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Pharm Flashcards

1
Q

MPTP

A

1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine.

MPTP is metabolized to the free radical, MPP+, which produces oxidative stress resulting in cell death.

lead to the hypothesis that metabolism of dopamine could lead to the same effect via production of free radicals:

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2
Q

Pathway of Dopamine metabolism and leading oxidative stress

A

Dopamine > (MOA) > DOPAC + H2O2

H2O2

  1. Glutathione peroxidase > H2O
  2. Fenton reaction > OH (free radical)
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3
Q

Levodopa : Mechanism and Pharmacokinetics

A

The single most effective agent in treatment of PD
• Levodopa (3,4-dihydroxyphenylalanine) normally synthesized from L-tyrosine
• Largely inert, but decarboxylation converts to dopamine
• Unlike dopamine, levodopa penetrates the blood brain barrier
-Goal: Decrease in tremor, rigidity, bradykinesia

———-Pharmacokinetics——–
Rate and extent of absorption dependent upon
- Rate of gastric emptying
- pH of gastric juice
- Time of exposure to degradative enzymes of gastric and intestinal
mucosa
• Absorbed rapidly from small intestine by active transport system
- Competitive with aromatic amino acids
- High protein meal will delay absorption and reduce peak plasma
concentration

• Peak plasma concentration reached in 1-2 hours after oral dose
• Plasma half-life is 1-3 hours • Transported into the brain by active transport system
- Competitive with dietary protein - Transport is reduced with high protein diet

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4
Q

Describe the metabolism of Levodopa

A

L-amino acid decarboxylase converts Levodopa to Dopamine.

Then monoamine oxidase aldehyde dehydrogenase (MOA) converts dopamine to DOPAC

At any time levodopa, dopmaine and DOPAC can be metabolized by COMT (catechol-O-methyltransferase) to different metabolites.
____________________________________
Metabolized in peripheral tissues:
1. By L-aromatic amino acid decarboxylase (L-AAD, 60%)
to dopamine (does NOT enter the CNS)
2. By catechol-O-methyltransferase (COMT, 10%)
to 3-O-methyl-dopa (15 hr half-life) which competes with levodopa
for transport into the brain

  • If administered alone, only about 1-3% of dose enters the CNS * Peripheral conversion of levodopa to dopamine produces side effects
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5
Q

Carbidopa

A

an L-aromatic amino acid decarboxylase inhibitor
• Does not itself penetrate the blood-brain barrier
• Increases the fraction of levodopa that remains unmetabolized and
available to enter the CNS
• Plasma half-life of levodopa is longer
• Plasma concentration of levodopa is higher
• Allows reduced dosage of levodopa which reduces peripheral side
effects

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6
Q

Sinemet

A

levodopa + carbidopa

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7
Q

What are the side effects of Levodopa?

A

(GI)
If given without peripheral decarboxylase inhibitor
(carbidopa) then 80% of patients experience
– Anorexia
– Nausea
– Vomiting
• Stimulation of emetic center located in brain stem outside of blood-brain barrier
• Combination with carbidopa reduces GI effects to
occurrence in 20% of patients

(Cardio)
Arrhythmias
• Postural hypotension (activation of vascular dopamine
receptors) (at low concentrations)
• Administration with nonspecific MAO inhibitors markedly
accentuates levodopa actions and may precipitate a life-threatening hypertensive crisis
(too high will activate adrenergic receptors)

(CNS)
Abnormal involuntary movements (dyskinesias)
• Psychological disturbances:
confusion, hallucinations, anxiety
• conventional anti-psychotic agents (phenothiazines) are effective,
but worsen parkinsonism
• clozapine (“atypical” anti-psychotic) does not worsen parkinsonism
and can be used

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8
Q

Levodopa drug interactions and contraindications

A

Pyridoxine (vitamin B6 enhances extracerebral metabolism of levodopa) - activates L-amino acid decarboxylase

• MAO-A (or nonspecific MAO) inhibitors accentuate peripheral effects
(can cause hypertensive crisis)

Contraindications_________________
• Psychotic patients (because of CNS side effects)
• Angle-closure glaucoma (acute, nausea/vomiting) - some dopamine receptors are activated which increase IOP
• Active peptic ulcer must be managed carefully (GI bleeding)

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9
Q

What are long term effects of levodopa?

A

Response fluctuations____

» End-of-dose deterioration or wearing-off (predictable)
-In early PD, the duration of the beneficial effects of levodopa exceeds the plasma lifetime of the drug, because the nigrostriatal dopamine system retains some capacity to store and release dopamine (“buffering” effect).
• After the long-term use of levodopa therapy this “buffering“ capacity
is lost, and the patient’s motor state may fluctuate dramatically
with each dose of levodopa, also called “wearing off” phenomenon:
each dose of levodopa effectively improves mobility for 1-2 hours, but symptoms return rapidly at the end of the dosing interval.

» On-off phenomenon (unpredictable)
-patients fluctuate rapidly between having no apparent effects
of medication (“off”) and having effects of medication (“on”):
off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility, but often marked dyskinesia.

• For severe off-periods if not responding to other measures
apomorphine can be used.

• Increase in side effects
» Dyskinesias
» Psychiatric disturbances

• May require adjunctive therapy

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10
Q

Tolcapone (central and peripheral effects)

A

Adjunct to levodopa/carbidopa allowing reduction of levodopa dose
- Inhibition of COMT prolongs plasma half-life of levodopa and increases availability of levodopa to brain • Approved for patients with late PD who have developed response
fluctuations.

**only used if entacapone is not effective due to hepatotoxicity

More potent (100 mg,
3 times daily)
• t1/2 = 2-3 hrs
Hepatotoxicity: Can cause an increase in aminotransferase and transaminase activity - an indicator of liver damage. (stop drug if increase > 5x) => rarely associated with death;
use in US requires signed patient consent

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11
Q

Entacapone (peripheral effects)

A

Adjunct to levodopa/carbidopa allowing reduction of levodopa dose
- Inhibition of COMT prolongs plasma half-life of levodopa and
increases availability of levodopa to brain • Approved for patients with late PD who have developed response
fluctuations.

Less potent (200 mg, up to
5 times daily) •  t1/2 = 1-2 hrs
• No incidence of hepatotoxicity => therefore generally preferred!
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12
Q

Stalevo

A

Stalevo: levodopa/carbidopa/entacapone

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13
Q

Bromocriptine (ergot derivative)

A

Bromocriptine (ergot derivative)

well-absorbed orally
• plasma half-lives of 3-7 hours
• could be used as monotherapy in patients with mild disease
• could be used in combination with levodopa/carbidopa for advanced disease to smooth on/off response fluctuations

Adverse effects as ergot agents (vasoconstriction)

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14
Q

Ropinirole

A

Ropinirole

Metabolized by CYP1A2,
drugs metabolized by liver may
significantly reduce clearance

Effective as monotherapy in patients with mild disease
• Effective as means of smoothing response fluctuations in patients on
levodopa therapy with more advanced disease

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15
Q

Pramipexole

A

Excreted largely unchanged in urine

Effective as monotherapy in patients with mild disease
• Effective as means of smoothing response fluctuations in patients on
levodopa therapy with more advanced disease

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16
Q

Rotigotine

A

Non-ergot agonist

• Administered as a once-daily transdermal patch allowing continuous absorption leading to less serum fluctuation as compared to oral administration several times a day

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17
Q

apomorphine

A

Available as a subcutaneous injection to treat “off” episodes in
patients with advanced PD - is rapidly taken up in the brain leading
to clinical benefit that begins within 10 min of injection

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18
Q

selegiline

A

Selegiline: MAO-B metabolizes dopamine selectively.

Irreversible MAO-B inhibitor => B selective at 10 mg/day or less
(at higher doses also inhibits MAO-A).

• Retards breakdown of dopamine in striatum without inhibiting
peripheral metabolism of catecholamines.
• Has a modest beneficial effects when used alone; also used in combination with levodopa/carbidopa to decrease response fluctuations in late PD patients.

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19
Q

rasagiline

A

More selective MAO-B inhibitor than selegiline.

• Does not produce amphetamine metabolites.
• Studies indicate that rasagiline may prevent progression of the disease in early PD when used as a stand alone therapy.
• Also used in combination with levodopa/carbidopa to decrease
response fluctuations in late PD patients.

Recent studies suggest that rasagiline might have a neuroprotective effect, but they are not very conclusive.

(blocks MAO B production of DOPAC and H2O2 > OH free radical)

decrease the synthesis of toxic metabolites • neuroprotection by reducing oxidation of dopamine

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20
Q

Trihexyphenidyl

A

Anticholinergics

May improve tremor and rigidity,

Little effect on bradykinesia

If fail to respond to one drug try others

In PD dopamine is progressively lost and the effect of acetylcholine is relatively increased.

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21
Q

Benztropine mesylate

A

Anticholinergics

May improve tremor and rigidity,

Little effect on bradykinesia

If fail to respond to one drug try others

In PD dopamine is progressively lost and the effect of acetylcholine is relatively increased.

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22
Q

Biperiden

A

Anticholinergics

May improve tremor and rigidity,

Little effect on bradykinesia

If fail to respond to one drug try others

In PD dopamine is progressively lost and the effect of acetylcholine is relatively increased.

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23
Q

Orphenadrine

A

Anticholinergics

May improve tremor and rigidity,

Little effect on bradykinesia

If fail to respond to one drug try others

In PD dopamine is progressively lost and the effect of acetylcholine is relatively increased.

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24
Q

Procyclidine

A

Anticholinergics

May improve tremor and rigidity,

Little effect on bradykinesia

If fail to respond to one drug try others

In PD dopamine is progressively lost and the effect of acetylcholine is relatively increased.

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25
Q

Amantadine

A

Antiviral agent:

Mechanism is unclear
-all proposed enhance action of dopamine

Benefits short-lived, but may favorably influence bradykinesia, rigidity and tremor; it also has antidyskinetic properties
• Can be used as initial therapy of mild PD and as adjunct therapy in patients
on levodopa with dose-dependent fluctuations and dyskinesias.

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26
Q

What is the suggested regimen for treating Parkinson’s disease?

A
  1. In the beginning if only mild symptoms (tremor mostly), use anticholinergics
  2. Then maybe use selegiline/rasagiline which are possibly - neuroprotective.
  3. If younger <65 use dopamine agonist, can add on carbidopa to help later
  4. If older than 65, use levodopa since life expectancy is too low to develop complications
  5. in the end you develop motor and psychiatric complications.
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27
Q

3-O-methyl-dopa

A

The peripheral metabolite of Levodopa by COMT - catechol-O-methyltransferase.

This product will compete with dopamine transport to the brain.

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28
Q

tri bisexual ben, oral pro

A

Trihexyphenidyl

Biperiden

Benztropine

Orphenadrine

Procyclidine

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29
Q

Phenytoin:
1st line for generalized tonic-clonic
1st line prophylactic for status epileptic

A

Primary Mechanism of Action: Na+ Channel inhibition
 Indications: 1) Simple Partial 2) Complex Partial 3) Secondarily Generalized and 4) Primary Generalized tonic-clonic seizures
 Contraindications: May exacerbate myoclonic seizures and
absences, esp in Lennox-Gastaut syndrome

Therapeutic dose for most patients is 10-20µg/mL
2. ~90% bound to plasma protein 
• Only free, unbound phenytoin molecules can penetrate the blood-
brain barrier and exert pharmacological effects
• Conditions such as hypoalbuminemia and uremia can significantly impact plasma levels since it is heavily bound to plasma protein
-other protein binding ASDs, like valproate can compete also

  1. Hepatic elimination by conversion to inactive metabolites - as saturation of hepatic enzymes occurs, enters zero-order kinetics (exponential)

**phenytoin induces hepatic enzymes which impact metabolism of a number of drugs (like contraceptives)

Small increments in phenytoin dosage can have large impact on plasma levels and could result in toxic plasma doses i.e. toxicity may occur with only small increments in dosage.
• The phenytoin dosage should be increased each time by only 25–30
mg in adults, and ample time should be allowed for the new steady state to be achieved before further increasing the dosage.

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30
Q

Adverse effects of phenytoin

A
  • nystagmus
  • diplopia
  • ataxia
  • drowsiness
  • hirsutism & coarsening of facial features
  • gingival hyperplasia
  • decreased serum folic acid (B9), thyroxine, vitK
  • osteomalacia - vitD deficiency
  • megaloblastic anemia
  • rash (Stevens Johnson Syndrome)
  • teratogen
31
Q

Fosphenytoin

A 
Fosphenytoin is a prodrug of phenytoin designed for
parenteral use (first choice for status epilepticus)
32
Q

Carbamzepine

1st line for focal seizures (complex and simple)

also used for generalized tonic clonic

A

May exacerbate absence or myoclonic (rapid brief jerks) seizures.
• Blood disorders
• Liver disorders

Primary Mechanism of Action: Na+ Channel inhibition
• Slows the rate of recovery of voltage-activated Na+ channels from inactivation.

75% protein-bound
The t½ of the drug falls significantly over the first few weeks of
therapy due to the induction of hepatic enzymes (CYP) that
metabolize itself (autoinduction).

CYP-inducing drugs such as phenytoin may increase the metabolism of carbamazepine  Important consideration for combination therapy. • Similarly, co-administration of carbamazepine with other
drugs that are CYP substrates (such as hormonal
contraceptives, theophylline, warfarin and phenytoin) can
lower their concentrations.

33
Q

Carbamazepine adverse effects

A

-Drowsiness
-blurred vision
-diplopia,
-headache, dizziness, ataxia, nausea and vomiting.
 Cognitive effects can interfere with
learning.
 Hyponatremia is common.
 Leukopenia can be as high as 10% but
can be transient
 Aplastic anemia and agranulocytosis
 Teratogen: Pregnancy Category D

Rash, particularly with high starting doses or rapid dose escalation.

Carbamazepine-induced Stevens-
Johnson syndrome (SJS) incidence is
highest in Asian populations.

34
Q

valproate

broad spectrum:
used for partial and tonic-clonic, absence seizures

A

1) Na+ channel inhibition
Other Mechanisms of Action:
2) Inhibition of T-type Ca2+ channels.
3) Increases GABA production (stimulate GABA synthetic enzyme, glutamic acid decarboxylase), and decreases GABA metabolism (inhibit GABA degradative enzymes, GABA transaminase and succinic semialdehyde dehydrogenase)
Indications:
• 1) Simple Partial 2) Complex Partial 3) Secondarily Generalized and 4)
Primary Generalized tonic-clonic seizures 5) Absence 6) myoclonic, and 7) atonic seizures (“dropattack, sudden loss in muscle tone).
• Highly effective for photosensitive epilepsy and juvenile myoclonic
epilepsy.
**contraindicated in liver disease.

 Highly protein-bound, but the binding is saturable
 Elimination through hepatic metabolism at least one metabolite implicated for the
hepatotoxicity associated with valproate
 Crosses the placenta and concentrations in cord serum blood may be 5-X higher than the mother
**inhibits CYP enzymes, unlike phenytoin and carbamazepine

35
Q

Valproate adverse effects

A
  1. Transient GI symptoms, including anorexia, nausea, and vomiting
  2. Dose-related tremor, sedation, ataxia
  3. Temporary alopecia
  4. Significant weight gain with chronic valproate treatment for some patients 5. Decreased platelet function and thrombocytopenia
  5. *Hepatotoxicity-A rare complication is a fulminant hepatitis that is
    frequently fatal.
    Children below 2 years of age with other medical conditions were especially likely to suffer fatal hepatic injury.
  6. *Acute pancreatitis and hyperammonemia
  7. *Teratogenic effects such as neural tube defects (upto 20-fold higher risk than the general population),
    particularly spina bifida
    While the FDA still classifies valproate in Pregnancy Category D for epilepsy treatment, valproate was moved to Pregnancy Category X for migraine treatment in 2013.
  8. *SIADH
36
Q

Lamotrigine

not first line for anything but used to treat partial, tonic clonic, absence, status epileptics

-apparantly first line treatment for focal seizures

A

Multiple mechanisms of action:
1) Na+ channel inhibition by prolonging the
inactive state of the channel Other Mechanisms of Action
2) Inhibit synaptic release of glutamate 3) Inhibition of voltage-gated Ca2+ channels reported

While lamotrigine has not been shown to affect the efficacy of oral
contraceptives (OCs), it has been reported that OCs can reduce effective
concentrations of lamotrigine, and so women taking OCs may require
higher lamotrigine doses
– Co-administration with valproate can double the plasma concentration
of lamotrigine, while co-administration with phenytoin or carbamezapine
can reduce plasma concentrations of lamotrigine  consideration for
polytherapy

37
Q

Lamotrigine adverse effects

A

Dizziness, ataxia, somnolence, headache, diplopia, nausea,
insomnia
2. Rash (10%) – especially in children
• Rare progression to serious systemic illness (Stevens Johnson Syndrome* (only side effect listed in FA)

38
Q

Ethosuximide

A

Indications:
• Specifically used for absence seizures
2. Mechanism of Action
• Inhibits T-type Ca2+ currents.

39
Q

Ethosuximide adverse effects

A

Adverse Effects
• Most common is *gastric distress, including pain, nausea, and
vomiting.
*• Transient lethargy or fatigue
*• Urticaria and other skin reactions, including Stevens-Johnson
syndrome
• Leukopenia, thrombocytopenia, pancytopenia, and aplastic
anemia

40
Q

Phenobarbital

FA: used for partial and tonic clonic

A

Indications
 Virtually every seizure type, especially when attacks are difficult to control
 Status epilepticus
 Relatively low toxicity and low cost.

Binds GABAa receptor prolongs opening.

Good oral absorption
 Metabolized by hepatic microsomal enzymes (CYP).
 Phenobarbital also induces* hepatic enzymes, both CYP and
Drugs metabolized by hepatic enzymes (e.g. oral contraceptives ) can be more rapidly degraded when co-administered with phenobarbital.

41
Q

Phenobarbital adverse effects

A

Sedation and dizziness
 Cognitive impairment, decreased coordination, mental confusion, behavioral alterations
 Phenobarbital can produce irritability and hyperactivity in children, and agitation and confusion in the elderly.
 Rash, possibly with other manifestations of drug allergy,
occurs in 1-2% of patients.
 Megaloblastic anemia that responds to folate, and osteomalacia that responds to high doses of vitamin D,
occur during chronic phenobarbital therapy of epilepsy.
 CNS depression,
risk of *cardiorespiratory depression

42
Q

Clonazepam and Clobazam

A 
Lennox-Gastaut Syndrome, 
• Myoclonic 
• Atonic 
• Absence seizures resistant to
other ASDs (less effective
than valproate and
ethosuximide).

Tolerance develops after about 6 months

43
Q

Diazepam

Lorazepam

A

First line for treatment of
status epileticus.

• Intermittent use for control of
seizure clusters (diazepam)
44
Q

Adverse effects of benzodiazepines

A

Adverse Effects:
• *Sedation and Dependence
• Hypotonia, Dysarthria, Muscle incoordination
• CNS depression •
Behavioral disturbances (especially in children)
• Aggression, Hyperactivity, Irritability and difficulty concentrating
*tolerance and sedation are limiting effects.

45
Q

Tiagabine

A

inhibits GABA reuptake, used for partial seizures as adjunct
-renal clearance

Mechanism of Action: Inhibition of GABA transporter (GAT-1) – reduces reuptake of GABA by neurons and glial cells. Indications:
• Adjunct therapy for partial seizures.
Adverse effects: • GI and CNS distress

46
Q

Vigabatrin

A 
Mechanism of Action: Inhibit the breakdown of GABA by irreversibly inhibiting enzyme GABA transaminase (GABA-T) Indications: 
• Monotherapy for infantile spasms 
• Adjunct therapy for complex partial
seizures refractory to other ASDs.
-renal clearance 
Adverse effects: 
• Only available through a restricted
distribution program due to concerns
about retinal toxicity and permanent
**visual field loss 
• Weight gain
47
Q

Gabapentin and Pregabalin

A

Mechanism of Action:
• Originally designed to be GABA analogs.
• Selective inhibition of voltage-gated Ca2+ Indications:
• Adjunct therapy for PARTIAL secondarily generalized seizures
-*renal clearance
Adverse Effects:
• Weight Gain (5%) with edema
• Somnolence, dizziness, blurred
channels containing the α2δ1 subunit.
vision, ataxia, confusion

Garbapentin: Effective as monotherapy for focal seizures. 
• Can exacerbate myoclonic &amp;
absence seizures. 
• Behavioral problems in
children (6%)
Pregabalin: 
only effective as adjunct for focal seizures
Not effective for
absence, myoclonic, or
primary generalized
tonic-clonic seizures
48
Q

Levetiracetam

A

Mechanism of Action:
• Binds to Synaptic Vesicle Protein 2A (SVP2A) protein (and Indications:
• Adjunct therapy of partial seizures, Lennox-Gastaut syndrome
presumably inhibits neurotransmittor release?)
and primary generalized tonic-clonic seizures • Monotherapy for partial seizures
Contraindications:
• Renal dysfunction (majority cleared renally) Adverse Effects:
• Relatively mild
• Agitation/irritability/lethargy

49
Q

Lennox Gastaut syndrome

A

Lennox-Gastaut syndrome is a form of severe epilepsy that begins in childhood. It is characterized by multiple types of seizures and intellectual disability. People with Lennox-Gastaut syndrome begin having frequent seizures in early childhood, usually between ages 3 and 5

50
Q

Perampanel

A

Binds to AMPA receptor
• Non-competitive antagonist of glutamate Indications:
• Adjunct therapy for adults with partial seizures and generalized
tonic-clonic seizures
• July 2017: approved for monotherapy for partial seizures
Adverse Effects:
• The drug label has a black box warning that the drug cause may
cause “serious or life-threatening psychiatric and behavioral adverse reactions, including homicidal or suicidal thoughts.
• Dizziness, somnolence, vertigo, aggression, anger, loss of
coordination, blurred vision, irritability, and slurred speech.

51
Q

Which ASD’s interact with hormonal contraceptions?

A 
Carbamazepine
Phenytoin 
Primidone
Phenobarbital 
-high CYP inducers- decrease efficacy of oral contraceptives.

Lamotrigine - oral contraceptives will decrease efficacy of lamotrigine

CPPPL

52
Q

Which drugs have protein binding?

I C CP3 on TV

A
  • Carbamezapine
  • Clobazam/Clonazepam (benzodiazepines)
  • Perampanel
  • Phenobarbital
  • Phenytoin
  • Tiagabine
  • Valproate
53
Q

Treatment of cluster headaches

A

Abortive – 100%, oxygen, sumatriptan

 Preventive – verapamil
(not available in US), melatonin,

 Transitional - occipital nerve block, steroids

54
Q

What classes of drugs are used for prevention of headaches

A

Anti-depressants: tricyclics - amitriptyline
& SNRI

Anti-convulsants: valproate, divalproex,

-topiramate (the most extensively studied)

Beta-blockers - metaprolol, timolol, propanolol,

NSAIDS and Triptans
 Useful for the prevention of migraine headaches that occur in a predictable pattern, such as
menstrual migraine.  Medications should be taken at the time of vulnerability, commencing 1 to 2 days prior to the
expected onset of headache and continued during the period of vulnerability.

55
Q

Beta blockers

  • metoprolol
  • propranolol
  • timolol
A

- Although not first-line treatment for hypertension or anxiety, -blockers may be useful along with
other therapy in patients with comorbid hypertension or angina.
 Mechanism of Action:
 Unclear, but thought to raise migraine threshold by modulating adrenergic and serotonergic
transmission in cortical and subcortical pathways.
 Adverse effects can include drowsiness, fatigue, sleep disturbances, vivid dreams, memory
disturbance, depression, impotence, bradycardia, and hypotension.  Should be used with caution in patients with congestive heart failure, peripheral vascular
disease, asthma, depression, and diabetes.

56
Q

Antidepressants

Tricyclics, amitriptyline, SNRI: venlafaxine

A

May be particularly useful in patients with comorbid depression or insomnia.  Mechanism of Action:
 Independent of antidepressant activity.
 Thought to be related to downregulation of central 5-HT2 receptors, increased levels of
synaptic norepinephrine, and enhanced endogenous opioid receptor actions.
____________________________
 Adverse Effects and Cautions:
________________________________________
 Anticholinergic side effects are common with amitriptyline, and limit the use of this agent in
patients with benign prostatic hyperplasia and glaucoma.  Increased appetite and weight gain can also occur.  Most common adverse effects with venlafaxine are nausea, vomiting, and drowsiness.

57
Q

Anticonvulsants

  • valproate
  • divalproex
  • topiramate
A

May be particularly useful in patients with comorbid seizure disorder or bipolar illness.
 To minimize adverse effects, anticonvulsants should be initiated at low doses and slowly titrated
upward.
 Topiramate is the most extensively studied medication for migraine prophylaxis.
 The benefits of topiramate are observed as early as two weeks after initiation of therapy, with
significant reductions in migraine frequency within the first month.
 Approximately 50% of patients treated with target doses of topiramate are responders.
_________________________________________
 Mechanism of Action:
 Beneficial effects are thought to be related to multiple mechanisms of action that include:
1. Enhancement of (GABA)-mediated inhibition. 2. Modulation of the excitatory neurotransmitter glutamate. 3. Inhibition of sodium and calcium ion channel activity.
 Adverse Effects and Contraindications:
 Nausea and vomiting are the most common side effects of valproate and divalproex, but
these effects are self-limited and are less common with titration of doses.  Other adverse effects associated with valproate and divalproex include alopecia, tremor,
asthenia, somnolence, and weight gain.  The most serious side effect of valproate therapy is hepatotoxicity, but the risk appears to be
low in migraineurs.
 Baseline liver functions tests should be obtained, but follow up studies are
unnecessary in asymptomatic adults on monotherapy.
 Valproate is contraindicated in pregnant women (potential for teratogenicity) and patients
with a history of pancreatitis or chronic liver disease.  Paresthesia is the most common adverse effect of topiramate, occurring in about half of
patients at target doses.  Other adverse effects of topiramate include fatigue, anorexia, diarrhea, weight loss,
hypesthesia, difficulty with memory, language problems, taste perversion, and nausea.  Topiramate should be used with caution or avoided in patients with a history of kidney
stones or cognitive impairment.

58
Q

Analgesics and NSAIDs

  Analgesics that have demonstrated the most consistent evidence of efficacy include:
-  Acetaminophen (Tylenol®) 
-  Acetaminophen/Aspirin/Caffeine (Excedrin Migraine®)
  Aspirin 
  Ibuprofen (Motrin®, Advil®) 
  Naproxen (Aleve®) 
  Diclofenac (Cataflam®)
  NSAIDS that have demonstrated
A

Simple analgesics and NSAIDS are effective medications for the management of many acute
migraine attacks.
 They offer a reasonable first-line choice for treatment of mild-to-moderate migraine attacks.
 Suppository preparations are an option when migraine-associated nausea and vomiting are severe.
the most consistent evidence of efficacy include:
_________________________________
 Mechanism of Action:
 Appear to prevent neurogenically-mediated inflammation in the trigeminovascular system by
inhibiting cyclooxygenase (COX)-mediated prostaglandin synthesis.
___________________________________
 Adverse Effects and Contraindications:
 GI effects that include dyspepsia, nausea, vomiting, and diarrhea.
 CNS effects that include dizziness and somnolence.
 Should be avoided or used cautiously in patients with previous ulcer disease, renal disease,
or hypersensitivity to aspirin.

59
Q 
Serotonin Receptor Agonists (Triptans)
  Available triptans include:
  Sumatriptan  
  Zolmitriptan  
  Almotriptan  
  Frovatriptan  
  Eletriptan (Replax®) 
  Naratriptan (Amerge®) 
  Rizatriptan (Maxalt®)
A

The triptans are migraine-specific medications, and their introduction represented a major advance
in migraine pharmacotherapy.

 They are appropriate first-line therapy for patients with mild-to-severe migraine, and are used for
rescue therapy when non-specific medications (e.g., analgesics and NSAIDS) are ineffective.
 Selection of a triptan is based on the characteristics of the headache, convenience of dosing, and
patient’s preference.
 At all marketed doses, the oral triptans are effective and well tolerated. 
Selective agonists at serotonin 5-HT1B and 5-HT1D receptors.
 Relief of migraine is the result of three key actions:
1) Normalization of dilated intracranial arteries through enhanced vasoconstriction.
2) Inhibition of vasoactive peptide release from perivascular trigeminal neurons.
3) Inhibition of transmission through second-order neurons ascending to the thalamus.

60
Q

Triptans

A

Adverse Effects and Contraindications:
 Adverse effects are common, but typically mild in nature and of short duration.
 These include paresthesias, dizziness, fatigue, flushing, and somnolence.
 Up to 25% of patients receiving triptans report tightness, pressure, heaviness, or pain in the
chest, neck, or throat.
 The triptans are partial agonists at 5-HT coronary artery receptors, and are therefore contraindicated in patients with a history of ischemic heart disease, uncontrolled
hypertension, and cerebrovascular disease.
 The triptans should not be given to patients receiving selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), as 5-HT syndrome may occur.

61
Q

Ergot Alkaloids, Derivatives

A

Ergotamine tartrate and dihydroergotamine can be considered for the treatment of moderate-to-
severe migraine attacks.
 Their use, however, is limited by issues of efficacy and side effects.
 Ergotamine is available in oral, sublingual, and rectal preparations, with dihydroergotamine being
available for intranasal and parenteral administration.

Mechanism of Action:
 Non-selective agonists at serotonin 5-HT1 receptors.  Cause constriction of intracranial blood vessels and inhibit the development of neurogenic
inflammation in the trigeminovascular system.  Central inhibition of the trigeminovascular pathway has also been reported.

Adverse Effects and Contraindications:
 Nausea and vomiting are among the most common adverse effects.  Pretreatment with an antiemetic should be considered.  Other common side effects include abdominal pain, weakness, fatigue, paresthesias,
muscle pain, diarrhea, and chest tightness.  Contraindicated in patients with renal or hepatic failure; coronary, cerebral, or peripheral
vascular disease; uncontrolled hypertension, and sepsis.  Also contraindicated in women who are pregnant or nursing.

62
Q

Prophylactic management model

A
  1. Patient meets criteria
    - headaches reoccur in predictable pattern (menstrual migraine) - NSAID or triptan
  • healthy or cormorbid hypertension or angina
  • beta adrenergic antagonist (verapmil)

-comorbid depression or insomnia, tricyclic antidepressant

  • comorbid seizure or bipolar
  • anticonvulsants, if ineffective use beta adrenergic antagonist.

then consider combination therapy

63
Q

What is the difference between conscious sedation and general anesthetic

A

Conscious Sedation: Minimal amounts of amnestic and opioid; patient still able to converse, respond to stimuli and commands; able to protect airway
and maintain ventilation

Continuum to general anesthesia
-decreases in responsiveness to painful stimuli and commands, decrease in ability to protect airway and maintain normal ventilation

  • *once patient has lost ability to protect the airway, it is considered general anesthesia
  • most operators desire such a hiogh degree of immobility and unresponsiveness for their patients and that request for sedation is actually general anesthesia
64
Q

What is the driving force for induction of inhaled anesthetics

sevoflurane, isoflurane, desflurane

A
  • increased partial pressure (alveolar fraction) of anesthetic (turn up the vaporizer)
  • increased alveolar ventilation, how fast you run the vent (more gas gets into blood)

**insoluble agents have faster onset

solubility N2O < Des < Sevo < Iso

so nitrous is the fastest onset and isoflurane is the slowest

No dans see iris

65
Q

What are the pharmacokinetics for induction of inhaled anesthetics

sevoflurane, isoflurane, desflurane

A

ONset in reverse, except F1 is zero

Alveolar ventilation is the most important factor in emergence

metabolism is a minor factor

Sevo > Iso > Des > N2O

66
Q

What is MAC?

A

Minimal Alveolar Concentration

  • measure of potency
  • partial pressure of inhalational anesthetic in the alveoli which 50% of a population of non-relaxed patients remain immobile at skin incision
67
Q

Effect of inhalational anesthetics on

A

Cardiovascular: decrease in BP

Respiratory: increased RR, decrease tidal volume so overall decrease in minute volume
-opiod depress respiratory rate but tidal volume increases, overall also decrease in minute volume.

Hepatic” decreases portal vein flow - halothane (discontinued)

Uterine smooth muscle: decrease in uterine tone (helpful for delivery but it can lead to increase in uterine bleeding and vomitting)

68
Q

Malignant hyperthermia

A

rare life threatening condition in which inhaled anesthetics or succinylcholine induce fever and SEVERE muscle contractions. Susceptibility is often inherited as autosomal dominant with variable penetrance. Mutations in voltage sensitive ryanodine receptor

Prolonged muscle contraction leads to hyperthermia, hypercapnia, hypoxia, hyperkalemia

FA: Mutations in voltage-sensitive ryanodine receptor
cause increase Ca2+ release from sarcoplasmic reticulum. Reuptake of the calcium leads to increased AMP expenditure leading to hyperthermia. Treatment: dantrolene (a ryanodine receptor antagonist).

69
Q

What treats Malignant hyperthermia?

A

Dantrolene (inhibits release of calcium from sarcoplasmic reticulum)

70
Q

Propofol

A

Milk of amnesia _anterograde,
-gaba agonist
-non-analgesic
CV: vasodilatory and negatively inotropic
-decrease in Vt, RR and minute ventilation
-antiemetic

FA: used for ICU sedation, rapid anesthesia induction, short procedures

rapid redistribution from highly perfused tissues into lean tissues for quick offset of action.

-liver metabolism is rapid as well

Good context sensitive 1/2 time: the elimination 1/2 time after a continuous infusion, this is the important factor in a drugs suitability for maintenance sedation

71
Q

Etomidate

A

IV GA

  • used for induction and short sedation, aka vomidate
  • minimal hemodynamic effects: HR, BP, GABA agonist
  • nonanalgesic
  • respiratory depressant
  • burns on injection

rapid redistribution from highly perfused tissues into lean tissues for quick offset of action.

-liver metabolism is rapid as well

Good context sensitive 1/2 time: the elimination 1/2 time after a continuous infusion, this is the important factor in a drugs suitability for maintenance sedation

72
Q

Ketamine

A

IV GA

*Dissociative anesthesia w/ nystagmus

NMDA receptor antagonist, **analgesic!

increases in HR, BP and CO - can’t give it to older patients

-no respiratory depression

rapid redistribution from highly perfused tissues into lean tissues for quick offset of action.

airway reflexes are preserved mostly
-hallucinations and unpleasant emergence so you coadminister benzos

  • lacrimation and secretions are increased
  • subanalgesic doses may help in limiting opiod tolerance
73
Q

Dexmedetomidine

A

used for sedation or adjunct to general anesthetic

alpha 2 agonist

both sedative and analgesic

receptors are in the locus coeruleus and spinal cord

preserves respiratory drive
-significant decreases in BP and HR can be seen

-context sensitive half time is signficantly increased after 8 hrs

74
Q

Indomethacin

A

indicated to treat

  • paroxysmal hemicrania : severe, unilateral, orbital, supraorbital, temporal, <30 min (otherwise cluster), 1-40 attacks, sharp throbbing
  • cough induced
  • ice pick - V1,

SUNCT - moderate to severe unilateral lasting <600 seconds and occuring as single or series of stabs, can be up to 200 times a day

NBB2 (20 decks)

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