Lecture 28/29 Flashcards
Anticholinesterase - Masserano
Cholinesterase Characterisitcs
- Two main forms, 54% identical
1. ACh-terase - membrane bound, ACh specific, responsible for rapid ACh hydrolysis at cholinergic synapses
2. Butyrylcholinesterase (Pseudocholinesterase) - non-selective, occurs in plasma and many tissues - Both are serine hydrolases (esterases)
- Many prodrugs are designed to be hydrolyzed via this pathway
Pseudocholinesterases
- AKA plasma cholinesterases, false cholinesterases, serum cholinesterases, and butyrylcholinesterases
- Widely distributed, especially in liver and plasma with exception of RBCs
- Broader spectrum of chemical substances
- Synthesized in liver
Liver Disease + Pseudocholinesterases
- Acute/chronic hepatitus - shows a 30-50% decrease in the Pseudoch.
- Advanced cirrhosis/carcinomas - shows a 50-70% decrease in the Pseudoch.
- This could lead to increased half lives of drugs metabolized by this enzyme
Enzyme Function - Pseudochol.
-Genetic Alterations
-1:3000 people have homogeneous atypical genes for Pseudoch., autosomal recessive inheritance, tested to find
-Decreased levels lead to decreased hydrolysis of drugs that are metabolized this way which increases their therapeutic effect
EX: Succinylcholine (muscle relaxation) apnea for 60-120 minutes, Pilocarpine causing prolonged muscarinic activation, Procacine and Cocaine (30-50%) increased effect and toxicity
Drug Toxicities
- 30-50% of injected cocaine is rapidly metabolized by Pseudochol. in liver
- Decreased hepatic perfusion (hypotension, CHF) increases cocaine levels
- Decreased pseudochol. activity increases cocaine levels (babies, pregnant, geriatric)
- Genetic deficiency of pseudochol. increases cocaine levels
- Puts them at an increased risk of toxicity and sudden death due to sensitivity of small doses
- *Also explains use of cholinesterase inhibitors (carbamates or organophosphates) with cocaine to increase its effects and abuse it**
AChE
- “True” cholinesterase or eryhtrocyte cholinesterase
- Maintains homeostasis and metabolizes potent toxins like venom, insecticides, and chemical weapons
- Found in RBC, entire chol. NS, and other tissues
- Main function is hydrolysis of ACh released from nerves
- Located mainly in neurons on post-synaptic membrane and some in axonal presynaptic membranes
- High concentration in skeletal muscle synapse (fast reactions)
Binding Sites
- Hydrophobic products on anionic binding regions, N+ reacts with aspartate
- Ester binding region includes tyrosine, histadine, and serine
- Induced fit strains ACh and weakens bonds
- Positioned for reaction with serine
Mechanism of ACh Hydrolysis
- AChE anionic pocket binds to amine of ACh by electrostatic attraction
- Acetyl (ester) carbon of ACh goes through nucleophilic attack by serine’s hydroxyl
- Intermediate formed and decomposed to acetylated enzyme conjugate and choline
- Deacetylation step of hydrolysis is rate limiting
AChE Inhibitors
- One of the fastest neuronal enzyme reactions
- When inhibited, ACh builds up in synapse and produces an enhanced, prolonged response
- Enzyme inhibitor = same effect as cholinergic agonist (ACh can’t leave, so it returns to receptor and activates it)
AChE Drug Types
- 3 types
- Based on duration of action with enzyme
1. Short-acting Anti-ChE
2. Medium-druation Anti-ChE
3. Irreversible Anti-ChE
Short-Acting Anti-ChE
- Enrophonium (Enlon) is an example
- Quaternary ammonium compound
- Binds anionic pocket only and is reversible, brief action (2-10) minutes, used to diagnose myasthenia gravis
Medium-Duration Anti-ChE
- Neostigmine (Prostigmine) and Pyrodostigmine (Mestinon, Regonol) are examples
- All quarternary ammonium compounds , carbamyl ester binds to anionic site and is transferred to serine, but this is slower to hydrolyze than acetate (30 mins - 6 hours)
- Physostigmine (Eserine) - tertiary amine, used to treat anticholinergic drug toxicity, may precipitate seizures (small potential benefit v.s. risk)
Irreversible Anti-ChE
- Echothiophate
- Liable group like fluoride or organic group
- Released, leaving same -OH group phosphorylated with no spontaneous hydrolysis on serine
- Need to synthesize new enzyme to continue action, can take days
Non-Selective Cholinesterase Inhibitors
- Stimulation of muscarinic receptor - in autonomic effector organs
- Stimulation followed by depression or paralysis of all autonomic ganglia and skeletal muscle (nicotinic)
- Stimulation of cholinergic sites in CNS
Therapeutic Doses = More Selective
- Quaternary Ammonium can’t penetrate all membranes readily like CNS and has a preferential effect on NMJ of skeletal muscle (some direct action)
- Lipid soluble molecules affect CNS and PNS, which can be absorbed by the lungs and skin easily
Anti-ChE Drug Action Sites
- Eye
- Intestine
- NMJ
- CNS
Eye +Anti-ChE Drug
- Echothiophate (Phospholine)
- Contract ciliary muscle and pupil sphincter to produce miosis, rarely used since irreversible
- Used to treat glaucoma
- Onset ranges from hours to days
- IOP decreases by facilitating outflow of aqueous humor
- Reserved for those intolerant or not responding to other treatments due to systemic effects
GI Tract
- Neostigmine used for this site
- Increases secretion of gastric acid
- Enhances gastric contractions
- Lower portions of esophagus is stimulated and increased sphincter tone and peristalsis in patients with achalasia and dilation of esophagus
- Augments motor activity of large and small intestine, can increase propulsive waves in those with ileus
NMJ
- Quarternary Ammonium - direct effect on skeletal muscle, produces contraction (Ex: Neostigmine), each nerve impulse to the muscle gives rise to a single wave of depolarization since ACh is rapidly metabolized
- Cholinesterase Inhibitor prolong ACh action and availability and potentiates muscle contraction
NMJ Uses
- Removes competitive neuromuscarinic blocking agents
- Therapy in myasthenia gravis
* *Potential side effects = DUMBELS**
Pesticides
- Inhibit cholinesterases
- Organophosphates - inhibit irreversibly, “aging of complex” (treat early if possible), AChE must be resynthezides
- Carbamates - inhibit temporarily, no”aging”, reversible (rapid and dose related), AChE reactivates
Sources of Organophosphorous Pesticides
-Garden sheds
-Baits
-Shampoos for lice
-Pet preparations
-Terrorism/warfare
-Industrial/occupational
Acute Symptoms: DUMBELS + 3 Bs, hypotension, cardiac arrhythmia, respiratory failure, CNS (seizures), muscle weakness/paralysis
Treatment for Organophosphorous Poisoning
- Pyridostigmine - FDA-approved for prophylaxis against soman, an organophosphorous that rapidly “ages” after binding inhibitor of ChE
- Atropine IV - cholinergic muscarinic inhibition, titrate to clear chest on auscultations with resolution of bronchorrhea and heart rate of more than 80 b/min
- Oxmes Infusion - continuous until recovery, Pralidoxime chloride (protopram), use early before aging of reaction (or irreversible)
- Benzos, IV - treat agitation and seizures
- Decontamination - dermal spills (wash patient with soap and water and discard clothes), gastric lavage (within 1-2 hours when airway protected), activated charcoal (within 1-2 hours)
Therapeutic Uses of Anti-ChE Drugs
- Myasthenia Gravis
- Alzheimer’s Disease
- Reversal of NM blockade made by non-depolarized blocks
- Opthalmic - increasing aq. humor outflow (Echothiophate, irreversible)
- Atropine-type anticholinergic toxicities - reverses muscarinic blockage (Physostigmine, enters CNS)
- Relieves urinary retention by increasing tone of detrusor muscle (neostigmine)
- Increasing gastric tone and motility (neostigmine)
Myasthenia Gravis
-Autoimmune disorder from autoantibodies against nicotinic ACh receptors at NMJ
-Causes weakness and fatigue
-Bimodal peak of incidence:
1st peak = 3rd decade (mainly women)
2nd peal = 6-7th decade (mainly men)
Myasthenia Gravis Stages of Severity
- Ocular myasthenia - confined to ocular muscles
- Generalized myas. grav. of mild/moderate intensity
- Severe generalized
- Myasthenic crisis with respiratory failure
NMJ + Myasthenia Gravis
- Autoimmune attack of postsynaptic membrane
1. Decreases the number of ACh receptors
2. Shortening of synaptic folds
3. Widening of synaptic clefts
Myasthenia Gravis Therapies
-Edrophonium (Tensilon, Ensilon) - increases ACh in jxn
Uses
1. Diagnosis of mya. gra. (agent of choice), transiently increases muscle strength
2. Emergency treatment for mya. gra. crisis
3. Reversal of neuromuscular blockage produced by non-depolarizing blockers
Endophonium
- Quarternary ammonium has phenolic hydroxyl group that binds to enzyme
- Available IM or IV
- Little GI absorption
- Duration of action - 5-15 minutes
- Side Effects - SLUD, Bradycardia, Bronchoconstriction
Drug Interactions - Endophonium
- Other AChE compounds, potentiation of effects that can cause cholinergic crisis
- NMJ blocker Succinylcholine - could prolong blockage
- Digitalis, Pilocarpine - slows heart rate (additive vagus nerve)
Endophonium Contraindication
- Asthmatics
- Urinary or intestinal obstructions
Neostigmine (Prostimine)
- Oral: 15-375 mg each day, ~10 tablets/day
- Poor oral absorption, quarternary amine
- Doesn’t cross BBB
- Metabolized by pseudochol.
- Duration 0.5-2 hours
Neostigmine Uses
- Treating myas. grav. (injection form available too)
2. Relieves urinary retention by increasing tone of detrusor muscle and increasing gastric tone and motility
Neostigmine Side Effects
- Exaggerating pharmacologic effects - salivation and fasciculation (muscle twitching)
- Bowel cramp and diarrhea (DUMBELS) can also occur
Neostigmine Methylsulfate
- IM or SC - 0.25-0.5 mg
1. Sympathetic control of myas. gra. when oral is impractical
2. Prevent/treat post-operative gastric distention and urinary retention after mechanical obstruction is excluded
3. Reversal of non-depolarizing NM blocking agent effects post-surgery
Pyridostigmine (Mestinon, Regonol)
- Duration is 3-4 hours
1. Mya. gra. with mild muscle weakness use with corticosteroids for moderate to severe impairment, MOST USED FOR MYA. GRA.
2. Prophylaxis drug in Gulf War - potential nerve gas, 30 mg PO q8h, suspected agent of Persian Gulf War Syndrome
Pyridostigmine Side Effects
Standard dose - Fasiculations
High dose - muscle weakness, myscarinic effects - camps, diarrhea
-Use hyoscyamine as needed (anticholinergic)
-Hospital emergency - IV (1/2 oral dose) may cause bronchial secretions and cardiac arrhythmia
Physostigmine (Eserine)
- Crosses BBB, tertiary amine carbamyl ester
- Metabolized by pseudochol.
- Duration 0.5-2 hours
Physostigmine Side Effects/Contraindications
- Similar to Edrophonium but more severe due to increased duration and potency
- Contraindications - asthma, CV disease, urinary/intestinal block
Physostigmine Therapeutic Uses
- IV to reverse CNS effect from agents causing anticholinergic syndrome - reverses muscarinic blockage since increased ACh is competitive for receptor
- Opthalmic - glaucoma, increases aqueous humor outflow which decreases IOP (Echothiophate)
Mya. Gravis Therapy
- Graded approach with mild or initial symptoms managed with ChE inhibitors
- Progresses to oral immunosuppressants
- Most drugs have onset of action that take weeks to months (long term treatment)
Drugs + Clinical Effects
Pyridostigmine ==> 10-15 minutes
Prednisone ==> 2-8 weeks
Cyclosporine ==> 2-6 months
Azathioprine ==> 3-18 months
Immunomodulating Therapies
- Corticosteroids - Prednisone decreases ACh receptor antibody levels (60-100 mg/day, alternate dosing days). Side effects - weight gain, decreased bone density, and GI irritation
- Azathioprine, Cyclosporine, Tacrolimus, Mycophenolate - inhibit T & B lymphocytes and IL2
- Also plasmapheresis, IV immunoglobulin
Alzheimer Disease
- Most common cause of dementia (over half of cases)
- Progesses over 3-10 years, loss of memory, cognitive impairment, can become immobile and mute
Alzheimer Associations
- Sporadic - (~90%), increased risk if ApoE4 carrier
- Familial mutation of amyloid precursor protein (APP)
- Associated with Down Syndrome - trisomy 21
Alzheimer Risk and Protective Factors
- Risk: age, head trauma, menopause, low education
- Protective: anti-inflammatory, antioxidants, higher levels of education, physical activity
Amyloid-B Production Pathways
- Intracellular neurofibrillary fibrals
- Extracellular peptide amyloid senile plaques
Anti-ChE Drugs + Alzheimers
- Cholinergic hypothesis is that activation of this neural process decreases memory loss significantly
1. Link of progressive cholinergic neurons and cholinergic transmission within cortex and memory loss
2. Inhibitor of AChE improves cholinergic transmissions - 3 Anti-ChE inhibitors approved by FDA for mild to moderate Alz. - Donepezil (Aricept) and Rivastigmine (Exelon)
- May goes as far to benefit ALL dementia patients
Memory Emphasis
- Drugs delay cognitive decline that would occur within 6-12 months if not treated
- Patients and caregivers set different treatment goals
- Ability to treat slow, progressive changes, not to expect dramatic memory improvement
- *DOESN’T REVERSE ALZ**
Antichol Drug + Alz
- No proof of efficacy of one over another
- Rivastigmine patch may be more CNS selective with less N/V with its extended release
- Adverse effects: peripheral cholinergic effects, N/V, anorexia, diarrhea, bradycardia, some effects develop tolerances over time (slowly dose titrate to avoid these effects)
Drugs to Avoid with Anticholinergics
- TCA
- Antiemetics
- Antiparkinson
- Anticholinergics
- Antipsychotics
- Anxiolytics (Benzos)
- Antihistamines
Glutamatergic Transmission
- Learning and memory
- Overstimulation of glutamate receptors leads to neurodegeneration
- Over release of glutamate can cause calcium influx and neuron death
- Antagonist of NMDA receptor - neuroprotective
NMDA Receptor Antagonist - Memantine
- Prevent or slow the rate of memory loss in Vascular -associated & Alzheimer’s dementia, even in moderate to severe cognitive losses
- Well tolerated with few adverse events, low probability for drug-drug interactions, good for the elderly
- Side effects: confusion, agitation, restlessness, may be indistinguishable from Alzheimer’s symptoms
- High dose can produce ketamine of PCP-like effects (confusion, hallucinations, stupor)
