Cholinergic Drugs Flashcards
What is a cholinergic drug?
-substance that produces the same effect as Acetylcholine
Direct acting cholinergic drugs?
-stimulate cholinergic receptors
- synthetic- esters of choline (Bethanechol, Carbachol)
- natural- acetylcholine (eyes), alkaloids (nicotine, pilocarpine), marijuana
Indirect acting cholinergic drugs?
-function to elevate endogenous levels of ACh
- inhibition of acetylcholinesterase
- prevents ACh breakdown
- reversible, competitive, short acting
- irreversible, noncompetitive - enhanced release of ACh
- done via Guanidine
Acetylcholine as a drug?
Clinical use:
- short duration of action
- non specific cholinergic drug, affects all receptors muscarinic and nicotinic
- highly susceptible to acetylcholinesterase
Miochol:
- ACh for intraocular use
- causes smooth muscle of iris to contract (pupil constriction)
- duration of action 10-20 mins
ADR:
-burning and itching eyes along with headache
-some ACh makes it to systemic circulation when injected into eyes
Methacholine?
- somewhat susceptible acetylcholinesterase
- acts on muscarinic receptors only
- longer duration of action
Carbachol?
- synthetic choline ester, direct acting cholinergic
- acts on muscarinic and nicotinic receptors
- not degraded by acetylcholinesterase
Clinical use:
- treat open angle glaucoma (intraocular pressure)
- duration is up to 8 hours
Mechanism:
-pupillary constriction causes opening, allowing aqueous humor to exit via Canal of Schlemm
ADR:
- flushing
- sweating
- cramping
- increased GI activity (urination)
- severe headache
- systemic effects
Bethanechol?
- synthetic choline ester, direct acting cholinergic
- acts only on muscarinic receptors
- not degrade by acetylcholinesterase
Effects:
- increases GI peristalsis and defecation
- increases detrusor muscle tone
- stimulates urination
Clinical use:
- non obstructive urinary retention
- neurogenic atony of urinary bladder (loss of muscle tone)
- post op abdominal distention
ADR:
- flushing
- sweating
- cramping
- increased GI activity
- urinary urgency
- severe headache
- salivation
When not to use drug (contraindication):
- asthma like attacks (those with asthma are given anticholinergic drugs)
- parksonism (increasing ACh, diminishes the balance between Dopamine)
- usual ANS responses to systemic ACh (ADR above)
Pilocarpine?
- natural, direct acting cholinergic
- cholinomimetic alkaloid, precursor of ACh
Effects:
- contraction of ciliary muscle, pupil constriction
- decreases intraocular pressure
- systemic salivation, sweating
- bradycardia
Clinical use:
- treat open and narrow angle glaucoma
- reversal of mydriatics (dilation) after eye exam
- ocular therapeutic system- unit inserted into conjunctival sac for continuous release of pilocarpine to open angle glaucoma (for elderly patients, could cause infections)
Nicotine?
- natural, direct acting cholinergic
- cholinomimetic alkaloid
Effects:
- activates receptors in ANS ganglia, neuromuscular junctions, adrenal medulla, and brain
- causes people to become physically dependent, not carcinogenic
- stimulates cerebral cortex (alertness, cognition increase)
- stimulates limbic system (reward and pleasure)
- Tachycardia
- peripheral vasoconstriction (net effect of sym and parasym)
Clinical use:
-helps someone quit smoking (could OD if smoking still)
ADR:
- hypertension from tachycardia
- Buergers disease- interference of circulation due to vasoconstriction
- diarrhea
- insomnia
- increase cognition
- dysmenorrhea
Varenicline (Chantix)?
- partial agonist of nicotinic receptors, weaker than nicotine
- increases cholinergic system
- blocks nicotine, releases Dopamine
- could cause schizophrenia, bipolar disorder, depression
Cholinergic crisis?
-see sawing between cholinergic and anticholinergic drugs
Effects:
- sweating
- increased bronchial and salivary secretions
- bradycardia
- muscle weakness (overstimulation)
Physostigmine (Antilirium)?
- short acting, reversible, indirect acting cholinergic
- inhibit acetylcholinesterase
- topical, systemic
- highly lipid soluble, tertiary structure, can cross BBB
Clinical use:
- treat open angle glaucoma
- reverse myadriasis from anticholinergic
- antidote to toxic neurological effects caused by having central anticholinergic activity (Scopolamine, antidepressants)
- clinical trials in treatment of alzheimers, short half life, slight increase in memory performance
ADR:
- typical systemic reactions
- bradycardia
- diaphoresis
- bronochospasm
- respiratory paralysis (overstimulation of muscles and too much ACh, can’t get repolarization and relaxation)
Edrophonium?
- short acting, reversible, indirect acting cholinergic
- inhibit acetylcholinesterase
- given by IV
Clinical use:
- diagnose Myasthenia Gravis (autoimmune disease)
- treat poisoning of non depolarizing skeletal muscle relaxants
- test for cholinergic OD in those with Myasthenia
Neostigmine?
- short acting, reversible, indirect acting cholinergic
- inhibit acetylcholinesterase
- quaternary compound, does not cross BBB
Clinical use:
- treat Myasthenia Gravis
- treat poisoning of nondepolarizing skeletal muscle relaxants
- reverse neuromuscular blocking agent used for surgeries
Pyridostigmine?
- short acting, reversible, indirect acting cholinergic
- inhibit acetylcholinestase
Clinical use:
- treat myasthenia gravis
- treat poisoning of non depolarizing skeletal muscle relaxants
- occupies receptors so irreversible nerve gas does not damage
ADR:
- increased salivary secretions
- sweating
- GI and urinary functions increase
- may lose ability to control GI and urinary
How do indirect acting irreversible cholinergic drug work?
- cause permanent inactivation of acetylcholinesterase via phosphorylation
- remains impaired until new enzymes are synthesized (weeks or months)
- chemical warfare, pesticides
- very lipid soluble, must wear gloves
Echothiophate?
- irreversible, indirect acting cholinergic
- inactivate acetylcholinesterase
- long duration of action, may persist weeks
Clinical use:
- treat glaucoma
- pupillary constriction, miosis
- angle closure after an iridectomy (remove part of iris)
Isoflurophate?
- irreversible, indirect acting cholinergic
- inactivate acetylcholinesterase
- similar to echothiophate
- water insoluble, readily absorbed into skin, systemic effects
Clinical use:
-maintenance therapy for glaucoma applied every 8-72 hours
Pralidoxine?
-cholinesterase inhibitor antidote
Mechanism:
-disrupts bond between phosphorous group of irreversible enzyme inhibitor and binding site of cholinesterase enzyme
Clinical use:
-treat OD of irreversible cholinesterase inhibitor due to insecticide poisoning
Guanidine?
- indirect acting cholinergic
- stimulates release of endogenous ACh
- relatively high toxicity
Clinical use:
- alleviate muscle weakness in myasthenia gravis
- alleviate symptoms of Eaton Lambert syndrome (muscle cancer)
ADR:
- diarrhea
- abdominal cramping
- tachycardia
- rash and bone marrow depression
- anemia
What changes occur to cholinergic neurons as people age?
- reduced activity of choline acetylcholine transferase
- reduced synthesis of ACh
- reduced responsiveness of post synaptic M1 receptors in frontal cortex and hippocampus
- loss of cortical neurons
How does a person reduce risk of losing memory/alzheimers?
-keep brains active and engaged to strengthen synapses
Additional neuronal changes seen in patients with alzheimers?
- increased deposition of beta amyloid protein
- reduced number of synapses
- reduced activity of acetylcholinesterase
- possible genetic factors
- can also develop due to head trauma - exposure to excessive aluminum
Lecithin (phosphatidylcholine)?
- drug to try to increase synthesis of ACh
- precursor of ACh
- 26 mg daily PO
Effects:
- increase levels of ACh in central synapses
- reduces tardive dyskinesia
- increase in plasma choline levels
- no improvement in memory or cognition in alzheimers patients, presynaptic uptake of choline may be impaired
- therapeutic only when combined with Physostigmine or Tacrine
4-Aminopyridine (4-AP)?
- drug to try to increase release of ACh
- used in clinical trials for treatment of alzheimers
Mechanism:
- blocks K+ channels
- reduces K+ exiting the cell
- longer time to repolarize the cell
- increased calcium influx, increased vesicle fusion
- increased release of ACh
Effects:
- could improve memory and cognition
- placebo effect
ADR:
- xerostomia (dry mouth)
- disorientation
- confusion
Treatments to reduce alzheimers?
Enhance cholinergic activity
- increase synthesis of ACh
- increase release of ACh
- reduce catabolism of ACh (primary method)
Tacrine (tetrahydroaminoacridine, THA, Cognex)?
- centrally acting reversible cholinesterase agent
- inhibits acetylcholinesterase
- short half life (2-4 hours)
- dose 40-120 mg daily PO
Effects:
-increase cognitive performance
ADR:
-HEPATOTOXIC (increase bilirubin)
Donepezil (Aricept)?
- centrally acting reversible anti cholinesterase agent
- inhibits acetylcholinesterase
- long half life (70 hours), less frequent dosing, lower rate of ADR
- first product approved by FDA for treatment of dementia and alzheimers
Effects:
- cognitive improvement (disappears when drug therapy is withdrawn)
- NOT HEPATOTOXIC
ADR:
- diarrhea
- anorexia
- muscle cramps
- insomnia
Rivastigmine?
Effects:
-inhibits acetylcholinesterase and butyrylcholinesterase
Clinical use:
-treats mild to moderate dementia of alzheimers
Galantamine?
Effects:
- inhibits acetylcholinesterase
- stimulates nicotinic receptors at sites different from those of acetylcholine
- enhances action of nicotinic receptors in presence of acetylcholine
- stimulates central cholinergic sites without causing concomitant desensitization
Clinical use:
-treat alzheimers, dementia
Memantine?
- Glutamate is excitatory and acts as NMDA receptor
- in some alzheimers, there is over activity of NMDA which may be tearing down receptors
- this promotes excess calcium influx which cause synaptic or dendritic damage, necrosis or apoptosis
Mechanism:
-Memantine binds to NMDA receptor and noncompetitively blocks it
Effects:
- slows progression of alzheimers
- may reduce pain
Deferoxamine?
Effects:
- approved as iron chelator to treat acute iron intoxication and chronic iron overload
- may reduce aluminum levels in bones of patients presenting with renal failure, patients with dialysis induced encephalopathy
Clinical use:
- drug to treat alzheimers
- use parenteral form
- could slow rate of cognitive deterioration
ADR:
- hearing loss
- impaired vision
- diarrhea
- leg cramps
- tachycardia
- reversible upon discontinuation
1-Deprenyl?
Effects:
- irreversible inhibitor of MAO-B
- stops degradation of ACh in presynaptic membrane
- slows degeneration in patients with Parkinson’s
- improves cognition
- additive with cholinesterase inhibitors
Clinical use:
- help treat alzheimer’s
- alzheimers may be caused by free radicals
- combine with Tacrine or Physostigmine
- dose 10mg daily PO
