Lecture summary Flashcards
What is the postganglionic sympathetic neurotransmitter?
NE (ACh in sweat glands and arterioles)
postganglionic parasymp. neurotransmitter?
ACh
What is the neurotransm. at the NMJunction?
ACh
What is the neurotransm at the presynaptic synapse in both the SNS and PNS?
ACh
Drugs that mimic NE
fight/flight responses
Heart rate UP
Drugs that mimic ACh
rest/digest responses
Heart rate DOWN
Precursors of ACh
Choline (diet) + Acetyl CoA
Where is ACh made?
Liver then goes to nerve terminal.
Done by high affinity Na- choline co-transporter
Inhibition of ACh synthesis
HEMICHOLINIUM (inhibits choline transporter)
Inhibition of ACh vesicular transporter?
VESAMICOL
By what mechanism is ACh released into the synaptic cleft?
Ca-dependent exocytosis
what breaks down ACh?
acetylcholinesterases-acetate and choline
Blockade of cholinesterase enzymes eg. Neostigmine (indirect)
increased autonomic activity but primary with increased cholinergic effects
At postganglionic nerve terminal with increased stimulation of muscarinic receptors, enhancing synaptic cholinergic activity, causing excessive salivation, bradycardia, bronchospasm and hypotension
increasing NMJ activity with muscle fasciculation and twitching and may result in a depolarisation block and paralysis
3 places where muscarinic receptors are located?
Cardiac
Smooth muscle
Exocrine glands
Nicotinic receptors: where?
Ganglia
Adrenal glands
NMJ
What is the precursor of NE
L-tyrosine
What is the rate limiting step of cat synthesis
Tyrosine hydroxylase
How is NE created from dopamine?
dopamine is formed in the cytoplasm of the nerve terminal is actively transported by vesicle transporter (VMAT: Vesicular MonoAmine Transporter) into the storage vesicle, where it is converted to norepinephrine by the enzyme dopamine beta-hydroxylase
Reserpine
Adrenergic blocking agent-blocks catecholamine STORAGE
ANTIHYPERTENSIVE
Adrenergic homeostasis
- Negative feedback: high NE in cytosol=inhibition of tyrosine hydroxylase
- NE binds to alpha2 receptors
- NET transporter for reuptake
- Diffusion and metabolism
Metyrosine
Blocks NE synthesis (Blocks tyrosine hydroxylase)
Anti-hypertensive
Muscarinic ACh receptors
GPCRs
Nicotinic ACh receptors
ligand-gated
ACh receptors 2
Muscarinic and Nicotinic
Adrenergic receptors 2
Alpha and Beta
7-transmembrane GPCRs
Alpha receptors
a1: postsynaptic
a2: presynaptic
Beta receptors
b1: heart, intestinal smooth muscle
b2: bronchial, vasc, uterine smooth muscle
b3: fat
Muscle contraction
a1, a2
Muscle relaxation
a1,a2,b2
Increase heart rate and contraction force
b1
PNS and bronchi
bronchoconstriction
PNS and bladder
contracts
Cholinergic drugs
Direct and indirect acting
Direct cholinergic
Choline esters and natural alkaloids
Indirect cholinergic
Anti-cholinesterase
Choline ester
Bethanechol-longer half life ACh, not hydrolysed by cholinesterase
MUSCARINIC
Natural alkaloid
Pilocarpine-closed angle glaucome
Anticholinesterases
do not cross BBB-no central effects
4 reversible anticholinesterases
EDROPHONIUM
Neostigmine
Physostigmine
Pyridostigmine
Closed angle glaucoma
angle between cornea and iris is abnorm. small
raised IOP
3 drugs that reduce IOP
- Pilocarpine-contracts ciliary muscle, aqueous outflow increased
- Timolol-beta blocker, it block B-2 receptors on the ciliary processes and reduce aqueous production. They may block vessels supplying the ciliary processes. The resulting vasoconstriction produces reduced ultrafiltration and aqueous formation.
- Brimonidine-reduce aqueous production.
Alpha 2 adrenoceptor agonists, they decrease aqueous by stimulating alpha 2 adrenoceptors on the adrenergic nerve terminal innervating the ciliary body
Myasthenia Gravis
autoimmune-induced decrease (70-90%) in the number of nAChRs at the NMJ
Immediate and diagnostic treatment MG
Edrophonium
then Neostigmine and Pyridostigmine longterm (NM transmission rather than autonomic NS)
Adverse effects AChE inhib.
too much ACh symptoms D-diarrhoea U-urination M-miosis B-bronchoconstriction E-excitation L-lacrimation S-salivation and sweating
Anticholinergic drug
Antimuscarinic
Nonselective
Atropine
Cholinergic ANTAGs
atropine: OP poisoning, muscarinic receptors, HR incr, mydriasis
(PRALIDOXIME ALSO IN OP POISONING-CHOLINESTERASE regen)
scopolamine: increase HR, mydriasis
Ipatropium bromide: anticholinergic, bronchodilator, nasal agent
Nicotine recep antag
Pancuronium-inhibit skeletal muscle contraction
Muscarinic recep antag
Glycopyrrolate – antimuscarinic/bronchodilator; used for reversal of neuromuscular blockade (preop)
Oxybutynin – antimuscarinic/urinary antispasmodic (urge incont)
Imipramine – TCA with strong antimuscarinic action, reduces incontinence
Sympathomimetics
Sympathomimetics agonists may directly activate their adrenoceptors OR they may act indirectly to increase concentration of endogenous catecholamine transmitter in the synapse
Indirectly acting sympathomimetics
Amphetamine derivatives and tyramine causes the release of the stored catecholimines
TCA and Coke: don’t like NET
Directly acting sympathomimetics-non-cats
Clonidine (alpha 2 agonist-decr NE, decr BP)
what does clonidine treat?
Resistant hypertension
Sympathomimetics-
Direct acting
ALPHA 1
Phenylephrine – topical to eye for mydriasis and nasal decongestant
Sympathomimetics-
Direct acting
ALPHA 2
Clonidine (anxiolytic, sedation, antihypertensive),
methyldopa (antihypertensive),
oxymetazoline (nasal decongestant)
Sympathomimetics-
Direct acting
ALPHA 1 AND 2
Phenylpropanolamine (nasal decongestants)
Sympathomimetics-
Direct acting
BETA 1
Dobutamine
mild α1 properties and greater inotropic than chronotropic effect
Sympathomimetics-
Direct acting
BETA 2
Salbutamol
Formoterol, Salmeterol (LABA)
(asthma, pre-term labour)
Epinephrine: topical
adjuvant of local anaes.
glaucoma
bleeding
Epinephrine: systemic
Cardiac arrest
Anaphylactic shock
Acute bronchial asthma
Amphetamine
CNS stimulant
Indirectly acting sympathomimetic
Amphetamine increases the release of norepinephrine, dopamine and serotonin from nerve terminal
Amphetamines bind to presynaptic membrane transporters responsible for the reuptake of norepinephrine ( NET), dopamine ( DAT) and serotonin ( SERT)
Uptake of amphetamine resulting in efflux of these monoamines from the cytoplasmic pool into extracellular space
Amphetamine causes the intracellular vesicular release of catecholamines within the nerve terminal causing redistribution of monoamines from the storage vesicles into the cytoplasmic pool
The will be release of NE in the synaptic junction
Tyramine
Tyramine is an indirectly acting sympathomimetic ( a by-product of tyrosine metabolism)
Mechanism of action
Tyramine is taken up into nerve terminals by NET ( the norepinephrine reuptake transporter) and causes the release of cetacholamines. It is because of the feverse transport of NET
The effects of tyramine are increased in the presence of MAO inhibitors. MAO present in the nerve terminals metabolises both cytosolic amines such as NE as well as Tyramine converting them into inactive metabolites
Normally the bioavailability of dietary tyramine ( present in red wine and cheese) is relatively low due to the expression of MAO in the GUT tract and liver. When MAO is inhibited, high level of tyramine is absorbed , resulting in a “Hypertensive crisis” due to the release of NE from nerve terminals
Alpha receptor antagonist
alpha 1: prazosin (BPH)
Doxazosin-HPT, BPH
Tamsulosin
Beta recep antagonist
non-selective 1st gen: timolol-Glaucoma, HPT
non-selective 3rd gen: carvedilol
non-selective: propanolol (lipophilic)-HPT, MI, AP, hyperthyroid, migraine
Beta 1: atenolol, IHD
alpha and beta antag
Carvedilol (hypertension, congestive heart failure) and Labetalol (hypertensive crisis)
TCAs
These are important group of antidepressants in clinical practice, include amitriptyline and imipramine
TCA adverse effect profile is due to their ability to block muscarinic receptors, alpha 1 adrenoceptors and histamine receptors H1.
Anticholinergic effects atropine like effects, blurred vision, urinary retention, dry mouth
Sympathetic effects postural hypotension, reflex tachcardia
Histamine antagonism leading to sedation
