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173 Cards in this Set

  • Front
  • Back
Autonomic Nervous System
Site for receptor - drug reactions.
Efferent Neurons
carry nerve impulse from the CNS to the effector organs
Ganglia
'relay stations' between a preganglionic neuron and a second nerve cell, the postganglionic neuron
Where do the messages terminate?
on effector organs, such as smooth muscles of the viscera, cardiac muscle and the exocrine glands
Afferent neurons:
important in the reflex regulation of the ANS.
What does the Afferent neurons sense?
pressure in the carotid sinus and the aortic arch. Then signals the CNS to influence the efferent branch of the system to respond
Parasympathetic neurons
fibers arise from the cranium and from the sacral region of the spinal cord. Synapse in ganglia near or on the effector organs
Enteric neurons:
nerve fibers that innervate the GI tract, pancreas, and gallbladder....constitutes the 'brain of the gut'
Enteric neurons function
independently of the CNS; controls the motility, exocrine and endocrine secretions and microcirculation of the GI tract
Enteric neurons are modulated by
the SNS and the PNS
SNS is responsible for
maintenance of vascular tone. Adjusts in response to stress. Trauma, fear, hypoglycemia, cold and exercise
Reflex arcs:
Most afferent impulses translated into
reflex responses w/o conscious involvement
Reflex arcs of the autonomic nervous system
comprised of a sensory (or afferent) arm
• and a motor (or efferent, or effector) arm. compensatory rise in blood pressure and tachycardia
vagal parasympathetic innervation
slows heart rate
Histamine and prostaglandins
examples of local mediators....do not enter blood
Hormones:
Secreted by specialized endocrine cells into the bloodstream
 Travel throughout the body exerting effects on broadly distributed
target cells in the body
Communication between nerve cells, and
between nerve cells and effector organs—occurs
through the release of specific chemical signals
Neurotransmitters
Neurotransmitters
rapidly diffuse across the synaptic cleft (synapse)
between neurons and combine with specific receptors
on the postsynaptic (target) cell
Acetylcholine and norepinephrine
primary
chemical signals in the ANS
Cholinergic drugs
act on receptors
that are activated
by acetylcholine.
Adrenergic drugs
act on receptors
that are stimulated
by norepinephrine or
epinephrine
Cholinergic and adrenergic drugs
both
act by either stimulating or blocking
receptors of the autonomic nervous system.
Sympathomimetic drugs
Drugs that mimic the actions of
epinephrine or norepinephrine
 Grouped by mode of action and receptors they
activate
Direct agonists
directly interact with and
activate adrenoceptors
 norepinephrine and epinephrine
Sympathomimetic drugs. Indirect agonists
actions are dependent on
the release of endogenous catecholamines
Sympathomimetic drugs Indirect agents
one of two mechanisms
 1. displacement of stored catecholamines from
the adrenergic nerve ending
 2. inhibition of reuptake of catecholamines
already released
Both typesmpathomimetic drugs of Sy, direct and indirect,
cause activation of adrenoceptors. Leading to some or all of the characteristic
effects of endogenous catecholam
Adrenoceptor agonists
 pharmacologic actions
important in the treatment of
asthma
Relax airway smooth muscle
 Inhibit release of
bronchoconstricting mediators
from mast cells
 Possibly inhibits microvascular
leakage and increase
mucociliary transport by
increasing ciliary activity
Stimulation of β2
receptors
→ relaxes airway smooth
muscle
 → Inhibits mediator release
 Causes tachycardia and
skeletal muscle tremor as ADE
Adrenoceptor agonists
optimally delivered by
inhalation
→ results in
greatest local effect on airway
smooth muscle w/ the least
systemic toxicity
Goal of Asthma therapy : contol; Reducing impairment
prevent chronic and troublesome symptoms
 infrequent use (≤ 2 days a week) of inhaled
SABA for symptoms
 maintain (near) “normal” pulmonary function
 maintain normal activity levels
 meet patients’ and families’ satisfaction with care
Reducing risk
prevent recurrent exacerbations of asthma
(ED/inpatient)
 prevent progressive loss of lung function
 provide optimal pharmacotherapy
What are teh best form of mediation for asthma?
inhaled corticosteroids
What is good for a pt not managed with single inhaled brochodilator
Anticholinergic + B2 agonist
(albuterol + ipratropium....greater bronchodilation than either drug alone)
What allows less frequent dosing
Salmeterol and tiotropium
Beta adrenergic agonis bronchodilators: short/rapid acting (SABA)
albuterol, levalbuterol, erols...and ipratropium
AE of Beta adrenergic agonist
tremor, cough, GI, h/a, nervousness, n/v, HTN palpitations, insomnia
Serious AE of Beta adrenergic agonist bronchodilators
paradoxical bronchospasm, hypokalemia, arrhythmias, angioedema, Inc LFT
Duration of action and elimnation of Beta adrenergic agonist?
2-4 hours; renal elimination
Beta adrenergic agonist bronchodilators long acting (LABA) drugs=
Salmeterol, formoterol
AE of LABA
tremor, nervousness, tachycaria, h/a, palpitaitons, nasal congestion, insomnia
Serious AE of LABA
bronchospasm, rash, angina, hypersensitivity rxn, angioedema, arrhythmia, hypokalemia, metabolic acidosis
Metabolism of LABA
liver
Elimination of LABA
renal and biliary
Inhaled adrenergic agonists (Beta 2)
drug of choice only for mild, intermittent symptoms. Also rescue therapy for all levels of persistent asthma
Direct acting beta 2 agonist
potent bronchodilator; relaxes airway smooth muscle
What are the adverse effects are associated with inhaled adrenergic Beta 2 adonists
tachy, hyperglycemia, hypo kalemia, hypomagnesemia
Ipratropium
cholinergic antagonist: antimuscarinic agent acts on post ganglionic recept. in ANS; blocking this receptor promotes bronchodilation (INHALE ONLLY)
What does ipratropium do?
block vagal mediated contraction of airway smooth muscle and mucous secretion....
Serious AE of ipratropim
Anaphylaxis, worsening of glaucoma, bronchospasm, worsening of COPD, tachy, urticaria, CP
When caution with Atrovent
myasthenia Gravis, glaucoma, BPH, and bladder neck obstruction
Tiotropium (spiriva)
Anticholinergic: long acting antimuscarinic bronchodilator
corticosterioids
Modify immune response via suppression of cytokine
production, airway eosinophils, and release of
inflammatory mediators
inhaled corticosteroids:
therapeutic effect with minimal AE, compared to systemic steroids....reduction of symptoms, improve lung function
What do corticosteroids do?
Reduce airway
hyperresponsiveness
(AHR)
 Control inflammation
 Reduce frequency and
severity of exacerbations
 Reduce asthma mortality
drug of
choice in patients with any degree of
persistent asthma
Inhaled corticosteroids (ICS)....no other meds are as effective
Since ICS have no direct effect on airways smooth muschele how do they work?
target underlying airway inflammation....ICS reduce the
hyperresponsiveness of the airway smooth
muscle to some stimuli (allergens, irritants, c
Why a spacer?
doesnt deposit med in mouth....Spacers improve delivery of inhaled glucocorticoids and
are advised for virtually all patients
Theophylline
used when maximal
medical therapy has sub‐optimal results
 Chemically related to caffeine
 Phosphodiesterae (PDE) inhibitor
Pharmacokinetics of Theophylline
Liver metabolism
 CP450 ‐ Multiple drug interactions
 Renal elimination
 Therapeutic level @ 5‐15 mcg/ml
 ***Toxicity @ > 20 mcg/ml
 can cause seizures, fatal arrhythmia, SIADH,
hypotension, hematemesis
Leukotriene Angtagoinsts
Antagonize the action of various leukotriene
receptors on airway smooth muscle and
vascular endothelium
 Effective in:
 Moderate persistent asthma
 Exercise induced bronchoconstriction (EIB)....not a rescue med
Omalizumab (Xolair)
Recombinant DNA–derived monoclonal antibody
selectively binds to human IgE
 decreased binding of IgE to IgE receptors on
the surface of mast cells and basophils
 Reduction of IgE limits release of allergic mediators
 Used for tx moderate to severe allergic asthma in
patients poorly controlled w/ conventional therapy
Inhaled corticosteroids improve
asthma control more
effectively in children and adults than any other single
long‐term controller medication.
key asthma concepts
All patients w/ asthma should be educated recognize
symptoms r/t inadequate asthma control.
 Validated questionnaires useful in following Pt. control
 All patients need a prescription for a short‐acting beta
Cromolyn and nedocromil
Effective prophylactic anti‐inflammatory agents...not for acute asthma exacerbation
Cromolyn info
Inhalation
 Only 8% reaches the lung, but this portion
well absorbed
 Time to peak 15 minutes
 Excreted equally by urine and feces
 Oral
 1% absorbed
 Nasal (allergic rhinitis)
 Response to treatment @ at 1‐2 wks
 Maximum therapeutic effect in 2‐4 wks
Pharmacokinetics if Steriods
Prednisone metabolized
in liver to prednislone
 Well absorbed GI
 High plasma protein
binding
 Liver metabolism
 Renal excretion
antiinflammatory action of glucocorticoids
Dramatically reduces the inflammatory response
and suppresses immunity.
 Exact mechanism complex and incompletely understood
 Blocks release of arachidonic acid
 precursor of prostaglandins and leukotrienes
 interference in mast cell degranulation
 results in decreased histamine and capillary permeability
First line Rx of allergic rhinitis
Combinations of oral antihistamines
w/decongestants
 Adverse effects: sedation, insomnia, (rare cardiac
fexofenadine hydrochloride: allegra
Seasonal allergic rhinitis in patients > 2 yrs
 Tx of chronic idiopathic urticaria in > 6 months
FDA recommends combination of
caffeine and pseudoephedrine is NOT safe
gold‐standard Rx for cough suppression
Codeine. Decreases sensitivity of CNS cough centers
 action in the medulla
 Decreases mucosal secretion
 Therapeutic effect @ doses lower than analgesia doses
non narcotic antitussive: dextromethorphan
Synthetic derivative of morphine
 Suppresses central cough center responseequally
effective to codeine for cough suppression
 No analgesic effects, low addictive profile*
 potential drug of abuse‐ lg. doses causes
euphoria, hallucination, seizure and death *
 Significantly better side effect profile than codeine
 Can cause histamine release‐ caution in atopic
children
Expectorants; Guaifenesin: only ingredient
recognized as effective
FDA
 Decreases adhesiveness &
surface tension of mucous ‐
thinning secretions for
improved clearance w/ cough.
Also promotes ciliary action
Drug of choice for asthma
bronchodilators
corner stone of treatment for asthma is
inhaled corticosteroids
Blackbox warning for LABA
increased mortality in asthma patients with LABA
what is the only thing that reduces mortality in COPD
oxygen
COPD – combination therapy
Anticholinergic + Beta2 agonist
-Albuterol + ipratropium=greater bronchodilation than either drug alone
what drug has inc toxicity with asthma
with methylxa (thyllophilline)
Salmeterol – Adverse effect –
paradoxical bronchospasm and immediate hypersensitivies ….can inc risk of death
Shortacting inhaled adrenergic agonist
drug of choice for mild sx….as monotherapy
Long term steroids problems
immunosuppression masked s/s of infection!!Acne, straie,sodium and water retention
Autocoids
target for some drug actionsas either agonists or antagonists
leukotriene Receptor Antagonists…..are for
Exercise induced bronchoconstriction (EIB)
-not a rescue medication
Pharmacokinetics –
Elevated LFT possible
Common AE of leukotriene Receptor antagonists
URI symptoms; neuropsychiatric warning!
Cromolyn
reduces sx of allergic rhinitis
Etiology of parkinsons
destruction of dopaminergic neurons in substantia nigra. reduction of dopamine action in brain basal ganglia....affects motor control
Excitatory pathways
Stimulation of excitatory neurons causes a
movement of ions that results in a
depolarization of the postsynaptic
membrane.
Inhibitory pathways
Stimulation of inhibitory neurons causes
movement of ions that results in a
hyperpolarization of the postsynaptic
membrane
Pharmacological therapy of parkinsons
to restore dopamine in the basal ganglia and antagonizing
the excitatory effect of cholinergic neurons,
→ reinstates dopamine/acetylcholine balance
 Drugs provide temporary relief from symptoms
 Does not arrest or reverse the neuronal
degeneration caused by the disease.
Levadopa and carbidopa (Sinemet)
Enhances synthesis of dopamine in the surviving neurons of the
substantia nigra
 conversion of levodopa to dopamine
Mechanisms of Action
• Levadopa:
Attempts to replace dopamine that is deficient
 Levadopa can cross BBB and convert to dopamine in
the brain
• Large doses required d/t decaroxylated in periphery
• (results AEs of n/v, hypotension and arrhythmia
• Carbidopa
Enhances effect of levadopa via diminishing
metabolism of levadopa in GI tract and peripheral
tissues…
→ Increasing availability of levadopa to cross into the CNS
Levodopa /carbidopa combination
• → Potent & effective in treating Parkinson's Dx
Action: Levodopa decreases rigidity, tremors,
and other parkinsonism symptoms
levodopa–carbidopa Rx - significantly reduces
severity of dx symptoms in first few yrs of Tx in
about 2/3 of patients w/ Parkinson’s Dx
Typical decline in response in 3rd to 5th year
of Tx
When should levadopa be taken?
on empty stomach
on-ff phenomenon
causes sudden loss of normal
mobility, tremors, cramps, immobility
adverse effects of levadopa
Peripheral effects:
• Anorexia, N/V
• d/t stimulation of chemoreceptor trigger
zone of the medulla,
•Tachycardia, PVCs
• d/t dopaminergic action on the heart
•Hypotension, mydriasis
• d/t adrenergic action on the iris
• Blood dyscrasias
• Brown tint to saliva and urine
•d/t pigment produced from catecholamine
oxidation
•CNS effects:
•Visual and auditory hallucinations, abnormal
involuntary movements (dyskinesias),
• effects opposite of parkinsonian symptoms
•Mood changes, depression, psychosis, and
anxiety.
Monamine oxidase B (MAO-B) inhibitors
selegiline (Eldepryl) & rasagiline (Azilect)
MOA not fully understood,
• Do not combine w/ fluoxetine or merperidine
(additive effect)
Glutamate antagonist (antiviral):
 amantadine (Symmetrel) accidently discovered
to have antiparkinsonism activity
 Less effective than levadopa, but less side
effects
 Caution in seizure disorders and CHF,edema
Dopamine Receptor Agonists
 ropinirole hydrocholoride (Requip)
 pramipexole (Mirapex)
 Other drugs:
• Apomorphine - injectable
• Rotigotine - transdermal newer agent
• Bromocriptine (not used often d/t ADE)
• Cautions/Warnings
 Pramipexole- monitor renal function, caution w/
w/ other drugs w/ renal implications
 Robinirole- caution w/ other CYP450 drugs
• * other uses for these drugs
Anticholinergic Agents
Benztropine: (Cogentin)
• Caution: in elderly, BPH, urinary retention, liver, renal or
GI or GU disease
• Can precipitate narrow-angle glaucoma
 Trihexyphenidyl HCL (Artane)
• Adjunctive tx w/ levadopa
• Assists in controlling drug induced extrapyramidal effects
Catechol-O-methytransferase (COMT) inhibitors
Entacapone (Comtan) increases uptake of levadopa –
greater concentration of dopamine in the brain
 Warning: MAO and COMT both major enzymes that
metabolize catecholamines- DO NOT use concomitantly
First line therapy
levodopa, dopamine agonists
 Carbidopa/levodopa most effective
Pramipexole and ropinirole
effective in early and
late Parkinson’s
Amantadine
patients w/ mild symptoms
Apomorphine injection
used for acute tx of
immobility
Anticholinergics
reduce tremor, rigidity and
drooling (limited use d/t ADE)
COMT inhibitors
reduces motor fluctuations in
advanced dx- but, increase dyskinesias (use after
other adjunctive tx failed)
MAOI
selegline, rasagiline
Cholinesterase Inhibitors
Management of mild to moderate Alzheimer’s-type
dementia
 Often initiated by PCPs or after consultation
What do cholinesterase inhibitors do?
Block enzyme that degrades acetylcholine in the
brain resulting in more acetylcholine at the synaptic
cleft and enhances cholinergic transmission
 Diminishes signs and symptoms of dementia and
improves function and slows progression
NMDA Receptor Antagonists
Moderate to severe dementia of Alzheimer’s type
 May be given in addition to cholinesterase
inhibitors
 May be initiated by PCP or after consultation
Acetylcholinesterase inhibitors
based on concept that
inhibition of acetylcholinesterase w/i the CNS improves
cholinergic transmission (at least at the still functioning
neurons)
Donepezil or galantamine ER usualy
first line, daily
dosing increases adherence
• All metabolized via CYP450 system- potential drug
interactions
Overstimulation of glutamate receptors
shown to
result in excitotoxic effects on neurons &
suggested as a mechanism for neurodegenerative
or apoptotic processes
NMDA-glutamate receptor antagonists are often
neuroprotective, preventing the loss of neurons
following ischemic and other injuries
What is the first line treatment for Alzheimer?
Donepezil
Evidence suggests cholinesterase inhibitors
stabilize
cognitive and functional ability for approx. 1 year
Patients with moderate to severe dementia may be
started on
memantine,
• may be given concurrently w/ donepezil
 ID and treat concurrent depression and/or delirium
 Avoid medications w/ sedating or anticholinergic effects
precautions with donepezil (Aricept)
May exaggerate succinylcholine-type muscle relaxation in
anesthesia
 Vagotonic effects on HR may be provoked; use with caution
in patients with conduction abnormalities
 May increase gastric acid secretion
 May cause bladder outflow obstruction
 Use with caution in patients with asthma
memantine (Namenda)
• Drug Interactions
 acetazolamide, cimetidine, dichlorphenamide
 Hydrochlorothiazide, methazolamide, Nicotine,
ranitidine, sodium bicarbonate
• Precautions
 Seizures, severe renal impairment, GU conditions,
concomitant use of other NMDA antagonists
All Medications increase the threshold of the CNS
to convulsive stimuli or inhibit the spread of
seizure activity
 blockade of voltage-gated channels (Na+ or Ca2+)
 enhancement of inhibitory impulses, or interference
with excitatory glutamate transmission
 some drugs appear to have multiple targets w/i
CNS
 MOA for some agents poorly defined
 Antiepilepsy drugs suppress seizures, do not
“cure” or “prevent” epilepsy
Hydantoin:
phenytoin
succinimide
ethosuximide
GABA analogs
• valproic acid, divalproex
sodium,(Depakene, Depakote),
gabapentin (Neurontin), lamotrigine
(Lamictal), topiramate, (others)
Mechanisms of Action
• GABA Analogs
• All drugs increase the actions of GABA
• May inhibit voltage-dependent sodium channel,
thereby stabilizing neuronal membranes
Hydantoins (phenytoin) mechanisms of action
 Primary site of action: Primary motor cortex
 Prolongs effective refractory period by blocking
neuronal sodium channels
 Stabilizes threshold against hyperexcitability
 Exhibits antiarrhythmic properties
Mechanisms of Action
• Benzodiazepines: diazepam, clonazepam
 Mechanism similar to barbiturates
 Increase the number of chloride channels,
suppressing spread of seizure activity
mechanism of action Carbamazepine: Carbamazepine (Tegretol),
oxcarbazepine,
Limits seizure propagation- blocks postsynaptic
transmission
mechanism of action Barbiturate
phenobarbital, primidone (Mysoline)
 Inhibits depolarization of neurons by binding to the
GABA receptor
 Increases threshold for electrical stimulation of the
motor cortex
Choice of Anticonvulsant Therapy -
- Based on Multiple Factors
Classification of seizures being treated
• Patient specific variables
 (age, comorbid conditions, lifestyle, other preferences)
• Characteristics of the drug: cost, drug interactions
w/ other pharmacological therapy
 partial onset tonic-clonic seizures treated
differently than primary generalized seizures
 Several drugs may be equally effective,
making toxicities and characteristics of the
patient major considerations in drug
selection
Anticonvulsant Therapy
Newly diagnosed patients: monotherapy
instituted w/ single agent until seizures are
controlled or toxicity develops
• Patients receiving monotherapy usually w/
better adherence and fewer ADEs
 Compared to those receiving combination
therapy
• Consider vagal nerve stimulation
Discontinuation may be considered in patients who have been
seizure-free for
> 2 years
rules of treatment
Choose agent appropriate to type of seizure
 Choose least toxic option
 Initiate monotherapy
 Titrate dose upward until control is achieved or ADE occur
 Choose alternative monotherapy if necessary
 Phenobarbital is effective for prevention of febrile seizures in
children
• Long-term prophylactic treatment of febrile seizures is not
recommended by the AAP
What to monitor for sz meds
Hepatic enzymes prior to initiation, annually, and/or more
frequently in hepatic dysfunction
 Common for mildly elevated LFTs in patients on anticonvulsants
 Children <10 yrs of age on valproic acid -monitor for hepatotoxicity
• Thyroid function tests
• Baseline and periodic CBC
• Geriatrics
 No specific guidelines for use in the elderly population
 Careful monitoring of renal and hepatic function
• Pediatrics
 Febrile seizure treatment common
 Phenytoin and carbamazepine - not effective for febrile seizures
 Pediatric neurology consult prior to initiation of medication
 Dosages based on patient weight and age
Benzodiazepines bind
to GABA inhibitory
receptors to reduce firing rate.
Carbamazepine reduces
transmission of
abnormal impulses in the brain by blocking
sodium channels
 effective for treatment of partial seizures and
secondarily generalized tonic-clonic seizures
 also used to treat trigeminal neuralgia and bipolar
Divalproex sodium (Depakote)
Combination of sodium valproate and valproic acid - reduced to
valproate when it reaches the GI tract
 (developed to improve GI tolerance of valproic acid)
• All available salt forms equivalent in efficacy
 (valproic acid and valproate sodium)
• Commercial products available in multiple-salt, dosage forms
and extended-release formulations
 High risk for medication error, essential to be familiar w/ all
preparations
• Multiple proposed MOA: sodium channel blockade, blockade of
GABA transaminase, and action at some calcium channels
 Multiple mechanisms provide broad spectrum of activity
against seizures
• Teratogenic- do not use in pregnancy
• Monitor LFTs
Gabapentin
• Analog of GABA, however
does not act at
GABA receptors nor enhance GABA actions,
nor is it converted to GABA
 Precise mechanism of action not known
• Approved as adjunct therapy for partial seizures
and treatment of postherpetic neuralgia
• Excreted unchanged through the kidneys-
 reduced dosing is required in renal disease
• Gabapentin well tolerated in the elderly
population w/ partial seizures
 relatively mild adverse effects
 Limited pharmacokinetic drug interaction
Lamotrigine
Blocks Na channels as well as some Ca channels
• Well tolerated in elderly population w/ partial
seizures due to the relatively minor adverse effects
when titrated slowly
• Effective in a wide variety of seizure disorders
 including partial seizures, generalized seizures,
typical absence seizures
 approved for use in bipolar disorder
Phenobarbital
Primary MOA: enhancement of inhibitory
effects of GABA-mediated neurons
• Primary use for phenobarbital in epilepsy is in
treatment of status epilepticus
• Interaction w/ CYP450,
• adverse effects of sedation, cognitive
impairment, and potential for osteoporosis
• Should only be considered for chronic therapy if
refractory to other drugs, and the benefits
outweigh the multiple risks
Phenytoin and fosphenytoin
Mechanism of Action
 Blocks sodium channels - Can block some calcium
channels and interfere w/ release of
monoaminergic neurotransmitters
• Indications:
 Effective for tx partial seizures, generalized
tonic-clonic seizures, and status epilepticus
• Zero- order pharmacokinetics
• Small increase in daily dose - can produce large increase in
plasma concentration, resulting in toxicity
Phenytoin and fosphenytoin (cont)
• Drug Side Effects
 Depression of CNS (particularly cerebellum & vestibular system)
• Can cause nystagmus and ataxia
• Elderly highly susceptible to this particular AE
 Gingival hyperplasia (can cause gums to grow over the teeth)
 Long-term use: peripheral neuropathies & osteoporosis
• Fosphenytoin is a prodrug
 rapidly converted to phenytoin in the blood - high levels of
phenytoin w/i minutes
 May be administered IM
• Phenytoin should never be given IM
– can cause tissue damage and necrosis
• Fosphenytoin: drug of choice and standard of care (IV and IM)
Topiramate
Several actions contribute to broad spectrum of antiseizure
activity:
 Topiramate blocks voltage-dependent sodium channels, shown
to increase chloride channel opening by binding to the GABA
receptor
 a carbonic anhydrase inhibitor, may act at glutamate (NMDA)
sites
• Topiramate effective and approved for use in partial and
primary generalized epilepsy
 also approved for treatment of migraine.
• Renal elimination- has inactive metabolites
• inhibits CYP2C19 - induced by phenytoin, and carbamazepine
Specific migraine therapy
triptans and
dihydroergotamine
 leads either to vasoconstriction or to inhibition of
the release of proinflammatory neuropeptides
ptans: Class of drugs includes sumatriptan,
• naratriptan, rizatriptan, eletriptan, almotriptan, etc…
All serotonin receptor agonists w/ similar
chemical structure and a comparable mechanism
of action
 results in cranial vessel constriction, inhibition of
neuropeptide release, and reduced transmission
in trigeminal pain pathways
• rapidly and effectively aborts / markedly
reduces the severity of migraine headaches in
about 70% of pts
Ergotamine Derivative: Ergotamine tartrate
 Partial agonist and/or antagonist activity against
tryptaminergic, dopaminergic, or α-adrenergic
receptors, depending on binding site
• α-Adrenergic–blocking agent with direct stimulating
effect on smooth muscle of the peripheral and cranial
vessels
 Constrict peripheral and cranial blood vessels
and depress central vasomotor centers,
reducing extracranial blood flow and decreasing
hyperperfusion of the basilar artery area
Prophylactic Agents migranes
β-Blockers: Stabilize vascular tone
• Propranolol is drug of choice
 Calcium channel blockers:
• Regulate vascular smooth muscle contraction,
neurotransmission, and hormone secretion enzyme activity
 Tricyclic antidepressants:
• Increase availability of synaptic norepinephrine or serotonin
“downregulation” of 5-HT receptors and β-receptor activity
 Selective serotonin receptor inhibitors (SSRIs):
• Potent-specific receptor reuptake inhibitors; reduce frequency
and intensity; prevent venoconstrictive effect of decreased
serotonin levels during headache
 Anticonvulsants:
• Exert activity through their influence on cerebral arteries and
circadian rhythms; may help regulate secretion of hormones
Pharmacologic Treatment Recommendations
 Mild to moderate migraines
• Analgesics: ASA, NSAIDs, or combination
• Isometheptene: OTC (found in Midrin)
• Nausea and vomiting
– Medications administered via nasal spray or injection
– Antiemetics
 Moderate to severe migraines
Triptans are first line
• Ergotamine if triptans are not effective
Pharmacologic Acute Treatment
 Choosing between ergots and triptans
Triptans have become first-line treatment
– (more expensive than ergots)
• Generally, triptans have fewer adverse reactions
– Taken at earliest onset of the HA, ergots are usually effective
• If patient wakes up with HA or has difficulty “catching
the headache in time,” triptans are more effective
Triptans: sumatriptan (Imitrex)
Contraindications:
 CAD, cerebrovascular disease, stoke, TIA, PAD, ischemic
bowel dx, pregnancy, concomitant use of SSRIs, <18yrs,
severe hepatic impairment
• Warnings:
 do not give if CVD risk factors unless disease ruled out,
consider 1st dose in office and ECG after administration,
caution in renal or hepatic impairment
• Serious ADE:
 chest pain, coronary artery vasospasm, MI, VT, Vfib, TIA,
seizure, hypertensive emergency
• Common ADE:
 dizziness, fatigue, flushing, h/a, nausea, dry mouth,
somnolence
• Drug Interactions:
 OCP, ketoconazole, triptans elevate SSRI levels,
ergotamine tartrate (Cafergot)
• Contraindications:
 CAD or vasospasm, uncontrolled HTN,
renal/hepatic impairment, pregnancy, do not use
w/i 24hrs of a triptan
• Warnings:
 vasospasm, overuse results in ergotism (intense
arterial constriction-peripheral ischemia pain,
pallor- can progress to gangrene)
• Precautions:
 can result in drug dependence and abuse
• Drug Interactions:
 numerous d/t CYP3A-4,
• SSRIs block the reuptake of serotonin, leading to
increased concentrations of the neurotransmitter
• Resulting in greater postsynaptic neuronal activity.
 Antidepressants, including SSRIs, typically take at least 2
weeks to produce significant improvement in mood, and
maximum benefit may require up to 12 weeks or more
SSRI: Fluoxetine (Prozac)
differs from other members of the class
Much longer half-life (50 hours)
• available as a sustained release once-weekly dosing
preparation
 2. Metabolite is as potent as the parent compound
• half-life of the metabolite averages 10 days
• Fluoxetine and paroxetine: potent inhibitors of a
hepatic P450 enzyme responsible for elimination
 Of (TCA) tricyclic antidepressant drugs, neuroleptic drugs,
some antiarrhythmic and β-adrenergic–antagonist drugs.
 About 7% of the Caucasian population lack this P450
enzyme and, therefore, metabolize fluoxetine, and other
substrates of this enzyme, very slowly
• These individuals may be referred to in the literature as poor metabolizers
Serotonin-Norepinephrine
Reuptake Inhibitors, (SNRIs)
• Venlafaxine and duloxetine selectively inhibit
re-uptake of both serotonin and norepinephrine
 Effective in treating depression in patients in whom
SSRIs are ineffective
Venlafaxine
potent inhibitor of serotonin reuptake and, at
medium to higher doses, an inhibitor of norepinephrine reuptake.
Mild inhibitor of dopamine reuptake at high doses
 Minimal inhibition of the CYPP450 isoenzymes
 Half-life of parent compound plus active metabolite approx.11
hours.
• Most common side effects: nausea, headache, sexual
dysfunction, dizziness, insomnia, sedation, and constipation.
 At high doses, possibly an increase in blood pressure
SNRI Duloxetine:
inhibits serotonin and norepinephrine
reuptake at all doses
• Extensively metabolized in the liver to numerous
metabolites. Duloxetine should not be administered to
patients with hepatic insufficiency.
• Metabolites excreted in urine, not recommended in patients
with end-stage renal disease
• Food delays absorption of the drug
 half-life approx. 12 hrs.
• Common ADE: GI- nausea, dry mouth, constipation –
(diarrhea, and vomiting less often) insomnia, dizziness,
somnolence, and diaphoresis, sexual dysfunction, possible
risk increase in blood pressure or heart rate
Atypical Antidepressants:
Bupropion
• Bupropion
acts as a weak dopamine and
norepinephrine reuptake inhibitor
 Short half-life may require more than once-a-day dosing
or an extended-release formulation.
 Unique in that it decreases the craving and attenuating
symptoms of nicotine withdrawal
• Side effects may include dry mouth, sweating,
nervousness, tremor, a very low incidence of sexual
dysfunction, increased risk for seizures at high doses
• Metabolized by the CYP2D6 pathway- relatively low
risk for drug-drug interactions.
Atypical Antidepressants:
Mirtazapine (Remeron)
• Mirtazapine: enhances serotonin and
norepinephrine neurotransmission via mechanisms
related to its ability to block presynaptic α2
receptors
 Sedative properties, but does not cause the
antimuscarinic side effects of the TCAs, or interfere
with sexual functioning, as do the SSRIs
 Increased appetite and weight gain frequently occur.
• Mirtazapine is markedly sedating
 may be used to advantage
Atypical Antidepressants:
Nefazodone and trazodone
Weak inhibitors of serotonin reuptake
 therapeutic benefit appears r/t ability to block
specific postsynaptic receptors
 chronic use may desensitize the presynaptic
autoreceptors and increase serotonin release.
• Both agents sedating, probably r/t potent
H1-blocking activity.
• Trazodone associated w/ causing priapism
• Nefazodone associated w/ risk of hepatotoxicity
Tricyclic Antidepressants (TCAs)
 Block
norepinephrine and serotonin reuptake into the
neuron
• if discovered today, may be referred to as SNRIs except for
differences in ADEs compared to newer antidepressants
 Imipramine, amitriptyline, clomipramine, doxepin, trimipramine
 Also includes the secondary amines: nortriptyline (Pamelor)
desipramine, and protriptyline,
– Maprotiline and amoxapine are related “tetracyclic”
antidepressant agents (are commonly included in the general
class of TCAs)
All drugs in the class have similar therapeutic efficacy
• choice of agent may depend on patient tolerance, side
effects, preexisting medical conditions,
 Patients who do not respond to one TCA may benefit from a
different drug in this group.
• TCA drug class - a valuable alternative for pts who do not
respond to SSRIs
TCAs:
blocking of receptors, actions
 TCAs also block
serotonergic, α-adrenergic,
histaminic, and muscarinic receptors
 Not known if any of these actions produce
therapeutic benefit.
 Actions at these receptors are probably
responsible for many adverse effects of TCAs.
• Actions: TCAs elevate mood, improve mental
alertness, increase physical activity
 Onset of mood elevation is slow, (2 wks or >)
• Does not commonly produce CNS stimulation or
mood elevation in normal individuals
Monoamine Oxidase Inhibitors
• The MAO inhibitors and SSRIs should not be
coadministered d/t
risk of the life-threatening
“serotonin syndrome.”
• Both types of drugs require washout periods of
at least 2 weeks before the other type is
started,
 (except fluoxetine, should be d/c at least 6 wks
before a MAO inhibitor is initiated)
• Combination of MAO inhibitors and bupropion
can produce seizures.
First line: depression
SSRIs-(except fluvoxamine), SNRIs, NDRIs
• First line in certain situations: TCAs, mirtazapine
Second line in depression
SNRIs, NDRIs, TCAs
3rd line in depression
SARIs, MAOIs,
Benzodiazepines do not have
antipsychotic activity, do not affect the
ANS
• Flumazenil:
a GABA-receptor antagonist that can
rapidly reverse the effects of benzodiazepines
 available for intravenous administration only
 Rapid onset, short duration, w/ a half-life of about 1 hr
 Frequent administration may be necessary to maintain
reversal of a long-acting benzodiazepine
Buspirone (Buspar)
Buspirone: Used in treatment of generalized
anxiety disorder (GAD)
• Efficacy comparable to benzodiazepines
 relieves anxiety without marked sedative, hypnotic, or
euphoric effects
Hydroxyzine:
antihistamine with antiemetic
activity. Low risk for dependence, useful for patients
with anxiety who have a history of drug abuse
 It is also often used for sedation prior to dental
procedures or surgery. (drowsiness is a SE)
Zolpidem (Ambien):
GABA-BZ Receptor Agonists
not a benzodiazepine in structure
 but acts on a subset of the benzodiazepine receptor family
 no anticonvulsant or muscle-relaxing properties
 few withdrawal effects, minimal rebound insomnia, little or
no tolerance w/ prolonged use
 Caution in renal impairment
 Rapidly absorbed GI, rapid onset of action
• short elimination half-life ( 2- 3 hours)
– extended-release now available