Medchem Exam 2

First Generation Antipsychotics

SAR

• Chlorine substituent desymmetrizes the compound - an electron withdrawing substituent is important to activity

• Side chain amine is protonated at pH 7 - associates with chlorinated ring

• Side chain has three carbo chain linker, often separated by two amines

Chlorpropazine

First antipsychotic

Usually administered as injectable

D2 antagonist

• Elderly patients with dementia related psychosis treated with antipsychotic drugs are at an increased risk of death

SE: sedative, EPS

Long acting Neurolpetics

Have long chain fatty acid esters released slowly into blood stream from lipophilic tissue

Helps with adherence issues in schizophrenic patients

• Some believe they do not have an illness that needs to be treated

• Patients forget to take medication on schedule

• SE can lead to patients avoiding medication

• Poor efficacy of therapy used

Increasing DOA of a neuroleptic means administering medication less often

• Patients who need injection

• Drugs that are poorly absorbed

Haloperidol

D2 antagonist (greater affinity than chlorpromazine)

Less weight gain that chlorpromazine

Used for manic phase of bipolar disorder, schizophrenia

Haloperidol Decanoate

D2 Antagonist

Injection (every 4-6 weeks)

Has long-chain fatty ester

Droperidol

D2 antagonist

Short-acting

Use: anesthesia for its sedating and antiemetic effects, psychiatric emergency as a sedative-neuroleptic

Lumateperone

-Second Gen Antipsychotic

D2 antagonist and 5-HT2 receptor

Treats positivve and negative symptoms of schizophrenia

Oral administration

Clozapine

Atypical Neuroleptics - Second Generation Antipsychotics

5-HT2A, moderate D4 and weak D2 receptor antagonism → Antipsychotic properties

• Good for patients who don’t respond to 1st gen neuroleptics

Minimal EPS

Also treats negative symptoms of schizophrenia (with positive symptoms)

1-2% patients suffer fatal agranulocytosis (uncommon for drugs in this class)

Olanzapine

Atypical Neuroleptics—Second Generation Antipsychotics

High affinity at D2 and 5-HT2 receptors than Clozapine

Antagonist activity at these receptors

Similar side effect profile to Clozapine

Minimal EPS

Treats negative and positive symptoms of schizophrenia

Orally Active

T1/2 20-50 hrs

Longer acting injectable formulation also available

Schizophrenia and bipolar disorder

Quetiapine

-Atypical Neuroleptics —> Second Gen Antipsychotics

-DA, D2 and 5-HT2 recptor Antagonists

-Minimal EPS

Treats negative/positive symptoms

Loxapine

Atypical Neuroleptics - Second Gen Antipsychotics

• High affinity at D2, 5-HT2 and H1 receptors (not muscarinic)

• N-Dealkylation of loxapine —→ Amoxapine —> Moderate SERT and NET blocking activity, which gives it some antidepressants

• Schizoprhrenia and Biopolar disorder

Lybalvi

Olanzapine —> Atypical Neuroleptics—Second Generation Antipsychotics

High affinity at D2 and 5-HT2 receptors than Clozapine

Samidorphan —> An opioid receptor antagonist which reduces weight gain associated with olanzapine

• Oral tablet

• Contraindicated in patients using opioids

Asenapine

-Atypical Neuroleptics —> Second Gen Antipsychotics

-DA, D2 and 5-HT2 recptor Antagonists

-Minimal EPS

Treats negative/positive symptoms

Ziprasidone

Schizophrenia treatment

Treats both positive and negative symptoms

Lower incidence of EPS

High affinity for 5HT2A, D2, H1 and a1/a2 —> antagonist at each

• Partial Agonist activity at 5-HT1

• Blocks reuptake of SERT and NET

Risperidone

Atypical Neurolpetics —> Second Generation Antipsychotic

Attempt to combine high levels of D2 and 5-HT antagonist activity

• Schizophrenia treatment

• Treats both positive and negative symptoms

• Injectables last 2-4 weeks

• Weight gain is a SE

• Higher incidecne of EPS than other 2nd gen neuroleptics

• Very high affinity for 5-HT2 antagonist

• High affinity for dopmaine D2 - antagonist

• High affinity for H1 and a1 receptors

• No affinity for muscarinic receptors

Paliperidone Palmitate

Atypical Neuroleptics—Second Gen Antipsychotics

Attempt to combine high levels of D2 and 5-HT antagonist activity

Abilify

Atypical Neuroleptics—Second Generation Antipsychotic

Aripiprazole

Partial agonist at D2

Partial agonist of 5-HT2

Moderate affinity for H1 and a1/a2

Low chance of hyperprolactinemia and EPS

T1/2 of 90 hrs

Oral tablet or solution, injectable forms available

Brexpiprazole

Atypical Neuroleptics - Second Generation Antipsychotics

Partial agonist at D2

Used to treat Schizophrenia / adjunct therapy for MDD

Less EPS and maybe less weight gain than Abilify

Cariprazine

Atypical Neuroleptics - Second Generation antipsychotics

Partial agonist at D2 and D3

• Used to treat schizophrenia / adjunct therapy for MDD

• Used for biopolar mania / depression

Oral capsule, once a day treatment

Treats negative and positive symptoms

Cons (-)

• Cost compared to other options, fewer dosage forms than Abilify

Pros (+)

• Longer half life (21 days or ~ 3 weeks)

• Missing a dose may be not be as problematic (avoiding relapse)

Environmental Toxins effect on PD

MPTP selectively binds MAO-B which is highly concentrated in human substantia nigra area

MPP+ concentrates in mitochondria

• inhibits mitochondria complex I

• ATP depleted at mitochondrial level

• In PD patients, 30-40% reduction in mitochondrial complex I activity in substantia nigra

• MAO-B inhibitors shown to inhibit MPTP-induced PD in primates – further evidence of this pathway primates – further evidence of this pathway

L-DOPA

L-DOPA crosses the blood brain barrier but dopamine does not

• Most exogenous L-DOPA is rapidly decarboxylated in peripheral tissues including heart, lung, and kidneys

• Only ~ 1% of an oral dose reaches the brain

• typically 3-6 grams administered daily to compensate

• Vitamin B6 is a co-factor for aromatic L-amino acid decarboxylase (high vit B6 can increase activityreducing L-DOPA)

Carbidopa

Inhibits aromatic L-amino acid decarboxylase peripherally 2.5-30-fold lower dose is possible with Sinemet (0.2 to 1.2 g/day)

• Vitamin B6 is a co-factor for aromatic L-amino acid decarboxylase (high vit B6 can increase activityreducing L-DOPA concentrations)

• Side effects: nausea, vomiting; “on-off” effects after 5-15 years of continuous treatment; behavioral/psychological disturbances

Apokyn

•  Agonizes D1 and D2 type receptors

• Crosses BBB

• Short duration of action

•  No oral bioavailability

• Subcutaneous administration/self

  injector or continuous pump

• Controls motor dysfunction in PD

• Improves on-off syndrome

• Dizziness, nausea can be side effects

Bromocriptine

• Ergot alkaloid peptide

• Partial agonist at D2 and D3 receptor

• Inhibits prolactin release from pituitary cells which

exclusively expresses D2 receptors

• Orally absorbed

• Half life 3 hrs
  

Pramipexole and Ropinirole

Both commonly prescribed for PD
 First line treatment sometimes before L-DOPA

(L-DOPA associated with motor fluctuations and reactive intermediate formation risk)  Both are D2 receptor agonists

 Side effects: initial nausea, vomiting, postural hypotension, fatigue
 Hallucinations, delusions, confusion – especially in elderly dementia patients with PD

Selegiline

Irreversible, MAO-B selective

• Reduces dosage needs of L-DOPA

• N-dealkylated by CYPs to (-) methamphetamine [L isomer]

(+)-methamphetamine [D isomer] is the abused substance

• (-) Methamphetamine metabolized to (-) amphetamine vasoactive activity

• metabolites derived thereof associated with cardiovascular (orthostatic hypotension) and psychiatric (hallucinations) side effects

Rasagiline

Irreversible, MAO-B selective

• Reduces dosage needs of L-DOPA

• N-dealkylated by CYPs

Safinamide

Multiple mechanisms of action:
Reversible, MAO-B selective inhibitor (preserves DA)  Inhibits glutamate release

(reduces excess “excitability” neurotransmitter)

Add-On therapy:
Reduces dosage needs of L-DOPA

Oral administration

Contraindications:

• Patients with severe liver impairment

• Patients with retinal disorders (can exacerbate)

• Pregnancy and breast feeding

• In combination with certain other MAOIs / SSRIs / tyramine containing foods

Entacapone

Reversible COMT inhibitor

• Short duration of action 2 hrs

• Works only in periphery

• Side effect: severe diarrhea

Tolcapone

Reversible COMT inhibitor

• Long duration of action 8-12 hrs

• Works in brain and periphery

• Side effect: Hepatic toxicity – 3 fatalities after marketing

• Side effect: severe diarrhea

Stalevo

Helpful as a combination therapy to:

• replace equivalent dosage of individual components

• Help with wearing off effects of L-Dopa/carbidopa alone (low dose/no dyskinesia)

Benzatropine

• Adjunct therapy

• Muscarinic antagonist

• (relaxes muscles to avoid spasm)

• Control extrapyramidal effects well so still used despite adverse effects

Amantidine

• Adjunct therapy

• Antidyskinetic (helps with sudden uncontrolled movements)

• Causes release of DA and NE from storage vesicles

• Blocks reuptake of DA

• N-methyl-D-aspartate (NMDA) glutamate receptor antagonist

Nourianz

• Adjunct therapy with L-dopa/carbidopa

• For treating “off time” in PD

• Adenosine A2A receptor antagonist

Oral, once a day dosing
Metabolized by CYP3A4avoid grapefruit juice or other CYP3A4 inhibitors to avoid high plasma concentrations Renal excretion is important – patients with renal failure may need to adjust dose down

Baclofen

muscle relaxant

GABAB1 agonist

Chlordiazepoxide

• Anxiolytic

• Sedative properties

• Oral tablets

• Half life 24-48 hrs

• Light sensitive

Diazepam

• anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects

• increased risk of congenital malformations and other developmental abnormalities in pregnancy

• Passes into breast milk

• Half-life: 20-50 hours

• N-dealkylation (CYP3A4) - one of several metabolic pathways observed (active, common metabolite with Librium)

N-Desmethyldiazepam

– Active metabolite undergoes slower metabolism than parent. – Common intermediate from both Valium and Librium
– Accumulates with repeated administration
– After 1 wk discontinuation, it is detected in blood

Flurazepam

• Oral formulation

• Rapidly N-dealkylated (CYP3A4)

• Accumulation with chronic usesedation

Oxazepam

• Active metabolite of diazepam and chlordiazepoxide  Marketed separately

• Short acting anxiolytic

• Half life 4-8 hrs

• Accumulation with chronic use occurs less for this one

Anxiolytic Benzodiazepines

Midazolam

• Anxiolytic BZ

• Use: Premedication for anesthesia

• Quick onset 1-2 min

• Recovery to full alertness (40 minutes)

• Injectable or oral formulation

• pH dependent solubility: Highly water soluble at pH <4 and lipid soluble at pH > 4

Flumazenil

GABA receptor antagonist A

• Bind with high affinity to BZR and blocks effects of classical benzodiazepines (same binding site)

• Binding is not affected by GABA or ions that induce receptor conformation changes

  insensitivity to conformation changes suggests the drug does not induce structural changes to impart a response (pure antagonist)

•  Used to treat benzodiazepine overdose

  Flumazenil can cause seizures – care to be taken in those patients with low threshold for seizure

Zopiclone

Not subtype selective (high affinity for alpha-1 and alpha-3 receptors)

• Affinity for alpha-1 subunit-containing GABAA receptors is less than for other nonbenzodiazepines

• Rapid onset, moderate duration (T1/2 = 6 h) - of the nonbenzodiazepines, longest half life

• Binds an allosteric site away from BZ binding site

• Binding is not affected by GABA

• Sedative hypnotic

• Improves sleep onset and maintenance
  

Zaleplon

High affinity for α1-containing BZRs

• Produce effects at other BZRs/GABAA subtypes too

• Improves sleep onset - no evidence that it helps with sleep maintenance or duration

• No withdrawal symptoms or rebound insomnia on discontinuation in studies with use up to 5 weeks

• Cimetidine and grapefruit can increase blood plasma concentrations (CYP3A4 interference)extends the half-life and effects

Zolpidem

Highly selective for α1 subunit-expressing GABAA receptors (5-10 fold higher affinity over α2 and α3 receptors)

• Lack of affinity for α5 –containing receptors
  Weaker anxiolytic activity, anticonvulsant and muscle relaxant properties than classical BZs

• Low risk of withdrawal and tolerance; does not accumulate

• Women clear Ambien more slowly than men

• Good for initiating sleep (within 15-20 min)

• Controlled release formulation used for maintaining sleep (Intermezzo ®)

• AE (adverse events): sensory distortion, amnesia, psychotic symptoms, “sleep-actions”  Flumazenil reverses sedative/hypnotic and memory-impairing effects

• Elderly dose adjustment required due to 50% increase in elimination half life

Ganaxolone

Treats certain types of seizure (those with CDKL5 deficiency disorder) Reduces seizure potential

Binds allosteric site of GABA-A receptor

• opens chloride channel

• hyperpolarization (desensitization towards stimuli)Treats certain types of seizure (those with CDKL5 deficiency disorder) Reduces seizure potential

Brexanolone

Used for PPD
IV only

More expensive

SE of sedation during administration and need to be monitored

Zuranolone

Used for PPD
Oral dosage form

Less expensive

SE of sedation during administration and need to be monitored

Barbituates

Sedative hypnotics, anesthetic, anticonvulsant activities

Sedative hypnotic agents of choice until benzodiazepines discovered

Side effects: tolerance, dependence, withdrawal (seizures, respiratory spasm), memory impairment, potential for abuse, low therapeutic index

• overdose and death

No antidote to overdose!

GABA A partial allosteric modulators - Experimental

Side effects (sedation and potentiation of alcohol) are less extreme and potential for abuse is less for partial agonists compared to full agonist BZs

Because they are partial agonists, higher doses are required for anxiolytic activity which then introduces sedative properties

SSRIs

Block serotonin reuptake

• First line treatment for some anxiety disorders

• Use: OCD, Panic disorder, social phobia

• Lack the addictive effect associated with benzodiazepines

• Dampens brain excitability – mechanism differs from mechanism in depression

Gabapentin

FDA approved for:
Anticonvulsant; adjunctive therapy for treating partial seizures Certain types of nerve pain (shingles, diabetic neuropathy) Restless leg syndrome

Does not affect GABA metabolism or modulate GABA receptors or affect GABA reuptake

• Reduces abnormal brain excitability by modulating voltage gated calcium channel density —> reducing excitatory activity

off-label use: alcohol withdrawal, neuropathic pain, fibromyalgia, bipolar disorder, postmenopausal hot flashes, essential tremors, anxiety, resistant depressant and mood disorders, irritable bowel syndrome (IBS), alcohol withdrawal, postoperative analgesia, nausea and vomiting, migraine prophylaxis, headache, interstitial cystitis, painful diabetic neuropathy, social phobia, generalized tonic-seizures, pruritus (itching), insomnia, post-traumatic stress disorder (PTSD), and refractory chronic cough

Histamine

Synthesized in many tissues (mast cells, gastric mucosa, neurons in CNS and periphery)

• Stored in granules/vesicles within mast cells and basophils

• Mediator in allergic inflammatory response and secretion of gastric acid

Nodocromil

Mast cell stabilizer

Ophthalmic solution
Seasonal/perennial allergic conjunctivitis

Lodoxamine

Mast cell stabilizer

Ophthalmic solution
Seasonal/perennial allergic conjunctivitis

Cromolyn

Mast cell stabilizer

Prophylactic Use for:
Exercise induced bronchospasm (Inhaled powder) Bronchial asthma (Inhaled powder) Seasonal/perennial allergic rhinitis (nasal solution) Allergic conjunctivitis (ophthalmic solution)

Pemirolast

Mast cell stabilizer

Ophthalmic solution
Relieves itching due to allergic conjunctivitis

First gen H1 receptor antihistamines - Anticholinergics

Significant anticholinergic side effects include dry mouth, blurred

vision, tachycardia, urinary retention, constipation

SAR

• Two aryl groups (Ar1, Ar2) attached to X

• X = N, CH-O-, CH2-N-, or CH

• Spacer = un/branched methylene linker (CH2)n n = 2 or 3

• R1, R2 = usually a small alkyl group, sometimes an alkylaryl

Diphenhydramine

First Gen H1 Antihistamine

Used for allergic conditions Oldest marketed antihistamine Oral tablet
Short half life
Wide safety margin

Sedation is a side effectused as an OTC sleep aid (Tylenol PM)

Clemastine

First Gen H1 Antihistamine

First stereocenter influences potency significantly

Second stereocenter is less important to potency

Indicated for the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea (runny nose), pruritus (itching), and lacrimation (watery eyes)

(R,R) isomer is most potent – sold as single diastereomer Less sedative than diphenhydramine
Oral tablet

First Gen H1 Antihistamines - Alylamines/Propylamines

First Gen H1 Antihistamine

Have longer half lives that permits once-a-day dosing Extended duration of action
Significantly fewer CNS side effects
Decreased anticholinergic affects

Decreased antiemetic effects

Cyclizine

First Gen H1 Antihistamine

Primary Uses:
vertigo, motion sickness (antiemetic effect)

Significant antihistamine and anticholinergic effects Drowsiness common

Hydroxyzine

First Gen H1 Antihistamine

Used for pruritus (itchy skin)

Significant antihistamine and anticholinergic effects Drowsiness common

Cetirizine

Second generation H1 receptor antihistamine

“Nonsedating”

Oxidative Metabolized from Hydroxyzine (OH group attacked) and Cyclizine

No cardiotoxicity

Promethazine

First Gen H1 Antihistamine

• Usually have long durations of action

• Pronounced sedative effects

• Potent antihistamines

• Also treats nausea/vomiting associated with anesthesia and motion sickness

*Sometimes combined with codeine for cough

Cyproheptadine

First Gen H1 Antihistamine

• Usually have long durations of action

• Pronounced sedative effects

• Potent antihistamines

• Also treats nausea/vomiting associated with anesthesia and motion sickness

Tefinidine

Second Gen H1 Antihistamine

High concentrations of parent lead to hERG K+ channel inhibition

• prolonged QT interval of heart

• ventricular arrhythmias

Allegra

Second Gen H1 Antihistamine

Metabolite of Terfenidine/Seldane
Lacks hERG problem (no cardiac toxicity) Accounted for antihistamine activity of Seldane

Xyzal/Levocetirizine

Second Gen H1 Antihistamine

Claims of increased efficacy and fewer side effects: (R) isomer dissociates from receptor more slowly than (S) isomer

Desloratadine

Second Gen H1 Antihistamine

Loratadine:

Parent half-life ~ 8 h

Desloratadine:

Major metabolite of Loratadine and Rupatadine

Half-life ~ 24 h

More potent H1 inverse agonist than loratadine

Rupatadine:

Parent half life: 5-6 h

Also has anti-inflammatory activity: inhibits release of tumor necrosis factor (TNFα) and IL-6 in human mast cells and monocytes

Topical Antihistamines

MAST CELL STABILIZERS—> inhibit release of inflammatory mediators (including histamine)

H1 RECEPTOR INVERSE AGONISTS —> block histamine at its receptor

Applied to eye for relief of itching and congestion of the conjunctiva

Outside of US, some approved for systemic use

Azelastine

3 MOA:

• Antihistamine at H1 receptor as inverse agonist

• Stabilizes Mast cells to attenuate release of histamine and other allergy mediators

• Anti-inflammatory (reduces production and concentrations of inflammatory mediators)

Most often used as nasal spray
Fast onset (minutes)
1-2 times daily application
Astepro Nasal Spray: hay fever/seasonal allergy (allergic rhinitis) Optivar Eye Drop: itchy eyes due to allergy (allergic conjunctivitis)

Thiourea

H2 Selective Inverse Agonist

Antihistamine

In clinical trials,
patients developed agranulocytosis

Thiourea responsible for toxicity

Cimetidine

H2 Selective Inverse Agonist

Active H2 antihistamine
Does not cause agranulocytosis
CYP450 inhibitor (due to imidazole) —> drug interactions

Ranitidine

H2 Selective Inverse Agonist

Was most widely used

Caused formation of NDMA which is a carcinogen

Famotidine

H2 selective inverse agonist

can be combined in formulations with antacid

Proton Pump inhibitors

Proton pump inhibitor

• Among the most widely sold drugs in the world

• Inhibit the H+/K+-ATPase (proton pump)

• Inhibits acid secretion even if receptors are activated by agonists

• Sometimes combined with antibiotics to treat H. pylori infection

• Irreversible, covalent inhibitors

• Targets activated proton pumps that are acid-exposed

MOA:

The drug is unchanged in the blood – but at low pH (gastric acid), it rearranges to form an electrophilic intermediate A Cysteinyl sulfhydryl groups (SH) of the proton pump attack A to afford a covalently modified complex
The result is a disulfide bond (S-S) and an inactive enzyme

Voquenza

Potassium-Competitive Acid Blocker (PCAB)

• Inhibits the H+/K+-ATPase (proton pump) – like PPIs

• Inhibits acid secretion even if receptors are activated by agonists – like PPIs

• No acid activation/ no PPIs) – NOT A PRODRUG

• REVERSIBLE inhibitor (ionic bonding)

• Targets activated proton pumps that are acid-exposed and resting state pumps

Jouravx

Approved for treating moderate to severe acute pain in adults
Oral drug
Selectively inhibits peripheral sodium NaV1.8 channels that modulate pain

Non-addictive - no evidence of withdrawal or drug-seeking behaviors (not linked to reward centers in brain)

• Risk of Drug Interactions with Certain Hormonal Contraceptives

• Risk of Adverse Reactions in Patients with Moderate and Severe Hepatic Impairment

• Increased Risk of Adverse Reactions with Concomitant Use with Strong or Moderate CYP3A Inhibitors

Heroin

PRODRUG: INACTIVE AT OP RECEPTORS AS IS!

More lipophilic than morphine

better BBB access

6-MAM

Heroin —→ (fast hydrolysis) This intermediate —→ (slow hydrolysis) Morphine

Morphine

Mu agonist

Metabolized by CYP450 to Normorphone

Codeine

poor μ agonist
but effective anti-tussive

Morphine Sulfate

Full Mu agonist

• More potent than codeine sulfate

• Poor oral bioavailability due to GI and first pass (liver) metabolism

• Metabolite can accumulate in patients with renal failure or poor function—>overdose
   Extended release forms (Avinza ® and Kadian ®) available only for opioid tolerant patients

Codeine Sulfate

Full Mu agonist

(~ 10x less potent than morphine)

Prodrug: requires O-demethylation

Hydromorphone

Multicyclic Full Mu Agonist

(8-10x more potent than morphine)

Also increases toxicity, constipation, especially respiratory depression (black box warning)

Oxymorphone

Multicyclic Full Mu Agonist

(~ 10x more potent than morphine)

Uses: chronic pain, maintain anesthesia, and obstetric analgesic

Hydrocodone Barbituate

Multicyclic Full Mu Agonist

Only available as combo with acetaminophen (Vicodin), ibuprofen (Vicoprofen), or cough suppressant preps (Hycodan)

Prodrug

Good oral bioavailability; much more active than codeine

Oxycodone

Multicylic Full Mu Agonist

Extended release: oxycontin

High abuse potential

Prodrug

Good oral bioavailability; much more active than codeine

Buprenorphine HCL

Partial Mu agonist (note the alkylcyclopropyl group, aside from other structure changes) 25-40x more potent than morphine

Pseudo-irreversiblehalf life ~ 37 hours Can be useful in detoxification

Will precipitate withdrawal in patients dependent on full agonists but will also suppress symptoms of full blown withdrawal

Formulations: IV, sublingual, transdermal patch

Transdermal patch (Butrans ®) – avoid high temperatures or release of drug is higher

• Use: Opioid Addiction Recovery

Methadone HCL

Flexible Opioid receptor agonist

Full mu agonist (and activity at non opioid receptors)

• Oral tablet/solution/IV inj for pain; ‘Swish and spit’ – 2.5 minutes, 85% dose absorbed; avoids 1st pass metabolism

• Use: IV addiction recovery (most common); neuropathic and opioid resistant pain

• Respiratory depression and cardiac toxicity side effect

• outlast the analgesia effects

• Metabolized to seve

Meperidine Hydrochloride

Flexible Opioid receptor agonist

• 1/10th the potency of morphine

• Full mu agonist

  No GI motility inhibition

• No cough suppression

• Half life ~ 3-4 h

• Use: obstetrics, post operative pain, low dose short term pain management

Normeperidine

Flexible Opioid receptor agonist

• Full mu agonist

About 1⁄2 potency as meperidine
T1/2 = 14-21 h (normal renal function)
Can induce seizure not easily reversed by naloxone

Fentanyl Citrate

• Flexible Opioid receptor agonist

• Full mu agonist

• Rapid onset, short duration, half life ~ 30-60 min

• Use: IV adjunct to anesthesia (most common);

  chronic pain due to cancer, pediatric burn patients

• CAUTION: overdose risk, esp kids handling patches

SE:

High abuse potential
Respiratory depression risk is significant
Fentanyl effects can outlast reversing agents

Black box warning

Sufentanyl citrate

Flexible Opioid receptor agonist
600-800x the potency of morphine

Full mu agonist
Rapid onset, short duration
Half life ~ 15-20 min

Shorter post-anesthesia recovery

Use: IV adjunct to anesthesia in opioid tolerant/dependent patients

Remifentanil

Flexible Opioid receptor agonist

• Full Mu agonist

• Use: IV adjunct to anesthesia: has sedative effects in addition to analgesic effects

• less hypnotic anesthesia needed

  (enables use of high dose opioid/low dose anesthesia)

• Administration: continuous infusion during surgery or post-operative

• Very short post-anesthesia recovery

Seglentis

Atypical Opioid Receptor Agonist

Combines an analgesic (tramadol) + anti-inflammatory (celecoxib)

Tramadol

Atypical Opioid Receptor Agonist

used to treat severe acute pain; Second line for neuropathic pain!!!

Dual action – inhibits serotonin and norepinephrine reuptake (SNRI) AND is a mu (μ) agonist

• Must be careful with other 5-HT-NE reuptake of 5-HT enriching agents to avoid toxicity

Methylnaltrexone Bromide

Multicyclic Opioid Receptor antagonist

• 4° salt - can’t penetrate CNS

• Effective in periphery

• Use: reverse opioid

• induced constipation

• subQ, every other day