Indirect sympathomimetics

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Indirect Sympathomimetics are drugs that mimic the effects of the autonomic nervous system. Indirect sympathomimetics enhance the actions of endogenous catecholamines which are epinephrine, norepinephrine, and dopamine by two main mechanisms: displacing them from nerve endings or inhibiting their reuptake or metabolism, leading to increased catecholamine concentration at the synapse.

Adrenergic neurons transport tyrosine into the nerve ending, which is then converted to L-dopa and eventually, to dopamine. The conversion of tyrosine to L-dopa can be blocked by metyrosine. Catecholamines are stored in vesicles inside the nerve terminal and once inside, dopamine is converted to norepinephrine. The transport of catecholamines into the vesicle can be blocked by the vesicular monoamine transporter (VMAT), which can itself be inhibited by reserpine. Synaptic transmission is discontinued by neurotransmitter diffusion or reuptake, and the transporters for this include the norepinephrine transporter (NET) and the dopamine transporter (DAT). Cocaine is an indirect sympathomimetic that inhibits both NET and DAT, leading to accumulation of neurotransmitters at synapses.

Indirect-acting sympathomimetics can also work by displacing stored catecholamines from the nerve ending, as is the case with amphetamines. They have wide-ranging effects, from alerting to sleep deferring actions, and are used to treat conditions like ADHD (methylphenidate) and narcolepsy(modafinil).

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What are indirect sympathomimetics and what cells do they act on?

Indirect sympathomimetics are drugs that stimulate the sympathetic nervous system indirectly by causing the release of the neurotransmitters norepinephrine and dopamine. These neurotransmitters are stored in vesicles in the presynaptic neuron. The adrenergic nerve terminal is the primary site of action of these sympathomimetics.

How does cocaine interact with the norepinephrine and dopamine transporters?

Cocaine is an indirect sympathomimetic that inhibits the norepinephrine transporter (NET) and dopamine transporter (DAT). This inhibition prevents norepinephrine and dopamine from being transported back into the presynaptic neuron, thus amplifying and prolonging their effects in the synapse. This is the physiological basis for the stimulant and euphoric effects of cocaine.

How can indirect sympathomimetics such as amphetamines and atomoxetine be used therapeutically?

Indirect sympathomimetics can be used to treat a number of conditions. Amphetamines, for instance, displace catecholamines into the synapse and can be used to treat attention deficit hyperactivity disorder (ADHD). Atomoxetine, another indirect sympathomimetic, is also effective at treating ADHD by inhibiting the norepinephrine transporter (NET), thus increasing the availability of norepinephrine in the synapse.

What is the relationship between dopamine dose and receptor activation?

Low doses of dopamine act on D1 receptors to increase renal blood flow, providing a renal-protective effect. Medium doses activate beta-1 receptors, leading to cardiac activation, while high doses activate alpha-1 receptors, with pressor effects. D2 receptors, found mostly in the central nervous system (CNS), cause inhibition of adenylate cyclase, reducing the concentration of cyclic AMP in the cell.