Indirectly acting adrenergic agents
These drugs doesn’t act directly on adrenergic receptors instead increase the norepinephrine levels within the synaptic cleft thereby increase adrenergic transmission.
This can be achieved by two mechanisms.
- Displacement of norepinephrine from storage vesicles
- Inhibition of uptake
Displacement from storage vesicles
Two drugs working by ths mechanism are amphetamine and tyramine.
Amphetamine is a modified structure of catechol amines with absence of catechol and alky hydroxyl groups and additional methyl group as side chain.
Amphetamine is basically a CNS stimulant which can be further modified into several derivatives like methamphetamine and dextromethamphetamine all show high euphoria hence act as drugs of abuse. So usage of this drug is under strict regulations and we will see the pharmacology of this drug more detailed in the section.
Tyramine is a dietary amine present in various foods like cheese, meet, soya sauce, chocolate and fish. Structurally it is a simple decarboxylated product of tyrosine. It displaces norepinephrine from storage vesicles and thereby increases adrenergic transmission. One of the important effects of tyramine is on blood vessels increasing the blood pressure.
Since it has mono amine group, it is metabolised by monoamine oxidase enzyme within the gut wall. Not only tyramine any dietary mono amine is metabolised by MAO enzyme.
Note: MAO enzyme is of two types, MAO-A and MAO-B. Former is mainly present within the cytoplasm of monoaminergic presynaptic neurons and responsible for metabolism of free monoamines within the cytosol. On the other hand, MAO-B is present in the plasma and gut wall and responsible for metabolism of dietary amines.
In presence of MAO inhibitors, tyramine present in the diet is not metabolised by MAO-B leading to accumulation of tyramine in the body. This accumulated tyramine levels suddenly increase noradrenergic transmission resulting in severe hypertension, hyperthermia and muscle rigidity which are fatal to patient. This serious drug and food interaction is called as cheese reaction.
Note: Cheese reaction is mainly shown by non-selective MAO inhibitors which inhibit both MAO-A and MAO-B. Selective MAO inhibitors like moclobemide show less risk as they doesn't inhibit MAO-B enzyme.
Tyramine is not used as drug instead it can be employed as flavouring agent.
Inhibition of uptake
Drugs like cocaine and tricyclic antidepressants increase adrenergic transmission by inhibition of uptake1. Tricyclic antidepressants also work by inhibition of serotonine uptake. Again these drugs are centrally acting and produce CNS stimulation.
Cocaine is obtained from dried leaves of Eryhtroxylon coca which produces high euphoria and therefore acts as drug of abuse.
Many of the actions of cocaine are unwanted and include
- High euphoria
It also blocks voltage gated sodium channels leading to local anaesthesia. It also produces nasal decongestion but due to euphoric and sympathetic effects it is not preferred for this use.
So, currently cocaine use only limited to local anaesthetic effect.