Exam 3 Flashcards

Opiods

The opium poppy is the source of all natural opiods, but morphine is made from the crude opium (sense of feeling good while also taking away pain). Most powerful, so gold standard in pain management with strong analegtic action.

Natural Opiods

Morphine and Codeine (most prevalent)

Semi-synthetic (co or mor in middle of name)

hydromorphone, hydrocodone, oxycodine, and oxymorphone

Synthetic (no 4 fused rings in structure)

Fentanyl, tramadol, methadone, meperidine, and tapentadol

Opioid receptors (G protein coupled receptors)

Mu MOST IMPORTANT (natural ligand is Endorphins), Delta (Enkephalins), kappa (Dynorphins) opioid peptides

Opioid MOA

Bind to specific rhodopsin GPCRs in brain and spinal cord regions which transmits and modulates pain.

They close voltage gated Ca channels on presynaptic nerve terminals and reduce transmitter release (glutamate, NE, ACh, P)

They also open K channels which causes hyperpolarization to inhibit postsynaptic neurons. Further inhibits the system on both synapses

Opioid CNS Effects (Morphine and surrogates)

Analgesia, euphoria, sedation, resp. depression, cough supression, Miosis (due to receptor stimulation and can cause toxicity with pinpoint pupil), Nausea and vomiting

Opioid Peripheral Effects (Morphine and surrogates)

Bradycardia, hypotension, emesis/constipation, bronchoconstriction (due to histamine release), higher bilary tract pressure, also causes decrease of uterine contraction in labor

Opioids Absorption

Mostly well-absorbed but will suffer first-pass effect (morphine)

Interpatient variability in this metabolism makes prediction of an effective oral dose difficult to see

Codeine+oxycodone are the exception, but things like oral mucosa via lozenges, and transdermal routes of admin can help

Opioid Metabolism

Goes through 2 rounds of metabolization. Goes through hepatic P450 mainly by CYP3A4 and CYP2D6. Plasma esterase metabolism

Opioid Uses

Analgesia- pain releif without loss of consciousness

Antidiarrheal (morphine specifically)- decreases gastric motility and increases intestinal circular smooth muscle

Antitussive- Relieves coughs (mostly dry)

Acute pulmonary edema- Relieves dyspnea due to pulmonary edema associated with left ventricular failure

Anesthesia (supported therapy and sustain)

Opioid AE Acute

Respiratory depression, pruritus, nausea, constipation, urinary retention, delirium, and myoclonus

Opioid AE Chronic

MORE HORMONAL Hypogonadism, immunosuppression, increased feeding, increased growth hormone, tolerance, dependence, withdrawal, hyperalgesia, and impairment while driving

Withdrawal Symptoms of Opioids

8 hrs- anxiety and craving

8-24 hrs- insomnia, GI disturbance, mydrasis, diaphoresis

72 hrs- Nausea, Diarrhea, Tachycardia, hypertension, chills, tremors, seizures, and muscle spasms

Opioid Overdose Treatment (Narcan)

IV injection of naloxone which will reverse the come associated with the overdose. It is also suggested that there should be respiratory support with antagonists if there are other intoxicants suspected. Naloxone is available via IM and intranasal in pharmacies

Opioid Drug Interactions

Sedative-hypnotics: Increased CNS depression

Antipsychotics- increased sedation, respiratory depression, augmenting cardiovascular effects

MAO inhibitors- high incidence of hyperpyrexic coma and hypertension

Contraindications Opioids

-Use of pure agonist with weak partial agonists (can diminish analgesia or even withdrawal symptoms

-Use in patients with head injuries (respiratory depression causes CO2 retention)

-During pregnancy (Neonatal abstinence syndrome)

-Patients with impaired pulmonary function (respiratory failure)

-impaired hepatic or renal function (longer half-life due to poor metabolism and elimination

Patients with endocrine disease (longer and worse response)

Morphine

•Prototype for strong opioids and a strong µ-agonist.

-Morphine in the least lipophilic of the common opioids.

•ER formulations provide more consistent plasma levels.

•Hepatic metabolism ( not through P450 system  though);    First pass metabolism reduces oral bioavailability   (parenteral administration may circumvent that).

•Undergoes glucuronidation at either   - the 3 position (morphine-3-glucuronide; M3G; inactive) or   - the 6 position (M6G; active, renally excreted).

•Morphine has relatively few interactions with other drugs              (does not undergo metabolism by the cytochrome P450 system).

Hydromorphone

- Morphine derivative with similar properties to morphine

  - 5 to 10 times higher potency

  - Metabolism:  Glucuronidation but not cytochrome P450-based metabolism.

  - Hydromorphone is preferred in renal impairment because of its less accumulation.

Codeine

•Naturally occurring opioid

•Antitussive (i.e., cough-suppressing) and antidiarrheal

•Higher oral bioavailability than morphine

•A low-potency opioid analgesic                  ( a prototype for weak opioid agonists)

oHepatic demethylation by CYP2D6 accounts for its analgesic effect.

oDrug interactions associated with CYP2D6 account for reduced efficacy of codeine.

oGenetic polymorphisms account for interindividual variation in response to codeine treatment.

oIn some cases, most notably in children, ultrarapid metabolism of codeine to morphine has resulted in  accidental death due to unanticipated opioid overdose.

Oxycodone:

•- More potent analogues of codeine   (twice as potent as morphine)

  - Orally available and are widely used

  - Metabolized by the P450 system to   oxymorphone (more potent than morphine)  - Oxymorphone has less drug interactions.

Hydrocodone:

•- More potent, orally available and   widely used

•Metabolized by cytochrome P450 system to hydromorphone                (8-10 times more potent than morphine)

•Hydrocodone can accumulate in the body during renal impairment   - Hydromorphone may be a better alternative because of its less accumulation.

Tramadol

- Centrally acting analgesic

•Modest μ-opioid receptor affinity     ( Note: naloxone becomes ineffective)

•Block serotonin ( 5-HT) and norepinephrine (NE) reuptake

  5-HT >> NE

•No clinical effect on respiration or CVS

•It is metabolized by CYP2D6, CYP3A4 and CYP2B6

Tramadol Uses

- Management of mild to moderate pain.

  - An adjunct with full μ-opioid receptor agonist for   managing chronic neuropathic pain.

Tramadol AR

- Seizures and serotonin syndrome in liable patients

- Nausea and dizziness ( usually abate in days)

Tapentadol

•A full μ-opioid  receptor agonist with modest affinity      ( Note: naloxone  becomes ineffective)

•Norepinephrine (NE) reuptake-inhibitor;  NE >> 5-HT                  - It increases NE in the spinal cord and activates the    inhibitory α₂-adrenoceptors  - Analgesia is reduced by an α₂-adrenoceptor antagonist.

•Compares to oxycodone with less gastrointestinal effects as nausea.

Tapent

Symptoms of anxiety

Unpleasant tension, apprehension, uneasiness

Resembles fight or flight response (fear, tachycardia, sweating, trembling, and palpitations)

Antianxiety drugs- used for clinical management of chronic anxiety, while anxiolytics can also cause sedation

Benzodiazepines

Central depressants that cause sedation, hypnosis.

They are used to reduce convulsions, anxiety, muscle spasms

WIDELY used anxiolytics and replace barbiturates because of their efficacy and relative safety

Tolerance and dependence levels classify BDZs as the best option for anxiety and insomnia

ALL CONTROLLED SUBSTANCES

Benzodiazepines MOA

They bind to GABA receptors on Cl channels which allows the ions to influx which causes hyper polarization, which then inhibits action potential and decreases neurotransmission. This causes conformational changes. Both BDZs and GABA have distinct binding sites and the actions depend on the GABA availability.

BDZs Actions

When they bind to a1GABA subunits it causes Sedation, hypnosis, amnesia, and anti convulsion

Binding to a2 GABA can reduce anxiety and causes muscle relaxation because they bind presynaptically in the spinal cord

BDZs Uses

-Anxiety disorders like secondary GAD and SAD along with performance anxiety, depression, schizophrenia, and extreme phobias

Note- Can have addiction potential, so they are used for severe anxiety

Chronic anxiety requires long-term treatment from long-acting BDZs (DCL)

-Sleep Disorders

Temazepam- useful with frequent waking (1-2 hrs before sleep) Works about 1-3 hours after oral intake

Triazolam- Short-acting BDZs for people who have a hard time falling asleep

Tolerance develops within a few days and withdrawal causes rebound insomnia (not best agent)

-Amnesia- Useful premedication for anxiety-provoking procedures

Midazolam can facilitate amnesia while causing while causing sedation prior to anesthesia

BDZs other Uses

-Seizures

Clonazepam is used as adjunctive therapy

Lorazepam and Diazepam are used to terminate status epileptics

Chlordiazepoxide, clorazepate, diazepam, lorazepam, and oxazepam are useful in the acute treatment of alcohol withdrawal and reduce the risk of withdrawal-related seizures.

-Muscular Disorders

Diazepam is useful for skeletal muscle spasms and for spasticity from degenerative disorders

BDZs Pharma

-well absorbed orally (very lipophilic) and has a large Vd and excellent penetration

-Classified into short, intermediate, and long acting, which determines therapeutic application

-long acting BDZs have active metabolites with long half life, but the clinical duration doesn’t correlate with actual half-life

It is metabolized by CYP 450 system, by oxidation and glucouronidation, and eliminated by excretion and tissue redistribution

BDZs AE

Drowsiness, confusion, ataxia, cognitive impairment, tolerance, and contraindications like pregnancy, lactation, liver impairment, acute angle closure glaucoma

Dependence can develop with prolonged use

Abrupt discontinuation can cause withdrawal symptoms

Short-acting BDZs cause more abrupt and severe withdrawal symptoms

BDZs Antagonist (Flumazenil)

MOA- GABA receptor antagonist that can reverse effects of BDZs

Pharma- available by IV admin only, has rapid and short duration of actions and requires frequent admin

Used as an antidote for BDZ toxicity

AE- Dizziness, nausea, vomiting, agitation. Can cause precipitate withdrawal or cause of seizures in dependent patients

-Can cause seizures if mixed with tricyclic antidepressants or antipsychotics

Anxiolytic Agent (Buspirone)

Chronic treatment of GAD and has an efficacy comparable to BDZs, but has a slow onset of action and is not effective short term or “as-needed” treatment of acute anxiety states

Buspirone MOA

mediates its anxiolytic effect by stimulating serotonin receptors and dopamine receptors

Distinct from BDZs MOA

Buspirone Actions

Has no anticonvulsant and muscle-relaxant effects

Minimal sedation , psychomotor effects and cognitive dysfunction (particularly useful in elderly) and dependence is unlikely

Doesn’t potentiate the CNS depression of alcohol

Buspirone AE

Headaches, dizziness, nervousness, nausea, and light headedness

Barbiturates

CNS depressants that are chemically derived from barbituric acid

used before to induce and maintain sleep but are associated with severe intolerance, physical dependence and withdrawal symptoms. They're all controlled substances

Barbiturates MOA

interact with GABAa receptors and enhance GABAergic neurotransmission

Potentiate GABA effect widen Cl opening causing hyperpolarization

Directly open the Cl channels without being bound to GABA and increase how long Cl channels are open with greater influx and stronger CNS depression

They also block the excitatory glutamate receptors

Anesthetic doses of pentobarbital block high frequency Na channels

Barbiturates Actions

Ultra short acting- thiopental with onset seconds and durations 30 mins

Short acting- pentobarbital, secobarbital, butalbital with duration of 3-8 hours

long acting- phenobarbital and duration is greater than a day

Barbiturates Actions con.

CNS depression (does dependent)- low causes sedation, high causes hypnosis, then anesthesia, and death

Has no analgesic effect and may exacerbate pain. chronic use leads to tolerance

-Respiratory depression- they suppress hypoxic responsive receptors, and CO2 responsive chemoreceptors

Overdose can cause respiratory depression and death

Barbiturates Uses

Anesthesia- Ultra short acting IV admin for short surgeries or procedures (ECT therapy), trauma brain injuries, intracranial pressure and for those unresponsive to other therapies

Sedative/hypnotic- Relieves anxiety, nervousness, and insomnia. Is not longer accepted because of tolerance and dependence issues.

-Butalbital is used in combo with acetaminophen or aspirin and caffeine in managing tension or migraine headaches.

Anticonvulsant- Phenobarbital is specific for this and is used for tonic-clonic seizures and refractory status epilepticus, but can decrease cognitive functions, so should be last resort

Barbiturates Pharma

Is well absorbed orally with large Vd with CNS and placental penetration. They undergo tissue redistribution which accounts for short duration of action. Metabolized hepatic ally and eliminated in urine.

Barbiturates AR

-drowsiness, impaired concentration, and mental/psychomotor impairment

-CNS depression synergies with ethanol

-hangover

-Many drug interactions

-Gradual withdrawal is a must because there are severe symptoms leading to death

-Abrupt withdrawal causes tremors, anxiety, weakness, restlessness, nausea, seizures, delirium, and cardiac arrest

-There is also no reversal agent or antidote, so supportive care and gastric decontamination for recent ingestion sis used as therapy

Hypnotic Agent (Zolpidem) MOA

Binds to GABAa receptors with relative selectivity for the BDZ site with a1 subunit

Has little withdrawal effects, minimal rebound insomnia, little tolerance, with few anticonvulsant or muscle relaxing properties

No significant altercation to various sleep stages (preferred hypnotic over BDZs)

Zolpidem Pharma

Rapidly absorbed orally with rapid onset of action, short elimination half-life (2-3 hrs), and about 5 hrs of hypnosis

Sublingual tablet can be used for middle of the night awakening

Metabolized by CYP450 system and has many drug interactions

Zolpidem AR

Headache, dizziness, anterograde amnesia, and next-morning impairment. Also can cause complex sleep behaviors like walking and driving. Has warning for dependency. Antidote for overdose is flumazenil (BDZ antagonist)

Zaleplon MOA

Same as Zolpidem

Zaleplon Actions

Fewer residual effects on psychomotor and cognitive function compared with zolpidem or the other benzodiazepines

Doesn’t have significant effects on sleep stages

Also controlled substance with dependency issues

Antidote is also flumazenil

Zaleplon

Rapid absorption and rapid elimination with about a 1 hr half-life

Eszopiclone MOA+Actions

Same MOA as both Z drugs

Effective for insomnia for up to 6 months

Eszopiclone Pharma

Rapid oral absorption about 1 hr for peak and half-life of 6 hrs

Extensive hepatic metabolism by oxidation and demethylation via the CYP450 system with excretion mainly in urine

Eszopiclone AR

Anxiety, dry mouth, headache, peripheral edema somnolence, and unpleasant taste. Dependency and same antidote as both Z drugs

Melatonin receptor antagonists (ramelteon and tasimelteon) MOA

Hormone secreted by pineal gland that helps to maintain the circadian rhythm underlying the normal sleep-wake cycle. They’re both selective agonists at the MT1 and MT2 subtypes of melatonin. When u stimulate these receptors it promotes sleep

Melatonin Actions

Minimal abuse potential, dependence or withdrawal symptoms (useful long-term)

Has less cognitive effects as compared to other hypnotics

Melatonin Uses

Ramelteo is used to treat insomnia characterized by having a hard time falling asleep (increased sleep latency)

Melatonin AR

Dizziness, fatigue, somnolence, and increased prolactin levels

Antihistamines

•Antihistamines with sedating properties are useful for mild situational insomnia       (e.g., diphenhydramine, hydroxyzine, and doxylamine).

•They are available in many over-the-counter ( OTC) products.

•Adverse effects:   Anticholinergic effects   - make them less useful than BDZs   and the nonbenzodiazepines

Antidepressants

•Sedating antidepressants with strong antihistamine activity are useful for anxiety.

 

Doxepin is an older tricyclic agent with SNRI mechanisms of antidepressant and anxiolytic action, is approved at low doses for the management of insomnia.

 

•Other antidepressants, such as trazodone, mirazapine, and older tricyclic antidepressants with strong antihistamine properties are used off-label for the treatment of insomnia

Orexin receptor antagonists  ( Suvorexant and lemborexant )

•Orexin is a neuropeptide that promotes wakefulness.

•The loss of orexin-producing neurons is believed to be     an underlying pathology for narcolepsy.

•Antagonizing orexin suppresses the wake drive from this neuropeptide.

•Suvorexant and lemborexant are antagonists of the orexin receptors OX1R and OX2R.

Orexin Pharma

Mainly hepatic metabolism by CYP3A4   ( potentially have drug interactions)

Orexin AR

•Daytime somnolence | Narcolepsy |   Increased suicidal ideation

•Orexin antagonism may explain the signs of narcolepsy      ( e.g., sleep paralysis, cataplexy, and hypnogogic or hypnopompic hallucinations).

Major Depressive Disorder

characterized by depressed moods, loss of interest or pleasure in life, sleep disturbances, feelings of worthlessness, diminished ability to think or concentrate, and recurrent thoughts of suicide. (also irritable and anxious)

Bipolar Disorder

recurrent fluctuations in mood, energy, and behavior that shows the extremes of human experiences

Biogenic amine theory

•Depression is caused by a deficiency in monoamines     (e.g., NE and 5-HT) in certain areas of the brain

•Mania is caused by overproduction of monoamines in these certain areas in the brain.

•Antidepressant drugs are thought to potentiate the action of serotonin and norepinephrine in the brain.

Theory is too simple

-Doesn’t fully explain the actions of antidepressant drugs and anti mania drugs on neurotransmission

-Clinical effects take several weeks to manifest benefits (mood changes take 6-8 weeks)

-Decreased reuptake of neurotransmitters is only an initial effect of the drugs which may not be directly responsible for the antidepressant effect

-Some candidate antidepressant agents don’t act directly act on the monoamine system

-Reduced glutamate level of SF appears to be important in the pathophysiology of depression

SSRIs Actions

Block the reuptake of serotonin in the brain

Safer and have fewer adverse effects compared to TCAs and MAOIs

Increases the concentration of serotonin in the synaptic cleft

Takes about 2 weeks to produce significant improvement in mood and about 12 weeks to achieve maximum benefit

80% will respond to at lease one agent, one cannot work but another agent may

SSRI, Uses

Treatment of depression, OCD, GAD, PTSD, SAD, premenstrual dysphoric disorder

SSRIs Pharma

Well absorbed orally with peak between 2-8 weeks, food has no effect, long half-lives (50 hrs) because of it being an active metabolite

Metabolized by P450 system which can cause a lot of drug interactions and inhibits CYP2D6

SSRIs AR

Gastrointestinal (GI) effects (N/V/D) |   Headache |   Sweating | Anxiety | Agitation | Hyponatremia |   Weakness  |   Fatigue | Sexual dysfunction | Weight changes | QT prolongation MAINLY Sleep disturbances (insomnia and somnolence) |.
-Citalopram is more likely to cause QT prolongation

SNRIs Actions

Inhibit the reuptake of both serotonin and NE

Depression can also cause chronic pain like back and muscle aches because the pain is modulated in part by the serotonin ad NE pathways in the CNS

This drug is used to help alleviate that pain because it inhibits both

SNRIs are also used for similar pain syndromes (diabetic neuropathy, posttherpic neuralgia, fibromyalgia, and low back pain)

Do not block a-adrengergic, muscarinic, or histamine receptors and have fewer AR than TCA

SNRIs AE

Nausea, sexual dysfunction, dizziness, diaphoresis, and discontinuation syndrome which may precipitate if treatment if abruptly stopped

SNRIs (Venlafaxine and desvenlafaxine) MOA

lower dose Inhibit reuptake of serotonin and at a medium to higher doses inhibits reuptake of NE

SNRIs Pharma

Venlafaxine has minimal inhibition of the P450 system isoenzymes and is a substrate of the P2D6 system.

SNRIs AR

•Nausea | Headache | Dizziness | Sedation |  Insomnia |Constipation | Sexual dysfunction

•At high doses, BP and HR  increase.

SNRIs (Duloxetine) MOA

Inhibits both serotonin and NE reuptake at all doses

Duloxetine Pharma

Extensively metabolized hepatic ally to inactive metabolites and should be avoided with liver dysfunction

Duloxetine AR

•Nausea | Constipation | Dry mouth | Insomnia |  Dizziness | Somnolence | Sweating |   Sexual dysfunction

•Duloxetine increases BP and HR

•Duloxetine is a moderate inhibitor of CYP2D6.

Atypical Antidepressants

mixed group of agents that target many different sites of action

Brexanolone MOA

Typically excreted during pregnancy

After delivery he allopregnanolone levels declines, which accounts for postpartum depression

An analog of a metabolite of progesterone that can modulate GABA2 receptors by positive allosteric modulation. This works against postpartum depression and is due to keep levels of Brexanolone even

Brexanolone Use

Treats postpartum depression

Brexanolone Pharma

Has to be delivered by IV over 60 hrs in an inpatient setting for women struggling with PPD

Brexanolone AR

Excessive sedation, sudden loss of consciousness, hypoxia, and patients should be supervised when interacting with her child during the treatment

Bupropion MOA

Weak (more specific) dopamine and NE reuptake inhibitor Mood elevation because of dopamine increasing

Bupropion Uses

Decreases craving and attenuate withdrawal symptoms of nicotine in patients trying to quit smoking, and can possibly decrease the stimulant effects of nicotine

Bupropion Pharma

Metabolized by the CYP2B6 pathway and has a relatively low risk for drug-drug interactions

Bupropion AR

Dry mouth, sweating, nervousness, tremor, dose-dependent increased risk for seizures. Should be avoided in patients with higher risk of seizures, concurrent electrolyte abnormalities or those with a history of anorexia or bulimia

Mirtazapine MOA

presynaptic a2 receptor antagonist that blocks the reuptake of catecholamines as serotonin and NE in the CNS, and some antidepressant activity may be relative to antagonism at the serotonin receptors. Sedation is due to the antihistaminic activity. NO antimuscarinic or SD interference

Mirtazapine Uses

MDD and off-label for insomnia

Mirtazapine AR

Sedation | Dry mouth | Increased appetite     |Weight gain

Trazodone and nefazodone MOA

•They weakly inhibit the reuptake of 5-HT and NE.

•Some of the antidepressant activity may be related to antagonizing 5-HT_2areceptors postsynaptically.

•Sedation is due to its antihistaminic activity.

Trazodone and nefazodone Uses

Used for MDD, and   off-label for insomnia

Trazodone and nefazodone Pharma

Metabolized by CYP3A4

Trazodone and nefazodone AE

Nausea | Dry mouth |   Drug interactions |   Priapism (trazodone) |  Hepatotoxicity (nefazodone) |  Orthostasis and dizziness   ( due to mild-to-moderate α₁ receptor antagonism).

Vilazodone MOA

•Vilazodone is a serotonin reuptake inhibitor and a 5-HT_1a receptor partial agonist.

Vilazodone Pharma

Vilazodone is   metabolized by CYP3A4

Vilazodone AE

•resembles SSRIs;

•Nausea, diarrhea, sexual dysfunction, and dizziness.

•Risk for discontinuation syndrome if abruptly stopped.

Drug-drug interactions