L2 ANS Flashcards
Therapeutic Uses of Cholinesterase Inhibitors for the EYE
– constriction of the pupil
– decrease intraocular pressure in open-angle glaucoma
– in cycloplegia
* ciliary muscle contracts, lens thickens, pupil constricts
* eye accommodates for near vision
Therapeutic Uses of Cholinesterase Inhibitors for the Skeletal neuromuscular junction
– nicotinic receptors
– reversal of paralysis caused by curare-like drugs
– diagnosis and treatment of myasthenia gravis
Therapeutic Uses of Cholinesterase Inhibitors for the Gastrointestinal system
– lack of normal smooth muscle tone or stretch
* lower oesophageal and gastric contraction
* paralytic ileus
Therapeutic Uses of Cholinesterase Inhibitors for the Treatment of atropine poisoning
– acute toxicity caused by atropine
* muscarinic antagonist will bind to muscarinic receptors to prevent ACh from binding so that there is more ACh
Long-acting, Irreversible Cholinesterase Inhibitor
- Organophosphates
Organophosphates
- Long acting
- Irreversible
- – insecticides and nerve gases
- Spontaneous hydrolysis of phosphorylated acetylcholinesterase very slow
- Pralidoxime re-activates phosphorylated acetylcholinesterase if administered before bonding within the enzyme ages
Organophosphates: Risks
- Insecticides – parathion
– agriculture, horticulture, urban gardening
– accidental deaths due to poisoning - Nerve gases
– sarin
– assassination, terrorist attacks
– deadly at extremely low concentrations
– toxicity due to increase ACh at cholinergic synapses
– persistent stimulation -> neurotransmission paralysis
Acute Poisoning with Cholinesterase Inhibitors
- Signs and symptoms due to activation of muscarinic and nicotinic receptors
- Death may result from respiratory failure following neuromuscular junction blockade in respiratory skeletal muscles
– bronchoconstriction, accumulation of respiratory secretions, weakened or paralysed respiratory muscles, central respiratory paralysis
– bradycardia
– sweating, salivation, lacrimation
– constriction of the pupils
– increase gastrointestinal activity (all para)
Cholinesterase Inhibitor Poisoning: Treatment
- Stop exposure to cholinesterase inhibitor to prevent further absorption
- Assist respiration
- Administer cholinergic antagonist e.g., atropine
- Administer pralidoxime in the case of organophosphate poisoning
- Administer anticonvulsant if required
- Monitor for potential cardiac irregularities
- Administer diazepam to treat agitation and provide sedation
Muscarinic Antagonists - Atropine
- Typical competitive muscarinic antagonist
- Highly soluble belladonna alkaloid from Atropa belladonna (deadly nightshade)
- Cause pupil enlargment
- Muscarinic antagonists compete with acetylcholine at the muscarinic receptor
- Atropine inhibits acetylcholine effect
Major Pharmacological Effects of Muscarinic Antagonists (Atropine)
- ↓ sweating, salivation, lacrimation
- ↓ gastrointestinal motility
- ↓ gastric acid secretion
- ↓ production of bronchial mucus in airways
- Bronchodilatation
- ↑ heart rate
- Side effects
– dry mouth & skin, urinary retention, cycloplegia, glaucoma, depression, hallucinations, ↑ body temperature
Therapeutic Uses of Muscarinic Antagonist
motion sickness
for motion of short duration
Therapeutic Uses of Muscarinic Antagonist
ophthalmology
mydriasis and cycloplegia to examine the retina
Therapeutic Uses of Muscarinic Antagonist
acute myocardial infarction
bradycardia opposed due to excess vagal tone
Therapeutic Uses of Muscarinic Antagonist
asthma
airway tone reduced
Therapeutic Uses of Muscarinic Antagonist
peptic ulcers
gastric acid secretion reduced
Therapeutic Uses of Muscarinic Antagonist
irritable bowel
spasms reduced
Therapeutic Uses of Muscarinic Antagonist
Parkinson’s disease
tremor, involuntary movements, rigidity reduced
Therapeutic Uses of Muscarinic Antagonist
premedication
airway mucus secretion decreased
Therapeutic Uses of Muscarinic Antagonist
organophosphate poisoning
antidote to poison
Treatment of Atropine Poisoning
- Gastric lavage
– prevent further absorption - Cholinesterase inhibitor
– ↑ ACh at cholinergic synapse by competing - Body temperature is lowered
– counter rise in temperature that happens with atropine
– CNS effects
– ↓ sweating - Anticonvulsant e.g., diazepam
– counter CNS effects
Noradrenergic Neurotransmission: Noradrenaline
- Primary neurotransmitter released from sympathetic autonomic neurones
- Sympathomimetic catecholamine
- Synthesised and stored in sympathetic nerves
- Released upon electrical excitation of the nerve varicosities
Catecholamine Synthesis
tyrosin (→neurones)
↓
Dihydroxyphenylalanine (cytosol)
↓
Dopamine (cytosol)
↓
Noradrenaline (vesicle)
↓
Adrenaline (adrenal medulla)
Adrenal Medulla: Adrenaline
- Inner portion of adrenal gland that sits above each kidney
- Synthesises and stores adrenaline – similar struc & func to noradrenaline
- Modified sympathetic ganglion
– innervated chromaffin cells contain adrenaline - Adrenaline is synthesised from noradrenaline by phenylethanolamine N-methyltransferase
- Adrenaline is stored in vesicles and released upon electrical stimulation of preganglionic nerves innervating the adrenal gland
Structures of Catecholamines
Structural modification of noradrenaline to produce synthetic catecholamines
– ↑ bulkiness of substituents on the N-atom
* resistance to monoamine oxidase (MAO)
– modification of catechol –OH groups
* resistance to catechol-O-methyl transferase (COMT)
Adrenoceptors: Location and Function APLHA
BV, Lung, GI, eye
- Alpha1-receptors (post-synaptic)
–bloodvessels: vasoconstriction
–lung: ↓ secretion
– GI tract: ↓ smooth muscle motility and tone
– eye: radial muscle contraction (mydriasis, dilation)
Beta-adrenoceptors: Location and Function
Heart, BV, GI, lung, eye
- Beta-receptors
– heart: ↑ rate and force of contraction
–bloodvessels: vasodilatation
– GI tract: ↓ smooth muscle motility and tone
–lung: bronchodilatation, ↑ secretion
– eye: ciliary muscle relaxation (distant vision)
Adrenoceptor agonists types
– direct-acting sympathomimetics
– indirect-acting sympathomimetics
– mixed-acting sympathomimetics
Type of adrenergic drugs
- Adrenoceptor agonist
- Adrenoceptor antagonst
- Monoamin oxidase inhibitors
Potencies of various stimulatory catecholamines alpha
noradrenaline > adrenaline > isoprenaline
Potencies of various stimulatory catecholamines beta
isoprenaline > adrenaline > noradrenaline
Adrenoceptors are classified into a or b subtypes based on what?
– molecular cloning of distinct protein moieties
– functional characteristics
– potencies of various stimulatory catecholamines
alpha-1 found where and affect what?
- primarily at postjunctional sites
- smooth muscle cells, contraction
alpha-2 found where and affect what?
- mostly on prejunctional sympathetic nerve endings
- activation inhibits noradrenaline release
- negative feedback loop
Beta-1 found where and affect what?
- Adrenoceptors in abundance in heart
- increase in heart rate and force
Beta-2 found where and affect what?
- Adrenoceptors in abundance in respiratory tract, blood vessels and liver
- relaxation of airway and vascular smooth muscle, glycogenolysis/ gluconeogenesis in the liver
Beta-3 found where and affect what?
- Adrenoceptors in adipose tissue, bladder, brain,
- potential treatment for diabetes; overactive bladder; anxiety and depression
Direct effects of an adrenoceptor agonist on an effector cell depends on what?
- receptor selectivity of the drug
- adrenoceptor profile of the cell
- cellular response to receptor activation
Relative potency at a-receptors:
NOR > ADR > ISO
Relative potency at b-receptors:
ISO > ADR > NOR
Clinical Uses of Catecholamines: Adrenaline in anaphylatic reactions
(b-adrenoceptors)
– first-line treatment for acute anaphylactic reactions caused by bee stings and drugs (e.g., penicillin)
– administered in conjunction with antihistamines and glucocorticoids
Clinical Uses of Catecholamines: Adrenaline in cardiac arrest
(b1-adrenoceptors)
– helps to restore cardiac rhythm
Clinical Uses of Catecholamines: Adrenaline in local anaesthetic solutions
(a1-adrenoceptors)
– vasoconstrictor effect
– ↑ duration of action
– ↓ risk of systemic toxicity
Amphetamine as an Indirect-Acting Sympathomimetic
- No direct agonist activity at a- or b-receptors
– release noradrenaline from nerves
– block noradrenaline uptake
– Inhibit noradrenaline metabolism - noradrenaline activates a- and/or b-receptors
Mixed-Acting Sympathomimetics: example
Ephedrine
Ephedrine as a mixed acting sympathomimetic
- Exert action by a combination
– direct actions on adrenergic receptors
– releases noradrenaline from sympathetic nerves - First orally active sympathomimetic
- Not a substrate for COMT or MAO
– prolonged duration of action - Used clinically to relieve nasal congestion
– vasoconstrictor
– pseudoephedrine is the stereoisomer l-ephedrine
Adrenoceptor Antagonists
Prevent endogenous adrenoceptor agonists from binding to and stimulating adrenoceptors
* Clinical used for alpha-1 in hypertension treatment
* Clinical use for beta-1 for treatment in angina, arrhythmia, hypertension, post-myocardial infarction etc.
* Antagonism not useful for alpha or beta -2 and has adverse effects
b-Adrenoceptor Antagonists
Prevent endogenous adrenoceptor agonists from binding to and activating b-adrenoceptors
* Used to treat cardiovascular diseases
– hypertension, angina, cardiac remodelling, myocardial infarction, heart failure, arrhythmia
Metoprolol
* different spectrum of properties
Non-Selective b-Adrenoceptor Antagonists: Adverse Effects
- Most adverse reactions are due to excessive b- adrenoceptor blockade and the greatest danger occurs when the drug is first given
- Precipitate congestive heart failure (b1-blockade)
- induce bronchoconstriction in asthmatics (b2-blockade)
- potentiate hypoglycaemia in diabetics
last point: inhibiting catecholamine-induced mobilisation of glycogen stores (b2-blockade) and masking symptoms of hypoglycaemia such as tachycardia (b1-blockade)
