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Neuro II Exam 2 > Cholinergic Agonists And Antagonists DSA > Flashcards

Cholinergic Agonists And Antagonists DSA Flashcards

1
Q

List direct-acting cholinomimetics

A 
Acetylcholine
Bethanechol
Carbachol
Cevimeline
Methacholine
Pilocarpine
Varenicline (Chantix)
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2
Q

List cholinesterase inhibitors

A 
Ambenonium
Donepezil
Echothiphate
Edrophonium
Galantamine
Neostigmine
Physostigmine
Pyridostigmine
Rivastigmine
Tacrine
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3
Q

Cholinesterase regenerator

A

Pralidoxime

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4
Q

Ganglion blocker

A

Mecamylamine

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5
Q

Describe choline esters

A

Contain permanently charged quaternary ammonium groups that result in their poor absorption and distribution into CNS

Hydrolyzed in GI tract and less active when given PO

All hydrolyzed by cholinesterase but at different rates (ACh>methacholine>carbachol=bethanecol) which leads to varying durations of action

MOA: act as agonists on cholinergic recepors

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6
Q

Describe alkaloids

A

Direct-acting cholinergic agonists (muscarine, nicotine, pilocarpine)

Uncharged tertiary amines (muscarine is exception) that are well absorbed from most sites of administration (nicotine absorbed well through skin)

Muscarine: quaternary amine. Highly toxic when ingested (mushrooms) and can enter brain

Chiefly excreted by kidneys. Acidification of urine accelerates clearance

MOA: act as agonists on cholinergic receptors

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7
Q

Describe effects of direct-acting cholinergic agonists on skeletal muscle (somatic effects)

A
  • only nAChRs on skeletal muscle, so only those agents that activate these receptors will produce effects (muscle contraction)
  • Prolonged agonist occupancy of nAChR abolishes effector response: postganglionic neuron stops firing, and skeletal muscle cell relaxes (similar to succinycholine)
  • eventually a state of depolarizing blockade is produced (flaccid paralysis)
  • nicotine itself has greater affinity for neuronal nAChRs than skeletal muscle nAChRs
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8
Q

Describe direct-acting cholinergic agonist effects on eye

A

Contraction of iris sphincter and ciliary muscle results in increased aqueous humor outflow into canal of Schlemm, which drains anterior chamber

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9
Q

Describe direct-acting cholinergic agonist effects on CV system

A
  • all cardiac actions mediatd by M2 mAChR
  • primary effects of muscarinic agonists are reduction in peripheral vascular resistance and changes in heart rate
  • parasympathetic innervations of ventricles is much less extensive than that of atria, and activation of ventricular mAChRs cause much less physiologic effects than mAChR activation in atria
  • muscarinic agonists release endothelium-derived relaxing factor (EDFR) from endothelial cells that relaxes smooth muscle surrounding blood vessels (must have endothelium and smooth muscle together)
  • EDFR is largely NO, which activates guanylyl cyclase and increases cyclic guanosine monophosphate (cGMP) in smooth muscle, resulting in relaxation
  • Minimally effective doses of agonists (ACh) cause vasodilation, resulting in a reduction in blood pressure and often accompanied by a reflex increase in heart rate (homeostatic reflex)
  • Larger doses of ACh produce bradycardia and decrease atrioventricular node conduction velocity in addition to hypotension
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10
Q

Describe direct-acting cholinergic agonist effects on GI and GU tracts

A
  • increase in glandular secretions affects salivary and gastric glands more so than pancreas and small intestinal glands
  • M3 mAChR is required for direct activation of smooth muscle contraction
  • M2 mAChR reduces cAMP formation and reduces relaxation caused by adrenergic effects (results in contraction)
  • Sphincter relaxation is via NO signaling (M3 mAChRs)
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11
Q

Describe direct-acting cholinergic agonist effects on CNS

A
  • brain is relatively richer in mAChRs, while spinal cord contains predominantly nAChRs
  • generally, excitatory mAChRs are involved in increased cognitive function (learning and memory) and seizure activity, while inhibitory mAChRs play a role in tremors, hypothermia, and analgesia
  • activation of nAChRs is dose dependent: moderate concentrations of nicotine cause a mild alerting action in brain (tobacco smoke). High concentrations can induce tremor, emesis, and stimulation of respiratory center. Lethal doses can cause convulsions and may lead to fatal coma (nicotine as insecticide)
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12
Q

Describe direct-acting cholinergic agonist effects on PNS

A
  • nAChR agonist nicotine causes receptor activation in autonomic ganglia, and its actions are similar in both parasympathetic and sympathetic ganglia. Initial response resembles simultaneous discharge of both parasympathetic and sympathetic nervous systems
  • CV system: effects of nicotine are mainly sympathomimetic (hypertension and possible alternating of tachycardia and bradycardia mediated by vagal discharge)
  • GI/GU tracts: effects are mainly parasympathomimetic (nausea, vomiting, diarrhea, voiding of urine)
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13
Q

Describe clinical use of direct-acting cholinergic agonists for glaucoma

A
  • muscarinic stimulants cause contraction of ciliary body, which facilitates outflow of aqueous humor and reduces intraocular pressure
  • replaced by topical beta-blockers and prostaglandin derivatives
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14
Q

Describe clinical use of direct-acting cholinergic agonists for accommodative esotropia

A
  • misalignment of eyes caused by hypermetropic accommodative error (young children who are farsighted overcorrect for farsightedness, and their eyes become crossed)
  • can be diagnosed and treated with cholinomimetic agonists
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15
Q

Describe clinical use of direct-acting cholinergic agonists for GI/GU tract disorders

A
  • behtanechol is most widely used choline ester for these, including postoperative ileus (atony or paralysis of stomach or bowel following surgical manipulation), congenital megacolon, urinary retention, esophageal reflux (to increase tone of lower esophageal sphincter)
  • physician must be certain there is no obstruction. Otherwise, drug may exacerbate problem and may even cause perforation
  • pilocarpine and cevimeline are used to increase salivary secretion (dry mouth associated with Sjorgren’s syndrome)
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16
Q

Describe toxicity of muscarinic stimulants

A
  • overdoses of pilocarpine and choline esters cause predictable muscarinic effects (nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, bronchial constriction) and are blocked by antimuscarinic compounds such as atropine
  • mushrooms of genus Inocybe contain muscarinic alkaloids and can cause poisoning
  • many contraindications to use of mAChR agonists that are distributed systemically are asthma, hyperthyroidism, coronary insufficiency, and acid-peptic disease
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17
Q

Describ toxicity of nicotinic stimulants

A
  • nicotine is only common cause of nicotinic poisoning and can come in form of tobacco and insecticides
  • lethal dose of nicotine is present in 2 cigarettes, though most of nicotine is destroyed by burning
  • acute toxicity: effects include CNS stimulation (convulsions progressing to coma and respiratory arrest), skeletal muscle end plate depolarization leading to depolarizing blockade and respiratory paralysis, and hypertension and cardiac arrhythmias
  • -treatment includes atropine for excess muscarinic stimulation from parasympathetic ganglia and parenteral anticonvulsants (diazepam) for CNS stimulation
  • -neuromuscular blockade is not responsive to pharmacologic treatment
  • chronic toxicity: though not well established due to fact that there are many other well-documented adverse effects associated with chronic tobacco use, nicotine probably contributes to increased risk of vascular disease, sudden coronary death, and ulcer recurrences in smokers with peptic ulcer
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18
Q

Clinical use of acetylcholine

A
  • approved for intraocular use during surgery and causes miosis (reduction in pupil size)
  • rarely given systemically
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19
Q

Clinical use of methacholine

A
  • administered by inhalation for diagnosis of bronchial airway hyperreactivity in pts who do not have clinically apparent asthma
  • rarely used due to need for emergency resuscitation equipment, oxygen, and medications to treat severe bronchospasm (beta2 adrenergic receptor agonists)
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20
Q

Clinical use of bethanechol

A
  • can be used to treat pts with urinary retention and heartburn
  • selective mAChR agonist
  • little CV stimulation
  • may produce urinary tract infection if sphincter fails to relax
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21
Q

Clinical use of carbachol

A

Nonspecific cholinergic agonist that is used for treatment of glaucoma or to produce miosis during surgery or ophthalmic exam

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22
Q

Clinical use of cevimelin

A
  • oral tablet used to treat dry mouth (xerostomia) in pts with Sjorgren’s syndrome
  • metabolized via P450 pathways and eliminated in urine
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23
Q

Clinical use of pilocarpine

A
  • approved for xerostomia treatment in pts with Sjogren’s syndrome or head and neck cancer treatment related xerostomia (PO), miosis during ophthalmic procedures (topical), and for glaucoma (topical)
  • pure mAChR agonist
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24
Q

Clinical use of Varenicline

A
  • FDA approved for smoking cessation
  • partial agonist that binds with high affinity and selectivity to alpha4beta2 nicotinic acetylcholine receptors located in brain to stimulate receptor-mediated activity but at a substantially lower level than nicotine
  • stimulation and subsequent moderate, sustained release of mesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation (reward pathway)
  • greater than 90% eliminated in urine as uncharged drug
  • nausea is most common adverse effect. Serious adverse effects include neuropsychiatric symptoms, including changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and completed suicide
  • treatment comes with warnign: if pts, their families, or caregivers notice agitation, depressed mood, or changes in behavior that are not typical for pt or if pt has suicidal thoughts or actions, pt should stop taking varenicline and contact their healthcare professional
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25
Q

Describe chemical groups of AChE inhibitors

A
  1. Alcohols
    - contain alcohol group and quaternary ammonium group (positive charge)
    - ex: edrophonium
    - binding to AChE is noncovalent and reversible
  2. Carbamic acid esters (carbamates)
    - bear quaternary or tertiary ammonium groups (positive or neutral)
    - ex: neostigmine, pyridostigmine, physostigmine, carbaryl)
    - binding to AChE is noncovalent and reversible
  3. Organophosphates
    - organic derivatives of phosphoric acid
    - more than 50,000 different compounds
    - ex: echothiphate, parathion and malathion (insecticides), and sarin, soman, and tabun (nerve gases)
    - often charge-neutral and highly lipid-soluble (echothiophate exception), resulting in CNS toxicity
    - binding to AChE is covalent and irreversible
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26
Q

Describe pharmacokinetics of AChE inhibitors

A
  1. Quaternary and charged
    - relatively insoluble in lipids and absorption from conjunctiva, skin, and lungs is poor
    - parenteral administration is preferred. When given orally, larger doses are required
    - no CNS distribution
    - duration of effect is determined by stability of inhibitor-enzyme complex rather than by metabolism or excretion
    - ex: neostigmine, pyridostigmine, edrophonium, echothiophate, ambenoium
  2. Tertiary and uncharged
    - well absorbed from all sites
    - CNS distribution
    - more toxic than polar quaternary carbamates
    - ex: physostigmine, donepezil, tacrine, rivastigmine, galantamine
  3. Organophosphates
    - lipid-soluble and readily absorbed from skin, lung, gut, and conjunctiva, which make them particularly dangerous to humans and highly effective as insecticides
    - distributed to all parts of body including CNS (exception echothiophate due to charge)
    - oragonphosphate poisoning includes CNS toxicity
    - since interaction between organophosphates and AChE is covalent and irreversible, virtually little metabolism and excretion via common biotransformation pathways
    - regeneration of AChE is required in order to reestablish termination of ACh signaling at neuromuscular junction
27
Q

Mechanism and duration of action for AChE inhibitors

A
  1. MOA
    - inhibition of AChE
    - ACh accumulates throughout body, which results in activation of nAChRs and mAChRs
    - consequences deleterious or beneficial
  2. Duration of action
    - dependent upon chemical properties of AChE inhibitor
  • Alcohols
  • -bind reversibly through electrostatic interactions and hydrogen bonding at binding site for ACh
  • -relatively weak interactions are short-lived and result in short duration of action (2-10 min)
  • Carbamic acid esters
  • -undergo 2-step hydrolysis sequence analogous to ACh
  • -second step involves formation of covalent bond between enzyme and carbamic acid group of inhibitor that requires 30 min to 6 hours to hydrolyze
  • organophosphates
  • -covalent phosphorus-enzyme bond is extremely stable and hydrolyzes at a very slow rate (hundreds of hours)
  • -after initial binding step, phosphorylated enzyme complex may undergo process called aging
  • -aging involves breaking of one of oxygen-phosphorous bonds of inhibitor and further strengthens phosphorus-enzyme bond
  • -once aging has occurred, enzyme-inhibitor complex is even more stable and difficult to break
28
Q

General organ system effects of AChE inhibitors

A
  • quaternary AChE inhibitors are absorbed poorly form GI tract or across skin, are excluded from CNS by BBB (at moderate doses), act preferentially at NMJ of skeletal muscle, and have less effect at autonomic effector sites and ganlgia
  • organophosphates and tertiary AChE inhibitors are well absorbed after oral administration, have ubiquitous effects at both peripheral and central cholinergic sites, and my abe sequestered in lipids for long periods of time
  • lipid-soluble organophosphate agents are well-absorbed through skin, and volatile agents are transferred readily across alveolar membrane
  • depending on site of action, AChE inhibitors have ability to
  • -stimulate mAChRs at autonomic effector organs
  • -stimulate, followed by depression or paralysis, all autonomic ganglia and skeletal muscles (nAChRs)
  • -stimulate, with occasional subsequent depression, cholinergic receptor sites in CNS
29
Q

Effects of AChE inhibitors on CNS

A
  • low concentrations: diffuse activation on electroencephalogram and subjective altering response
  • high conc: generalized convulsions due to neuronal hyperstimulation (may be followed by coma and respiratory arrest)
30
Q

Effects of AChE inhibitors on eye, respiratory tract, GI tract, urinary tract

A
  • similar to direct acting cholinomimetics (bethanechol, carbachol, pilocarpine)
  • these organs are innervated by mAChRs (parasympathetic nervous system)
31
Q

Effects of AChE inhibitors on CV system

A
  • can increase activity of both sympathetic and parasympathetic ganglia (nAChRs and mAChRs) supplying heart and at mAChRs on cardiac cells
  • parasympathetic tone dominates, and cardiac output decreases
  • net CV effects of moderate doses is modest bradycardia, a fall in cardiac output (due to bradycardia, decreased atrial contractility, and some reduction in ventricular contractility), and modest increase in blood pressure
  • toxic doses cause more marked bradycardia, occasionally tachycardia, and hypotension
32
Q

Effects of AChE inhibitors on NMJ

A
  • therapeutic concentrations prolong and intensify actions of ACh, which increases strength of contraction
  • fibrillation of muscle fibers an fasciculations result with high concentrations
  • continued inhibition of AChE results in progression of depolarizing neuromuscular blockade to nondepolarizing blockade (as seen with succinylcholine)
  • some quarternary carbamate AChE inhibitors have additional direct nicotinic agonist effects on NMJ (neostigmine)
33
Q

AChE inhibitor use for reversal of pharmacologic paralysis

A
  • AChE inhibitors can reverse paralysis induced by neuromuscular blocking drugs during surgical anesthesia (neostigmine and edrophonium)
  • may be used to treat paralytic ileus (atony or paralysis of stomach or bowel following surgical manipulation), atony of urinary bladder, and congenital megacolon
34
Q

AChE inhibitor use for glaucoma

A
  • glaucoma characterized by increased intraocular pressure
  • inhibitors reduce intraocular pressure by stimulating mAChRs of ciliary body and causing contraction, which facilitates outflow of aqueous humor
  • therapy has largely been replaced by topical beta-blockers and prostaglandin derivatives
35
Q

AChE inhibitor use for dementia

A
  • Alzheimer pts found to have deficiency of intact cholinergic neurons
  • tacrine was approved to treat this condition, but due to high incidence of hepatotoxicity, newer agents preferred (donepezil, rivastigmine, galantamine, and physostigmine)
  • Parkinson pts also benefit
36
Q

AChE inhibitor use as antidote

A
  • over 600 compounds have anticholinergic properties (anticholinergic agents/atropine, antihistamines, tricyclic depressants, sleep aids, cold preparations)
  • intoxication due to anticholinergic agents can produce cutaneous vasodilation, anhidrosis, anhydrotic hyperthermia, nonreactive mydriasis, delirium, hallucinations, and reduction or elimination of desire to urinate, which are generally result of reduced or blocked mAChR stimulation
  • physostigmine can reverse above mentioned effects and is preferred because it crosses BBB
37
Q

Describe AChE inhibitor drug-drug interactions

A
  1. Nondepolarizing neuromuscular blocking agents: Combo with AChE inhibitors will enhance neuromuscular blockade. Exception is mivacurium (metabolized by plasma AChE), where neuromuscular blockade is prolonged
  2. Succinylcholine: combo with AChE inhibitors will enhance phase 1 block and antagonize phase 2 block
  3. Cholinergic agonists (direct-acting): direct-acting agents act predominantly on mAChRs. Combo with inhibitors will enhance effects of cholinergic agonists
  4. Beta-blockers: combo with inhibitors may enhance bradycardic effects
  5. Systemic corticosteroids: coadministration with inhibitors may enhance muscle weakness seen in pts with myasthenia gravis
38
Q

Describe acute intoxication of AChE inhibitor toxicity

A
  • dominant initial signs of AChE intoxication are those of mAChR stimulation: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea
  • route of administration dictate which symptoms are noted initially:
  • -after ingestion, GI symptoms occur earliest
  • -percutaneous absorption results in early symptoms of localized sweating and muscle fasciculations in immediate vicinity
  • with poisoning from lipid-soluble agents, CNS involvement follows rapidly (confusion, ataxia, generalized convulsions, coma, and respiratory paralysis)
  • time of death after a single acute exposure may range 5 minutes to 24 hrs and is caused primarily by respiratory failure
39
Q

Describe diagnosis and treatment of AChE inhibitor toxicity

A
  • diagnosis made from history of exposure and characteristic signs and symptoms
  • in suspected cases of deliberate poisoning with more mild signs of intoxication, measurement of AChE activity in erythrocytes and plasma can establish diagnosis
  • mAChR antagonist atropine is antidote recommended for cholinergic poisoning in combo with maintenance of vital signs (respiration) and decontamination (removal of clothing and washing of skin if exposed to dust and spray pesticides)
  • atropine ineffective against peripheral neuromuscular stimulation (nAChRs)
  • to regenerate AChE at NMJ, cholinesterase regenerators can be administered
40
Q

Describe cholinesterase regenerators

A
  • (ex: pralidoxime) capable of regenerating active enzyme from organophosphorus-cholinesterase complex via removal of phosphorous group from active site of enzyme (oxime group, NOH, has high affinity for phosphorous atom)
  • can restore response to stimulation of motor nerve within a few minutes following a dose of organophosphorous compound that produces total blockade of transmission
  • must be given before aging has occurred between organophosphate and cholinesterase (time-dependent process of aging further strengthens phosphorus-enzyme bond, making complex even more difficult to break)
  • current antidotal therapy for organophosphate exposure resulting from warfare, terrorism, or other source includes parenteral atropine, oxime (pralidoxime), and a benzodiazepine as an anticonvulsant
41
Q

Describe prophylaxis in AChE inhibitor poisoning

A
  • pretreatment with pyridostigmine reduces incapacitation and mortality associated with nerve agent poisoning, especially with agents such as soman that show rapid aging
  • based on animal efficacy rule, pyridostigmine approved for combat use in US military
  • approved dose is much lower than amounts used in pts with myasthenia gravis (30 mg every 8 hours vs avg 100 mg every 4 rs)
  • pyridostigmine should be discontinued at first sign of nerve gas exposure and treatment given
  • common side effects: stomach cramps, diarrhea, nausea, frequent urination, headaches, dizziness, shortness of breath, worsening of peptic ulcer, blurred vision, and watery eyes
42
Q

Describe cholinergic antagonists

A
  • divided into muscarinic and nicotinic subgroups based upon specific receptor affinities (mAChR and nAChR)
  • antinicotinic drugs elicit their effects at neuromuscular junction and on nAChRs in ganglia
  • agents that act on ganglia have limited clinical
  • most clinically useful are mAChR antagonists
  • mAChR blockers are often called parasympatholytic because they block effects of parasympathetic autonomic discharge
  • prototype antimuscarinic is atropine
43
Q

Source, chemistry, absorption, and distribution of mAChR-blocking drugs

A
  • atropine naturally occurring tertiary amine alkaloid ester found in plant Atropa belladonna
  • tertiary amines are used for their effects on eye or CNS (atropine, tropicamide, benztropine)
  • quaternary amines are charged and elicit their antimuscarinic effects in periphery (ipratropium, glycopyrrolate)
  • tertiary compounds are more readily absorbed and widely distributed than charged quaternary compounds, which are relatively free of CNS effects at low doses
44
Q

Metabolism and excretion of mAChR-blocking drugs

A
  • halflife of atropine is 2 hours. 60% excreted unchanged in urine
  • remaining 40% transformed by hydrolysis and conjugation reactions (phase I and II) and is excreted in urine
  • parasympathetic effects of antimuscarinic compounds decline rapidly in all organs except eye (ciliary muscle, iris) where effects can last for 72 hours or longer
45
Q

Mech of action of mAChR-blocking drugs

A
  • atropine is reversible antagonist of mAChRs. Blockade from small dose can be overcome by larger dose of ACh or equivalent muscarinic agonist
  • tissues most sensitive to atropine are salivary, bronchial, and sweat glands, while acid secretion by gastric parietal cells least sensitive
  • rate of onset: decrease in micturition speed and salivation at lower dose. Increase in heart rate and decrease in accommodation occur at higher dose
  • atropine antagonizes actions of all 5 mAChRs and does not distinguish between receptor types, while other antimuscarinic compounds can be selective for one or another of these subgroups
46
Q

Effects of antimuscarinic agents on CNS

A
  • At clinical doses, atropine has minimal stimulant effects on CNS (particularly parasympathetic medullary centers) and a slower, longer-lasting sedative effect on brain
  • tremor associated with Parkinson disease is reduced by centrally acting antimuscarinic compounds
  • scopolamine has more marked CNS effects producing drowsiness and amnesia (toxic doses can cause excitement, agitation, hallucinations, and coma)
  • vestibular disturbances (motion sickness) appear to involve muscarinic cholinergic transmission, and scopolamine is effective at prevention or reversal of these symptoms
47
Q

Effects of antimuscarinic agents on eye

A
  • blockade of papillary constrictor muscle mAChR activation (by atropine and other tertiary antimuscarinic agents) results in unopposed sympathetic dilator activity and mydriasis (dilation)
  • antimuscarinic agents weaken contraction of ciliary muscle (cycloplegia), which results in inability to focus for near vision (accommodation) and useful during ophthalmologic procedures
  • antiuscarinic agents reduce lacrimal secretion
48
Q

Effects of antimuscarinic agents on CV system

A
  • net CV effects of atropine in pts with normal hemodynamics are not dramatic: tachycardia may occur, but there is little effect blood pressure
  • atropine and other antimuscarinic agents prevent CV effects of administered direct-acting muscarinic agonists
  • low doses of atropine result in initial bradycardia before effects of peripheral vagal block manifest (attributed to block of presynaptic M1 receptors on parasympathetic postganglionic nerve terminals in SA node, which normally inhibit ACh release)
  • moderate to high doses of atropine cause tachycardia by blockade of vagal slowing
49
Q

Effects of antimuscarinic agents on respiratory system

A
  • smooth muscle and secretory glands of airway receive vagal innervations and contain mAChRs
  • blockade of airway mAChRs can cause bronchodilation and reduce secretion, which are positive effects in treatment of some respiratory disorders
50
Q

Effects of antimuscarinic agents on GI tract

A
  • decrease salivary secretion (reduction common side effect)
  • gastric secretion is blocked less effectively than salivary secretion. Volume and amount of acid, pepsin, and mucin are all reduced, but large doses of atropine may be required
  • pancreatic and intestinal secretions are mostly unaffected by atropine as these processes are primarily under hormonal rather than vagal control
  • gastric emptying time is prolonged, and intestinal transit time is lengthened due to inhibition of mAChRs (walls of viscera are relaxed and both tone and propulsive movements are diminished)
51
Q

Effects of antimuscarinic agents on GU tract

A
  • antimuscarinic agents relax smooth muscle of ureters and bladder wall and slow voiding, making them useful agents in treatment of urinary incontinence
  • mAChR antagonists have no significant effect on uterus
52
Q

Effects of antimuscarinic agents on sweat glands

A
  • atropine suppresses thermoregulatory sweating by inhibiting sympathetic cholinergic nerve fibers (no parasympathetic innervation of sweat glands)
  • in children, ordinary doses of antimuscarinic agents may cause “atropine fever” (body temp elevated only if large doses administered in adults)
53
Q

Effects of cholinergic antagonists on CNS disorders

A
  1. Parkinson disease
    - Less effective than standard dopaminergic therapy, antimuscarinic agents useful as adjunctive therapy in some pts
    - mAChR antagonists can reduce tremor associated with PD
    - ex: tertiary amines benztropine and trihexyphenidyl
  2. Motion sickness
    - in addition to antihistamines with antimuscarinic effects, agents that are solely antimuscarinic are useful in treating vestibular disorders
    - scopolamine is one of oldest agents for seasickness and can be administered by injection, PO, and transdermal patch
  3. Uses in anesthesia
    - atropine blocks vagal reflexes induced by surgical manipulation of visceral organs
    - atropine or glycopyrrolate is paired with neostigmine to block parasympathetic effects during reversal of skeletal muscle relaxation
54
Q

Effects of cholinergic antagonists on ophthalmologic disorders

A
  • exam of retina greatly facilitated by mydriasis, and topically administered antimuscarinic compounds (drops, ointment) useful during ophtho procedures
  • antimuscarinic agents should never be used for mydriasis unless cycloplegia or prolonged action is required (alpha-adrenergic receptor agonists are shorter-acting and produce less adverse effects)
  • mAChR antagonists (long-lasting homatropine) are used to prevetn synechia formation in uveitis and iritis (iris adheres to either lens or cornea)
55
Q

Effects of cholinergic antagonists on respiratory disorders

A
  • prior to inhalational anesthetics, which are less irritating to airways, atropine and scopolamine were useful in preoperative settings to limit increased airway secretions caused by irritant anesthetics (ether)
  • antimuscarinic agents are used to treat asthma and chronic obstructive pulmonary disorder (COPD)
  • -ipratropium is used as inhalational agent in treatment of asthma and COPD and is currently a first-line therapy
  • -recently approved agent tiotropium has a longer bronchodilator action than ipratropium (half life 120 hrs vs 2 hrs) and can be dosed once daily (vs 3-4 times/day) in pts with COPD
56
Q

Effects of cholinergic antagonists on CV disorders

A
  • antimuscarinic agents are rarely used for CV disorders on outpatient basis, although atropine is first drug of choice for symptomatic bradycardia in advanced cardiac life (ACLS) setting
  • some antimuscarinic agents are approved to treat impaired cardiac output due to depressed sinoatrial or atrioventricular node function that can result from reflex vagal discharge that sometimes accompanies myocardial infarction
  • pts with hyperactive carotid sinus reflexes that produce vagal discharge in response to pressure on neck (from tight collar) may also benefit from antimuscarinic therapy
57
Q

Effects of cholinergic antagonists on GI disorders

A
  • may be used in treatment of common traveler’s diarrhea and other mild or self-limiting conditions of hypermotility
  • often combined with opioid antidiarrheal drug to discourage abuse of opioid agent (classic ex: combo of atropine and diphenoxylate with Lomotil)
58
Q

Effects of cholinergic antagonists on urinary disorders

A
  • atropine and other antimuscarinic agents have been used to provide symptomatic relief in treatment of urinary urgency caused by inflammatory bladder disorders
  • selectivity for M3 subtype is preferred for agents that reduce urinary frequency (overactive bladder, urinary urge incontinence)
    1. Prototype is Oxybutynin, which is somewhat selective for M3 mAChRs with side effects that include dry mouth, dizziness, constipation, blurred vision, dry eyes, and UTI
    2. Trospium is nonselective antagonist that is comparable in efficacy and side effects of oxybutynin
    3. Darifenacin, solifenacin, and tolterodine are selective for M3 subtype and are advantageous because of their longer half-lives and reduced incidence of xerstomia and constipation
59
Q

Effects of cholinergic antagonists on cholinergic poisoning

A
  • severe cholinergic excess is a medical emergency that can be causd by cholinesteras inhibitor insecticides, wild mushrooms, and chemical warfare nerve gases
  • no effective treatment for nicotinic effects of cholinergic poisoning
  • tertiary antimuscarinic agents (preferably atropine) are used to treat both CNS and peripheral effects of excessive stimulation
  • in life-threatening situations, 1 g of atropine per day may be required for 1 month for full control of muscarinic excess
  • pralidoxime is a cholinesterase regenerator compound that can b usd to treat organophosphate poisoning by breaking bond between organophosphate and cholinesterase enzyme
  • pralidoxime is charged and thus is only effective in regenerating cholinesterase at neuromusclular junction
  • rapid onset poisoning caused by mushrooms is characterized entirely by signs of excess within 15-30 min (nausea, vomiting, diarrhea, urinary urgency, vasodilation, reflex tachycardia (occasionally bradycardia), sweating, salivation, and sometimes bronchoconstriction) and is adequately treated with atropine
  • atropine of no use in delayed-onset mushroom poisoning, which characterized by vomiting and nausea 6-1 hours after ingestion and cauess hepatic and renal cellular injury by amatoxins that inhibit RNA polymerase (caused by different mushrooms than those that cause cholinergic poisoning)
60
Q

Describe adverse effects and contraindications of mAChR antagonists

A
  • treatment with atropine or other antimuscarinic agents directed at one organ system typically induces undesirable effects in other (mydriasis and cycloplegia may be adverse effects of agents used to reduce micturation speed)
  • at high concentrations, atropine causes a block of all parasympathetic function (dry as a bone, blind as a bat, red as a beet, mad as a hatter, hot as a hare) but is still relatively safe in adults
  • moderate to high doses of atropine in children and infants can cause death due to hyperthermic effects
  • overdoses can be treated with cholinesterase inhibitors when necessary (physostigmine, others) but are generally treated symptomatically, such as temperature control with cooling blankets and seizure control with diazepam (benzodiazepine)
  • antimuscarinic agents contraindicated in patients with glaucoma (reduce secretions) and should be used with caution in elderly men with history of prostatic hyperplasia (difficult to differentiate between symptoms attributable to detrusor overactivity and those caused by bladder-outlet obstruction secondary to benign prostatic enlargement). Men with hyperplasia would be at risk for acute urinary retention
  • Nonselective antimuscarinic agents (atropine) should be avoided in pts with acid-peptic disease (potential to slow gastric emptying and increase discomfort). However, those that are selective may be of benefit
  • -M1 mAChR selective antimuscarinic agent pirenzepine are used to treat peptic ulcer diseas in Europe, Japan, and Canada (not approved in US due to adverse effects)
  • -Pirenzepine is selective for M1 and inhibits gastric secretion by acting at ganglia
  • -Pirenzepine has little effect on smooth muscle or CNS and doesn’t have GI and CNS associated side effects that nonspecific mAChR antagonists have
61
Q

Describe chemistry, pharmacokinetics, and mech of action of ganglion-blocking drugs

A

Chemistry/pharm:

  • all ganglion-blocking drugs are synthetic amines
  • mecamylamine (tertiary amine) was developed from initial ganglion blockers and has improved GI tract absorption

MOA:
Competitively block action of ACh and similar agonists at nAChRs of both parasympathetic and sympathetic autonomic ganglia (block all autonomic outflow)

62
Q

Describe organ system effects of ganglion-blocking drugs

A

-parasympathetic tone dominates autonomic nervous system except for vascular smooth muscle (no parasympathetic innervation). Blockers enhance sympathetic tone

CNS:
-Uncharged (mecamylamine) agents can cross BBB and cause sedation, tremor, choreiform movements and mental aberrations

Eye:

  • cycloplegia with loss of accommodation because ciliary muscle receives primarily parasympathetic innervation
  • moderate dilation of pupil because parasympathetic tone usually dominates, though iris receives both sympathetic (pupillary dilation) and parasympathetic (pupillary constriction) innervation

CV system:

  • marked decrease in arteriolar and venomotor tone, causing decrease in blood pressure due to decreased peripheral vascular resistance and venous return
  • diminished contractility and moderate tachycardia of heart

GI tract:
-reduced secretion and profoundly inhibited motility

GU system:

  • urination hesitancy and possible urinary retention in men with prostatic hyperplasia
  • erection and ejaculation may be prevented
63
Q

Clinical applications of ganglion-blocking drugs

A
  • Use is infrequent because more selective autonomic blocking agents are available and because toxicity limits willingness of pts to use these
  • mecamylamine is approved for use to treat hypertension and is being investigated for use in smoking cessation therapy

Neuro II Exam 2 (6 decks)

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