Mechanism

• They bind to the β₂ receptor, which then sets of a second messenger system leading to increased activation of cAMP from ATP, leading to activated protein kinases, which ultimately results in reduced circulating Ca²⁺ and thus smooth muscle relaxation.
• They also reduce mediator release from mast cells thus reducing overall inflammation, and allowing mucous clearance (mucociliary clearance).
• The dose relationship is log linear – which means that you need a 10x increase in dose to 2x the effect.
• The effect of the drug can be seen within 5 minutes
• They have NO EFFECT on bronchial hyper-reactivity, and their effect on the underlying inflammation is limited

Examples

• Their ‘long-action’ is due to a lipophilic side chain, that will stick to part of the cell membrane next to the receptor once the drug has bound to the receptor, and literally just hold it in place for longer.

Unwanted effects

• Fine tremor – this may be present if a patient is on a high dose of these for a long period. It is unlikely that inhaler use alone will cause this, and it most common occurs in patients who are taking nebulized forms of the drugs. This results from β₂ stimulation
• Tachycardia and arrhythmia can result when high doses are taken. This is a result of β₁ and  β₂ stimulation
• Headache
• Bronchospasm can sometimes occur the first time the drug is taken.
• Oral candidiasis can occur when the drugs are used long term. Some practicioners recommend to rinse the mouth and spit after the inhaler is used to reduce the likelihood of this.
• Acute metabolic responses – these will not persist long-term, but initially can include hypokalaemia, hypomagnesaemia and hyperglycaemia.
• Tolerance can occur if you overuse them. Protein kinase A (one of the proteins activated in the 2^nd messenger system) attacks the β₂ receptor and uncouples it from its G-protein, meaning that activation of the receptor will not result in activation of the 2^nd messenger system.

• E.g. if you see someone who is having a severe asthma attack, it is not unreasonable to give them 15-20 puffs into their mouth if they cannot take it in themselves. Remember much of the dose (80%?) is deposited on the back of the throat

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The term anticholingerics can be applied to many different types of medication that have anticholingeric effects. Anticholinergics are any drug that can block Ach (acetylcholine) receptors at the synapse in the central (or peripheral) nervous system. This tends to inhibit the parasympathetic nervous system which is primary responsible for controlling involuntary smooth muscle contractions in the gut, urinary tract, lungs and sweat glands.

Anticholingerics can be further divided into:

• Antimuscarinic argents – block neurotransmitters in the ganglion cells
• Antinicotinic agents – block neurotransmitters at the neuromuscular junction
• HOWEVER – generally the term anticholingerics mainly refers to antimuscarinic agents
• The anticholinergic bornchodilaotrs (see below) tend to avoid the systemic effects as they are generally given via inhalation to reach the lungs directly

Drugs are often described as having “anticholinergic side effects”. These can include:

• Confusion / delirium
• Dry mouth
• Constipation
• Urinary retention
• Dilated pupils
• Tachycardia / arrhythmias
• Blurred vision
• Peripheral vasodilation (flushed skin)
• Hyperthermia
• Tremor / grabbing at invisible objects

LIFTL has a great flashcard on anticholingeric toxicity

Many elderly patients are on anticholingerics and they are known to exacerbate the symptoms of dementia in these patients. It is important to be mindful of prescribing these drugs in the elderly population. Particularly – the use of antipsychotics in older patients with Alzheimer’s disease , although common, is not well supported by evidence, and for most patients, ceasing these medications does not have a negative impact on function or cognitive status.

Cholinesterase inhibitors (e.g. donepezil, rivastigmine and galantamine) are medications typically given in Parkinson’s disease that can help to improve symptoms of the disease. These have the opposite effect of anticholinergics by inhibiting the enzyme acetyl cholinesterase and thus preventing the breakdown of acetylcholine. This mechanism has been shown to slightly improve cognitive function in patients with dementia, and in Australia – this is a licensed indication for these medications. Despite being antagonists of each other, co-prescribing of these two medication groups is common and you should be mindful of this.

Examples

Commonly used medications with anticholinergic effects include (in bold indicates stronger anticholingeric effects):

• Antipsychotics
  • Chlorpromazine
  • Olanzapine
  • Haloperidol
  • Prochlorperazine (Stemetil)
  • Quetiapine
  • Risperidone
• Antidepressants
  • Tricycylics (amitrptyline, doxepin)
  • SSRIs – fluoxetine, duloxetine, paroxetine, venlafaxine, desvenlafaxine, mirtazepine
• Medications for urinary incontinence
  • Oxybutynin
  • Darifenacin
  • Solefenacicn
  • Tolteradine
• Antihistamines
  • Most of them!
• Others
  • Benztropine – used to treat extrapyramidal side effects – such as those from prochlorperazine (stemetil)
  • Atropine – used to treat arrhythmia – particularly bradycardia
  • Glycopyrrolate – used to treat unwanted oral secretions. Inhaled form sometimes used in COPD

Anticholinergic Toxicity

Refers to a patient suffering the significant side effects of an excess of anticholinergics.

Anticholinergic Bronchodilators

Anticholinergic bronchodilators (aka antimuscarinic agents) are usually inhaled, but can be given IV in hospital. They are used in respiratory conditions as adjuncts to steroids and β2 receptors agonists.

• It is also worth remembering that many other medications – particularly drugs that affect the nervous system and brain have many anticholinergic side effects. These are discussed in the relevant medication articles. 

Mechanism

• They essentially bind to and block ACh receptors. ACh is the main neurotransmitter involved in muscle contraction thus by blocking its action you prevent muscle contraction.
• They are mainly used as an adjuvant to β2 agonists – they are not very effective on their own.
• They also reduce mucous secretion
• There are 3 types of muscarinic receptor, and these drugs act on them all – thus they are not selective.
• They are virtually never used in asthma, and far more commonly used in COPD. They may be used in asthma during severe exacerbations where β2 agonists are not having the desired effect.
• They have a slow onset of action (30-60m) compared to salbutamol, probably because they are poorly absorbed from the respiratory tract.
• The half-life is short (about 15 minutes) – and the half-life is due to the removal of the drug from its receptor, and not due to removal of the drug from the blood.
• Triatropium has a much longer half life of up to 3.5 hours.

Examples of anticholinergic bronchodilators

• Ipratropium – this is the main drug that it used, and it is usually inhaled
• Tiotropium – this is longer acting

Pharmacokinetics

Unwanted effects

• Dry mouth
• Nausea
• Constipation
• Headache
• Urinary retention in men (triotropium – tends to occur in men who already have a large prostate)
• Can contribute to angle-closure glaucoma

Clinical uses of anticholinergic bronchodilators

• In asthma – as an adjunct to steroids and β2-receptor agonists
• In COPD – tiotropium (longer acting) tends to be used
• In bronchospasm –brought about by β2 receptors agonists

References

• Anticholinergic and sedative medicines Prescribing considerations for people with dementia – RACGP
• LITFL – Anticholinergic syndrome
• LITFL – Anticholinergic toxidrome
• LITFL – A fumbling, mumbling mess
• Donepezil – PBS
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

Read more about our sources

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