Test 2 Flashcards
Local anesthetic structure
Aromatic group Linker region (either amide or ester) Amino group (can accept a proton) Non ionized = traverse cell membrane Ionized/protonated = aqueous soluble (higher affinity for binding site in Na channel) - responsible for most of the blockade
Local anesthetics: Amides
all amides have an “i” before the “caine
Local anesthetics: molecular target
All local anesthetics bind/block within the pore of voltage-gated Na+ channels, thereby decreasing conduction velocity and increase threshold for APs (block APs, but do not affect K, so do not change membrane resting potential).
Little selectivity for subtypes of Na+ channels
Can affect neurons generally (CNS, PNS) and some cardiac cells
Lack of selectivity contributes to adverse effects
Physiological pH: LA
Most LAs are weak bases, with pKa = 7.5-9 - so most are protonated at physio pH. The remaining base that is membrane-permeable.
Two routes to the local anesthetic binding site in the channel:
The major route under most conditions is intracellular: Drug in the cytoplasm can enter the open channel and block it.
A quantitatively minor route is membrane-delimited: Drug diffuses from within the lipid bilayer to channel pore.
Other barriers for LAs besides axon cell membrane
In the nerve, LA must pass through a series of lipid and aqueous phases: Epineurium, perineurium, endoneurium, cell membrane.
Takes the longest to get to the center - more proximal regions are blocked first
LA Potency
correlates with hydrophobicity of the base - Highly hydrophobic base accumulates in the lipid bilayer.
Creates a reservoir of drug molecules that can be protonated at the cytoplasmic surface and enter the open channel
LA Sensitivity
The most sensitive are small-caliber C-type fibers.
Sensory are nociceptors for mediate 2nd pain (slow)
Motor confer sympathetic tone (a receptors, vasoconstriction)
Ad fibers also are quite sensitive (these carry 1st pain).
Larger fibers are relatively spared.
Factors affecting sensitivity to LA
Size: small are more sensitive (eg C pain fibers)
Firing rate
Location within nerve
Mylinated more sensitive than unmylinated
LA: vasoconstrictors
due to inhibition of sympathetic postganglionic fibers to the vasculature - increases blood flow and permeability carrying the drug away from the tissue into systemic circulation.
Epinephrine is often administered with LA to increase duration and reduce systemic adverse effects
LA: esters
Hydrolyzed by plasma pseudocholinesterases
Metabolized to PABA, which triggers a local hypersensitivity (allergic) reaction in some patients
Local metabolism reduces the risk of systemic effects, especially if the drug is administered with a vasoconstrictor
LA: Amides
metabolized by the liver, in part by cytochrome P-450 enzymes
The local anesthetic effect of an amide is terminated by systemic distribution.
Greater risk of systemic adverse effects than esters, esp in those with severe hepatic disease
Can bind to a1-acid glycoprotein and cant be metabolized in that form - affecting the rate of elimination
LA Adverse effects - CNS
At relatively low toxic levels, mainly sedation
At higher levels: seizures, loss of consciousness
May reflect blockade of inhibitory neurons
Typical progression with increasing dose:
drowsiness to sensory disturbances to dizziness to twitching to seizures to coma
LA Adverse - Cardiac
Generally occur at higher toxic levels than CNS symptoms
Cells specialized for conduction (eg Purkinjee) are most sensitive.
Arrhythmias include A-V block, ventricular arrest.
Mediated mainly by block of cardiac Na+ channels
Very high toxic doses can directly inhibit Ca2+ conductance and reduce cardiac contractility. Except Cocaine and prilocane, which are vasoconstrictors.
Cocaine
Ester. The only naturally occurring local anesthetic in clinical use
Introduced into practice by Koller (1884) for corneal anesthesia.
Notable for its vasoconstrictory activity – do not need epi
Inhibits monoamine uptake, including norepinephrine from sympathetic postganglionics
Subject to hepatic metabolism if systemically distributed, even though it is an ester
Approved for topical use on mucous membranes
Mainly used in eye, nose, and throat procedures
Procaine
Ester. developed as a replacement for cocaine; devoid of abuse potential, novocaine.
Low potency, slow onset, short duration
Not effective topically: too rapidly metabolized
Use is now confined largely to infiltration anesthesia
Tetracaine
Ester. Relatively slow onset of effect, but more potent and longer acting than procaine.
Used mainly for spinal block, and in topical preparations
Benzocaine
Ester. Unique structure: Lacks an ionizable group, so poor aqueous solubility – cant be protonated. Accesses Na channel binding site by diffusion in the bilayer.
Strictly for surface anesthesia
Lidocaine
Prototypical amide; the most commonly used local anesthetic
Rapid onset
Base is moderately hydrophobic
Relatively low pKa (7.9), so substantial fraction is in base form
High extraction drug
Elimination is flow-limited - avidly broken down by liver; extra caution in patients with liver disease
Used systemically to treat cardiac arrhythmias
Prilocaine
Amide. Weak vasodilator, so Epi not generally required
Has large volume of distribution (Vd): ~300 liters (in fat)
In regional block, this property reduces systemic concentration
Rapid systemic elimination (hepatic + renal)
Adverse effect: methemoglobinemia
Fe3+ (ferric) heme rather than normal Fe2+ (ferrous)
This effect can occur with benzocaine, but less likely
Bupivacaine
Amide. Blocks sensory > motor neurons; especially useful in labor
More cardiotoxic than equieffective anesthetic doses of lidocaine; due mainly to the S(+)-enantiomer (racemic drug)
Potentially serious ventricular arrhythmias, myocardial depression
Slowly dissociates from cardiac Na+ channel, retained during diastole, cumulative blockade; recovery hastened by intravenous lipid emulsion
Sustained-released liposomal formulation (24 h duration) for management of post-operative pain
Ropivacaine
Amide. Derivative of the R(-)-enantiomer of bupivacaine
Less cardiotoxic than racemic bupivacaine
Levo-bupivacaine, which contains only the R(-)-enantiomer of bupivacaine, has been withdrawn from US market.
Local ocular distribution
Most eye drugs are topical.
Transcorneal/transconjuctival route: Aqueous humor to intraocular structures including trabecular meshwork (which can allow systemic absorption)
Also systemic circ via nasal mucosa
Ocular metabolism
Determined by Tear and tissue proteins and Diffusion across cornea and conjunctiva
Metabolized by traditional hepatic metabolism after systemic absorption
Ocular elimination
Nasolacrimal drainage
Topical eye drugs can be systemically absorbed
First pass liver metabolism is avoided through absorption by nasal mucosa
Ocular sympathetic response (fight or flight, need more light)
Mydriasis (dilation) via stimulation of outer radial muscle of iris
βreceptors on ciliary epithelium promotes secretion of aqueous humor.
Blocking βreceptors will decrease intraocular pressure by reducing aqueous humor.
In the eye, the predominant βreceptor is β2.
Ocular parasympathetic response (rest and digest)
Miosis (constriction) via stimulation of inner circular muscle of iris
Ciliary muscle contraction (causing relaxation of the zonules and tension on trabexular meshwork), resulting in accomodation (lens is more convex and shifted forward)
Accommodation can be blocked by muscarinic cholinergic antagonists–cycloplegia
Intraocular pressure is decreased with increased aqueous humor outflow via outflow into the Canal of Schlemm & trabecular meshwork.
Tension is produced on trabecular meshwork by ciliary muscle contraction, opening pores and facilitating aqueous humor outflow into the Canal of Schlemm & trabecular meshwork.
Glaucoma
Second leading cause of blindness worldwide
Characterized traditionally by elevated intraocular pressure
Causes optic neuropathy
Cauess Damage of optic nerve causes progressive retinal ganglion cell axon loss
Can cause loss of visual field and irreversible blindness
Glaucoma is classified as either:
Open-angle glaucoma – some can drain by trabecular meshwork
Closed-angle (Angle-closure) glaucoma = emergency: requires surgical intervention – trabecular meshwork blocked
Open angle glaucoma
Rarely present with symptoms
Found on comprehensive ophthalmic exam
Central vision loss is a late manifestation
Increase uveoscleral outflow
Increase trabecular meshwork & Canal of Schlemm outflow
Decrease aqueous humor production – beta blocker
Closed angle glaucoma
Emergency - treat with lazer iridotomy Visual acuity loss Pain Conjunctival erythema Corneal edema
Glaucoma diagnosis
Fundoscopic exam
Cupping is a hollowed-out appearance of the optic nerve.
Glaucoma is associated with a cup’s diameter > 50% of vertical optic disc diameter.
Visual Field Testing
Intraocular Pressure
Treatment for glaucoma
Increase uveoscleral outflow
Increase trabecular meshwork & Canal of Schlemm outflow
Decrease aqueous humor production – beta blocker
Latanoprost
Prostaglandin Agonist.
Analog of PGF 2α
1st line medical therapy for glaucoma
Once a day dosing
Mechanism of action: Increased aqueous humor outflow via uveoscleral pathway. Unclear how.
Side effects: Blurred vision, Burning sensation in eye, Conjunctival hyperemia, Eye irritation, Foreign body sensation, Iris color change, Itching of eye , Punctate keratopathy or keratitis (white specs)-
Timolol
β1 an 2 Receptor Antagonists - autonomic
Blocks production of aqueous humor
Mechanism of action: Aqueous humor production seems to be stimulated by βreceptor mediated cyclic AMP-PKA pathway. Beta blockade decreases aqueous humor production.
2nd most commonly used for glaucoma
Side effects:
Ophthalmic: Blurred vision, Burning sensation in eye, Cataract, Conjunctival hyperemia, Corneal anesthesia, Dry eyes, Reduced visual acuity
Cardiovascular: Bradycardia, Hypotension
Respiratory: Cough, Dyspnea – beta blockers constrict airways
Most patients will not have systemic side effects, but they can occur.
Metabolized by CYP 2D6. So if a patient has significant respiratory disease (significant asthma or COPD) or if patient is on another drug that supresses CYP 2D6, you should be wary of the manifestations of these systemic side effects.
May want to avoid using βReceptor antagonists in these patients, but must weigh risks and benefits.
Brimonidine
Alpha 2 agonist
Mechanism of action:
Binding to presynaptic α2 receptor, which reduces the amount of norepinephrine release
Binding to postsynaptic α2 receptor stimulates Gi pathway, decreasing cAMP production
Both lead to decreased aqueous humor production because NE affect beta receptors and Gi limits cAMP’s role
Enhancement of uveoscleral outflow may also play a role
Side effects:
Ophthalmic: Allergic conjunctivitis, Burning sensation in eye, Conjunctival discoloration, Conjunctival hyperemia, Acute follicular conjunctivitis, Hypersensitivity reaction, (Ocular), Itching of eye, Lid retraction, Visual disturbance
Cardiovascular: (Hypertension); Hypotension
Dorzolamide
Carbonic Anhydrase Inhibitors
HCO3- is secreted from the blood into the aqueous humor by the ciliary body of the eye – mediated by CA. This process is also inhibited by CA inhibitor, thereby reducing the production of aqueous humor.
Side effects:
Ophthalmic: Burning sensation in eye, Immune hypersensitivity reaction (Ocular), Punctate keratitis
Immunologic: Immune hypersensitivity reaction (Ocular)
Rare via topical administration: Metabolic acidosis
Carbachol, Pilocarpine
Cholinergic Agonists
Less commonly used
Mechanism of action: Muscarinic (parasymp) induced ciliary muscle contraction helps aqueous humor outflow. No effect on aqueous humor production, improves outflow.
Side effects: Blurred vision, Burning sensation in eye, Itching of eye
LA routes of administration
Surface: mucus or skin
Infiltration, injection
Nerve block
Intravenous regional
Structure of the neuromuscular junction
Postsynaptic nicotinic acetylcholine receptors (nAChRs) are clustered on the motor end plate, opposite ACh release sites of the motor neuron terminal.
Acetylcholinesterase (AChE) is tethered on the postsynaptic side of the synaptic cleft and rapidly degrades ACh.
Acetylcholinesterase inhibitors
Increase the concentration of ACh in cholinergic synapses, including the neuromuscular junction
Major uses
To diagnose and treat myasthenia gravis
To treat Alzheimer’s disease
To reverse the effect of a neuromuscular blocker
Acetylcholinesterase inhibitors classes
Competitive inhibitors: Non-covalent interaction with the ACh binding site
Carbamates (“reversible” inhibitors): Most widely used clinically, eg MG
Include some insecticides
Organophosphates: (irreversible soon after binding)
Little clinical use
The sole clinically used drug is echothiophate, which is used rarely for glaucoma.
Include some insecticides
Nerve gases such as Sarin
Neostigmine
Acetylcholinesterase inhibitor, carbamate.
used to treat MG, post-surgical and neurogenic ileus, urinary retention
quaternary amine prevents it from crossing the BBB into CNS, so Reduced risk of seizures
IV: 1-2hr, IM: 2-4
Elimination: ~50% metabolized in liver; rest excreted by kidney
Pyridostigmine
Acetylcholinesterase inhibitor, carbamate.
First line in MG,reversal of non-depolarizing neuromuscular blockers
Closely related to neostigmine, but less frequent dosing
quaternary amine; limited to periphery
Available in a sustained release form for bedtime use.
Elimination:
80-90% eliminated by kidney
Edrophonium
Diagnosis of MG and Cholinergic crisis, acute treatment of MG
Non-covalently competes for binding (competitive inhibitor); not an AChE substrate
Rapidly hydrolyzed by plasma esterases = short acting AChE inhibitor, 10min
67% FEU
quaternary amine; limited to periphery
Donepezil and galantamine and Rivastigmine
inhibit AChE in the CNS competitively
Galantamine additionally potentiates signaling at nAChRs independently of AChE inhibition.
Cross BBB (all amines are tertiary)
For patients with mild to moderate Alzheimer’s. Also, Lewy body- and Parkinson’s-associated dementias
All appear to have similar efficacy: Modest short-term improvement; Long-term benefits not established
Mainly hepatic elimination
Donepezil is 96% protein bound, Affected by a decrease in plasma proteins (e.g., liver disease)
Galantamine is only 18% protein bound.
Rivastigmine - eliminated by cholinesterase-mediated hydrolysis in the brain
Less susceptible to reductions in liver or kidney function
Fewer interactions with enzyme inhibitors/inducers
Neuromuscular Blockers
Interfere with synaptic transmission by blocking nicotinic receptors of the NMJ, producing paralysis
Major uses: To relax skeletal muscle during surgical procedures, for tracheal intubation, and for mechanical ventilation
To prevent dislocations during electroconvulsive therapy
Mechanisms of NMJ blockade
Non-depolarizing blockade
By competitive antagonists at the acetylcholine binding sites of the nicotinic acetylcholine receptor (nAChR)
Depolarizing blockade
By nicotinic agonists that produce sustained membrane depolarization, leading to inactivation of voltage-gated Na+ and Ca2+ channels
Non-Depolarizing Blockers
All are permanently ionized and do not penetrate the BBB.
Distribution is largely restricted to blood, and their Vd’s are small.
As a class, they are resistant to degradation by acetylcholinesterase.
Their durations of action are determined by their routes of elimination:
Many of the longer-acting drugs (> 35 min) are excreted by the kidney.
Shorter-acting drugs tend to be those that metabolized by the liver or by plasma cholinesterases, or are excreted in bile
Tubocurarine
Non-Depolarizing NMJ Blocker
Alkaloid found in numerous toxic plant species
Active component of curare, used as an arrow poison by aboriginal societies in South America, Africa, Asia
Death by paralysis of diaphragm
quaternary amino groups: cannot cross the BBB
Stimulate hisatmine release leading to hypotension
block ANS ganglia
Cisatracurium
Non-Depolarizing NMJ Blocker
The cis-stereoisomer of atracurium, which it has largely replaced
Pharmacokinetics:
Elimination: mainly by spontaneous, non-enzymatic degradation
Duration of action: 25-45 min
A toxic metabolite (laudanosine, hypotension) does not significantly accumulate, even during prolonged use in mechanical respiration.
Mivacurium
Non-Depolarizing NMJ Blocker
Degraded by plasma and tissue cholinesterase
That is, elimination is organ-independent
High clearance
Duration of action is 10-20 min
Shortest-acting of available non-depolarizing NMJ blockers
Stimulate hisatmine release leading to hypotension
Pancuronium
Prototype of steroid NMJ blockers, non-depolarizing
Mainly renal elimination
Long duration of action (> 35 min)
Block cardiac muscarinic receptors
Rocuronium
steroid NMJ blocker, non-depolarizing
Mostly metabolized by liver
Duration of action: 20-35 minutes
Unique in having a very effective antagonist: sugammadex
Sugammadex
roncuronium antagonist
Encapsulates rocuronium
Has lower affinity for other steroid NMJ blockers, but has been used against pancuronium and vecuronium
Succinylcholine
The only depolarizing neuromuscular blocker in clinical use.
Two molecules of acetylcholine flexibly linked together
Binds both obligatory agonist sites of the nAChR.
Mechanism of action:
An agonist at the nAChR
Resistant to AChE; sustained activation.
Strongly depolarizes muscle
Voltage-gated Na+ and Ca2+ channels inactivate
Charged (two quaternary amino groups), so distribution limited largely to blood (very small Vd).
Rapidly degraded by cholinesterases in plasma (mostly) and in liver.
Esterase activity in plasma is so high that little of the injected dose actually reaches the NMJ; for those molecules that do reach the NMJ, termination by action is by diffusion away from the junction.
Time course depends on route of administration
Intravenous: complete paralysis in 30-60 sec; duration of action 4-6 min after single dose
Intramuscular: onset in 2-3 min, duration of 10-30 min)
Can lead to stimulate ANS ganglia, stimulate cardiac muscarinic receptors, transient increase in intraocular pressure, post-operative pain with inhaled anesthetics, malignant hyperthermia (excessive Ca2+ release from SR in skeletal muscle, treated with dantrolene
succinylcholine-induced paralysis
Phase I
Depolarization blockade
Not reversed by inhibitors of acetylcholinesterase, which would only further depolarize the membrane
Phase II
With sustained administration, the membrane repolarizes yet the muscle remains flaccid.
It is thought that the nAChRs become desensitized to succinylcholine (and to ACh as well).
Reversible by anticholinesterases
Looks like what one sees with non-depolarizing blockers; TOF fade
Can lead to hyperkalema, bad in burn patients
Opioids PK
Well absorbed, first pass effects
HIghly perfused in lungs, brain, liver, kidneys and spleen
Converted to polar metabolites by liver and excreted by kidneys
Opioids Mechanism of Action
Act on receptors in CNS that respond to endogenous peptides: mu, delta, and kappa.
GCPR acting on GABA neurotransmission
Mu receptor
Brain: cortex thalamus, PAQ, rostral ventromedial medulla, Spinal cord, Peripheral nerves, Intestinal tract
u1: analgesia
u2: respiratory drive, miosis, euphoria, GI motility
u3: vasodilation
Bound endogenously by endorphins, morphine
Delta receptor
Brain: pontine nuclei, amygdala, deep cortex, olfactory bulbs, Peripheral nerves
Analgesia, antidepressant effects, convulsant effects, respiratory drive
Bound endogenously byEnkephalins
Kappa receptor
Brain: hypothalamus, PAQ, neocortex, spinal cord, peripheral nerves
analgesia, anti convulsant effects, dissociative and delirum, diuresis, dysphoria, miosis, sedation
Bound endogenously by dynorphins
Morphine
Mu receptor agonist, very little kappa or delta
Pharmacologic effects are variable and impact multiple organ systems, including:
1) CNS: analgesia, drowsiness, euphoria/calming, nausea/vomiting (at CTZ), respiratory depression, cough suppression, lower seizure threshold
2) Cardiovascular: vasodilatation (histamine release, depressed baro- and chemoreceptor reflexes)
3) Gastrointestinal: decreased GI motility, decreased secretions
4) Renal/Urinary: decreased urination (increased ADH), increased urinary retention
5) Skin: produces flushing and warming of skin, accompanied by sweating and itching through peripheral histamine release
6) Immune: alteration in lymphocyte proliferation, antibody production, chemotaxis
Clinical Indications include the following:
1) Analgesia: Acute Pain (trauma, peri-operative related pain, Acute Coronary Syndromes, and Nociceptive > Neuropathic Pain); Chronic Cancer related Pain. Morphine is not good for other chronic pain syndromes, such as lower back pain and fibromyalgia.
2) Anti-dyspneic: Morphine is first line therapy for symptom relief (after treating underlying cause). Usually ½ the dose used for pain relief is effective as an anti-dyspneic.
Adverse Effect:
1) Sedation: this is common at initiation of therapy or with dose escalation. Tolerance to this effect develops within days-weeks
2) Nausea: this is common at initiation of therapy. Tolerance develops within 7 days. Antiemetics are used for treatment
3) Constipation: this is the most common side effect and no tolerance is developed to this effect. A bowel regimen should be prescribed for all patients receiving opioids around the clock. Chronically ill patients have increased risk of constipation because of other disease processes
4) Other Side Effects: include delirium, respiratory depression, dry mouth, urinary retention, myoclonus and pruritis.
Pharmacologic effects are variable and impact multiple organ systems, including:
1) CNS: analgesia, drowsiness, euphoria/calming, nausea/vomiting (at CTZ), respiratory depression, cough suppression, lower seizure threshold
2) Cardiovascular: vasodilatation (histamine release, depressed baro- and chemoreceptor reflexes)
3) Gastrointestinal: decreased GI motility, decreased secretions
4) Renal/Urinary: decreased urination (increased ADH), increased urinary retention
5) Skin: produces flushing and warming of skin, accompanied by sweating and itching through peripheral histamine release
6) Immune: alteration in lymphocyte proliferation, antibody production, chemotaxis
Clinical Indications include the following:
1) Analgesia: Acute Pain (trauma, peri-operative related pain, Acute Coronary Syndromes, and Nociceptive > Neuropathic Pain); Chronic Cancer related Pain. Morphine is not good for other chronic pain syndromes, such as lower back pain and fibromyalgia.
2) Anti-dyspneic: Morphine is first line therapy for symptom relief (after treating underlying cause). Usually ½ the dose used for pain relief is effective as an anti-dyspneic.
Adverse Effect:
1) Sedation: this is common at initiation of therapy or with dose escalation. Tolerance to this effect develops within days-weeks
2) Nausea: this is common at initiation of therapy. Tolerance develops within 7 days. Antiemetics are used for treatment
3) Constipation: this is the most common side effect and no tolerance is developed to this effect. A bowel regimen should be prescribed for all patients receiving opioids around the clock. Chronically ill patients have increased risk of constipation because of other disease processes
4) Other Side Effects: include delirium, respiratory depression, dry mouth, urinary retention, myoclonus and pruritis.
Do NOT use in Renal failure or dialysis. Use CAUTION with stable cirrhosis and do NOT use with severe cirrhosis.
Codeine
Mechanism of Action: Binds mostly to the mu receptor as an agonist. Its action may come from its conversion to morphine. It has a stronger action to depress the medullary cough reflex than does morphine.
Clinical Uses: Analgesia (although weaker than morphine), cough suppressant, and diarrhea Suppressant
Additional Side Effects: Nausea/Vomiting and pruritus ( may have more histamine release than morphine)
Some individuals may be ultra-rapid metabolizers, increasing levels of morphine.
Diacetylmorphine (Heroin)
Mechanism of Action: Diacetylmorphine is essentially a prodrug, being converted to morphine and 6-acetylmorphine (active metabolite); Primarily works at mu receptors but also has significant affinity for kappa and delta receptors
Clinical Uses: Heroin is illegal in US but used in UK for analgesia and sedation
Additional Side Effects: very similar to morphine, more rapid onset however
Pharmacokinetics:
Absorption: well absorbed, undergoes pre-systemic conversion to morphine when orally consumed
Distribution: lipid soluble and rapidly penetrate the blood-brain barrier
Metabolism: via blood, and morphine via liver.
Excretion: Urine- 42%-70% (up to 77% is morphine)
Oxycodone
Mechanism of action: very similar to morphine, pure mu receptor agonist
Clinical Uses: Analgesia (for moderate to severe) and Dyspnea; safer in patients with renal and liver disease (see kinetics)
Administration and Forms : Oral only –Oxycodone Immediate Release and Oral Solution; Oxycodone Extended Release (Oxycontin); Oxycodone w/ aspirin (Percodan); Oxycodone w/ acetaminophen (Percocet)
Metabolism: extensive liver
Excretion: Urine- 90%
Use caution and reduce dose and frequency with renal failure and dialysis. Use caution and reduce dose and frequency with stable or severe cirrhosis.
Hydromorphone
Mechanism of action: Mu receptor agonist; hydromorphone is a morphine derivative (hydrogenated ketone) and approximately 7 to 8 times as potent as morphine on a milligram to milligram basis.
Clinical Uses: used for moderate to severe analgesia and dyspnea; safer in patients with renal and liver disease
Excretion: 75% in urine
Preferred in kidney disease. Use caution and reduce dose and frequency with stable or severe cirrhosis.
Fentanyl
Mechanism of Action: mu receptor agonist. Fentanyl is an analogue of the structurally related drug pethidine for opioid activity. Unlike many other opioid analgesics, fentanyl does not cause clinically significant histamine release with therapeutic doses
Clinical Uses: Analgesia (for severe) and dyspnea. Fentanyl is a better medication for patients with liver or kidney failure.It is very potent, 100 times stronger than morphine
Metabolism: metabolized in Liver
Excretion: Urine- 75%
Preferred in kidney disease. Preferred with stable or severe cirrhosis.
Methadone
Mechanism of Action: acyclic analog of morphine; Mu opioid receptor agonist; also binds to glutamatergic NMDA receptor, antagonist of glutamate
Clinical Uses: Analgesia (Acute and Chronic), including for neuropathic pain (because of effects on NMDA receptor); Opioid Abuse Detoxification (NMDA receptor)
Additional Side Effects: Prolonged QTc, Arrhythmias
Metabolism: Liver metabolism; has slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs. Metabolism is up to 4 times greater after oral administration than after intramuscular administration; females may metabolize methadone faster than males
Excretion: Urine (20% unchanged), Feces, Bile and Sweat
Preferred in kidney disease. Preferred with stable or severe cirrhosis.
Loperamide
Mechanism of Action: mu receptor agonist with poor or no blood-brain cross-over. Drug slows intestinal contractions and peristalsis allowing intestines to draw out moisture and stop formation of loose and liquid stools. Loperamide is 2-3 more potent than diphenoxylate
Clinical Uses: Diarrhea- acute or chronic
Additional Side Effects: Necrotizing enterocolitis, Pancreatitis
Metabolism: undergoes significant first pass biotransformation
Excretion: Urine- 1%, Feces-50%
Tramadol
Mechanism of Action: It is a cross between levorphanol (a mu-agonist) and venlafaxine (a SNRI). Mechanisms include: Mu opioid receptor agonist (weak), Serotonin releasing agent, Norepinephrine reuptake inhibitor, NMDA receptor antagonist, Nicotinic receptor antagonist and M1 and M3 muscarinic acetylcholine receptor antagonists
Clinical Uses: Analgesia (moderate); in theory might be helpful for depression/anxiety but is not current used for that purpose
Additional Side Effects: nausea/vomiting, sweating, sexual dysfunction, lower seizure threshold. In contrast to other opioids, respiratory depression, sedation, drowsiness and constipation are less common.
Excretion: Urine- 30% unchanged, 60% as metabolites
Naloxone
Mechanism of Action: opioid receptor antagonist; synthetic N-alkyl derivative of oxymorphone; competitive antagonist at all receptor sites (mu, kappa, delta). Naloxone is almost completely devoid of agonistic effects and has no opioid effects in the absence of opioid agents (respiratory depression, sedation, analgesia, miosis)
Clinical Uses: opioid intoxication/overdose
Side Effects: anti-opioid effects
CV: hypertension, tachycardia (vtach or vfib),
Skin: flushing, sweating,
Endocrine: increased cortisol levels,
GI: nausea/vomiting, diarrhea
Neuro: tremors, parathesias, seizures
Psych: agitation, urinary urgency
Pulmonary: dyspnea/hyperventilation, pulmonary edema
Pharmacokinetics:
Absorption: rapidly absorbed
Metabolism: Liver
Excretion: Kidney 65-68% in 72 hours
TOLERANCE AND OPIOIDS
gradual loss in effectiveness. One hypothesis for development of tolerance is that there is up-regulation of the cyclic adenosine monophosphate (cAMP) system, failure of receptor recycling, and receptor uncoupling- dysfunction between receptor and G proteins.
Dependence
The development of a withdrawal syndrome following dose reduction or administration of an antagonist
Tolerance
change in the dose-response relationship induced by exposure to the drug and manifest as a need for a higher dose to maintain an effect
Addiction
Compulsive use despite harm, craving, impaired control of drug use
Risk factors for OUD
Biological, social, phychological
Methadone maintenance
- Suppressing desire/craving for other opioids
- Maintaining patients in treatment
- Help patients be more social and productive in life; reduce criminality
- Reduce Mortality
Buprenorphine
a. Mechanism of Action: mu receptor partial agonist
i. Antagonist of Delata and Kappa receptors
ii. Blocks voltage-gated sodium channels=local anesthetic properties
b. Clinical Uses:
vi. Analgesia
vii. Opioid Abuse Detoxification and Maintenance Therapy
iii. Metabolism: via the liver
v. Excretion: Biliary and Renal
c. Clinical Features for Maintenance/OUD Therapy
i. Induction Phase (1-2 days): given when individual has abstained from using opioids for 12-24 hours
ii. Stabilization Phase: begins when patient is no longer experiencing cravings for drug of abuse
iii. Maintenance Phase: reached when the patient is doing well on steady dose
iv. Detoxification- abrupt discontinuing of buprenorphine is less severe than other opioids
Moderate to no risk of abuse potential
Lower rates of birth issues
Better in methadone abuse patients
Naltrexone
hanism of Action: analog of naloxone and is a relatively pure opioid antagonist
a. Twice as potent as Naloxone
b. Longer lasting than Naloxone
B. Clinical Uses: opioid overdose/intoxication, alcohol intoxication, opioid abuse
C. Additional side effects: Deep vein thrombosis, hepatitis, eosinophilic pneumonia
c. Metabolism: liver metabolized
e. Excretion: Renal 53%-79%
E. OUD Maintenance/Treatment
a. Doses: Start at 25mg orally daily-> 50mg daily-> 100-150mg 3x weekly
i. Can be given as infrequently as 2-3x weekly
ii. Can be prescribed by any physician
b. Advantages:
i. Tolerance does not seem to develop
ii. Well absorbed orally and has a long duration of action
c. Contraindications:
i. Not to be given in liver failure
ii. Cannot be given in patients receiving opioid analgesics or patients with dependence or withdrawal
d. There is a high drop out rate compared to other forms of opioid use disorder treatments
Clonidine
Alpha-2 adrenergics; best form of non-opioid therapy for withdrawal
Treatment for Withdrawal
i. Opioid Agonist therapy
1. Methadone is the best choice to give at 10mg IV or 20mg oral
2. Buprenorphine is second line therapy but can cause increased exacerbation
3. if iatrogenic withdrawal, recommended to restart opioid that patient was taking prior to withdrawal
ii. Non Opioid Therapy
1. Alpha-2 adrenergics: Clonidine is the best form of non-opioid therapy for withdrawal
2. Benzodiazepines
3. Antiemetics: ondansetron
4. Antidiarrheals: loperamide (opioid agonist)
iii. Supportive Therapy: Fluid resuscitation
Opioid withdrawal
a. Early/Moderate Symptoms:
i. Anorexia
ii. Anxiety, restlessness, irritability, depression, insomnia
iii. Craving and intense drug hunger
iv. Headache
v. Tachycardia
vi. Rhinorrhea, yawning, lacrimation
vii. Piloerection (goosebumps)
b. Moderate/Advance Symptoms:
i. Abdominal Pain, Nausea and Vomiting
ii. Muscle and bone pain, Muscle spasms
iii. Low grade fevers, increase blood pressure
iv. Hot/cold flashes
v. Mydriasis
Pain Management while on Maintenance Therapy for OUD
a. Methadone Therapy
i. Standard to slightly increased doses of opioids secondary to patient’s increased tolerance
b. Buprenorphine Therapy
i. For patients with mild to moderate pain
1. Use buprenorphine alone (up to 32mg/daily) or
2. Higher doses of short-acting opioids
ii. For moderate to severe pain
1. Discontinue buprenorphine and starting the short acting opioid
