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173 Cards in this Set
- Front
- Back
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Autonomic Nervous System
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Site for receptor - drug reactions.
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Efferent Neurons
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carry nerve impulse from the CNS to the effector organs
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Ganglia
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'relay stations' between a preganglionic neuron and a second nerve cell, the postganglionic neuron
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Where do the messages terminate?
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on effector organs, such as smooth muscles of the viscera, cardiac muscle and the exocrine glands
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Afferent neurons:
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important in the reflex regulation of the ANS.
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What does the Afferent neurons sense?
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pressure in the carotid sinus and the aortic arch. Then signals the CNS to influence the efferent branch of the system to respond
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Parasympathetic neurons
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fibers arise from the cranium and from the sacral region of the spinal cord. Synapse in ganglia near or on the effector organs
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Enteric neurons:
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nerve fibers that innervate the GI tract, pancreas, and gallbladder....constitutes the 'brain of the gut'
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Enteric neurons function
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independently of the CNS; controls the motility, exocrine and endocrine secretions and microcirculation of the GI tract
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Enteric neurons are modulated by
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the SNS and the PNS
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SNS is responsible for
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maintenance of vascular tone. Adjusts in response to stress. Trauma, fear, hypoglycemia, cold and exercise
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Reflex arcs:
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Most afferent impulses translated into
reflex responses w/o conscious involvement |
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Reflex arcs of the autonomic nervous system
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comprised of a sensory (or afferent) arm
• and a motor (or efferent, or effector) arm. compensatory rise in blood pressure and tachycardia |
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vagal parasympathetic innervation
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slows heart rate
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Histamine and prostaglandins
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examples of local mediators....do not enter blood
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Hormones:
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Secreted by specialized endocrine cells into the bloodstream
Travel throughout the body exerting effects on broadly distributed target cells in the body |
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Communication between nerve cells, and
between nerve cells and effector organs—occurs through the release of specific chemical signals |
Neurotransmitters
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Neurotransmitters
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rapidly diffuse across the synaptic cleft (synapse)
between neurons and combine with specific receptors on the postsynaptic (target) cell |
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Acetylcholine and norepinephrine
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primary
chemical signals in the ANS |
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Cholinergic drugs
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act on receptors
that are activated by acetylcholine. |
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Adrenergic drugs
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act on receptors
that are stimulated by norepinephrine or epinephrine |
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Cholinergic and adrenergic drugs
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both
act by either stimulating or blocking receptors of the autonomic nervous system. |
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Sympathomimetic drugs
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Drugs that mimic the actions of
epinephrine or norepinephrine Grouped by mode of action and receptors they activate |
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Direct agonists
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directly interact with and
activate adrenoceptors norepinephrine and epinephrine |
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Sympathomimetic drugs. Indirect agonists
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actions are dependent on
the release of endogenous catecholamines |
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Sympathomimetic drugs Indirect agents
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one of two mechanisms
1. displacement of stored catecholamines from the adrenergic nerve ending 2. inhibition of reuptake of catecholamines already released |
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Both typesmpathomimetic drugs of Sy, direct and indirect,
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cause activation of adrenoceptors. Leading to some or all of the characteristic
effects of endogenous catecholam |
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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 |
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Stimulation of β2
receptors |
→ relaxes airway smooth
muscle → Inhibits mediator release Causes tachycardia and skeletal muscle tremor as ADE |
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Adrenoceptor agonists
optimally delivered by inhalation |
→ results in
greatest local effect on airway smooth muscle w/ the least systemic toxicity |
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Goal of Asthma therapy : contol; Reducing impairment
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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 |
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Reducing risk
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prevent recurrent exacerbations of asthma
(ED/inpatient) prevent progressive loss of lung function provide optimal pharmacotherapy |
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What are teh best form of mediation for asthma?
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inhaled corticosteroids
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What is good for a pt not managed with single inhaled brochodilator
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Anticholinergic + B2 agonist
(albuterol + ipratropium....greater bronchodilation than either drug alone) |
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What allows less frequent dosing
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Salmeterol and tiotropium
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Beta adrenergic agonis bronchodilators: short/rapid acting (SABA)
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albuterol, levalbuterol, erols...and ipratropium
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AE of Beta adrenergic agonist
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tremor, cough, GI, h/a, nervousness, n/v, HTN palpitations, insomnia
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Serious AE of Beta adrenergic agonist bronchodilators
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paradoxical bronchospasm, hypokalemia, arrhythmias, angioedema, Inc LFT
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Duration of action and elimnation of Beta adrenergic agonist?
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2-4 hours; renal elimination
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Beta adrenergic agonist bronchodilators long acting (LABA) drugs=
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Salmeterol, formoterol
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AE of LABA
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tremor, nervousness, tachycaria, h/a, palpitaitons, nasal congestion, insomnia
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Serious AE of LABA
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bronchospasm, rash, angina, hypersensitivity rxn, angioedema, arrhythmia, hypokalemia, metabolic acidosis
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Metabolism of LABA
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liver
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Elimination of LABA
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renal and biliary
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Inhaled adrenergic agonists (Beta 2)
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drug of choice only for mild, intermittent symptoms. Also rescue therapy for all levels of persistent asthma
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Direct acting beta 2 agonist
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potent bronchodilator; relaxes airway smooth muscle
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What are the adverse effects are associated with inhaled adrenergic Beta 2 adonists
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tachy, hyperglycemia, hypo kalemia, hypomagnesemia
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Ipratropium
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cholinergic antagonist: antimuscarinic agent acts on post ganglionic recept. in ANS; blocking this receptor promotes bronchodilation (INHALE ONLLY)
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What does ipratropium do?
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block vagal mediated contraction of airway smooth muscle and mucous secretion....
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Serious AE of ipratropim
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Anaphylaxis, worsening of glaucoma, bronchospasm, worsening of COPD, tachy, urticaria, CP
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When caution with Atrovent
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myasthenia Gravis, glaucoma, BPH, and bladder neck obstruction
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Tiotropium (spiriva)
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Anticholinergic: long acting antimuscarinic bronchodilator
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corticosterioids
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Modify immune response via suppression of cytokine
production, airway eosinophils, and release of inflammatory mediators |
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inhaled corticosteroids:
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therapeutic effect with minimal AE, compared to systemic steroids....reduction of symptoms, improve lung function
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What do corticosteroids do?
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Reduce airway
hyperresponsiveness (AHR) Control inflammation Reduce frequency and severity of exacerbations Reduce asthma mortality |
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drug of
choice in patients with any degree of persistent asthma |
Inhaled corticosteroids (ICS)....no other meds are as effective
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Since ICS have no direct effect on airways smooth muschele how do they work?
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target underlying airway inflammation....ICS reduce the
hyperresponsiveness of the airway smooth muscle to some stimuli (allergens, irritants, c |
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Why a spacer?
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doesnt deposit med in mouth....Spacers improve delivery of inhaled glucocorticoids and
are advised for virtually all patients |
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Theophylline
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used when maximal
medical therapy has sub‐optimal results Chemically related to caffeine Phosphodiesterae (PDE) inhibitor |
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Pharmacokinetics of Theophylline
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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 |
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Leukotriene Angtagoinsts
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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 |
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Omalizumab (Xolair)
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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 |
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Inhaled corticosteroids improve
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asthma control more
effectively in children and adults than any other single long‐term controller medication. |
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key asthma concepts
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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 |
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Cromolyn and nedocromil
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Effective prophylactic anti‐inflammatory agents...not for acute asthma exacerbation
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Cromolyn info
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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 |
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Pharmacokinetics if Steriods
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Prednisone metabolized
in liver to prednislone Well absorbed GI High plasma protein binding Liver metabolism Renal excretion |
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antiinflammatory action of glucocorticoids
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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 |
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First line Rx of allergic rhinitis
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Combinations of oral antihistamines
w/decongestants Adverse effects: sedation, insomnia, (rare cardiac |
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fexofenadine hydrochloride: allegra
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Seasonal allergic rhinitis in patients > 2 yrs
Tx of chronic idiopathic urticaria in > 6 months |
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FDA recommends combination of
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caffeine and pseudoephedrine is NOT safe
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gold‐standard Rx for cough suppression
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Codeine. Decreases sensitivity of CNS cough centers
action in the medulla Decreases mucosal secretion Therapeutic effect @ doses lower than analgesia doses |
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non narcotic antitussive: dextromethorphan
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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 |
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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 |
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Drug of choice for asthma
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bronchodilators
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corner stone of treatment for asthma is
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inhaled corticosteroids
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Blackbox warning for LABA
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increased mortality in asthma patients with LABA
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what is the only thing that reduces mortality in COPD
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oxygen
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COPD – combination therapy
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Anticholinergic + Beta2 agonist
-Albuterol + ipratropium=greater bronchodilation than either drug alone |
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what drug has inc toxicity with asthma
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with methylxa (thyllophilline)
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Salmeterol – Adverse effect –
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paradoxical bronchospasm and immediate hypersensitivies ….can inc risk of death
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Shortacting inhaled adrenergic agonist
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drug of choice for mild sx….as monotherapy
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Long term steroids problems
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immunosuppression masked s/s of infection!!Acne, straie,sodium and water retention
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Autocoids
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target for some drug actionsas either agonists or antagonists
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leukotriene Receptor Antagonists…..are for
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Exercise induced bronchoconstriction (EIB)
-not a rescue medication Pharmacokinetics – Elevated LFT possible |
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Common AE of leukotriene Receptor antagonists
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URI symptoms; neuropsychiatric warning!
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Cromolyn
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reduces sx of allergic rhinitis
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Etiology of parkinsons
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destruction of dopaminergic neurons in substantia nigra. reduction of dopamine action in brain basal ganglia....affects motor control
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Excitatory pathways
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Stimulation of excitatory neurons causes a
movement of ions that results in a depolarization of the postsynaptic membrane. |
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Inhibitory pathways
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Stimulation of inhibitory neurons causes
movement of ions that results in a hyperpolarization of the postsynaptic membrane |
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Pharmacological therapy of parkinsons
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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. |
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Levadopa and carbidopa (Sinemet)
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Enhances synthesis of dopamine in the surviving neurons of the
substantia nigra conversion of levodopa to dopamine |
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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 |
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• Carbidopa
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Enhances effect of levadopa via diminishing
metabolism of levadopa in GI tract and peripheral tissues… → Increasing availability of levadopa to cross into the CNS |
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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 |
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When should levadopa be taken?
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on empty stomach
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on-ff phenomenon
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causes sudden loss of normal
mobility, tremors, cramps, immobility |
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adverse effects of levadopa
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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. |
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Monamine oxidase B (MAO-B) inhibitors
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selegiline (Eldepryl) & rasagiline (Azilect)
MOA not fully understood, • Do not combine w/ fluoxetine or merperidine (additive effect) |
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Glutamate antagonist (antiviral):
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amantadine (Symmetrel) accidently discovered
to have antiparkinsonism activity Less effective than levadopa, but less side effects Caution in seizure disorders and CHF,edema |
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Dopamine Receptor Agonists
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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 |
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Anticholinergic Agents
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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 |
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Catechol-O-methytransferase (COMT) inhibitors
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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 |
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First line therapy
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levodopa, dopamine agonists
Carbidopa/levodopa most effective |
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Pramipexole and ropinirole
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effective in early and
late Parkinson’s |
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Amantadine
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patients w/ mild symptoms
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Apomorphine injection
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used for acute tx of
immobility |
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Anticholinergics
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reduce tremor, rigidity and
drooling (limited use d/t ADE) |
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COMT inhibitors
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reduces motor fluctuations in
advanced dx- but, increase dyskinesias (use after other adjunctive tx failed) |
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MAOI
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selegline, rasagiline
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Cholinesterase Inhibitors
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Management of mild to moderate Alzheimer’s-type
dementia Often initiated by PCPs or after consultation |
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What do cholinesterase inhibitors do?
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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 |
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NMDA Receptor Antagonists
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Moderate to severe dementia of Alzheimer’s type
May be given in addition to cholinesterase inhibitors May be initiated by PCP or after consultation |
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Acetylcholinesterase inhibitors
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based on concept that
inhibition of acetylcholinesterase w/i the CNS improves cholinergic transmission (at least at the still functioning neurons) |
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Donepezil or galantamine ER usualy
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first line, daily
dosing increases adherence • All metabolized via CYP450 system- potential drug interactions |
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Overstimulation of glutamate receptors
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shown to
result in excitotoxic effects on neurons & suggested as a mechanism for neurodegenerative or apoptotic processes |
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NMDA-glutamate receptor antagonists are often
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neuroprotective, preventing the loss of neurons
following ischemic and other injuries |
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What is the first line treatment for Alzheimer?
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Donepezil
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Evidence suggests cholinesterase inhibitors
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stabilize
cognitive and functional ability for approx. 1 year |
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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 |
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precautions with donepezil (Aricept)
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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 |
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memantine (Namenda)
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• Drug Interactions
acetazolamide, cimetidine, dichlorphenamide Hydrochlorothiazide, methazolamide, Nicotine, ranitidine, sodium bicarbonate • Precautions Seizures, severe renal impairment, GU conditions, concomitant use of other NMDA antagonists |
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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 |
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Hydantoin:
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phenytoin
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succinimide
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ethosuximide
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GABA analogs
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• valproic acid, divalproex
sodium,(Depakene, Depakote), gabapentin (Neurontin), lamotrigine (Lamictal), topiramate, (others) |
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Mechanisms of Action
• GABA Analogs |
• All drugs increase the actions of GABA
• May inhibit voltage-dependent sodium channel, thereby stabilizing neuronal membranes |
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Hydantoins (phenytoin) mechanisms of action
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Primary site of action: Primary motor cortex
Prolongs effective refractory period by blocking neuronal sodium channels Stabilizes threshold against hyperexcitability Exhibits antiarrhythmic properties |
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Mechanisms of Action
• Benzodiazepines: diazepam, clonazepam |
Mechanism similar to barbiturates
Increase the number of chloride channels, suppressing spread of seizure activity |
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mechanism of action Carbamazepine: Carbamazepine (Tegretol),
oxcarbazepine, |
Limits seizure propagation- blocks postsynaptic
transmission |
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mechanism of action Barbiturate
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phenobarbital, primidone (Mysoline)
Inhibits depolarization of neurons by binding to the GABA receptor Increases threshold for electrical stimulation of the motor cortex |
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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 |
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Anticonvulsant Therapy
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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 |
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Discontinuation may be considered in patients who have been
seizure-free for |
> 2 years
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rules of treatment
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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 |
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What to monitor for sz meds
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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 |
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Benzodiazepines bind
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to GABA inhibitory
receptors to reduce firing rate. |
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Carbamazepine reduces
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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 |
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Divalproex sodium (Depakote)
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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 |
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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 |
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Lamotrigine
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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 |
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Phenobarbital
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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 |
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Phenytoin and fosphenytoin
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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 |
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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) |
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Topiramate
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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 |
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Specific migraine therapy
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triptans and
dihydroergotamine leads either to vasoconstriction or to inhibition of the release of proinflammatory neuropeptides |
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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 |
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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 |
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Prophylactic Agents migranes
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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 |
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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 |
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Moderate to severe migraines
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Triptans are first line
• Ergotamine if triptans are not effective |
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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 |
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Triptans: sumatriptan (Imitrex)
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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, |
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ergotamine tartrate (Cafergot)
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• 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, |
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• SSRIs block the reuptake of serotonin, leading to
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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 |
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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 |
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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 |
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Venlafaxine
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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 |
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SNRI Duloxetine:
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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 |
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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. |
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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 |
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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 |
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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 |
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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 |
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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. |
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First line: depression
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SSRIs-(except fluvoxamine), SNRIs, NDRIs
• First line in certain situations: TCAs, mirtazapine |
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Second line in depression
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SNRIs, NDRIs, TCAs
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3rd line in depression
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SARIs, MAOIs,
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Benzodiazepines do not have
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antipsychotic activity, do not affect the
ANS |
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• Flumazenil:
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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 |
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Buspirone (Buspar)
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Buspirone: Used in treatment of generalized
anxiety disorder (GAD) • Efficacy comparable to benzodiazepines relieves anxiety without marked sedative, hypnotic, or euphoric effects |
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Hydroxyzine:
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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) |
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Zolpidem (Ambien):
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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 |
