principles of drug action cholinergic agents exam 2 Flashcards
myasthenia gravis
Myasthenia gravis is an autoimmune disorder in which the patient produces autoantibodies against the acetylcholine (ACh) receptor. These autoantibodies most frequently target the nicotinic receptors found in the motor end plate of skeletal muscle. Over time, the number of ACh receptors in the synapse is significantly reduced. Thus, the disease is characterized by weakness and fatigability of skeletal muscle. More than 50 percent of patients present with ocular problems, including ptosis and diplopia. Proximal limb muscles (hip and shoulder), as well as muscles of respiration, are frequently affected.
Glaucoma
Increased intraocular pressure.
miosis
pupillary contraction (associated with cholinergic medications)
mydriasis
dilation of the pupil of the eye. ((associated with anticholinergic medications)
cyclopelgia
The term cycloplegia refers to a paralysis of the ciliary muscle and zonules (fibrous strands connecting the ciliary body to the lens) that results in decreased accommodation (adjustment of the lens curvature for various distances) and blurred vision. (associated with anticholinergic medications)
xerostomia
Dryness of mouth. This can be due to various factors such as surgery drugs.xer
dementia
Dementia is a syndrome characterized by decline in memory. Alzheimer’s Disease is a type of Irreversible Dementia, whereas, Delirium is a type of reversible dementia.
sjogren syndrome
Sjogren’s syndrome is an autoimmune disease. This means that your immune system attacks parts of your own body by mistake. In Sjogren’s syndrome, it attacks the glands that make tears and saliva. This causes a dry mouth and dry eyes. You may have dryness in other places that need moisture, such as your nose, throat, and skin. Sjogren’s can also affect other parts of the body, including your joints, lungs, kidneys, blood vessels, digestive organs, and nerves.
urge incontinence
Urge UI (also called as persistent PUI) is involuntary voiding characterized by precipitous urine leakage, most often after the urge to void is perceived. Urge PUI can be caused by a variety of genitourinary and neurologic disorders. It most often, but not always, is associated with detrusor motor instability (involuntary contraction of the bladder) or detrusor hyper-reflexia (detrusor motor instability caused by a neurologic disorder).
overflow incontinence
Overflow incontinence occurs when the weight of urine in a distended bladder overcomes outlet resistance. Leakage of small amounts of urine (dribbling) is common throughout the day and night.
nerve gas poisining
Use of Organophosphate to irreversibly inhibit AChE
bronchospasm/COPD
A group of lung diseases that block airflow and make it difficult to breathe.
What are cholinergic Agents
Indirect-acting cholinergic agents increase the availability of acetylcholine at the cholinergic receptors
Cholinergic drug, any of various drugs that inhibit, enhance, or mimic the action of the neurotransmitter acetylcholine, the primary transmitter of nerve impulses within the parasympathetic nervous system
cholinergic agonist
Cholinergic agonists are the name given to a group of medicines that mimic the actions of acetylcholine. … Currently, cholinergic agonists are only used to increase salivation in patients who suffer from a severely dry mouth caused by radiation therapy or medical conditions such as Sjogren’s syndrome.
two types of cholinergic receptors
- Nicotinic
- Muscarinic
nicotinic recerptor
muscarinic receptor
nicotinic : Activates cholinergic receptors at nerve synapsesand on skeletal muscle
Muscarine: Activates cholinergic receptors on smoothmuscle and cardiac muscle
nicotinic receptors
The nicotinic receptor is a channel protein that, upon binding by acetylcholine, opens to allow diffusion of cations.
two ligand binding sites on the a sununits
FVIYZJ
musirinic receptor
g protein or ligand gated
g protein
Where are Cholinergic Receptors Present
CNS (Somatic ): found in skeletal muscle
Autonomic (sympatetic and parasymp): adrenal medulla found in sympathetic
N receptor found in the synapse and M receptor fornd in cardiac smooth muscles in the parasympathetic.
what is acetyl choline
Quarternary Ammonium Salt. (lipophobic)
Ester group—Easily Hydrolyzed by AchE
Low bioavailibility
How is Acetylcholine Synthesized and Released
Acetylcholine is synthesized from acetyl CoA and choline by choline acetyltransferase, stored in synaptic vesicles, and then released in response to nerve stimulation
- Nerve 1 binds to nerve two which has the cholinergic receptor
- Vesicles fuse with membrane and release Ach
transmission process cont.
- Receptor binds Ach
- Induced fit triggers 2o message
- Triggers firing of nerve 2
Ach undergoes no reaction
- Ach departs receptor
- Receptor reverts to resting state
- Ach binds to acetylcholinesterase
Ach hydrolysed by acetylcholinesterase
Choline binds to carrier protein/ Choline transported into nerve
Ach resynthesised
E 1 = Choline acetyltransferase helps transfer choline to acetylcholine
Ach repackaged in vesicles
Biosynthesis of AcetylCholine
Ach is biosynthesized by cholinergic neurons by the enzyme transfer of acetyl group from acetyl coenzyme A (acetyl-S-CoA). Some of the choline (a quaternary ammonium alcohol) is biosynthesized by amino acid Serine.
Why would someone ever use a Cholinergic Agonist as a drug.
Cholinergic drug, any of various drugs that inhibit, enhance, or mimic the action of the neurotransmitter acetylcholine, the primary transmitter of nerve impulses within the parasympathetic nervous system
Cholinergic medications are a category of pharmaceutical agents that act upon the neurotransmitter acetylcholine
These drugs bind directly to the Cholinergic MuscarinicReceptor…
Acetylcholine as an agonist
advantages and disadvantages
Disadvantages of using Acetylcholine as an agonist
- Easily hydrolysed in stomach (acid catalysed hydrolysis)
- Easily hydrolysed in blood (esterases)
- No selectivity between receptor types
- No selectivity between different target organs
- Poorly absorbed across the biological membranes.
Advantages
- Natural messenger
- Easily synthesised
Nicotine and muscarine as cholinergic agonists
disadvatge and advatnages
Advantages
- More stable than Ach
- Selective for main cholinergic receptor types
- Selective for different organs
Disadvantages
- Activate receptors for other chemical messengers
- Side effects
Requirements for cholinergic agonists
- Stability to stomach acids and esterases
- Selectivity for cholinergic receptors
- Selectivity between muscarinic and nicotinic receptors
- Knowledge of binding site
- SAR for acetylcholine
Binding of Acetylcholine on muscarinic receptors has to be reviewed
- Tight fit between Ach and binding site
- Methyl groups fit into small hydrophobic pockets
- Ester interacting by H-bonding
- Quaternary nitrogen interacting by ionic bonding
So lets study the Structure Activity Relationship (SAR) between Acetylcholine and Muscarinic receptors
Minimum of two methyl groups on quaternary nitrogen
Quaternary nitrogen is essential
If on one CH3 is replace by ethyl group the following compound is 25% active as Ach. If all the 3 CH3 groups are replaced by ethyl group the following compound is an antagonist.
Replacing –CH3 Groups with H
Replacing –CH3 groups with H leads to diminishing muscurinic activity (3o >2o > 1o amine)
•Ethylene bridge must be retained
Design of cholinergic agonists
•Correct size
•
•Correct pharmacophore - ester and quaternary nitrogen
•
•Increased stability to acid and esterases
•
•Increased selectivity
How does Acetylcholine binds to AChE
- serine and histidine are binding sites of the AchE
- nucleophillic attack on the partial positive carbon of the carbonyl group of the hydroxyl group of the serine residue
- concerted protonation of the carbonyl oxygen by an imidazole proton from a histidine residue
- This mechanism for ester hydrolysis are proposed to be invovled in the mechanism of AchE-catalyzed hydrolysis of Ach. The binding of Ach to the catalytic site of AchE which consists of an ester binding site and an anioninc binding site. This figure reflects the binding of quarternary nitrogen of Ach to an area that has been described as an anionic site on the enzyme. Initially, this site was concluded due carboxylate of the glutamate residue. The concerted protonation of the carbonyl oxygen by an imidazole proton from a histidine residue and nucleophillic attack on the partial positive carbon of the carbonyl group of the hydroxyl group of the serine residue.
Which is more stable: Acetylcholine / Acetic Acid
Acetic acid
because acetylcholine is easily hydrolyzed by AcHE
How to Stabilize Acetylcholine -
Use of Urethane Stabilizes Acetylcholine
carbochol properties
- Resistant to hydrolysis
- Long lasting
- NH2 and CH3 are equal sizes. Both fit the hydrophobic pocket
- NH2 = bio-isostere of CH3
- Muscarinic activity = nicotinic activity
Used topically for glaucoma
which cholinesterase inhibitor is short acting
endrophonium
- Main Site of Action is Neuromuscular Junction
- Too short acting for generalized therapeutic use
Lack of carbamoyl group makes less potent and shortacting
Reversible binding to ACHE and rapid renal elimination
•Used primarily to diagnose myasthenia gravis.
Muscle strength tested after administration
Marked improvement is a positive test
Which of the following drugs would you recommend for this patient for long term treatment?medium to long-lasting acetylcholinesterase inhibitors (30 min to hours).
carbamates
