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Neuro 1 Final > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What are the 2 types of local anesthetics?

A

Ester-type

Amide-type

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2
Q

What are the 4 members of the ester local anesthetics (LA) and their pKa? Which 2 are topical*?

A

Cocaine*
Benzocain*
Procaine (novocaine)
Tetracaine (pontocaine)

pKa=8-9 (moderate bases)

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3
Q

Which ester LA would you use as an ointment for local pain due to sunburn or insect bites?

A

Benzocaine

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4
Q

Which ester LA would you use to topically apply the cornea? Is it a vasodilator or vasoconstrictor?

A

Cocaine

Vasoconstrictor

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5
Q

Which ester LA has low potency and short duration due to significant vasodilation and rapid metabolism? What is it used for and what prolongs its effect?

A

Procaine (novocaine)
Used for spinal anesthesia
Epinephrine prolongs its effect :)

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6
Q

Which ester LA is used for spinal anesthesia but lasts longer than procaine? (Longest duration of all the ester LA)

A

Tetracaine (pentocaine)

10x more toxic/potent than procaine

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7
Q

What are the 4 members of the amide local anesthetics (LA) and their pKa?

A

Lidocaine
Bupivacaine
Ropivacaine
Mepivacaine

pKa=7-8 (weak base)

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8
Q

TQ: Which amide LA is the most widely used, effective by all routes, fast onset and long lasting (>procaine), and preferred for those allergic to ester type LA?

A

Lidocaine

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9
Q

TQ: Since Lidocaine causes more sedation than other LA, which drug should be avoided while taking Lidocaine? In which pts especially?

A
  • Lidocaine + epinephrine

- Digital anesthesia in pts with peripheral artery dz

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10
Q

TQ: Which amide LA is used for sensory analgesia with minimal motor block (useful during labor)?

A

Bupivacaine

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11
Q

TQ: Which amide LA is more cardiotoxic than other LA?

A

Bupivacaine

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12
Q

TQ: Which amide LA is a good choice for longer procedures, for patients who have contraindications to epinephrine injection, for situations where there will be a delay between infiltration of local anesthetic and the procedure, or for instances in which prolonged post-procedure pain control is preferred?

A

Bupivacaine

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13
Q

What do LA reversibly block?

A

Nerve conduction of sensory impulses via Na channels

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14
Q

When you inject LA drug B (BH+) with a pKa equal to the extracellular pH, acid-base equilibrium occurs. What does this mean?

A

1/2 the drug is charged and protonated and 1/2 is uncharged and free (1:1 ratio)

BH+=B

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15
Q

Which form of the LA drug crosses the lipid membrane to enter the cytosol?

A

The uncharged free lipophilic form of the drug

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16
Q

What happens after the LA drug crosses the lipid membrane and enters the cytosol?

A

Acid-base equilibrium re-occurs and the flow of compound is generally towards the cytosol.

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17
Q

What keeps the inactivation gate closed once a LA drug has crossed the membrane?

A

When the drug crosses the membrane and undergoes acid-base equilibrium, the protonated form (BH+) keeps the gate closed, preventing Na+ from coming into the cell.

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18
Q

TQ: What is the MOA of ester and amide LA?

A
  • Reversible, voltage-gated Na channel blockers
  • Increase the threshold potential (do not alter resting potential)
  • Slows the rate of depolarization and conduction
  • Reduces the height of action potential
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19
Q

How does pKa influence LA drugs?

A

Influences speed of onset

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20
Q

How does lipophilicity influence LA drugs?

A

Influences potency (oil vs. water soluble)

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21
Q

How are esters cleared and what are the risks?

A
  • esterases (pseudocholinesterase)

- Hypersensitivity; overexposure

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22
Q

How are amides cleared?

A

Hepatic metabolism: cytoP450

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23
Q

What is protein binding directly related to?

A

Duration of action (ex: bound to albumin vs. free)

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24
Q

What is the order of blocking of sensory effect for LA?

A 
1st C fibers, a-delta fibers: 
Pain-->cold-->warmth 
2nd a-beta fibers: 
touch-->deep pressure
Last: motor

so..
pain to cold to warmth to touch to deep pressure to motor

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25
Q

What is the order of recovery of sensory effect for LA?

A

Opposite of blocking so…

motor->deep pressure->touch->warmth->cold->pain

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26
Q

What are the factors of nerve sensitivity to LA?

A
  • smaller more susceptible than larger
  • type of fiber
  • degree of myelination
  • fiber length
  • frequency-dependence of voltage-gated Na+ channel opening
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27
Q

Are c-fibers sensitive to LA?

A

YES; very thin and have no myelination

B-fibers are sensitive as well

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28
Q

Where should we apply LA to block nerve impulses and why?

A

Nodes of Ranvier have abundant voltage-gated Na+ channels

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29
Q

What is pKa? Why is it important for drugs?

A

-Acid dissociation constant:
BH+ H+ + B
-pKa how much of a drug exists in a charged, protonated, acidic form and how much exists in a neutral, free base form.

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30
Q

T/F: pKa never changes

A

TRUE

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31
Q

If we add B, pKa = 7.5, and B’, Pka= 8.5 into interstitial fluid at pH 7.5 what is the ratio
of [B]/[BH+] in each case ? Which drug is faster?

A

B is faster than B’:
pH = pKa + log [B]/[BH+]
7.5 = 7.5 + log [B]/[BH+] 0 = log [B]/[BH+] 100=1=1/1= [B]/[BH+]

Since only the charged species can cross the nerve membrane, dispersion of the LA through the tissue occurs more rapidly as the % of uncharged B increases.

(The pH of the solution and surrounding tissues and the pKa of the specific agent determine the proportion of charged and uncharged anesthetic)

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32
Q

The lower the pKa, the slower/faster the drug onset.

A

Faster

The higher the pKa, the slower the onset

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33
Q

Weak bases (amides) are faster than moderate bases (esters). Why?

A

Weaker bases (amides) have a lower pKa (faster)

Stronger bases (esters) have a higher pKa (slower)

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34
Q

Inflammation or an abscess may decr. pH and therefore slow the onset of drug action. What may be done to help prevent clinical failure?

A
  • Draining an abscess before injecting the drug will increase the local pH (removing acidic fluid)
  • Increases drug efficacy
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35
Q

The higher the lipid solubility, the more/less potent the drug.

A

The higher the lipid solubility, the more potent the drug

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36
Q

Which LA drugs have the lowest and highest relative potency?

A

Procaine has the lowest potency (1) while Tetracaine and Bupivacaine have the highest relative potency (16)

(directly related to the # of C’s; bupivicaine has 4 CH2, while ropivicaine has 3 and mepivocaine has 1 CH2)

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37
Q

The most cardiotoxic LA (Bupivacaine) is due to….

A

lipophilicity

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38
Q

Systemic toxicity of the Na+ channel starts at approx. 2 ug/ml then 10 then 20. What side effects are associated with each level of ug/ml?

A

2 ug/ml=numb tongue, tinnitus, light headed

10 ug/ml= muscle twitching, disorientation, loss of consciousness

20 ug/ml=*Convulsions, coma *Respiratory arrest, *Cardiovascular (Na+ channels in heart)

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39
Q

CASE: Too much bupivacaine in a highly perfused tissue. What are the options?

A

Heart transplant

Use drug Intralipid: lipid extraction of drug from heart

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40
Q

Since nerves and blood vessels are in close proximity, LA gets into the bloodstream and goes to highly perfused tissues! Therefore, drugs that cause vasodilation enhance drug distribution. Which LAs cause significant vasodilation? What are they at risk for?

A

Procaine, lidocaine
(Tetracaine, bupivacaine)

Shortens duration of action & increases risk of systemic toxicity

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41
Q

Why do many preparations of LA contain ____________, intended to counteract vasodilation?

A

Epinephrine constricts blood vessels and limits systemic exposure to LA

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42
Q

What does the epinephrine do to the duration of the drugs lidocaine and bupivacaine?

A

Lidocaine + epinephrine duration is longer (from 30-60 min to 120-260 min)

Bupivacaine + epinephrine duration is longer as well (from 120-240 min to 180-420 min)

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43
Q

TQ: What should we avoid giving patients that prescribed ergot alkaloids, such as ergotamine?

A

Epinephrine! ergotamine is an enhanced hypertensive drug and vasoconstrictor

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44
Q

Why should we be wary of applying epinephrine to the end of our fingers or toes (ingrown nail)?

A

Low perfusion areas can be damaged if we vasoconstrict too much

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45
Q

LA with _______lipophilic nature show __________penetration of the lipid nerve membane

Vasodilation promotes systemic absoprtion, _________local potency and __________risk for toxicity

A

LA with greater lipophilic nature show greater penetration of the lipid nerve membane

Vasodilation promotes systemic absoprtion, decreases local potency and increases risk for toxicity

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46
Q

Metabolism of esters vs. amides?

A

esters: rapid (1-5 min), plasma cholinesterase
amides: slow (1-4 hours), hepatic CYP 450

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47
Q

Hypersensitivity of esters vs. amides?

A

esters: PABA metabolite*** (tetracaine and procaine hypersensitivity)
amides: none

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48
Q

Systemic toxicity of esters vs. amides?

A

Esters: less likely*, cleared quickly

Amides: more likely b/c cleared by liver! and slower metabolism (lidocaine can lead to bronchio problems and overdose)

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49
Q

Lidocaine (amide) in pts with hepatic insufficiency may require dosage adjustment in order to avoid overexposure. Which patients will need to be adjusted?

A
  • CHF pts (poor perfusion of liver so poor clearance)

- Geriatric pts

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50
Q

1 in 3000 pts have a polymorphism in their pseudo-cholinesterase enzyme, which makes it less active and therefore…

A
  • Elimination of ester LA is slower!

- Be careful! Even tetracaine pts with a genetic variant of pseudo-cholinesterase could have side effects

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51
Q

A pt with a variant pseudo-cholinesterase could experience side effects of apnea and prolonged paralysis when given…..

A

succinylcholine or mivacurium (ester based)

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52
Q

T/F: Anti-seizure drugs, phenytoin, carbamazepine, and lamotrigine also block neuronal voltage-gated Na+ channels. Therefore, when treating LA induced seizures use phenytoin because it shares properties with lidocaine and enhances its toxicity.

A

FALSE. DO NOT USE phenytoin….Avoid use of phenytoin (Dilantin) in this situation because it shares pharmacologic properties with lidocaine and may potentiate lidocaine toxicity.

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53
Q

What agents can be used to treat muscle spasticity?

A

Baclofen

Diazepam

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54
Q

What is the MOA of Baclofen vs. Diazepam?

A

Baclofen: GABA B Receptor Agonist (B n B)

Diazepam: GABA A Receptor Agonist

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55
Q

MOA of Baclofen:

1) Excitatory afferent pre-synaptic GABA B Receptor K+ Channel
2) Baclofen GABA B agonist inhibits _______ release

A

Glutamate

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56
Q

MOA of Diazepam:

1) Inhibitory interneuron post-synaptic GABA A Receptor Cl- Channel
2) Diazepam GABA A agonist potentiates _______

A

GABA

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57
Q

Use and Adverse effects of diazepam

A

Use: spinal cord lesions, MS

AE: physical dependence and tolerence

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58
Q

Use and Adverse effects of Baclofen

A

Use: spinal cord lesions, cerebral palsy

AE: seizures, withdrawal

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59
Q

Other agents to treat muscle spasm and their risks?

A

Carisoprodol: high abuse potential due to addictive metabolite

Cyclobenzaprine: anti-depressant analog causing catecholamine re-uptake issues

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60
Q

List the generic names of soluble, bioavailable, opioid narcotic AGONISTS used for analgesia / other indications (11)

A 
Codeine
Fentanyl
Heroin
Hydrocodone
Hydromorphone
Meperidine
Methadone
Morphine
Oxycodone
Oxymorphone
Tramadol
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61
Q

List the generic names of opioid narcotic μ receptor ANTAGONISTS used for management of opioid narcotic overdose/ addiction / side effects (3)

A

Naloxone
Naltrexone
Methyl naltrexone (GI specific)

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62
Q

List the generic names of opioid PARTIAL AGONISTS or MIXED AGONISTS/ANTAGONISTS (3)

A

Buprenorphine
Buprenorphine-Naloxone
Pentazocine

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63
Q

List the generic names of ‘insoluble’, poorly absorbed opioid receptor agonists used for diarrhea (2)

A

Loperamide

Diphenoxylate

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64
Q

List the generic names of the most common opioid related anti-tussive agents (cough suppression) (3)

A

Codeine
Dextromethorphan
Hydrocodone

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65
Q

Is it safe to prescribe codeine for nursing mothers for post-labor pains?

A

No! Discontinue codeine after 2 to 3 days of use post-labor. Mother is making more morphine which is toxic to both her and the baby

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66
Q

What are the 3 types of opioid receptors and their ligands

A

Mu (μ) MOR: Peptides=Endorphins

Kappa (κ) KOR: Peptides=Dynorphins

Delta (δ) DOR: Peptides=Enkephalins, Endoprphins

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67
Q

What is the pain impulse? (starting with afferent sensory signal)

A

1) Afferent sensory signal
2) Pre-synaptic: Increases Ca2+ influx
3) Increases glutamate discharge
4) Post-synaptic: Increases NMDA receptor-Na+ influx

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68
Q

What happens in opioid agonist-mediated signaling?

A

1) Blunts afferent signal
2) Blunts Ca2+ influx
3) Blunts glutamate discharge
4) Increases K+ Efflux***

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69
Q

Drugs that bind to μ opioid receptors include full agonists, partial agonists/mixed, and antagonists. Which drugs from these categories bind to the μ opioid receptors?

A

Full Agonists:
Fentanyl & Morphine

Partial Agonist/Mixed: (potent!)
Buprenorphine

Antagonist:
Naloxone & Naltrexone

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70
Q

Opioids such as morphine are μ receptor agonists. What would we use them clinically for?

A

Tissue injury=acute stimuli≥ Nerve injury

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71
Q

The pain treatment ladder is based on an opioid-sparing rationale. What is the ladder? (mild, moderate, severe)

A

Mild pain: NSAID, Acetaminophen

Moderate pain, persisting, or uncontrolled pain: Codeine, Codeine-related + Acetaminophen, Tramadol

Severe pain, persisting, or uncontrolled pain: Morphine, Fentanyl, etc extended release

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72
Q

What are the clinical effects of agonists at the Mu (μ) opioid receptor? (6)

A
  • Analgesia (supra-spinal)
  • Euphoria
  • CNS & Respiratory depression
  • Drug dependence
  • Miosis (pupil contraction)
  • GI, uterine contraction/spasm
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73
Q

What are the clinical effects of agonists at the Kappa (κ)opioid receptor? (4)

A
  • Analgesia (spinal)
  • Sedation
  • Miosis
  • GI, uterine contraction/spasm
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74
Q

Tolerance (deteriorated response) to Morphine (μ Agonists) includes increased tolerance to…(5)

What are the exceptions? (2)

A 
Analgesia
Euphoria
Sedation
Nausea
Respiratory depression

Exception: no tolerance to miosis or constipation

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75
Q

What are the adverse effects of morphine?

A

Sedation
GI effects: constipation & biliary pressure
Emesis
Pruritis (scratching)

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76
Q

What puts morphine at an abuse liability?

A

Euphoria (altered limbic system)

Physical dependence

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77
Q

Why is morphine deadly?

A

Respiratory depression: depresses CO2 sensitivity in the brainstem

can have low O2 and high CO2 and brainstem doesn’t realize you need to breathe.

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78
Q

What are some contra-indications to morphine use?

A

Brain injury, emphysema, and heart failure (perfusion issue)

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79
Q

Can you use opioids in heart attack pts?

A

YES! cuts back anxiety and pain

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80
Q

What are some clinical indications for morphine?

A

-Post-operative pain (surgery)
-Cancer pain (Primary & metastatic malignancy)
-Other pain:
Sickle cell crisis, trauma, severe diarrhea, dyspnea caused by pulmonary edema from left ventricular failure

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81
Q

TQ: What is a major issue in pts post-surgery (esp. GI/ biliary) and chronic use of morphine?

A

Constipation!

-may be necessary to compromise analgesic to help GI and biliary SM

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82
Q

What opioid μ agonists drugs are full agonists and used in parenteral and oral tx? (6)

A 
Morphine**
Methadone 
Meperidine
(Hydromorphone
Oxymorphone
Levorphanol)
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83
Q

What opioid μ agonists drugs are full agonists and short acting? (3)

A

Fentanyl**
Sufentanil
Remifentanyl

84
Q

What are opioid μ agonists that are codeine related? (2)

A

Hydrocodone

Oxycodone

85
Q

What is important when switching from parenteral to oral dosing or switching between opioids? (2)

A

Potency and bioavailability

86
Q

Which 2 μ Opioid Full Agonists have the high good oral bioavailability?

A

Methadone and Levorphanol

87
Q

Morphine has a 10 mg dosage. How does meperidine potency compare? What about hydromorphone, oxymorphone, and levorphanol?

A

Meperidine: 60
Hydromorphone: 1.5
Oxymorphone: 1.5
Levorphanol: 2-3

88
Q

Oral morphine is first-pass metabolism so has POOR bioavailability. What should we do?

A

Give high bioavailability parenteral opioids (i.v.) with it!

89
Q

Why do various patients react differently to morphine?

A

Active metabolites such as M-3-glucuronide, M-6-glucuronide, and hydromorphone

Inactive metabolites such as Normorphine

90
Q

Methadone is a μ Agonist that can be taken once daily and has better bioavailability than morphine. What is it used for?

A

Withdrawal and maintenance
Detox

(stays at steady state so no peaks in euphoria or dysphoria)

91
Q

TQ: Methadone can affect cardiac electrical conduction, producing what?

A

QT-interval prolongation in acute overdose or during long-term methadone treatment

92
Q

Meperidine effects on the uterus and biliary tracts and the eye

A

Less effects on smooth m and therefore less effect on uterus and biliary tracts (used on pain during delivery)

Eye: Pupil dilation (risk of abuse by docs because no pinpoint pupils)

93
Q

Risks of meperidine?

A

Normeperidine is a toxic metabolite that may accumulate and cause seizures

94
Q

Rank the onset and duration of the following analgesics in order from quick and short to slow and long….
(Fentanyl, Morphine, Meperidine)

A

Fentanyl: quick onset but short duration

Meperidine: quick onset but longer duration

Morphine: slow onset but longer duration

95
Q

Which short acting-high potent full agonist is a κ, δ and μ

agonist?

A

Sufentanil

96
Q

Which is more potent? short acting full agonists or morphine and methadone?

A

The short acting full agonists! (Fentanyl, Sufentanil, Alfentanil, Remifentanil)

100x more potent!

97
Q

Which short acting full agonists is the most short-acting?

A

Remifentanil

98
Q

What is remifentanil used for recently?

A

childbirth! Since it is metabolized by plasma and tissue esterases, its rapid metabolism lowers the risk for neonatal depression. Rapid onset=1 min

99
Q

Which drug should be used for breakthrough pain?

A

Fentanyl

100
Q

How do we give fentanyl to the pt?

A
  • Transmucosal (lollipop): tie to hand!

- Transdermal patch delivery: slows onset and prolongs delivery but risk of abuse via heating patches

101
Q

What is codeine used for?

A
  • moderate pain and cough

- less potential for drug dependence and respiratory depression because only partial agonist

102
Q

What dictates strength of μ receptor response?

A

Partial vs. full agonists

ex: oxycodone strong agonist so high efficacy

103
Q

Codeine comes in combination with acetaminophen. Why is this important to know?

A

Complicates overdose! Symptoms would be sedation and respiratory depression

104
Q

Deaths have occurred after tonsillectomy in children with sleep apnea who received what drug?

A

Codeine for pain relief

105
Q

Codeine is a prodrug for…? What is the enzyme?

A

morphine (enzyme=CYP2D6)

106
Q

T/F: There is an ultrafast CYP2D6 codeine metabolizer, intermediate metabolizer, and poor metabolizer

A

TRUE: CYP2D6 polymorphisms affect rate of metabolism

Ex: fast allele causes issues in breastfeeding baby

107
Q

Why is the ultrafast metabolizer CYP2D6 a concern when giving coedine?

A
  • Overexposure of morphine

- Delayed acetaminophen metabolism can cause liver damage

108
Q

Name the active metabolite:
Codeine
Oxycodone
Hydrocodone

A

Codeine: Morphine*
Oxycodone: Oxymorphone
Hydrocodone: Hydromorphone

(all have CYP2D6 polymorphisms)

109
Q 
Name the active metabolite:
Morphine
Heroin
Meperidine
Fentanyl
A

Morphine: M6G and M3G, Hydromorphone*
Heroin: Morphine*
Meperidine: Normeperidine (toxic)
Fentanyl: NONE (good for someone at risk for abuse)

110
Q

Which anti-diarrheals interact with μ opioid receptors in gut?

A

Loperamide
Diphenoxylate

low risk for abuse!

111
Q

What drug is used for moderate pain and inhibits catecholamine reuptake?

A

Tramadol

112
Q

What is the active metabolite of Tramadol, a moderate μ agonist? What are its risks?

A
  • N-desmethyl=active metabolite
  • Assoc. w/ seizures
  • Caution in pts on tricyclic or SRI anti-depressants
113
Q

What two mixed agonists can precipitate withdrawal in abusers?

A

Pentazocine and Buprenorphine

114
Q

Which mixed agonist can be used in office-based detox/maintenance?

A

Buprenorphine

115
Q

Which drug relieves cough (antitussive) independently of opioid receptors and its therefore non-addictive and not analgesic?

A

Dextromethophan

116
Q

Why is heroin an addiction liability?

A

Its a di-acetylmorphine which can penetrate the blood brain barrier rapidly and cause exaggerated euphoria

117
Q

What would you diagnose in a pt who has a respiratory rate of <12 breaths/min, is in a stupor, with constricted pupils?

A

Opioid analgesic overdose

118
Q

What are the 2 μ receptor antagonists?

A

Naloxone (i.v. bolus-comatose pt) and Naltrexone (p.o.-conscious pts)

119
Q

TQ: How do naloxone and naltrexone work as an antidote for opioid overdose?

A
  • Occupy (but do not activate) μ receptors

- Competitively inhibit (displace) heroin, morphine, fentanyl etc. (other μ agonists) from μ receptors

120
Q

T/F: Naloxone CAN reverse coma and respiratory depression 1 min after i.v. bolus depending on the opioid and dosage with a short duration of 1-2 hrs. Versus naltrexone which has a long duration of action (48 hrs/oral dose).

A

TRUE

121
Q

Whats the downside to antidotes for overdose?

A

They can precipitate withdrawal.

122
Q

What strategies might work for opioid-induced side effects such as constipation?

A
  • Methylnaltrexone has restricted ability to cross the blood-brain barrier.
  • Functions as a peripheral acting opioid antagonist; inhibits opioid- induced constipation.
  • Does not affect opioid analgesic effects or induce opioid withdrawal symptoms.
123
Q

Subtype drug classes to treat Generalized Onset seizures (both hemispheres of brain are involved): (3)

A
  • Absence: Ethosuximide
  • Myotonic, Atonic, Clonic: Benzodiazepines
  • Tonic-Clonic: Narrow spectrum drugs - CBZ, phenytoin, phenobarbital
124
Q

Subtype drug class to treat Partial Onset seizures (only one hemisphere of brain is involved): (2)

A
  • Simple and complex: Gabapentin, pregabalin, OXCBZ, lacosamide, tiagabine, vagabatrin, ezogabin
  • Tonic-Clonic: Narrow spectrum drugs - CBZ, phenytoin, phenobarbital
125
Q

Drugs used to treat epilepsy target NT systems in order to slow (excitatory/inhibitory) glutamate transmission, and/or enhance (excitatory/inhibitory) GABA transmission.

A
  • Excitatory

- Inhibitory

126
Q

AEDs that limit pre-synaptic excitation primarily by blocking voltage-dependent Na+ channels:

  • Traditional AEDs: (2)
  • New AEDs: (4)
A

Traditional AEDs:

  • Carbamazepine
  • Phenytoin

New AEDs:

  • Lacosamide
  • Zonisamide
  • Lamotrigine
  • Oxcarbazepine
127
Q

MOA for AED antagonists of voltage-dependent Na+ channels: (2)

A
  1. Blockage of voltage-gated Na+ channel

2. Blunt excitation (blunt glutamate discharge)

128
Q

Drugs modulate voltage gated Na+ channels via 2 distinct mechanisms:
Have been recently asked on boards

A
  1. Enhance FAST inactivation of Na+ channels

2. Enhance SLOW inactivation of Na+ channels

129
Q

Drugs that enhance FAST inactivation (inactivation phase) of Na+ channels:

  • Traditional AEDs: (2)
  • New AEDs: (2)
A

Traditional AEDs:

  • Phenytoin
  • Carbamazepine

New AEDs:

  • Lamotrigine
  • Oxcarbazepine
130
Q

Drugs that enhance SLOW inactivation (repolarization phase) of Na+ channels:
-New AED: (1)

A

New AED: Lacosamide

131
Q

Carbamazepine and phenytoin are widely used for tx of various types of partial or generalized seizure disorder, but they’re NOT USED for treating what specific type of seizure?

A

Absence seizures

132
Q

Complications with phenytoin: (2)

A
  • Zero-order pharmacokinetics** (dose adjustment is difficult)
  • Induces hepatic CYP450 enzymes
133
Q

Distinct toxicities of phenytoin: (3)

A
  • Gingival hyperplasia**
  • Hirsutism
  • Hypocalcemia, osteoporosis
134
Q

Complications with carbamazepine (CBZ): (3)

A
  • Induces hepatic CYP450 enzymes
  • Leukopenia, neutropenia, thrombocytopenia** (infxns, bruising)
  • Hypocalcemia, osteoporosis
135
Q

CBZ and phenytoin have been associated with causing what syndrome? The effect is more common in pts with what allele?

A
  • Stevens-Johnson syndrome and toxic epidermal necrolysis

- HLA-B*1502 allele (Asian ancestry) - 5% population

136
Q

TQ: Osteopenia/osteoporosis is a serious AE assoc with chronic administration of CBZ, phenytoin, phenobarbital and valproic acid.
What hepatic enzyme do all 4 of these drugs induce?
What is the mechanism by which osteopenia/osteoporosis results?

A
  • All 4 drugs induce CYP450-dependent Vit. D catabolism, which reduces circulating Vit. D levels.
  • The resultant decreased absorption of intestinal Ca++ can trigger compensatory PTH-mediated responses that demineralize bone to maintain Ca++ levels in the blood.
137
Q

Starting CBZ can (increase/decrease) clearance of oral contraceptives (estrogen) metabolized by CYP isoenzymes.

A

Increase

-4-fold rise in oral contraceptive failure rate… risk for unplanned pregnancy

138
Q

Starting CBZ can (increase/decrease) clearance of warfarin (oral anti-coagulant) metabolized by CYP isoenzymes.

A

Increase

-Too rapid coagulation… elevated risk for arterial/venous thrombosis

139
Q

AEDs therapeutic window is (narrow/broad).

A

Narrow

140
Q

What clearance mechanism helps new AEDs to minimize drug interactions?
What drug combos are involved?

A

Mixed clearance of renal-hepatic

  • Topiramate / Oxcarbazepine
  • Levetiracetam / Zonisamide
141
Q

What is the distinct advantage of oxcarbazepine (OXCBZ) over CBZ?

A

-Fewer AEs due to its lack of formation of an active metabolite (10,11-CBZ epoxide in CBZ metabolism)

142
Q

Hyponatremia assoc with both _____ and ___ is due to increased responsiveness of collecting tubules to ADH, and it is considered to be an example of SIADH.

A
  • OXCBZ

- CBZ

143
Q

Drugs that are 100% cleared renally: (2)

A
  • Gabapentin

- Pregabalin

144
Q

Serious toxicity assoc with Lamotrigine:

A

Stevens-Johnson syndrome

145
Q

TQ: Valproate and lamotrigine inhibit conjugation of drugs by ___ enzymes, which causes what?

A
  • UGT enzymes*

- Causes accumulation of parent drug

146
Q

Serious AEs assoc with:

  • OXCBZ:
  • Tiagabine:
  • Topiramate:
  • Zonisamide:
A
  • OXCBZ: Hyponatremia (elderly)
  • Tiagabine: Stupor
  • Topiramate: Nephrolithiasis
  • Zonisamide: Rash, renal calculi, hypohidrosis (children)
147
Q

T-type Ca++ ion channels mediate _______ (petit mal) seizures.

A

Absence

148
Q

Antagonists of T-type Ca++ channels target ______-________ oscillation.

A

Cortex-thalamus

149
Q
  • Narrow spectrum drug
  • Only used for absence seizures
  • Only limits excitation (Ca++ channel)
  • Non-sedating drug** (TQ/Boards)
A

Ethosuximide

150
Q

Lamotrigine is interesting in that it blocks what 2 channels?

A
  • Na+ channels

- Ca++ channels

151
Q

2 mechanisms by which AEDs augment inhibitory pathways:

A
  • Block GABA re-uptake or metabolism

- Potentiate GABA(A) receptor Cl- currents

152
Q

_________ (drug) inhibits GABA re-uptake (transporters).

A

Tiagabine inhibits GABA re-uptake (transporters).

153
Q

__________ (drug) inhibits GABA metabolism (GABA-T).

A

Vigabatrin inhibits GABA metabolism (GABA-T).

154
Q

3 drugs that enhance post-synaptic GABAergic neuronal transmission:

A
  • Phenobarbital (and other barbiturates)
  • Primidone (active metabolite = phenobarbital)
  • Benzodiazepines (diazepam/lorazepam)
155
Q

Benzodiazepines (BZD) bind to a distinct site, which does what in terms of GABA binding and Cl- channels?

A

-BZDs bind to potentiate GABA binding (GABA-dependent), causing Cl- channels to open

156
Q

Why is Phenobarbital is unique from BZDs?

A

-High doses of phenobarbital are lethal because it is GABA-independent and will bind regardless of whether or not GABA is present

157
Q

Complications of phenobarbital: (3)

A
  • Sedation
  • Lethal respiratory depression**
  • Abuse/addiction potential
158
Q

Benzodiazepines (Diazepam or Lorazepam) are indicated for tx of:

A

Status epilepticus**

  • Drug withdrawal - EtOH, BZD, AEDs
  • Cocaine
  • Poisons (strychnine)
  • Brain tumor
  • High fever
159
Q

Abrupt withdrawal of AEDs (e.g., natural disasters) may cause:

A

Status epilepticus

160
Q

TQ: Standard protocol used to manage status epilepticus: (2)

A
  • i.v. lorazepam/diazepam for 5 min (repeat 3x)

- Then add i.v. fosphenytoin (Na+ channel antagonist)

161
Q 
Multiple MOA:
Valproic acid (older): (3)
A
  • Voltage-gated Na+ channels
  • T-type Ca++ channels
  • Increases GABA
162
Q

Multiple MOA:

Topirimate (newer): (4)

A
  • Voltage-gated Na+ channels
  • Ligand-gated Na+ channels (AMPA/glutamate receptor)
  • Increases GABA
  • Potentiates GABA(A) receptors
163
Q

Topirimate is specifically an ____ receptor antagonist.

A

Topirimate is specifically an AMPA (glutamate) receptor antagonist.
(Inhibits depolarization)

164
Q

Mechanism of:

  • Gabapentin
  • Leviteracetam
  • Pregabalin
  • Ezogabine
A
  • Gabapentin: Binds to voltage-dependent Ca++ channels (No drug interaction)
  • Leviteracetam: Binds to synaptic vesicle protein SV2A - blunts glutamate release (well-tolerated; no CYP interaction)
  • Pregabalin: Multiple (100% renal clearance)
  • Ezogabine: Opens voltage-gated K+ channels (new drug)
165
Q

Boxed warnings of:

  • CBZ: (2)
  • Lamotrigine: (1)
A

CBZ:

  • Stevens-Johnson syndrome (allergic rxn)
  • Aplastic anemia

Lamotrigine:
-Stevens-Johnson syndrome (allergic rxn)

166
Q

Teratogenic effects assoc with: (3 drugs)

A
  • Valproic acid (Valproate)**
  • Carbamazepine (CBZ)
  • Phenytoin
167
Q

Broad spectrum AEDs: (5)

A
  • Valproate
  • Lamotrigine
  • Topirimate
  • Leviteracetam
  • Zonisamide
168
Q

Major AEDs used to treat partial onset seizures
Simple and complex seizures: (7)
Tonic-Clonic: (3)

A

Partial onset:

Simple and complex seizures:

  • Gabapentin
  • Pregabalin
  • OXCBZ
  • Lacosamide
  • Tiagabine
  • Vigabatrin
  • Ezogabin

Tonic-Clonic: Narrow spectrum drugs

  • CBZ
  • Phenytoin
  • Phenobarbital
169
Q

The iris _________ muscle is innervated by cholinergic fibers to muscarinic M3 receptors.

A

The iris SPHINCTER muscle is innervated by cholinergic fibers to muscarinic M3 receptors.

170
Q

Agonists at M3 receptors (acetylcholine, carbachol, pilocarpine*) cause pupil (constriction/dilation).

A

Agonists at M3 receptors (acetylcholine, carbachol, pilocarpine*) cause pupil CONSTRICTION (miosis).

171
Q

Antagonists of cholinergic tone at M3 receptors (cyclopentolate, atropine, scopolamine) cause pupil (constriction/dilation).

A

Antagonists of cholinergic tone at M3 receptors (cyclopentolate, atropine, scopolamine) cause pupil DILATION (mydriasis).

172
Q

The ______ muscle is innervated by adrenergic fibers to alpha-1 receptors.

A

The RADIAL muscle is innervated by adrenergic fibers to alpha-1 receptors.

173
Q

Agonists at alpha-1 receptors (phenylephrine,dipivefrin, epinephrine) cause pupil (constriction/dilation).

A

Agonists at alpha-1 receptors (phenylephrine,dipivefrin, epinephrine) cause pupil DILATION (mydriasis).

174
Q

Cholinomimetics (parasympathomimetics): (2)

-Cause pupil constriction (miosis)

A
  • Carbachol

- Pilocarpine

175
Q 
Cholinesterase inhibitors (Anticholinesterase Agents): (3)
-Cause pupil constriction (miosis)
A
  • Organophosphates (pesticides)
  • Echothiophates
  • Physostigmine
176
Q 
Cholinergic Antagonists (Parasympatholytics): (3)
-Cause pupil dilation (mydriasis)
A
  • Cyclopentolate
  • Atropine***
  • Scopolamine
177
Q

Sympathomimetic: (1)

-Causes pupil dilation (mydriasis)

A

-Phenylephrine

178
Q

Increase in intraocular pressure (IOP) due to build up of aqueous humor:

A

Glaucoma

179
Q

Open-angle glaucoma can be treated with drugs to: (2)

A
  1. Limit aqueous humor production; or

2. Maintain uveascleral flow

180
Q

Cholinergic drugs to treat glaucoma:
Cholinomimetics: (3)
Anticholinesterases: (2)

A

Cholinomimetics:

  • Pilocarpine
  • Carbachol
  • Acetylcholine

Anticholinesterases:

  • Echothiophate
  • Physostigmine
181
Q
  • What is the main action and of both cholinomimetics and anticholinesterases in treating glaucoma?
  • What is the effect?
A
  • Ciliary muscle contraction = Open trabecular network

- Increase drainage via canal of Schlemm (outflow)

182
Q

Adrenergic drugs to treat glaucoma: (3)

A
  • Timolol*, betaxolol

- Apraclonidine

183
Q

Timolol* and betaxolol

  • Action:
  • Effect:
A

Beta-adrenergic receptor antagonists
-Beta-1 selective* (cardioselective = less risk in asthmatics)

Decrease aqueous humor secretion from ciliary epithelium

184
Q

Apraclonidine

  • Action:
  • Effect:
A

Alpha-2 adrenergic receptor agonist (pre-synaptic)

Decrease aqueous humor secretion from ciliary epithelium

185
Q

TQ: Latanaprost

  • Action:
  • Effect:

Question will say something about prostaglandins and nothing about cholinergic/adrenergic stuff …. therefore choose drug with suffix “-prost”

A
  • Action: Prostaglandin F receptor agonist

- Effect: Increase drainage via canal of Schlemm (outflow)

186
Q

Latanaprost AEs: (4)

A
  • Darkening of the iris**
  • Lengthening and thickening of eyelashes**
  • Intraocular inflammation
  • Macular edema
187
Q

Frontline agent for migraines:

A

Triptans
(5HT1B/1D receptor agonists)
-Must be used in Prodrome phase - when pt sees “aura”

188
Q

Preventive agents (given in asymptomatic phase)

  • Beta-blockers: (2)
  • Tricyclic antidepressants: (2)
  • Anticonvulsants: (2)
  • Ca++ channel blockers: (1)
A

Preventive agents

  • Beta-blockers: Propranolol and timolol
  • Tricyclic antidepressants: Amitriptylene and imipramine
  • Anticonvulsants: Topirimate and valproate
  • Ca++ channel blockers: Verapamil
189
Q

Sensory nerves assoc with migraine attack: (2)

A
  • Trigeminal nerves and ganglion

- Trigeminal Nucleus Caudalis

190
Q

Neurogenic inflammation mediated by: (2)

A
  • Neuropeptides (CGRP)

- Nitric oxide (NO)

191
Q

Type of receptor assoc with migraine attack:

A

Serotonin receptors - 5HT1B/1D
1B = Blood vessels
1D = Nerves

192
Q

MOA of Triptans
5HT-1B: (2)
5HT-1D: (2)

A

5HT-1B:

  • Lowers cAMP
  • Stimulates vasoconstriction (opposes vasodilation)

5HT-1D:

  • Lowers cAMP
  • Inhibits pre-synaptic release of CGRP
193
Q

The main problem with Sumatriptan has to do with:

A

Clearance

half-life is only 1-2 hours … needs to be longer

194
Q

Even if one Triptan drug doesn’t work, should you prescribe a different Triptan?

A

YES - individual pts value different aspects of pain relief

195
Q

Triptan contraindications and cautions: (3)

A

Contraindicated in pts with:

  • Coronary disease
  • CV disorder
  • Uncontrolled HTN
196
Q

Sumatriptan, rizatriptan and zolmitriptan are contraindicated in pts taking:

A

MAO inhibitors

197
Q

Ergot alkaloids (dihydroergotamine) are still used for:

A

Severe or refractory migraine

198
Q

T/F: NEVER use a triptan and DHE together.

A

TRUE

199
Q

Ergot alkaloids AEs: (2)

A
  • Strong emetic action

- Vasoconstriction (St. Anthony’s Fire) - worse than that seen with triptans

200
Q

T/F: DHE or other ergot alkaloids are contraindicated in pregnancy.

A

TRUE - DHE and other ergot alkaloids are teratogens

201
Q

Triptans can be taken with:

A

Analgesics

acetaminophen, ibuprofen, naproxen

202
Q

Sumatriptan + naproxen = ?

A

Treximet (clinically effective)

203
Q

First choice drug for migraine prevention due to good side effect profile:

A

Verapamil

Ca++ channel blocker

204
Q

Mechanisms proposed for Ca++ channel blockers for migraine prevention: (2)

A
  • Normalizes vessel tone

- Lessens Ca++-dependent vesicle fusion

205
Q

Main caution for using beta-adrenergic receptor blockers (propranolol, timolol) for migraine prevention:

A

Bronchoconstriction

Contraindicated in asthma pts

Neuro 1 Final (5 decks)

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