A6. Adrenergic transmission and its presynaptic modification Flashcards
List the steps in the adrenergic transmission.
- Tyrosine → DOPA (dihydroxyphenylalanine) via Tyrosine Hydroxylase. Rate limiting step. • Metyrosine inhibits here, antihypertensive effect
- DOPA → dopamine (DA) via DOPA decarboxylase enzyme. Dopamine is the first active monoamine / catecholamine in this process. • Carbidopa, Benserazide inhibit here (peripherally)
- Dopamine is transported into a vesicle via VMAT (vesicular monoamine active transporter) • Reserpine inhibits here - an outdated antihypertensive
- Inside the vesicle, dopamine → norepinephrine (NE) via dopamine- β-hydroxylase
- An action potential triggers vesicular release • Guanethidine, Debrisoquine, and Bretylium inhibit here
- NE acts locally on as a neurotransmitter on alpha or beta receptors. • [Alternatively: in some cells in the adrenal medulla NE is converted to epinephrine which functions as hormone rather than just a neurotransmitter]
- Termination: 2 options • NE can be reuptaken into the presynaptic cleft (*most common pathway*) and then 2 other options: o Re-enters vesicle (NE completely recycled) o Broken down by monoamine oxidase (MAO) enzymes in mitochondria • Broken down in presynaptic cleft by COMT, then oxidized again by MAOs.
Adrenergic receptors:
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Presynaptic stimulation:
provides additional norepinephrine (NE), epinephrine (Epi), and dopamine (DA) • L-DOPA: providing more substrate increases synthesis of dopamine and other products. Used for Parkinson’s. o Importantly, this substrate is used instead of tyrosine because tyrosine hydroxylase is the rate-limiting step and is already working at its maximum rate. • Reuptake inhibitors: o NE and DA reuptake inhibitors: Cocaine, Bupropion • Cocaine of causes strong sympathetic response with euphoria. Buprenorphine is an anti-depressant that can also be used to help quit smoking o Antidepressants: all covered later • tricyclic antidepressants (e.g. amitriptyline) • selective norepinephrine reuptake inhibitors (reboxetine, atomoxetine) • selective serotonin-norepinephrine reuptake inhibitors (venlafaxine). 18 • Indirect sympathomimetics: “monoamine releasers” → calcium-independent exocytosis of NE. [also in topic A10] o Tyramine: very similar structure to dopamine. Exists in cheese and red wine, but not normally a problem because intestinal monoamine oxidases (MAOs) degrade it. However, if someone is taking MAO inhibitors (MAOIs), then ingesting these foods can cause a hypertensive crisis. o Ephedrines: Ephedrine, Pseudoephedrine, Norephedrine. Also have some weak α and β agonism o Amphetamines: Amphetamine, Methamphetamine, Dexedrine • Also release dopamine. Can easily cross BBB, making them abusable drugs (dopamine in limbic system → feeling of reward) • Most of these are used for ADHD and narcolepsy. Used to be used for weight loss (suppress appetite) • Cause hypertension, tachycardia • Methylphenidate (better known as Ritalin) has similar effects despite different structure. • MDMA (ecstasy): has some stronger dopamine and serotonergic effects, club drug. Not used medically. • Alpha 2 antagonists: α2 → presynaptic inhibition of NE-releasing neurons. o Mirtazapine, Mianserine: These drugs are atypical antidepressants, have some other effects on serotonin. o Yohimbine: not really used in human medicine. Large dose also inhibits α1 • MAO inhibitors: aka MAOIs. Allow norepinephrine to persist in the nerve terminal. Remember the risk of tyramine toxicity (sometimes called “cheese effect”) mentioned earlier. o MAO-A is used to degrade dopamine, tyramine, serotonin, NE, and epinephrine o MAO-B is used to degrade dopamine, tyramine, norepinephrine, epinephrine (importantly not serotonin) o Irreversible inhibitors: • Non-selective: Phenelzine. Not really used, but still licensed. • MAO-A blocker: Clorgyline • MAO-B blockers: Selegeline, Rasagiline. Used to treat Parkinson’s. o Reversible blocker: only one is Moclobemide, an MAO-A blocker. Used as an anti-depressant
Presynaptic inhibition:
• Tyrosine hydroxylase inhibitor: metyrosine. inhibits whole process, including dopamine • DOPAdecarboxylaseinhibitors:Carbidopa,Benserazide o Used to treat Parkinson’s: these drugs only work peripherally and therefore prevent peripheral consumption of the supplemented L-DOPA that people with Parkinson’s must take. Allows more L-DOPA to enter the CNS. • VMAT inhibition: Reserpine. Could be used for hypertension but isn’t anymore. Risk of depression and Parkinson’s o [Side effects of this drug → monoamine theory of depression. NE and dopamine clearly have a role in depression.] • False transmitters: α-methyl-DOPA o converted to α-methyl norepinephrine, which agonizes α2 receptors + has no effect on α1 receptors o can be used to treat hypertension during pregnancy. side effects: sedation, dry mouth (similar to clonidine) • Adrenergic neuron blockers: Guanethidine, Debrisoquine, Bretylium o Can be used for hypertension, but it’s rare o Cause an initial increase in blood pressure, then afterwards a longer-lasting decrease in BP o Bretylium also inhibits K+ channels (class III anti-arrhythmic) • α2 agonists: also anti-hypertensive drugs. Most important is Clonidine, but also guanfacine and guanabenz o Mechanisms of action (MOA)s: - see all in topic A10. • Enhanced negative feedback: Clonidine activates presynaptic α2 receptors which are on both sympathetic and the parasympathetic nervous system (affects the side effect profile). • Central α2 Effects - medullary postsynaptic α2 agonism > ↓ sympathetic + ↑ vagal tone • Imidazoline 1-receptor Agonism - medullary imidazoline receptor agonism also ↓ sympathetic vasomotor effects. Some imidazole receptor agonist drugs: Moxonidine, Rilmenidine. o Side effects: sedation, dry mouth, constipation (note these are parasympatholytic effects) • Apparently it can initially increase blood pressure when given intravenously – before it reaches CNS it may act at periphery to cause hypertension. Relates to a competition question.
