Alfentanil (11)
• Remifentanil (33)
• Morphine (76)
• Sufentanil (80)
• Fentanyl (91)
• Meperidine (93)

BASIC drugs!

• Morphine (1.4)
• Remifentanil (17.9)
• Meperidine (38.8)
• Alfentanil (130)
• Fentanyl (860)
• Sufentanil (1778)

refers to lipid solubility

• ++ Morphine
• +++Meperidine, Fentanyl, Remifentanil
• ++++Sufentanil & Alfentanil

• + Meperidine & Fentanyl
• ++ Morphine & Sufentanil
• +++ Remifentanil
• ++++ Alfentanil

Alfentanil

• High non-ionized fraction at physiologic pH
• Small Vd

• Prior accumulation of another drug - ↓ uptake
• History of tobacco use - ↑ uptake
• Inhalation anesthesia -↓ uptake

See a delay in onset of action at effect site (Brain) w/regard to fentanyl as opposed to alfentanil.

Hemming's: refers to this as latency to peak effect. (new terminology in that text).

• Time to equilibration between brain and effect site (which produces rise in effect site concentration)
• Alfentanil, Fentanyl, and then Sufentanil is last.

• Alfentanil (238)
• Sufentanil (900)
• Meperidine (1020)
• Morphine (1050)
• Fentanyl (1530)
• Remifentanil (4000)

• Alfentanil (27)
• Remifentanil (30)
• Sufentanil (123)
• Morphine (224)
• Meperidine (305)
• Fentanyl (335)

• Morphine conjugated with glucuronic acid to active metabolite
• Meperidine is de-methylated to normeperidine (active metabolite)
• Fentanyl, sufentanil, alfentanil, to inactive
• Remifentanil by ester hydrolysis

• Morphine (glucoronic acid)
• Meperidine (normeperidine)

hepatic blood flow

small Vd

• the resulting water-soluble glucuronides (morphine 3-glucuronide & morphine 6
• glucuronide) which are excreted via the kidneys.

Morphine 6 glucuronide is more potent and long lasting than Morphine itself.

If pt. as renal failure (normeperidine not eliminated) then can have seizure activity.

• Remifentanil (0.17-0.33)
• Alfentanil (1.4-1.5)
• Morphine (1.7-3.3)
• Sufentanil (2.2-4.6)
• Fentanyl (3.1-6.6)
• Meperidine (3-5)

• Remifentanil (4)
• Sufentanil (30)
• Alfentanil (60)
• Fentanyl (260)

• Remifentanil (1.1)
• Alfentanil (1.4)
• Sufentanil (6.2)
• Fentanyl (6.8)

• Rapid biotransformation. (Esters)
• Terminal elimination ½ life is less than 10min.
• Remifentanil is great because you can titrate but need analgesia on board in PACU so it requires a bit of a plan. (give Morphine or Fentanyl towards end of case for adequate pain control post-op)
• Remifentanil metabolized by ester hydrolysis.
• Pseudocholinesterase deficiency does not effect its metabolism

huge difference in protein binding and partition coefficient.

• Protein binding (Fentanyl 84 & Morphine 35)
• Partition coefficient (Fentanyl 955 & Morphine 1)

• generally stable
• Morphine & meperidine cause histamine release so ↓BP & ↓ SVR
• Fentanyl family associated with vagus mediated bradycardia (high doses)

• depression (rate)
• ↓response to CO2
• ↓ hypoxic drive
• ** chest wall rigidity: centrally mediated hypertonus of striated muscle
• (more depression of  RR than TV)

• ↓ CBF, ICP, CMRO2 but < barbs/benzos
• Stimulate chemoreceptor trigger zone

• block stress hormone release > volatiles
• --Catecholamines
• --Cortisol
• --ADH

• is a centrally mediated hypertonus of all striated muscle.
• It can be severe enough to prevent ventilation
• that you need neuromuscular blocker.
• Most common w/highly lipid soluble opioids,
• most assoc. w/fentanyl.
• Dose related, more likely to occur the higher the dose (all at once)
• It’s refered to as chest wall or truncal but involves all striated muscle (includes pharyngeal and laryngeal muscle—narrow)

they increase it

Meperidine

MUCH less of reduction

Morphine

• 1. Low lipid solubility
• 2. Metabolism to:
•     a)  Morphine-3-glucuronide (75-85%) - inactive
•     b)  Morphine-6-glucuronide (5-10%) – active with potency & duration greater than that of morphine

Sue said the metabolites were IMPT :)

TRUE

• Takes about 15-30min to peak in CNS (After IV injection).
• Probably only a 1/10th (0.1%) reaches CNS at time of peak, because of lipid solubility as well as high degree of ionization.

• The non-ionized fraction will increase, and therefore passage of drug into CNS will be enhanced.
• If resp acidosis (Flip side) then we would expect more ionized however w/resp acidosis what happens there will be increase CBF d/t hypercarbia, increase in CBF will deliver whatever non-ionized drug is there, better delivery to CNS. This is thought to be a more important factor (Inc. CBF) than the increase in ionization d/t hypercarbia.

• Histamine release – minimize by slow injection, IV fluids (preload)
• --Pruritus
• --Urticaria
• --Erythema 
• Orthostatic hypotension → venous pooling
• Respiratory depression

• Analgesia
• Acute pulmonary edema
• --↓ perception of SOB
• --↓ preload & afterload (because of venous pooling)

• Dosing:
• --Analgesia: 1 -15 mg IV
• --Induction: 1 mg/kg IV
• Onset: less than 1 minute
• Peak: 5-20 minutes
• Duration: 2-7 hours

the fentanyl family

phenylpiperidine

TRUE!

1/10th as potent as morphine so 75-100 mg = 10 mg morphine

• Metabolism by demethylation & hydrolysis to:
• --Normeperidine which has elimination ½ life of 15 hours, is ½ as active as meperidine as
• analgesic, produces CNS stimulation with toxicity & can cause seizures & myoclonus
• --Meperidinic acid

• ↑ HR – remember structurally similar to atropine (rarely bradycardia)
• *↓ myocardial contractility in large doses (unique among opioids)*
• Delirium & seizures (2° normeperidine-metabolite)

• Suppressing postop shivering (kappa receptors)
• Small doses 12.5mg will help w/that

• Contraindicated in patients on MAOIs (serotonin syndrome)
• Serotonin syndrome: excess availability of serotonin in CNS characterized by confusion, fever, shivering*, diaphoresis, ataxia, hyperpyrexia, myoclonus, & diarrhea. 

Morphine and Codeine ok, alfentanil and remifentanil are ok.

• Dosing:
• --Analgesia: 12.5-100 mg (0.5-2 mg/kg)
• Onset: less than 1 minute
• Peak: less than 1 hour
• Duration: 2-4 hours

• Semisynthetic opioid
• Phenathrene (hydrogenated ketone of morphine)

5 - 6 times as potent as morphine

• Less opioid-related side effects than with morphine
• May cause chest wall rigidity
• Caution in the elderly

• Vd: 4 L/kg
• 8-20% protein bound
• Biotransformed in the liver
• Active metabolites are:
•    a) Dihydromorphine
•    b) Dihydroisomorphine
• Inactive metabolite is hydromorphone-3-glucoronide
• Has been the preferred opioid for patients with renal impairment BUT hydromorphone-3-glucuronide can accumulate in renal failure & cause neuroexcitation & cognitive impairment
• (caution is advised)

• Slightly more duration of action than morphine.
• More sedation and less euphoria than morphine.

• Dosing
• --Analgesia: 0.5-2 mg
• Onset: 15 min
• Peak: 30-60 minutes 
• Duration: 4-5 hours
• (0.2mg incremental doses in 5min for total of 1mg) Small doses, received a lot of drugs in OR, don’t want to leave in PACU w/resp compromise.

Phenylpiperidine derivative synthetic opioid structurally related to meperidine (w/out nasty effects)

75-100 times more potent than morphine

• Faster onset & shorter apparent duration than
• morphine because it is more lipid soluble and larger Vd. Faster onset, lipid soluble can go across BBB fast

Lungs act as large & inactive store w/estimated 75% of initial fentanyl dose undergoing first-pass pulmonary uptake which limits the amount of initial dose reaching systemic circulation

Saturation of inactive tissue sites → ↑ duration of action & context-sensitive half time (Repeated boluses will stack and saturate fat stores. Similar to thiopental, not high clearance and very lipid soluble)

• Fentanyl is extensively metabolized to norfentanyl by N-dimethylation.  Norfentanyl is structurally similar to normeperidine.  It is excreted by the kidneys and has less analgesic potency than fentanyl.
• ** note longer elimination ½ time (3-6 hours) compared with morphine (1.7-3.3 hours) even with apparent shorter duration (short acting, but not d/t eliminatioin...highly lipid soluble)

• Stable hemodynamics
• --No myocardial depression
• --No histamine release
• Suppression of stress response

• Carotid sinus reflex control of heart is depressed → ↓HR
• Chest wall rigidity
• ----Because it is so highly lipid soluble

prolonged elimination. ½ time, decreased clearance could be r/t hepatic blood flow

• Dosing:
• a) Premedication/analgesia:  25-100 mcg (1.5 – 5 mcg/kg) IV
• b) Induction:
• --With hypnotic: 1.5-5 mcg/kg
• --With 70% nitrous oxide: 8 -23 mcg/kg
• --High dose opioid: 50 mcg/kg
• c) Intermittent bolus: 25 -100 mcg
• d) infusion: 0.05-0.2 mcg/kg/min (anesthesia
• supplement)

• Onset: 30 sec
• Peak: 5- 15 minutes
• Duration 0.5-1 hour

• spontaneous breathing, give small dose of opioid, give 25mcg of fentanyl decrease
• RR but 50mcg will make them apnic.
• So give 25 and then another 25 a few min. later, achieve same analgesic effect without knocking out their RR.

• Fentanyl and droperidol
• (Referred to as neurolept anesthesia) because of issues w/droperidol (prolonged QT) inobar is no longer used

Fentanyl derivative, 10 times as potent as fentanyl

• Similar to fentanyl
• Higher degree of ionization & protein binding than fentanyl so smaller Vd & shorter elimination ½ life
• Metabolism by dealkylation & demethylation in the liver 
• *More lipophilic than fentanyl, 93% protein bound, as apposed to 80% of fentanyl (makes Vd smaller than fentanyl)*

sympatholysis with vasodilation but hemodynamic stability prevails

• Dosing
• a) Induction:
• --With hypnotic: 0.1 – 1 mcg/kg
• --With 70% nitrous oxide 1.3 – 2.8 mcg/kg
• --High dose opioid: 10 – 30 mcg/kg
• b) Intermittent bolus: 5 -20 mcg
• c) Infusion: 0.005 – 0.015 mcg/kg/min (anesthesia supplement)
• Onset: 1-3 minutes
• Peak: 3-5 minutes
• Duration: 30 minutes – 1 hour

• 1/5th as potent
• (Derivative of fentanyl)

• Peak brain effect in less than 1 minute
• pKa of 6.8 so almost 90% is non-ionized at
• physiologic pH
• Moderate lipid solubility but less than fentanyl so…
• ---Vd  is smaller than fentanyl
• ---Highly protein bound (92%)
• Metabolized by dealkylation & demethylation to inactive metabolites

• Chest wall rigidity in 90-100% of pts at dose of 150-175 mcg/kg (high dose)
• ? More hypotension & bradycardia than fentanyl or sufentanil
• ? More N/V

• Dosing
• a) Induction: 
• --With hypnotic: 10 - 50 mcg/kg
• --High dose opioid: 120 mcg/kg
• --Intermittent bolus: 250-500 mcg (5-10 mcg/kg)
• b) Infusion: 0.5-1.5 mcg/kg/min (anesthesia
• supplement)
• Onset: less than 1 min
• Peak: 1-2 min
• Duration: 10-15 min

Ultra short acting approved for use in 1996

• Short duration of action due to metabolism (not redistribution)
• Metabolism by blood & tissue esterases (not pseudocholinesterase)
• Small Vd
• Rapid recovery with return of spontaneous
• ventilation in 2-5 minutes
• No lingering analgesia (great for cases that need analgesia intraop but not a lot of pain post-op. Need to give another opioid prior to  discontinuing infusion. Want to stay ahead of pain.)

• Induction: not suitable alone
• Analgesia: intraop as continuous infusion 0.3-1 mcg/kg/min

• Nalbuphine (Nubain)
• Butorphanol (Stadol)
• Buprenorphine (Buprenex)
• Pentazocine (Talwin)

• Nalbuphine (Nubain)
• Butorphanol (Stadol)
• Buprenorphine (Buprenex)

• Nalbuphine (Nubain)
• Butorphanol (Stadol)
• Pentazocine (Talwin)

They don’t cause significant respiratory depression (ceiling effect) increasing dose doesn’t increase the response.

Stoelting: should be reserved for pt. that can’t tolerate the opioid agonist.

• Hemming's: most common use periop is to
• reverse resp depression from other opioids while maintaining analgesia.

** not commonly used in practice

• fentanyl, as tissue stores get saturated, its different than remifentanil which is completely independent of infusion duration.
• So the context sensitive 1/2 time of Fentanyl is very long (especially w/a long infusion) and Remifentanil, infusion time doesn't really matter