ANS

Question 1

Recap the role of the ANS

Answer 1

• Activities of the ANS are not under direct conscious control
  
  • Cardiac Output
  • Blood Flow to various organs
  • Digestion
  • Smooth muscle (visceral and vascular)
  • Contraction and relaxation of smooth muscle
  • Glandular secretions
• Uses chemical transmission of information
  
  • By using drugs that mimic or block the actions of chemical transmitters we can selectively modify many autonomic functions.

Question 2

Recall the actions of cholinergic and adrenergic fibres

Answer 2

Cholinergic fibers

• Synthesize and release acetylcholine
• Almost all efferent fibers leaving the CNS are cholinergic -> release acetylcholine ->acts on muscarinic receptors
• All postganglionic parasympathetic fibres release acetylcholine -> acts on muscarinic receptors

Adrenergic fibers

• Work by releasing noradrenaline
• Almost all postganglionic sympathetic fibers release noradrenaline ->acts on alpha or beta-adrenoceptors.
• EXCEPTION sympathetic innervation of sweat glands (acetylcholine ->muscarinic receptors)

Most autonomic nerves also release co-transmitter substances

Question 3

Describe the muscarinic agonists

Answer 3

• Mimic the action of acetylcholine -Produce effects similar to parasympathetic stimulation
  
  • cardiovascular: decreases CO by decreasing HR and force of contraction
  • PVR: vasodilation
  • smooth muscle: contraction
  • exocrine glands: stimulation leading to secretion

Question 4

Describe the muscarinic antagonists,their effects and some examples of muscaranic antagonists and their use

Answer 4

• Competitively block the action of ACh at muscarinic receptors
• Peripheral anticholinergic effects
  
  • dry skin, dry mouth, mydriasis, tachycardia, urinary retention, gastrointestinal ileus (decreased bowel sounds) and hyperthermia (children).
• Central anticholinergic effects
  • hallucinations, delirium, agitation, aggression and, occasionally, sedation and seizures.
• atropine targets cardiovascular system and is indicated in symptomatic bradycardia
• hyoscine targets GI and is indicated in motion sickness and abdominal cramps
• glycopyrolate targets oral and is indicated in drying up oral secretion e.g. in palliation and perioperatively
• tropicamide targets ocular and is indicated in pupil dilation i.e. for eye examination
• ipratropium targets respiratory and is indicated in bronchodilation
• oxybutinin targets genitourinary and is indicated in urinary incontinence
• benztropine targets peripheral smooth muscle and central NS, and is indicated in treatment of parkinsonism with antipsychotic medications

Question 5

Describe anticholinergic side effects

Answer 5

Many medications have anticholinergic side effects (even if those whose primary mechanism is not targeting the PNS). There is a very specific set of symptoms (or toxidrome) that occurs when patients are suffering from too much anticholinergic effect.
- anticholinergic toxidrome: hyperthermia, blind, mydriasis, confusion, dry mouth ad urinary retention, shaking, grabbing invisible objects, tachycardia, absent bowel sounds, flushed skin

Drugs with anticholinergic adverse effects include:
- antispasmodics e.g. hyoscine and atropine
- antidepressants e.g. amitriptylline (other tricyclics)
- antiparkinsonian eg. benztropine
- antipsychotic e.g. chlorpromazine
- antihistamines e.g. chlorphenamine
- others e.g. bladder instability e.g. oxybutynin, antiemetic e.g. cyclizine

Question 6

Describe anticholinesterases

Answer 6

these increase cholinergic activity and acetylcholine concentrations, by inhibiting the metabolic breakdown of acetylcholine by cholinesterases.

Used for conditions such as:

• Alzheimer’s disease
  • Donepezil, galantamine, rivastigmine
• Myasthenia Gravis
  • pyridostigmine
• Reversal of neuromuscular block after anaesthesia
  • Neostigmine
• Also used in pesticides:
  • Organophosphate anticholinesterases

Short acting drugs reversibly bind to anionic target site and are hydrolysed quickly e.g. donepezil and Galantamine.

Medium acting drugs bind to both anionic and esteratic sites and hydrolyse at a slower rate increasing duration of action

Bind to the esteratic site and inactivate the enzyme (new enzyme must be made)
e.g. neostigmine, pyridostigmine, rivastigmine.

Irreversible drugs bind to the esteratic site and inactivate the enzyme (new enzyme must be made). e.g. pesticides and chemical warfare agents

Side effects of anticholinesterases are cholinergic effects including:
- increased GI motility: diarrhoea and increased saliva
- pupillary miosis
- bradycardia
- vivid dreams, muscle cramps, peptic ulcer disease, rarely seizures

Question 7

Descrube drugs used in Alzheimer’s disease

Answer 7

Accumulation of beta-amyloid peptide appears to be central to the degenerative changes seen in the brain in Alzheimer’s disease. It results in the destruction of cholinergic neurones and a fall in acetylcholine concentration.

None of the available drugs prevent Alzheimer’s disease or modify its pathology.

Anticholinesterases and memantine (not an anticholinesterase) show, at best, modest efficacy in improving cognition and/or reducing the rate of cognitive and functional decline; their clinical usefulness and effect on quality of life remains uncertain.

• A beneficial effect, if any, is generally observed within 3–6months of starting treatment.
• The optimal duration of treatment with these drugs is unclear; use ongoing assessment of benefit and adverse effects to guide continuation of treatment

Question 8

Describe memantine, donepazil, galantamine, rivastigmine

Answer 8

Memantine
Antagonist of N-methyl-D-aspartate (NMDA)which may reduce glutamate-induced neuronal degradation. Alzheimer’s disease is thought to be associated with excess glutamate.

For moderate-to-severe Alzheimerdisease.

There are conflicting data on whether memantine provides benefit when added to a cholinesterase inhibitor in patients who are deteriorating following an initial response to a cholinesterase inhibitor.

SEs: Confusion, dizziness, drowsiness, headache, insomnia, agitation, hallucinations, dyspnoea, hypersensitivity, GIT upset, hypertonia, VTE, seizures, rash, renal failure, cholestatic hepatitis, heart failure, bradycardia.

Donepezil
Synthetic reversible inhibitor of acetacholinesterase (AChE).

• High selectivity for neuronal AChE

Short acting

Metabolised by CYP2D6 and CYP3A4 (consider drug interactions)

Neuroleptic malignant syndrome (unique to donepazil)

GIT upset, vivid dreams, muscle cramps, seizures, peptic ulcer disease, seizures, heart block.

Galantamine

Inhibitor of AChE and allosteric modulator (enhancer) of nicotinic acetylcholine receptors.

Short acting

Metabolised by CYP2D6 and CYP3A4 (consider drug interactions)

Hypersensitivity, serious skin reactions (unique to galantamine); adverse effects same as donepezil

Rivastigmine
Reversible inhibitor AChE

High lipid solubility ->crosses BBB

Longer acting

Hydrolysis by cholinesterase - not metabolised by CYP enzymes

Skin hypersensitivity (at patch site); adverse effects same as donepazil

Question 9

Describe catecholamines and adrenaline

Answer 9

Catechlamines

• Act on adrenoceptors to cause general physiological changes in the body that prepare for the “_fight or flight”_response
• 3 pharmacologically significant endogenous catecholamines in the body
  
  • Dopamine – metabolic precursor of noradrenaline and adrenaline
  • Noradrenaline – neurotransmitter between sympathetic postganglionic nerves and organs they innervate (adrenergic transmission)
  • Adrenaline – hormone secreted by adrenal medulla

Noradrenaline

• Once noradrenalinehas bound to an adrenoceptor its action must be rapidly terminated to prevent prolongation of its effects
• 3 mechanisms aid in this process:
  
  • 1. Reuptake into nerve terminals occurs via NET transporter at presynaptic membrane
  • 2. Uptake into extraneuronal cells via ENT transporter ->then metabolised
  • 3. Diffusion into the bloodstream and metabolism at non-neuronal sites

Question 10

Describe the adrenergic agonists

Answer 10

• Direct acting – aka sympathomimetic drugs
• Directly STIMULATE alpha and beta adrenoceptors mimicking the effects of sympathetic stimulation

Alpha1 agonists most important action is on vascular smooth muscle ->strong vasoconstriction

• ↑central venous pressure, ↑peripheral vascular resistance->↑Systolic and Diastolic arterial pressure & ↑cardiac work and output

Beta agonists stimulation in most cases causes relaxation of smooth muscle (beta 2) or stimulation of cardiac contractility (beta 1).

Question 11

Describe the adrenergic antagonists

Answer 11

Compete with catecholamines for binding at adrenoceptors and INHIBIT sympathetic stimulation

• Selective antagonists
• Non-selective alpha-1 and alpha-2 antagonists
• Non-selective alpha-1 and beta antagonists
• Ergot Alkaloids

Alpha-1 adrenoceptor antagonists

↓ PVR as a result of inhibition of catecholamine-induced vasoconstriction

• Minor ↑ HR
• Does not cause ↑ NA release from nerve terminals
  • Due to negligible alpha-2 adrenoceptor antagonist
• Less issues with postural hypotension
• Prazosin
• Non-selective alpha 1 and 2 antagonists (phenoxybenzamine and phentolamine are used for phaeochromocytoma)

Beta-adrenoceptor antagonists:

Competitively block the actions of catecholamines

• Beta-1 –located in the heart
  
  • Beta-1 selective blockers AKA cardioselective blockers ->receptors located on the heart
  • High doses selectivity diminishes
  • Atenolol, betaxolol, bisoprolol, metoprolol, nebivolol
• Beta-2 - smooth muscle
  
  • Non-selective (beta-1 & beta-2 receptors)
  • All contraindicated in asthma due to inhibition of bronchodilation mediated by beta-2 adrenoceptors
  • Carvedilol (also alpha), labetalol(also alpha), propranolol, sotaolol, timolol
• Intrinsic sympathomimetic activity (ISA)
  
  • Causes partial stimulation of beta receptors
  • Thought to reduce AE howevernot established
  • Oxprenolol, pindolol