Cholinergic Drugs

Autonomic nervous system drugs • classes of drugs that affect the autonomic nervous system • uses and varying actions of these drugs • how these drugs are absorbed, distributed, metabolized, and excreted • drug interactions and adverse effects of these drugs. Cholinergic drugs • promote the action of the neurotransmitter acetylcholine. • These drugs are also called parasympathomimetic drugs because they produce effects that imitate parasympathetic nerve stimulation. There are two major classes of cholinergic drugs: • Mimickers • Inhibitors • Cholinergic agonists mimic the action of the neurotransmitter acetylcholine. • Anticholinesterase drugs work by inhibiting the destruction of acetylcholine at the cholinergic receptor sites. • By directly stimulating cholinergic receptors, cholinergic agonists mimic the action of the neurotransmitter acetylcholine. cholinergic agonists include: • bethanechol • carbachol • cevimeline • pilocarpine. anticholinesterase drugs include: • Ambenonium • Edrophonium • Neostigmine • Physostigmine • pyridostigmine Pharmacokinetics • The action and metabolism of cholinergic agonists vary widely and depend on the affinity of the individual drug for muscarinic or nicotinic receptors. • Cholinergic agonists rarely are administered by I.M. or I.V. injection because • they’re almost immediately broken down by cholinesterases in the interstitial spaces between tissues and inside the blood vessels. • Moreover, they begin to work rapidly and can cause a cholinergic crisis (a drug overdose resulting in extreme muscle weakness and possibly paralysis of the muscles used in respiration). Cholinergic agonists are usually administered: • topically, with eye drops • orally • by subcutaneous (subQ) injection. **SubQ injections begin to work more rapidly than oral doses. All cholinergic agonists are metabolized by cholinesterases: • at the muscarinic and nicotinic receptor sites • in the plasma • in the liver. • All drugs in this class are excreted by the kidneys. • When a neuron in the parasympathetic nervous system is stimulated, the neurotransmitter acetylcholine is released. • Acetylcholine crosses the synapse and interacts with receptors in an adjacent neuron. • Cholinergic agonists stimulate cholinergic receptors, mimicking the action of acetylcholine. • Anticholinesterase drugs inhibit acetylcholinesterase. • As a result, acetylcholine isn’t broken down and begins to accumulate, leading to prolonged acetylcholine effects. • Cholinergic agonists work by mimicking the action of acetylcholine on the neurons in the target organs. • They bind with receptors on the cell membranes of target organs and stimulate the muscles Cholinergic agonists produce; • salivation • bradycardia (a slow heart rate) • dilation of blood vessels • constriction of the bronchioles • increased activity of the GI tract • increased tone and contraction of the bladder muscles • constriction of the pupils. Pharmacotherapeutics- Cholinergic agonists are used to: • treat atonic (weak) bladder conditions and postoperative and postpartum urine retention • treat GI disorders, such as postoperative abdominal distention and GI atony • reduce eye pressure in patients with glaucoma and during eye surgery • treat salivary gland hypofunction caused by radiation therapy or Sjögren’s syndrome. Drug interactions • Cholinergic agonists have specific interactions with other drugs. • Examples include the following: • Other cholinergic drugs, particularly anticholinesterase drugs boost the effects of cholinergic agonists and increase the risk of toxicity • Cholinergic blocking drugs such as – Atropine – belladonna – Homatropine – Methantheline – Methscopolamine – propantheline, and – Scopolamine reduce the effects of cholinergic drugs. • Quinidine reduces the effectiveness of cholinergic agonists Adverse reactions to cholinergic agonists • Because they bind with receptors in the parasympathetic nervous system, cholinergic agonists can produce adverse effects in any organ innervated by the parasympathetic nerves. These adverse effects can include: • nausea and vomiting • cramps and diarrhea • blurred vision • decreased heart rate and low blood pressure • shortness of breath • urinary frequency • increased salivation and sweating. Anticholinesterase drugs • Anticholinesterase drugs block the action of the enzyme acetylcholinesterase at cholinergic receptor sites, preventing the breakdown of acetylcholine. • As acetylcholine builds up, it continues to stimulate the cholinergic receptors • Anticholinesterase drugs are divided into two categories – reversible and – irreversible. Reversible anticholinesterase drugs have a short duration of action and include: – ambenonium – demecarium – donepezil – edrophonium – Galantamine – . – guanidine – neostigmine – physostigmine – pyridostigmine – rivastigmine – tacrine. Irreversible anticholinesterase drugs • have long-lasting effects • are used primarily as – toxic insecticides and – pesticides or – as nerve gas in chemical warfare. **Pyridostigmine enhances the effects of antidotes used to counteract nerve agents.) **Only one has therapeutic usefulness: echothiophate. Pharmacokinetics • Many of the anticholinesterase drugs are readily absorbed from the – GI tract, – subcutaneous tissue, and – mucous membranes. • Because neostigmine is poorly absorbed from the GI tract, the patient needs a higher dose when taking this drug orally. • Because the duration of action for an oral dose is longer, therefore, the patient doesn’t need to take it as frequently. • When a rapid effect is needed, neostigmine should be given by the I.M. or I.V. route. Distribution • Physostigmine can cross the blood-brain barrier. • Donepezil is highly bound to plasma proteins • tacrine is about 55% bound • rivastigmine is 40% bound, and • galantamine is 18% bound. Metabolism and excretion • Most anticholinesterase drugs are metabolized by enzymes in the plasma and excreted in urine. • Donepezil, galantamine, rivastigmine, and tacrine are metabolized in the liver. Pharmacodynamics • Anticholinesterase drugs promote the action of acetylcholine at receptor sites. • Depending on the site and the drug’s dose and duration of action, they can produce a stimulant or depressant effect on cholinergic receptors. • Reversible anticholinesterase drugs block the breakdown of acetylcholine for minutes to hours • irreversible anticholinesterase drugs do so for days or weeks. Anticholinesterase drugs are used for a variety of therapeutic purposes, including: • to reduce eye pressure in patients with glaucoma and during eye surgery • to increase bladder tone • to improve tone and peristalsis (movement) through the GI tract in patients with reduced motility or paralytic ileus (paralysis of the small intestine) • to promote muscle contractions in patients with myasthenia gravis • to diagnose myasthenia gravis (neostigmine and edrophonium) • as an antidote to cholinergic blocking drugs (also called anticholinergic drugs), tricyclic antidepressants, belladonna alkaloids, and narcotics • to treat mild to moderate dementia and enhance cognition in patients with Alzheimer’s disease (donepezil, galantamine, rivastigmine, and tacrine). Drug interactions • Other cholinergic drugs, esp cholinergic agonists increase the risk of a toxic reaction when taken with anticholinesterase drugs. • Carbamazepine, dexamethasone, rifampicin, phenytoin, and phenobarbital may increase donepezil’s rate of elimination. • Aminoglycoside antibiotics, • anesthetics, • cholinergic blocking drugs, • magnesium, • corticosteroids, and • antiarrhythmic drugs - procainamide and quinidine can reduce the effects of anticholinesterase drugs and can mask early signs of a cholinergic crisis. • Other medications with cholinergic-blocking properties e.g. – tricyclic antidepressants – bladder relaxants, and – Antipsychotics • can counteract the effects of anticholinesterase drugs. • The effects of tacrine, donepezil, and galantamine may be increased when these drugs are combined with known inhibitors of cytochrome P-450 enzymes, such as cimetidine and erythromycin. • Cigarette use increases the clearance of rivastigmine. Adverse reactions to anticholinesterase drugs • Most of the adverse reactions caused by anticholinesterase drugs result from increased action of acetylcholine at receptor sites. Adverse reactions associated with anticholinesterase drugs include: • cardiac arrhythmias • nausea and vomiting • diarrhea • shortness of breath, wheezing, or tightness in the chest • seizures • headache • anorexia • insomnia • pruritus • urinary frequency and nocturia. Cholinergic blocking drugs • Cholinergic blocking drugs interrupt parasympathetic nerve impulses in the central and autonomic nervous systems. • also referred to as anticholinergic drugs because they prevent acetylcholine from stimulating cholinergic receptors. • Cholinergic blocking drugs don’t block all cholinergic receptors • Only block the muscarinic receptor sites. • Muscarinic receptors are cholinergic receptors that are stimulated by the alkaloid muscarine and blocked by atropine. The major cholinergic blocking drugs are the belladonna alkaloids: • atropine (the prototype cholinergic blocking drug) • belladonna • homatropine • hyoscyamine • methscopolamine • scopolamine. • Synthetic derivatives of belladonna alkaloids (the quaternary ammonium drugs) include: – glycopyrrolate – propantheline. The tertiary and quaternary amines • The tertiary amines include: – benztropine – dicyclomine – Oxybutynin – trihexyphenidyl – tolterodine. • Quaternary amines – trospium..

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