Chemical Mediators 1 Flashcards
What is chemical transmission?
In order to coordinate the diverse actions of the
body, communications between cells is necessary,
and major mechanism for mediating this involves
discrete chemical substances
Chemical signalling molecules:
1.)neurotransmitters
2.)hormones
3.)local transmitters (autacoids)
1.)Neurotransmitters
They mediate rapid, specific and short-lived actions.
Confined to the nervous system and are released from nerve terminals at specialized junctions called synapse.
Typically, nerve action potential causes depolarisation of the pre-synaptic nerve terminal leading to an enhancement of the Ca2+ permeability of the membrane.
The resulting Ca2+ influx facilitates the release of neurotransmitter by exocytosis.
The released neurotransmitter then diffuses a short distance across the synaptic cleft and elicit its effects through the activation of postsynaptic receptors.
The neurotransmitter is then inactivated either by enzymatic degradation or by uptake into the presynaptic terminal, or in many cases a combination of both.
Pharmacologically, many agents commonly affect neurotransmission by modulating any one of these processes.
How are neurotransmitters classified?
-Excitatory
-Inhibitory
However, some transmitters are excitatory at one synapse and inhibitory at another: eg Acetylcholine is excitatory at the neuromuscular junction but inhibitory on the heart.
Since the actions of neurotransmitters on nerve cells are determined by the post-synaptic receptors to which they bind and not by the transmitter itself, they are usually grouped according to chemical structure.
Classification of transmitters by chemical structure
TYPE I: Amino acids eg GABA (gamma amino butyric acid), glutamate and glycine
TYPE II: Ach, monoamines eg serotonin, adrenaline and purines (eg ATP). Sometimes called the ‘classical’ transmitters
TYPE III: Neuropeptides - opioids eg endorphin and non-opioids eg oxytocin, arg-vasopressin.
Peripheral Neurotransmission
Acetylcholine (Ach) and Noradrenaline (NA) are important peripheral neurotransmitters.
Ach & NA are the two important neurotransmitters in the autonomic nervous system (ANS).
Acetylcholine and noradrenaline as transmitters in the peripheral nervous system. The main two types of ACh receptor, nicotinic (nic) and muscarinic (mus), are indicated. NA, noradrenaline (norepinephrine).
How is acetylcholine released?
Is released from all preganglionic autonomic nerves, postganglionic parasympathetic nerves and from nerves innervating the adrenal medulla.
Is also released from some postganglionic sympathetic nerves innervating sweat glands, piloreceptor muscles and some blood vessels supplying skeletal muscles.
Acetylcholine as a transmitter:
Also found in the CNS.
ACh is made in the terminal, from acetyl-CoA and choline
Stored in vesicles, ready for release
Degraded in synapse by enzyme acetylcholinesterase (AChE)
Presynaptic terminal recycles the choline (active reuptake)
Cholinergic nerve transmission:
In nerve terminal mitochondria
pyruvate——->AcCoA—->citrate
Citrate diffuses out into cytoplasm, where it is converted (by citrate lysase enzyme) into oxaloacetate and AcCoA
AcCoA then undergoes conversion shown in diagram (CholineAcetylTransferase ChAT enzyme makes ACh)
ACh goes into vesicles, and is released, binds to receptors, is broken down by AChE, and reuptake occurs for recycling
In the autonomic nervous system, Ach acts at both nicotinic and muscarinic ach receptors
Drugs can influence cholinergic transmission
either by acting on postsynaptic ACh receptors as agonists or antagonists, or by affecting the release or destruction of endogenous Ach:
muscarinic agonists (parasympathomimetic)
muscarinic antagonists
ganglion-stimulating drugs
ganglion-blocking drugs
neuromuscular-blocking drugs
anticholinesterases and other drugs that enhance cholinergic transmission.
Muscarine:
Muscarine was isolated from Amanita Muscaria (Wild Mushrooms)
10,000 cases per year
Muscarine poisoning
5,000 mushroom species
100 “bad”, 10 “deadly”
Muscarine, agonist used to distinguish between these two classes of receptors. Not normally found in the body.
Ach, natural agonist of muscarinic and
nicotinic receptors.
Muscarinic receptors:
Muscarinic receptors (mAChRs) are those membrane-bound acetylcholine receptors that are more sensitive to muscarine than to nicotine.Those for which the contrary is true are known as nicotinic acetylcholine receptors (nAChRs).
The mAChRs are a type of G protein-coupled receptor
Muscarinic Ach Receptors:
7 transmembrane
- M1 -autonomic ganglia, CNS
- M2 -heart
- M3 -smooth muscle, glands
- M4, M5—– possibly in the CNS
- M135 act as excitatory ↑ PLC through PI-IP3-DAG pathway
M24 acts inhibitory ↓AC- cAMP pathway
- All G-protein coupled receptors
Muscarinic effects on organ systems
• Heart (M2)
- ↓ HR, ↓ contractility, ↓conduction velocity
• - vasodilation: (M3) thro release of nitric oxide (NO)
• Other smooth muscle (M3)
• - Eye: pinpoint pupil (miosis), focus for near vision
• - GI-tract: ↑tone to intestine, bladder, ↓ tone to sphincters
• - Lung: contract bronchial SM. → ↑resistance, ↑ secretions
• - Exocrine glands:
↑ sweating (M3), ↑ salivation (M3), ↑ gastric acid secretion (M1)
Muscarinic receptor agonists:
Main use clinically in treating glaucoma:
Choline esters
- ACH (muscarinic & nicotinic action)
- *bethanechol (muscarinic action, oral or sc, never iv or im → urinary retension)
- methacholine (not common)
- carbachol (muscarinic & nicotinic)
• Alkaloids:
- muscarine (mushrooms)
- *pilocarpine (used in glaucoma)
- oxotremorine (synthetic) CNS action (basal ganglia)
• Uses:
- ophthalmic (Ach, brief miosis)
- diagnostic for bronchial hyperactivity (methacholine)
- urinary retention (bethanechol)
- reverse GIT depression by causing contraction (bethanechol)
*Only bethanechol and pilocarpine are now used clinically.
Adverse Reactions - Cholinergics
Adverse reactions: (SLUDE)
- Salivation
- Lacrimation
- Urination
- Diarrhoea
- Emesis (vomiting)
- cardiac slowing (arrest, esp. bethanechol)
- nausea, cramps
- bronchoconstriction, can precipitate asthma
- involuntary defecation
- tremor, CNS induced convulsions
Non-selective muscarinic Ach receptor antagonists
used in the treatment of:
Parkinson’s disease (eg. Benzhexol, benztropine or orphenadrine)
Asthma (eg ipratropium, oxitropium)
Cardiac arrhythmias (eg, atropine)
Adverse effects (anticholinergic effects):
Dry mouth, urinary retention, constipation & sedation
What are mAChR Blockers/Agonists are used for?
pupil dilation (atropine) (M1-M5 antagonist)
motion sickness (scopolamine) (M1 antagonist)
asthma treatment (ipratropium) (M1-M5 antagonist)
Ophthalmic surgery (carbachol, pilocarpine)(M1-M5 agonist
Nicotinic Ach receptors:
3 main classes:
Muscle type—skeletal NMJ
Ganglionic type—involved in transmission at symp & parasym ganglia
CNS type—widespread in the brain
All are ligand-gated ion channels
Have pentameric structure
Difference in the composition of subunits, and their pharmacology
Nicotinic Ach receptor subs-types: Muscle type
Main molecular form: α1)2β1δε(adult form),
Main synaptic location: Skeletal neuromuscular junction: mainly postsynaptic
Membrane response: Excitatory Increased cation permeability (mainly Na+, K+)
Agonist: Acetylcholine Carbachol Succinylcholine
Antagonist: Tubocurarine, Pancuronium, Atracurium, Vecuronium, α-Bungarotoxin, α-Conotoxin
Nicotinic Ach receptor subs-types: Ganglion type
Main molecular form: (α3)2(β4)3
Main synaptic location: Autonomic ganglia: mainly postsynaptic
Membrane response: Excitatory Increased cation permeability (mainly Na+, K+)
Agonist: Acetylcholine , Carbachol, Nicotine, Epibatidine, Dimethylphenyl-piperazinium
Antagonist: Mecamylamine , Trimetaphan , Hexamethonium α-Conotoxin
Nicotinic Ach receptor subs-types: CNS type
Main molecular form: (α4)2(β2)3
Main synaptic location: Many brain regions: pre- and postsynaptic
Membrane response: Pre- and postsynaptic excitationIncreased cation permeability(mainly Na+, K+)
Agonists: Nicotine, Epibatidine, Acetylcholine, Cytosine
Antagonist: Mecamylamine Methylaconitine
Nicotinic Ach receptor subs-types: CNS type
Main molecular form: (α7)5
Main synaptic location: Many brain regions: pre- and postsynaptic
Membrane response: Pre- and postsynaptic excitationIncreased Ca2+ permeability
Agonist: EpibatidineDimethylphenyl-piperazinium
Antagonist: α-Bungarotoxinα-ConotoxinMethylaconitine
Nicotine and lobeline:
Nicotine and lobeline are tertiary amines found in the leaves of tobacco and lobelia plants, respectively
Only nicotine is used clinically (to help people to stop smoking.
Nicotinic receptors are the little ‘beasts’ in the advertisements for smoking cessation; these receptors are stimulated by nicotine absorbed from cigarette smoke, which is highly addictive. Supplying nicotine via a skin patch or gum helps to moderate the urge to smoke another cigarette and so aids the ‘quitter’.
In the past Lobeline was used for smoking as a deterrent agent which acts similar to nicotine but at high dose induces emesis/nausea.
Drugs affecting autonomic ganglia: ganglion stimulants
Ganglion stimulants:
Most nAChR agonists affect both ganglionic and motor endplate receptors, but nicotine, lobeline and dimethylphenylpiperazinium (DMPP) affect ganglia preferentially.
Drugs affecting autonomic ganglia: Ganglion blocking drugs:
Ganglion block is often used in experimental studies on the autonomic nervous system but is of little clinical importance.
It can occur by several mechanisms:
By interference with ACh release, as at the neuromuscular junction. Botulinum toxin and hemicholinium work in this way.
By prolonged depolarisation. Nicotine can block ganglia, after initial stimulation, in this way, as can ACh itself if cholinesterase is inhibited so that it can exert a continuing action on the postsynaptic membrane.
By interference with the postsynaptic action of ACh.
The few ganglion-blocking drugs of practical importance act by blocking neuronal nAChRs or the associated ion channels.
Hexamethonium, although no longer used, deserves recognition as the first effective antihypertensive agent. The only ganglion-blocking drug currently in clinical use is trimetaphan (controlled hypotension in surgery)
Neuromuscular blocking drugs:
Drugs can block neuromuscular transmission either by acting presynaptically to inhibit ACh synthesis or release, or by acting postsynaptically, the latter being the site of action of all the clinically important drugs (except for botulinum toxin.
Clinically used only as an adjunct to anaesthesia, when artificial ventilation is available; it is not a therapeutic intervention.
Drugs that interfere with the postsynaptic action of ACh fall into two categories (Reminder):
1. non-depolarising blocking agents (the majority), which act by blocking ACh receptors (and, in some cases, also by blocking ion channels)
2. depolarising blocking agents, which are agonists at ACh receptors, such as Suxamethonium.
Non depolarising blocking drugs:
Mechanism of action
All act as competitive antagonists at the ACh receptors of the endplate (nicotinic receptors).
Non-depolarising effects can be reversed by anticholinesterases.
Some non-depolarising blocking agents also appear to block presynaptic autoreceptors, and thus inhibit the release of ACh during repetitive stimulation of the motor nerve.
Depolarising blocking drugs
Depolarising Blocking drugs:
These drugs cause a prolonged depolarisation of the end plate membrane. Eg suxamethonium.
Since the depolarisation lasts a long time, the junction does not return to its resting state after an action potential, and no further action potentials are able to stimulate the muscle.
The blockade of nerve transmission will be intensified if there is more acetylcholine at the junction, so the anticholinesterases enhance this type of neuromuscular block.
Drugs that act presynaptically:
Drugs that inhibit Ach synthesis :
In the synthesis of Ach, the rate-limiting process appears to be the transport of choline into the nerve terminal.
Hemicholinium blocks this transport and thereby inhibits ACh synthesis.
It is useful as an experimental tool but has no clinical applications.
Its blocking effect on transmission develops slowly, as the existing stores of ACh become depleted.
Drugs that inhibit Ach release:
Acetylcholine release by a nerve impulse involves the entry of Ca2+ into the nerve terminal; the increase in [Ca2+]i stimulates exocytosis and increases the rate of release.
Agents that inhibit Ca2+ entry include Mg2+ and various aminoglycoside antibiotics (e.g. streptomycin and neomycin), which occasionally produce muscle paralysis as an unwanted side effect when used clinically.
Two potent neurotoxins, namely botulinum toxin and β-bungarotoxin, act specifically to inhibit ACh release.
Drugs that enhance cholinergic transmission
(Indirectly-Acting Parasympathomimetics)
Drugs that enhance cholinergic transmission act either by inhibiting cholinesterase or by increasing ACh release, pseudocholinesterase
4.Inhibitors of cholinesterase:
- Reversible inhibitors (eg. physostigmine)
- Irreversible inhibitors (eg. organophosphates)
