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Flashcards in Neuro Drugs Deck (119):
1

Principles of Anti-epileptics: monitoring

Epilepsy patients need 24-hour coverage
- t 1/2 < 24 hours--> BID dosing
- t 1/2 < 12 hours--> TID dosing
* Some drugs have short t 1/2 but work on BID schedule- have secondary effects that exceed pharmacokinetic half-lives

Serum levels: often easured
- Therapeutic range= guideline, low-end more meaningful
- Seizure= level not enough
- Side effect= level too high
** Toxicity ALWAYS determined by patient symptoms, NOT serum level (high levels do not endanger patient)

Protein-binding:
- Phenytoin, Valproate= 90% protein bround
- Can measure bound and unbound levels
* free fraction is what's relevant (change in protein binding, as in pregnancy, chronic liver disease, malnutrition) will change free but not total serum level
* Monitor interactions with other protein-bound drugs

2

Principles of anti-epileptics: metabolism

Metabolism:
- Most AEDs metabolized by the liver
* Space out doses in pts w/hepatic failure
- Gabapentin, pregabalin, levetiracetam, oxcarbazepine’s active metabolite are renally excreted
* Reduce doses in renal failure
- Topiramate 2/3 kidney, 1/3 liver

Hepatic induction:
Barbiturates, phenytoin, carbamazepine are potent inducers of CYP450 system
- Induce metabolism of many other drugs
- Ex: oral contraceptives
- Another Ex: vitamin D (-> osteomalacia)
** Topiramate, oxcarbazepine induce only a couple of CYP enzymes (but same effect on OCP)
** CBZ autoinduces metabolism

** Valproate is a potent inhibitor of CYP450 enzymes
- Raises levels of other drugs
- All of these AEDs may also have their own levels changed, by each other (and sometimes by other drugs)
- Ex: erythromycin causes ↑ CBZ level

3

IV epilepsy meds

Urgent use for seizures
- Phenytoin (and fos-phenytoin)
- Valproate
- Benzodiazepines
- Barbiturates
- Levetiracetam
- Lacosamide

4

IV phenytoin, phenobarbitol

Long half-lives (30 hrs, 96 hrs), so can’t wait for steady state -- must load IV
- Serum level = dose / volume of distribution (Vd)

For quick & dirty mgmt, assume Vd ~ 1. So, if you want a level of 20 ug/dl, load with 20 mg/kg
- Vd actually varies by pt, around 0.8
- Maintenance doses different story

5

Benzodiazepines

Lorazepam, diazepam Rx of choice for acute seizures
- Lorazepam shorter half-life, but longer brain half-life than diazepam (diffuses into adipose tissue)
- Midazolam (ultrashort acting) for status
- Clonazepam used for chronic Rx, but benzos lose effect when given chronically (except for myoclonic sz)and can be addictive

MOA: Bind to an allosteric modulation site on the GABAA receptor, which is coupled to a Cl- channel
- Benzo causes channel to open more frequently --> hyperpolarization, greater inhibition

** Flumazenil: competitive antagonist at benzodiazepine receptor
- Can cause sz in pts taking benzos

6

Barbituates

1. Phenobarbital (t1/2 = 96 hrs)
- Used for acute & chronic sz Rx
2. Pentobarbital (PB pro-drug)
- Refractory status epilepticus
- Induction of deep coma
3. Primidone metabolized into PB + PEMA
- Epilepsy
- Essential tremor

MOA:
- Bind to another allosteric modulation site on the GABAA receptor
- Different from the one used by the benzodiazepines
- Barbiturate binding causes the Cl- channel to remain open longer (not to open more frequently)

AEs:
- Acute IV use: respiratory depression -
- Sedation
- Depression
- Cognitive impairment
- Hepatotoxicity
- Allergic rashes
** Not first-line drugs
- Exceptions: infants, severely financially challenged

7

Gabapentin

Designed as a GABA-analog, but it’s not!
- Effective only for focal seizures
- Neuropathic pain major use: only 10% of prescriptions are for epilepsy

MOA:
- Binds to α2δ subunit of presynaptic Ca++ channel
- leads to (usually modest) reduction in release of a host of neurotransmitters (e.g. substance P)

AEs: Mild:
- Sedation
- Weight gain (at higher doses)

PK:
- Neutral AA transporter gets saturated
- Total dose limited by gastric absorption
- Renal elimination

** Pregabalin very similar, but much more potent, and not limited by gastric absorption (more AEs, still used for pain)

8

Phenytoin

MOA:
- Voltage- and frequency-dependent block of Na+ channels
- Prevents high-frequency firing, allows firing at more typical frequencies

Works for GTC and focal seizures
* Ineffective for absence, myoclonic sz

Odd properties:
- Non-linear pharmacokinetics (CLOSE MONITORING REQUIRED)
- Induction of CYP450 enzymes
- 90% protein bound
- Half-life longer with higher doses
- Absorption erratic
- IV solution precipitates with dextrose

PK:
- T 1/2 24 - 30 hrs; QD dosing

AEs:
1. Acute: sedation, ataxia, dizziness, diplopia
2. Chronic: gingival hyperplasia, hirsutism, acne, coarsening of facial features, osteomalacia
3. Dangerous: rash, hepatatoxicity, myelosuppresion

9

IV Phenytoin

Diluted in ethanol & propylene glycol

AEs:
- Hypotension
- Cardiac arrythmias
- Thrombophlebitis,“purple glove” syndrome


** Fos-phenytoin: IV phenytoin pro-drug
- Water-soluble, doesn’t precipitate w/dextrose
- Less local irritation

10

Carbamazepine

MOA:
- Tricyclic ring structure
- Blocks voltage-sensitive Na+ channels just like phenytoin

PK:
- Half-life 8 - 10 hrs;
- sustained release formulations can be given BID
- Induction of hepatic CYP450 enzymes
- Autoinduction of metabolism

Uses:
- Effective for partial and GTC seizures
** Can worsen absence, atonic, and myoclonic seizures Rx for bipolar d/o, trigeminal neuralgia

AEs:
- Acute side effects like phenytoin (ataxia, dizziness, diplopia, sedation)
- No cosmetic side effects
- Chronic: hyponatremia, leukopenia
- Serious: rash, aplastic anemia

11

Oxcarbazepine

Carbamazepine has an epoxide metabolite that may contribute to toxicity
- Oxcarbazepine is very similar, but no epoxide metabolite

Better tolerated:
- No hepatic or hematologic toxicity
- Limited hepatic inducer (CYP3A4, 3A5)
** Hyponatremia more common

12

Lamotrigine

Na+ channel drug, but also enhances slow inactivated state of channel
- Developed from cancer chemo drugs

Broad-spectrum:
- works on all seizure types

T 1/2= 18-30 hours (BID dosing)

AEs:
- Stimulating, not sedating
- Insomnia, headaches
- Rash
- Less common if titrated slowly
- Few drug interactions (inducers, VPA)
- Non-teratogenic?!

Uses:
- Effective for bipolar depression

13

Lacosamide

Na+ channel: enhances SLOW inactivation through different mechanisms

- Available IV, same dosing
- Safe, well-tolerated

AEs: dizziness when combined with other Na+ channel blockers

14

Ethosuximide

MOA: voltage-dependent block of "transient" T-type Ca+2 channels in thalamus
- Blocks corticothalamic interactiosn responsible for 3 Hz spike and wave in Absence seizures

Use: Absence seizures
** Patients with other concomitant seizure conditions will need more drugs

15

Valproate

First broad-spectrum AED
** Most commonly used for bipolar disorder

MOA: ethosuximide-like effects on T-type Ca+2 channels
- Phenytoin-like effects on Na+ channels
- Increases brain GABA levels
- Unclear

AEs:
- GI upset, sedation, cognitive probs
- Weight gain, hair loss, tremor
- Serious: hepatic failure (mainly infants), pancreatitis, thrombocytopenia, hyperammonemia (transiently "out of it")
- Causes reversible form of polycystic ovary syndrome
- 2% incidence of neural tube defects, cognitive teratogenicity

16

Topiramate

Substituted fructose ring

MOA:
- Broad-spectrum; many (possible?) mechanisms
- Some effects on Na+ channels
- Inhibition of voltage-sensitive Ca2+ channels
- Benzo-like effects in GABA-induced Cl- currents
- Inhibits AMPA/kainate type Glu receptors
- Inhibits carbonic anhydrase
- Not clear which, if any, of these actions is relevant to anticonvulsant effects

PK:
- T1/2 20 hrs; dosed BID

Uses:
- Migraines, bipolar, essential tremor

AEs:
- Sedation, paresthesias, cognitive impairment (esp. aphasia- word finding problems)
- Can be very prominent, yet transient
- Nephrolithiasis (1%)
- Weight loss
- Few drug interactions

17

Zonisamide

MOA:
- Broad-spectrum drug
- Phenytoin-like effect on Na+ channels
- Ethosuximide-like effect on Ca+2 channels
- Carbonic-anhydrase inhibition

PK:
- t1/2= 63 hours (QD dosing)

AEs:
- Sedation, dizziness, cog. impairment, decreased appetite
- Rash, nephrolithiasis (1%), agranulocytosis (very rare), oligohydrosis/hyperthermia
* No drug interactions

18

Levetiracetam

MOA:
- Recently shown to tightly & specifically bind to a synaptic vesicle protein called SV2A
- Affinity of SV2A binding correlates with strength of antiepileptic effect

PK:
Effective at starting dose (within 72 hrs)

AEs:
Safe and well-tolerated; sedation, irritability, psychosis (1%)

Uses:
Effective for partial seizures, myoclonic seizures

19

Prognosis of Refractory epilepsy

If focal epilepsy doesn’t respond to the first 2 or 3 drugs tried, chance of being seizure-free on medicine 10-20%

~50% of these may be candidates for resective epilepsy surgery
- In best-selected candidates, > 80% chance of long-term seizure freedom

20

Treatment prognosis

Large majority (>95%) of pts with idiopathic generalized epilepsy can be made seizure-free with medication

Symptomatic generalized epilepsy is rarely controllable
- Minimize atonic and GTC seizures

Focal epilepsy fully medically controllable in 60-70% of patients

21

Neurotransmitters of basal ganglia

Dopamine= Excitatory and inhibitory
- Striatonigral

Ach= Excitatory and inhibitory
- Striatal interneurons

GABA= Inhibitory
- Striatopallidal and pallidothalamic

Glutamate= Excitatory
- Corticostriatal, thalamocortical

22

Biosynthesis of Dopamine

Dopamine is the most important and well studied neurotransmitter in movement disorders.
In the central nervous system, dopamine is synthesized from the amino acid tyrosine.

1. Tyrosine is converted to L-dihydroxyphenylalanine by tyrosine hydroxylase. This is the rate limiting step and can be inhibited by Alpha-methyl-p-tyrosine.

2. L-Dopa is converted to dopamine by dopa decarboxylase.
- In the periphery, we use carbidopa to inhibit DDC in the periphery which helps reduce the side effects of dopamine such as nausea, vomiting, and hypotension.

3. In the presynaptic neuron, dopamine is stored in vesicles and released in both a phasic and pulsatile manner across the synapse.
- Tetrabenazine and reserpine are dopamine depleters that inhibit synaptic storage and allow for degradation of DA.

4. DA is degraded in 3 fashions.
- DA reuptake across the synapse occurs through DAT and this process is inhibited by amphetamine or cocaine.
- Catechol-O-methyltransferase and monoamine oxidase B both degrade DA into HVA.
- Rasagiline and Selegiline are selective MAO-B inhibitors, while tolcapone and entacapone are COMT inhibitors.

23

Competing Dopamine Pathways

In the presence of dopamine, D1 type receptors which project directly to GPi are activated, while D2 type receptors are inhibited. The indirect pathway projects

Direct Pathway:
- D1 (D1 and D5) receptors
- Project directly to GPi
- Activated by DA, increased cAMP
- “Accelerator”
- Shut off in Parkinson's disease= lesion in Substantia Nigra Pars compacta (SNpc)

Indirect pathway:
- D2 (D2, 3, 4) receptors
- Project to GPe--> STN--> then GPi
- Inhibited by DA, decreased cAMP
- “Brake”
- Shut off in Huntington's Chorea= lesion D2 receptor in Striatum
- Hemiballismus= lesion in subthalamic nucleus

24

Levodopa

Replaces dopamine

There are several types of motor complications that we see:
1. Wearing-off of the medication effect over several hours
2. Delayed onset of the medication effect
3. Random dose failures may occur
4. Sudden ON-OFF, when medications stop working or kick-in abruptly
5. Levodopa-induced dyskinesia, the overexpression of movement due to excess dopamine and receptor hypersensitvity.

MOA: Breaks on D1 and D2--> breaks on Subthalamic nucleus, GPi--> decreased VL/VA stimulation

25

Anticholinergics

Block central muscarinic receptors

26

Dopamine agonists

Stimulate dopamine receptor directly, bypass gut and neuronal metabolism

27

COMT inhibitors

Inhibit breakdown of dopamine by COMT

28

MAO-B inhibitors

Inhibit breakdown of dopamine by MAO

29

Deep Brain Stimulation

Microelectrode
Basal ganglia target
Implantable Pulse Generator (IPG) in clavicle
High frequency stimulation
Adjustable, reversible symptom control

30

Dopamine Receptor blockers/depleters

Antipsychotics, antiemetics

Risk for extrapyramidal side (EPS) effects:
1. Acute dystonia

2. Akathisia

3. Drug-induced Parkinsonism (DIP): reversible
- treat with anti-cholinergics

4. Tardive dyskinesia (TD): can be irreversible
- treat with anti-cholinergics, DA depleters

5. Neuroleptic Malignant Syndrome (NMS): Muscle rigidity, Altered mental state, Autonomic dysfunction (fever, tachycardia, BP)
- Features: Tremor, incontinence, metabolic acidosis, **CPK elevation**, leukocytosis may be secondary features
** Other causes of fever need to be excluded
- Treatment: DA agonists, dantrolene, ECT, benzo

** Clozapine does NOT induce EPS, BUT can cause agranulocytosis

31

Botulinum Toxin

Toxin produced in anaerobic acidic conditions by clostridium botulinum
- One gram of crystalline toxin sufficient to kill one million people

7 Distinct serotypes:
- A (BOTOX®), B (MYOBLOC®), C-G
- 150 kD Inactive pro-polypeptide --> HC (100kD) and LC (50kD) --> LC internalized
- LC is a zinc protease that cleaves vesicular membrane proteins
- Inhibits the release of acetylcholine from the presynaptic nerve terminal

Used to treat:
- cervical dystonia
- hemifacial spasm
- oromandibular dystonia

32

Acute migraine meds

Non-specific
- NSAIDs
- Combination analgesics
- Opioids
- Neuroleptics/antiemetics
- Corticosteroids

** Specific**
- Ergotamine/DHE (dihydroergotamine)
- Triptans

Rescue therapy (stop suffering, prevent ED visit):
- Opioids (or for pregnant patients- non-teratogenic)
- Neuroepileptics
- Corticosteroids

33

Drugs causing rebound headaches

High Probability
- Opioids
- Ergotamine
- Butalbital
- Caffeine

Low Probability
- ASA/APAP
- Triptans

Possibly
- NSAIDs
- Nasal decongestants

Unlikely
- DHE
- Neuroleptics

34

Triptans/Ergots

MOA:
- 5 HT1B/D Receptor Agonists
- Cerebral Vessel Vasoconstrictors
- Inhibit Neurogenic Inflammation
- Inhibit Pain Transmission in Trigeminal Nerve

35

Dihydroergotamine

Nonselective 5-HT1 agonist

Dosage forms
IV/IM/SC: 1mg/ml: -use up to 1mg
Nasal: 4mg/ml: -use 2mg
Pulmonary in development

AEs:
- Fewer side effects than ergotamine
- Less nausea, vomiting, leg cramps
- Low headache recurrence
- Rebound headache rare
**Teratogenic**

36

Triptans

Effective:
- In migraine with and without aura
- Both early and late in attack

Best to give early:
- Improves response to therapy
- Prevents attack progression
- Do not wait for allodynia to develop
- Second dose not effective in same attack if initial dose failed

AEs:
- Very low risk of severe AEs
- Rare reports of angina, MI, stroke, and significantly increased BP
- Common minor AEs: Chest tightness, asthenia, dizziness, somnolence, paresthesia
- Chest symptoms rarely due to ischemia
** Teratogenic**

Possible mechanisms for AEs:
- Activation of peripheral pain fibers
- Pulmonary vasoconstriction
- Not indicated for basilar or hemiplegic migraine

37

CGRP Antagonists in Migraine

NOT in current use
CGRP infusions triggers migraine

CGRP levels increase during migraine attacks and decrease with headache relief

Triptans and ergots inhibit CGRP release

CGRP receptor antagonists:
- Block CGRP in CNS and inhibit pain transmission
- Not direct vasoconstrictors
- AEs: comparable to placebo, lower than zolmitriptan
- Used for: cluster headache, rebound (med overuse) headache), patients with ergot/triptan contraindications

38

Indications for Migraine Prevention

1. Attacks significantly interferes with patients‘ daily routine, despite appropriate acute treatment
2. Frequency attacks (>4 attacks/month); risk of CDH
3. Acute Rx overuse (>2 days/week); risk of MOH
4. Contraindication, failure, or intolerance to acute Rx
5. Presence of certain disorders
- Prolonged, disabling, or frequent aura
- Hemiplegic Migraine
- Basilar Migraine
- Migrainous Infarction
6. Patient preference

Only 4 drugs in USA FDA-approved for prevention of migraine headaches:
- Divalpoex/Topiramate
- Propanolol/Timolol
- Methysergide
- Anabotulinum

39

Beta-blockers for migraines

Types:
- Propranolol
- Metoprolol
- Timolol
- Nadolol
- Atenolol

50% reduction in attack frequency

AEs:
- Drowsiness
- Nightmares
- Insomnia
- Depression
- Memory disturbances
- Decreased exercise tolerance

Contraindications:
- CHF
- Asthma
- Diabetes

40

Antidepressants for migraines

Mitriptyline (tricyclic): as effective as propanolol, superior to placebo
- Independent of depression, proven benefit

SSRI: fluoxetine
SNRI: duloxitine, venlafaxine
MAOIs: little evidence

AEs:
- Drowsiness, urinary retention, dry mouth, weight gain, constipation, mania, dizziness, tachycardia, blurry vision, tremor, confusion

Contraindications:
- Glaucoma, urinary retention; caution with heart block

41

Divalproex sodium

Valproic acid/sodium valproate (Depakote) 500-3000mg/d
Therapeutic level
50-120mcg/ml

AEs
Minor: Tremor, hair loss, weight gain, nausea, sedation
Major: Hepatotoxicity, pancreatitis

Comments
- Effective in 5 P-C, D-B migraine trials; used in, cluster, CDH
- Check LFTs before and as needed during therapy

42

Topiramate

Sulfamate-substituted monosaccharide
Fructose-1,6-diphosphate analog

Anticonvulsant: modulates kinase phosphorylation

Effective in migraine Positive trials in CM, and cluster headache

43

Opiate

Morphine-like activity
- Extracted from opium (poppy)
- Natural extracts: morphine, codeine

44

Opioids

Any molecule (ligand) that interacts with
opioid receptors

Includes – endogenous peptides (e.g.endorphins)
– Natural extracts
– Semisynthetic cogeners

May be agonists, antagonists, agonist-
antagonists, or “partial” agonists
- Believed to have no ceiling effect (but side effects may limit use)

Two different properties:
1. Narcotic: produces stupor, sleep
- Term associated with abuse
2. Analgesic: produces pain relief
- Refer to as opioid- poor amestics, better pain relief

45

Opioid receptor

G-protein coupled receptor
- Extracellular amino-terminal tail
- Intracellular carboxyl-terminal tail
7 hydrophobic regions
3 intracellular, 3 extracellular loops

Steps for painful stimulus and perception:
Mu receptors at each site can be blocked

Ascending Transmission
1. Peripheral neuron--> dorsal horn
2. Dorsal column--> thalamus
3. Thalamus--> cortex

Descending modulation:
1. Cortex--> Peri-aquaductal gray (PAG)
2. PAG--> Rostral Ventromedial Medulla (RVM)

Three major classes:
1. Mu: Beta-endorphin, morphine
2. Kappa: Dynorphin A
3. Delta: enkephalins

46

Mu receptors (OP-3)

Stimulation produces:
- Supraspinal analgesia
- sedation
- Euphoria
- Decreased GI motility (constipation)
- Respiratory depression
- N/V
- Miosis
- Tolerance
- Physical dependence

Agonist= Beta-endorphin, morphine
Antagonist= Naloxone (most specific for Mu)

47

Kappa receptors (OP-2)

Stimulation produces:
- Spinal analgesia
- Sedation
- Dysphoria
- Diuresis
- Psychomimetic effects
- Hallucinations

Peripheral effect: visceral pain relief
Central effect: dysphoria

Agonists: Dynorphin, pentazocine, oxycodone
Antagonists: naloxone (at high dose)

48

Delta Receptors (OP-1)

Stimulation produces:
- Spinal and supraspinal analgesia

Agonist: Enkephalines
Antagonist: Naloxone (at high dose)

49

Effects of opioids and metabolites

1. Analgesia

2. Convulsant:
- Neurotoxic metabolite (meperidine--> normeperidine) at high doses
- Metabolite renally excreted (avoid in renal dysfunction, seizure disorder)

3. Respiratory depression:
- Most feared opioid side effect
- Decreased sensitivity of chemo-receptors in medullar to CO2
- Respiratory drive reduced by pain
- Decreased rate, tidal volume, both
- High CO2 levels--> narcosis (beware in closed head injuries--> increased CSF pressure)
- Beware of sedated/obtunded patient--> impending respiratory arrest
** Use with caution in obstructive sleep apnea (can worsen obstruction due to sedation, can also depress central component of respiratory drive)

4. Emetic/anti-emetic

5. Antitussive (at lower doses than for analgesia)

6. C-V system effects (bradycardia)
- Parasympathetic, histamine (morphine)
- Stimulates central vagal nucleus

7. GI: constipation, decreased motility
- Most common side effect
- Disrupt coordinated contraction of circular muscles
- Significant dose-limiting side effect (tolerance does NOT develop over time)

8. Miosis (pupillary constriction)

9. Immunological: t-cell suppression (infection risk, tumor growth)

10. Opioid-induced hyperalgesia

11. Tolerance, abuse, misuse, diversion

12. Tumor angiogensis: opioid-free anesthetic used in cancer surgery--> better survival

13. Hormonal suppression

- Other: pruritis, sedation

50

Opioid Dependence

Dependence is NOT the same as addiction
- Tolerance to analgesic effects
- See withdrawal, abstinence syndrome

Physical Dependence=
state of adaptation manifested by drug-class specific withdrawal syndrome produced by abrupt cessation/antagonism

Addiction:
Primary, chronic, neurobiologic disease with genetic, psychosocial, environmental factors
- Chronic use
- Impaired control over use
- Compulsive use
- Continued use despite harm
- Craving

Tolerance:
- Need more drug to produce same effects

51

Risk factors for drug-associated aberrant behaviors

Biological:
- Age > 45 years
- Family history of Rx drug/alcohol use
- Cigarette smoking

Psychiatric:
- Substance use disorder
- Preadolescent sexual abuse
- Major psychiatric disorder (personality, depressive, bipolar)

Social:
- Legal problems, MVA
- Poor family support
- Problematic subculture involvement (gang)

** NEVER withhold opioids from opioid-dependent patient (lead to withdrawal)

52

ADME of Opioids

Administration:
- PO (Oral)
- IV, IM, PCA (= Patient Controlled Analgesia)
- Epidural
- Spinal (Intrathecal)
- Transdermal
- Iontophoretic
- Transmucosal
- Rectal (can be variable; generally a poor route for most drugs)
- Sustained release vs Patient-controlled: get bolus dose to control pain, then administer PCA
-Controlled release drugs= increased risk of respiratory depression, never in new pain/opioid naive patient, no evidence it improves pain control

Distribution:
- Good distribution
- Crosses BBB; placenta; in salivary excretions; into enterohepatic circulation (more lipophilic opioids- fentanyl- cross BBB easier)

Metabolism:
- Hepatic enzymes
- Active and inactive metabolites (morphine--> M-3-G, M-6-G)
- Toxic metabolites (meperidine--> normeperidine)

Excretion:
- Renal (metabolite accumulation in renal insufficiency)
- Free drug and glucuronide conjugates excreted
- Enterohepatic circulation

53

Naturally occurring opioids

- Paragoric= old remedy for colic in babies
- Morphine
- Codeine (constipation!!)

54

Semi-synthetic opioids

Based on naturally-occurring opioids:
- Heroin
- Apomorphine
- Oxycodone
- Hydromorphone
- Oxymorphone

55

Synthetic opioids

- Meperidine
- Fentanyl, Sufentanil
- Diphenoxylate
- Loperamide (peripheral-acting opioid)
- Methadone
- Propoxyphene

56

Mixed Opioid Agonist-Antagonists

Pentazocine, Nalbuphine, Butorphanol

Partial agonists at mu receptors, but have
limited capacity for activation (“ceiling effect”)

In presence of full agonists, act as antagonists at mu receptors

Can precipitate withdrawal in physically
dependent patients

May be used to treat (antagonize) mu-opioid receptor side effects

Typically are agonists at peripheral Kappa receptors- analgesia (visceral pain)
- Central Kappa effect: dysphoria

57

Nalaxone

Pure antagonist
IV, short acting
- Use caution- acute reversal of opioid analgesia can precipitate acute withdrawal

- Naltrexone= oral, long-acting

* Both reverse analgesia (dose-dependent)
- Can be titrated slowly to reverse side effects (vs immediate for overdose in ER)

58

Buprenorphine

Partial agonist (ceiling effect)
- High affinity, long half-life
- Prevents withdrawal in opioid dependence
- Used to treat addiction /dependence
- Suboxone= buprenorphine with sequestered naltrexone (anti-abuse built in)

- Patch made available for pain management

59

Alvimopan, Methylnaltrexone

Selective opioid antagonism
- Peripheral acting mu-Opioid receptor antagonist
- Reduces constipation, bowel dysfunction after surgery (ileus), nausea
- Don't cross BBB (won't interfere with analgesia effects)

60

Tramadol

Dual action opioid:
- Weak μ opioid agonist
- Inhibits reuptake of norepinephrine and
sserotonin
- May precipitate serotonin syndrome
- Activates α-adrenergic receptors 2
- Multiple sites of action produce analgesia by several mechanisms

Parent compound is inactive; must be metabolized to active form by P450-2D6
- Not everyone has this pathway; codeine shares this problem.

61

Tapentadol

Recently approved dual-action analgesic
- μ opioid agonist= 2 to 4 times less potent than morphine
- Inhibits NE reuptake
- Parent compound is active (doesn’t require intact P450-2D6)
- No 5-HT activity –(no seizures)
- Reduced GI side-effects (nausea, constipation), less withdrawal when terminated

* May precipitate serotonin syndrome

62

Opioid rotation

Equianalgesic tables for opioids established for opioid naive patients
- When patients highly tolerant to one mu-opioid switch to another--> far more sensitive than anticipated
- Reduce dose 50-75% (methadone is extreme example)
- Why? incomplete cross-tolerance among mu opioid splice variants

Potency= term comparing doses of different agents
* Potency will vary between subjects, especially opioid naive vs opioid tolerant

Efficacy= intrinsic activity of agent at opioid receptor (binding)

63

Fentanyl vs Morphine

Morphine= pruritis, respiratory depression, nausea, somnolence, confusion in elderly

Fewer side effects with Fentanyl

64

Opioid-induced hyperalgesia

Opioids may increase pain sensitivity!
- Opioid exposure may produce progressive and lasting reductions of nococeptive thresholds.
- Paradoxical increased pain with opioids.

Ex:
- Former opioid addicts have lasting increased pain sensitivity that appears worsened by methadone maintenance.
- Evidence argues against opioids as a choice for preemptive analgesia.
- NMDA receptor antagonists (ketamine) may reduce or prevent opioid tolerance and hyperalgesia.

Opioid induced pain may be more diffuse, less defined in quality, beyond distribution of pre-existing pain
- May indicate presence of opioid-induced analgesia

65

Anesthetic agents: possible neural-circuit mechanisms

Drug blocks excitatory impulses, allows inhibition of:
- Hypothalamus
- Basal forebrain nucleus
- Ventral tegmental area
- Dorsal raphe nucleus
- Lateral dorsal tegmental nucleus
- Locus ceruleus

66

Drug targets of anesthetics

Ligand-gated ion channels

Ion channels (leak and voltage-gated channels: K+, Na+, Ca+2, ATP activated)

Intracellular: mitochondrial function

67

IV induction drugs (group I)

Barbiturates, propofol, benzodiazepines

Potent

Mainly act on gama-aminobutyric acid-A (GABAA) receptor

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Volatile Anesthetic (group II)

Ethers, substituted hydro-carbons

Less potent

Molecular targets: GABAA , glycine, N-methyl-D- aspartate (NMDA), potassium channels.

Why continue to use inhaled agents?
- Can provide all needs: anesthesia, analgesia, immobility
- Low cost as single drug
- Great control (breath by breath) of anesthesia state
- Administration and elimination via lungs
- Always accessible route (respiration and gas exchange vital to life)
- Reliable means to control delivery/removal

Risks:
- Flammability
- Toxicity (liver, kidneys)
- Heart conduction changes

Halogenated anesthetics reduce AEs, increase potency
- but still have hepatotoxicity, myocardial sensitization to catecholamines

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Xenon, NO, Ketamine (Group III)

Minimal effect on GABAA receptor

Marked blockade of NMDA action

70

Minimum alveolar concentration (MAC)

Measurement of potency
- Prevents movements in 50% of subjects in response to surgical stimulus (minimum concentration needed)

Effectiveness (MAC) decreased by increasing:
- Narcotics
- Age
- Temperature

71

Solubility of inhaled anesthetic

Relative concentration in two phases= affinity

Solubility= relative affinity of inhaled anesthetic for two phases (Blood/gas)
- Concentration in blood twice that of gas= affinity of anesthetic for blood is 2x the affinity in gas phase

Ex: halothane very soluble in blood compared to desflurane

Factors affecting uptake:
- Inspired concentration increase--> increased uptake
- Alveolar ventilation increase--> increased uptake
- Solubility (in blood) increased--> decreased uptake (by tissue)
- Cardiac output increase--> decreased uptake
** lower solubility indicates rapid increase and decrease in alveolar conc. (rapid induction and rapid recovery)- high uptake in blood-> takes longer to take effect, lasts longer in blood

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Respiratory effects of inhaled anesthetics

Halogenated hydrocarbons:
- Decrease bronchial smooth muscle tone
- Decrease PVR
- Depress mucocilliary function
- Reduce tidal volume and increase respiratory frequency
- Depress respiratory response to CO2
- Block respiratory drive due to hypoxemia

73

Cardiovascular effects of inhaled anesthetics

All volatile anesthetics depress myocardial contractility

Effects on BP and CO vary based on effects on heart rate and systemic vascular resistance

74

IV anesthetics

All CNS depressants can act as general anesthetics in high doses

Clinically used:
1. Ketamine
2. Propofol
3. Etomidate

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Ketamine

- IV, IM, PO
- Metabolized via oxidation and demethylation
- Produces state called “dissociation anesthesia”. Patients are pain-free and unconscious, but show nystagmus and random movements

AEs:
- Increased intra-cranial pressure
- May produce emergence reactions, hallucinations

CV effects:
- Direct myocardial depressant
- Increases blood pressure and heart rate
Respiratory effects:
- Normal response to CO2 in anesthetic doses
- Bronchial smooth muscle is relaxed
- Used in large quantities in Haiti

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Propafol

A di-isoproylphenol

Discarded after 6 Hr due to blend:
- 1% solution in an emulsion
- Soybean oil 1%
- Egg phosphatide 1.2%
- Glycerol 2.25%

pH – Neutral / slightly alkaline

Administered intravenously
- Widely used as an induction agent
- IV infusion provides a complete anesthetic

Benefits:
- Faster, cleaner recovery than barbituates and ketamine
- Anti-emetic

AEs:
- Depresses BP, respiration

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Etomidate

Non barbiturate hypnotic
- Minimal cardiovascular effects
- Causes reversible adrenocortical suppression after a single dose

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Anesthetic-induced neurotoxicity

It is well documented that anesthetics cause brain cell death, apoptosis, in rodents and primates and cause long-term neurocongnitive dysfunction

Administration of ketamine and propofol to rodent pups potentiated neonatal brain cell death and resulted in impaired learning and memory functions

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Local anesthetic principles

Block sodium channel on nerves--> prevents Na influx--> block AP
- Can be administered topically or injection
- Can be restricted to localized area
- Administered IV--> effect other tissues

Ideal:
- Water soluble/stable in solution
- Non-irritating
- Low systemic toxicity
- Short induction period
- Adequate duration of action
- No post-anesthetic side effects
- Vasoconstrictive effect (prevent spread, bleeding)

Chemistry:
- Lipophilic group (aromatic ring)
- Connected by intermediate chain (ester/amide) to
- Ionizable group (tertiary amine)

pKa= affects onset (base/cation form)

Lipid solubility= affects potency

Protein binding= affects duration of action
- Increased protein binding--> duration of AP increased

Vasoconstriction= duration, potency
- Slows blood flow (prevents removal of anesthetic from region)
- Longer-acting agents less dependent on coadministration of vasoconstrictors

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Cocaine

Precursor for local anesthetic
Used for intranasal surgery
- Strong addictive potential

ONLY local anesthetic that is a vasoconstrictor
- intrinsic sympathomimetic action by inhibiting norepinephrine reuptake into nerve terminals

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Procaine

Reduce local irritation, tissue damage
- Minimize systemic toxicity
- Faster onset of action, longer duration of action

82

Lidocaine

Prototype local anesthetic

83

Esters

- Benzocaine
- Chloroprocaine
- Cyclomethycaine
- Dimethocaine/Larocaine
- Piperocaine
- Propoxycaine
- Procaine/Novocaine
- Proparacaine
- Tetracaine/Amethocaine


NO injectable ester anesthetic (only used topically

Metabolized by tissue esterases, shorter 1/2 lives than amides

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Amides

- Articaine
- Bupivacaine (longer duration)
- Cinchocaine/Dibucaine
- Etidocaine
- Levobupivacaine
- Lidocaine/Lignocaine (2%)
- Mepivacaine
- Prilocaine
- Ropivacaine
- Trimecaine

Liver metabolism- use caution in liver dysfunction (increased 1/2 life)

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Local anesthesia effects

Temporal progression:
- Interrupt transmission of autonomic impulses
- Block sensory impulses
- Block motor impulses (skeletal muscle)

C and B fibers are blocked first followed by A delta, A beta, A gamma fibers and finally A alpha fibers.

Order of blockage:
- Smaller fibers are blocked more easily than larger fibers
- Myelinated are blocked more easily than unmyelinated
- Peripheral fibers are blocked sooner than core fibers because they are exposed sooner to higher concentrations of anesthetic

** All drugs= mild vasodilators EXCEPT for cocaine

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Local anesthetic additives

Epinephrine/ phenylephrine= added to cause vasoconstriction
- Little effect on rate of onset
- Reduces diffusion away from site, increases therapeutic duration
- NOT recommended on end-organ surgery (fingertips, low circulatory organs)

Risks:
- may contribute to cardiac dysrhythmias or accentuate hypertension in vulnerable patients
- Not recommended in patients with cardiac dysrhythmias, uncontrollable hypertension, unstable angina

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Surface Anesthesia

- anesthesia of mucous membranes
- not submucosal structures
- produced by topical application
- mostly nose and mouth, eyes (optho)

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EMLA

Eutectic mixture of local anesthetics (EMLA) is a topical anesthetic cream, that consists of lidocaine 2.5% and prilocaine.
- EMLA cream requires 45 to 60 minutes to exert its peak effect.

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Nerve block anesthesia

produced by injection into specific areas or by infusion into vessel of a limb (tourniquet up to one hour)
- peripheral and extremity surgery

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Spinal anesthesia

- produced by injection of LA into CSF of lumbar region
- spread of LA can be affected by gravities of the injected solution and position of the patient
- goal is to block somatic sensory and motor fibers
- diagnostic procedures and surgery of lower abdomen, perineum and extremities

Vs epidural anesthetics= longer-acting, leave catheter in spine

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Epidural anesthesia

- produced by injection into epidural space from where it diffuses into subarachnoid space and paravertebral area
- doses injected can produce significant blood levels
- repeated injections cause tachyphylaxis
- child birth, post operative pain control

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Interactions of anesthetics

Excess extracellular K= enhance local aesthetic activity

Excess extracellular Ca= antagonize anesthetic activity

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Toxicity of anesthetics

Administration:
- systemic toxiciy,
- neurotoxicity and
- allergic reactions.

The most common cause of local anesthetic systemic toxicity is accidental, intravascular injection of local anesthetic solution during the performance of a nerve block

CNS effects:
- light headedness or sedation
- restlessness
- nystagmus
- tonic clonic convulsions
- coma and respiratory and cardiovascular depression

Cardiovascular effects:
- Vasodilation
- Arrrhythmia
- Hypotension (IV)
- Cocaine--> severe HTN, cerebral hemorrhage, cardiac arrhythmias, MI

Hematologic:
Prilocaine, benzocaine--> metabolized--> methemoglobinemia
- Signs and symptoms within 3-4 hours: lethargic, respiratory distress, cyanotic mucous membranes, nail beds, ashen skin
- Will not improve with 100% O2
- reverse with methylene blue: converts iron back to ferrous state

Ester-type anesthetics can cause antibody formation

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Treatment of anesthetic toxicity

Severe toxicity is treated symptomatically
- Convulsions are treated with intravenous diazepam or short acting barbiturate

Hyperventilation with oxygen is useful

Bupivacaine overdose is difficult to treat and has caused fatalities in healthy young adults

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Indications for anti-tussive agents

Appropriate for non-productive coughs:
- Where coughing results in sleep loss and contributes to debilitation
- To prevent visceral herniation due to increased pressure (e.g. Post-op)
- To reduce the spread of infection by droplet spray
- To facilitate repair of the tracheobronchial tree
- SOMETIMES recommended for nighttime treatment of a productive cough

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Anodynes

Agents acting centrally to suppress cough center
- Non-specific reduction in excitability

Types:
1. Opioid
2. Non-opioid
3. Other

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Codeine, Hydrocodone

Opioid antitussives
- Smaller dose needed for anti-tussive effect than analgesia effect

AEs:
- Respiratory depression
** caution using codeine in children <2– more sensitive to this (OTHERS:)
- Constipation
- Miosis
- Sedation
- Addiction potential

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Dextromethorphan

Non-opioid antitussive
- Isomer of opioid, doesn't bind to classical opioid receptors (mu, delta, sigma)
- Binds in cough center
- d-isomer of codeine analog
- Binds to receptors: NMDA antagonist; Sigma opioid agonist; nicotinic antagonist; serotonin reuptake pump block)
- Effective at suppressing cough with fewer side effects than codeine or opioids.
- Efficacy in children questioned

AEs:
- Dose-related side effects
- Confusion, excitation, nervousness, irritability, and respiratory depression can occur with high doses.
- Reduce doses for debilitated patients
- Do not use with MAOIs (dextromethorphan is a weak blocker of serotonin reuptake)
- Additive CNS depression with other sedating medications

** Potential for abuse (esp. in teens): 6 oz taken to induce hallucinations, loss of motor control, out of body sensations, hyperthermia
- does NOT respond reliably to naloxone

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Promethazine (+/- codeine)

Phenothiazine, antihistamine
- Used in combination cough syrups
- Antihistamine with sedative/antiemetic effects

100

Diphenhydramine

2nd line antitussive
- May be useful when treating multiple symptoms

101

Peripherally-acting antitussives

Local anesthetics- act primarily on afferent input--> reduce input to cough center

102

Benzonatate

Chemically related to procaine (ester anesthetic)

MOA: Local anesthetic effect on the stretch receptors in the respiratory passages, lungs, and pleura (thus depressing the cough reflex at its source).
* No effect on respiratory center in recommended doses.

AEs:
- hypersensitivity reactions can occur—bronchospasm, laryngospasm, CV collapse.
* Contraindicated if hypersensitive to related drugs such as procaine and tetracaine.
** Oropharyngeal anesthesia can occur if capsules are chewed or dissolved in mouth (don't chew!)

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Mucokinetic agents

1. Expectorants= stimulate or modify mucous production in bronchi
- increase secretions, thin mucus (good for thick sputum coughs)

2. Mucolytics= break down sputum aggregates (mucopolysaccharides) to smaller components

3. Demulcents= sticky substances that protect lining of respiratory tract from irritation
- syrups, honey, hard candy (self-care)

** ALL can be also used with productive cough

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Guaifenesin

Expectorant

MOA: Stomach irritant which reflexly affects the CNS to increase bronchial secretions.

Adverse reactions: GI tract (e.g., N/V, irritant to gastric mucosa).

** Frequently underdosed (esp due to common presence in combination dosing)

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N-acetylcysteine

Mucolytic

MOA: The sulfhydryl groups of acetylcysteine splits the disulfide bridges of the mucopolysaccharides present in mucous secretions, thus lowering the viscosity of the mucus.

Administration: By spray (nebulizer) or directly with a bronchoscope.

AEs:
Bad taste, smell

Uses:
- Bronchopulmonary disease with viscous mucous secretions (cystic fibrosis)
- Antidote to acetaminophen poisoning

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Pharmacologic methods to control emesis

1. Raise threshold/or decrease excitability of the neurons of the CTZ (central)

2. Directly depress the emetic center (central).

3. Modify input to emetic center, both by drugs that act peripherally and/or in the CNS (central).

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Chlorpromazine
Prochlorperazine
Promethazine
Thiethylperazine

Dopamine Antagonists: phenthiazine derivatives

MOA:
1. depresses excitability of the CTZ by blocking dopamine (D2) receptors and transmission.
2. peripheral action blocking dopamine (D2) receptors in the GI tract.
** Promethazine also binds H1 histamine receptors (antihistamine)

- Available as suppository, oral tablets, liquids, IM, IV

Uses:
- Radiation and drug-induced N/V in patients receiving mildly emetogenic drugs.
- Thiethylperazine is used for post-operative N/V.

AEs:
- Sedation
- Extrapyramidal symptoms (E.P.S.)
- Allergic
** Caution with promethazine= IV risk of intra-arterial injection; contraindicated in children < 2

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Droperidol

Dopamine antagonist: Butyrophenone derivative

MOA:
1. depresses excitability of the CTZ by blocking dopamine (D2) receptors and transmission.
2. peripheral action blocking dopamine (D2) receptors in the GI tract.

- Given orally, IV, IM

Uses:
- For preventing mildly emetogenic antineoplastic drug-induced emesis
- Premedication/ induction/ adjunct in anesthesia maintenance postsurgical emesis.
- Some tranquilization effects.

AEs:
- Sedation
- Extrapyramidal symptoms (E.P.S.)
- Allergic

109

Trimethobenzamide

Dopamine antagonist: benzamide derivative

MOA:
1. Antiemetic- Depresses CTZ by blocking dopamine (D2) receptors.
2. Antitussive- Suppresses laryngeal and pharyngeal reflexes to cough center in medulla (rarely used for this purpose)

- Given orally, rectal, IV

Uses:
- Postoperative N/V
- Postoperative coughing

AEs:
- CNS depression
- Extrapyramidal side effects
- Reye’s syndrome in children (cause? association?)

110

Metoclopramide

Dopamine antagonist: benzamide derivative

MOA:
1. Prokinetic action stimulates motility of the upper GI tract by sensitizing gut to the action of ACh.
2. Anti-emetic action appears to result from its antagonism of dopamine (D2) receptors in the CTZ and GI tract.

- Oral, IV

Uses:
- Symptomatic gastroesophageal reflux
- Diabetic gastric stasis
- Radiologic examination of GI tract
- N/V associated with cisplatin therapy, other antineoplastic agents and radiation therapy.

AEs:
- CNS depression
- Extrapyramidal side effects (Dopamine antagonism)

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Scopalamine

Anticholinergic agent

MOA:
- Blocks Ach receptors in CTZ, vestibular nuclei, GI tract

- Dermal patch

Use:
- Motion sickness

AEs:
- Sedation
- Blurred vision
- Reduced GI bladder tone/urinary retention

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Dimenhydrinate,
Diphenhydramine

Antihistamines: ethanolamine derivatives
Used in motion sickness: anticholinergic activity

MOA: block Ach receptors in vestibular nuclei, CTZ

Uses:
- Motion sickness
- Mild N/V

AEs:
Sedation, blurred vision, dry mouth.  

113

Hydroxyzine
Meclizine
Cyclizine

Antihistamines: 1st generation piperazine derivatives

MOA: block Ach receptors in vestibular nuclei, CTZ

Uses:
- Vertigo
- Motion sickness

114

Ondansetron
Granisetron
- Setron drugs

Serotonin receptor antagonist anti-emetics

MOA: Selectively blocks serotonin receptors (5-HT3 subtype) in GI tract and CTZ
- Do not produce extra-pyramidal side effects

Uses:
- Post-op N/V for highly emetogenic surgical procedures (abdominal surgery, cholecystectomy, eye/ear surgery)
- N/V due to highly emetogenic agents (NO, ketamine, opioids, antineoplastics)
- N/V due to radiation therapy
** No effect on motion sickness

AEs:
- Headache, diarrhea, constipation, phlebitis, asthenia (weakness)

115

Aprepitant

Neurokinin-1 antagonist (anti-emetic)

MOA:
- Selective, high affinity antagonism of human substance P/ neurokinin 1 recepts

AEs:
- CYP3A4 inhibitor

116

Dronabinol

THC synthesized drug (schedule II)

MOA: binds to cannabinoid receptors in CTZ, vomiting center, cortex

Uses:
- N/V due to emetogenic antineoplastic drugs
- Anorexia-associated weight loss in AIDS patients

AEs:
- Impairs cognition, motor performance
- Induce dysphoria, psychotomimetic behavior

117

Dexamethazone
Methyprednisone

Glucocorticoids used for N/V

MOA:
- Inhibits proinflammatory PGs in CNS--> blocks cortical projections to emetic center

Uses:
- IV with other antiemetics for highly emetogenic agent administration

118

Bezodiazepines: alprazolam, lorazepam

Used for N/V due to emotional factors (anticipatory N/V)

119

Treatment for Alzheimer's Disease

Ach-Esterase Inhibitors:
- donepezil, rivastigmine, galantamine

NMDA antagonists:
- Memantine