Lecture 6- Adrenergic Receptors and its agonists/antagonists

Which system is affected by adrenergic agonists and antagonists?

The sympathetic nervous system.

These drugs will affect postganglia receptors that are adrenergic.

What are example catecholamines that are released in post-ganglionic fibres?

Most dominant- NA (noradrenaline)- released by the sympathetic nerve terminals

Adrenaline- released by the adrenal medulla

Dopamine- precursor to NA and A

Isoprenaline- not in the body

What are the subtypes of adrenergic receptors?

There are 2 alpha-adrenoceptor subtypes, alpha1 and alpha2.

3 beta-adrenoceptor subtypes with beta1 and beta2 as the predominant forms present

What are the roles and function of alpha1 and alpha2 adrenoceptors?

Alpha1 (‘excitatory”)- activate Gq (a G-protein) that will result in phospholipase C to produce IP3 and DAG as secondary messengers. IP3 to increase intracellular Ca2+ and DAG will activate PKC.

The activation will induce vasocconstriction, relaxation of gastrointestinal smooth muscle, hepatic glycogenolysis (to form glucose-6-phosphate)

Alpha2 (“relaxation”)- activate Gi protein for inhibitory effects- inhibiting adenylyl cyclase therefore reduce cAMP formation

Its activation will result in inhibiting the release of neurotransmitter

What is the order of affinity of the neurotransmitter to the alpha-receptor?

NA with highest affinity followed by A then isoprenaline

What are the roles and functions of the beta adrenergic receptors?

All will activate PKA (protein kinase A) with cAMP and adenylyl cyclase activation

Beta1 receptors- found in cardiac tissue to increase ino- and chronotropic effects

Beta2 receptors- found in smooth muscle, skeletal muscle for relaxation (broncho- and vasodilation) and hepatic glycogenolysis

What is the order of affinities for the neurotransmitters to beta-receptors?

Opposing alpha receptors therefore highest affinty is isoprenaline followed by A then NA.

What are example agonist and antagonist drugs for each type of adrenergic receptor?

Alpha 1 agonists- phenylephrine, metoxamine

Alpha 2 agonists- Clonidine

Beta 1 agonists- Dobutamine

Beta 2 agonists- Salbutamol, Terbutaline

Alpha 1 antagonists- Prazosin

Alpha 2 anatagonists- Yohimbine

Beta 1 antagonists- Atenolol

Beta 2 antagonists- Butoxamine

IMPORTANT: How is NA synthesised?

NA precursor is L-tyrosine. The enzyme tyrosine hydroxylase will catalyse the conversion of tyrosine to dopa.

Dopa is then converted to dopamine with DOPA decarboxylase.

NA formed from hydroxylase that converts dopamine. Dopamine is hydroxylated to form NA.

NA to A occurs with N-methyltransferase

What are some example alpha1 agonist and antagonist drugs?

Agonists:

Phenylephine

Methoxamine

Antagonists:

Prazosin

Doxazocin

What are some example alpha2 agonist and antagonist drugs?

Agonist:

Clonidine

Antagonists:

Yohimbine

Idazoxan

What are some example beta1 agonists and antagonists?

Agonists:

Dobutamine

Xamoterol

Antagonists:

Atenolol

Metoprolol

What are some example beta2 agonist and antagonist drugs?

Agonists:

Salbutamol

Terbutaline

Clenbuterol

Antagonists:

Butoxamine

How are catecholamines stored and released?

In the adrenal medulla, the conversion of NA to A occurs. Unlike Ach, production occurs in the cell bodies therefore needs packaging in vesicles to be taken to the axon, with vesicle monoamine transporters.

What is the release mechanism for catecholamines, such as NA?

Catecholamine release follows a similar mechanism to Ach as NA is calcium dependent since the post-ganglia are previously innervated by cholinergic neurons.

However, release of NA is also accompanied by neuroleptics Y as a co-transmitter.

What occurs of degradation of NA (catecholamines) and re-uptake?

Majority of NA is re-uptaken with a norepinephrine transporter consisting of 12 transmembrane domains. Other amount will be washed away or metabolized.

Degradation occurs with two enzymes: MAO (monoamine oxidase) and COMT (catecholamines-O-methyl transferase)

What is the fate of catecholamines at sympathetic nerve terminals (release of NA at axon terminal)?

Membrane depolarisation occurs to induce Ca2+ influx. This will result in inducing exocytosis of vesicles containing the NA into the synaptic cleft.

Note: presence of alpha2 receptors on presynaptic neuron with inhibitory effects on the influx of Ca2+. Therefore drugs mimicking alpha2 agonists will be adrenergic receptor antagonists.

Beta2 receptors also present, to activate adenylyl cyclase to increase NA release

What are direct and indirect agents for adrenergic receptor agonists?

Direct acting: drugs that share structural similarities with NA and therefore bind adrenoceptors to mimic/block NA effects

Indirect: increase NA synaptically by displacing NA from axon terminal

What drugs are example adrenergic receptor agonists?

Phenylethylamine

Tyramine

Dopamine

NA

What is the structural significance of catecholamines on its activity?

Presence of hydroxyl groups. Loss of these would reduce the affinity for COMT and therefore would lead to these agents lasting a longer time compared to endogenous biochemical catecholamines

What are the physiological effects of adrenergic compounds on organs/ tissues (heart, smooth muscle)

Heart: Increased NA and A= increased stroke volume (cardiac output and heart rate)

Increased force and velocity of contraction

Higher oxygen consumption, coronary arteries dilate

Note: these effects are most beta1 related (“excitatory”) but some alpha1 may have similar responses

Smooth muscle:

Activate alpha1 receptors to increase Ca2+, mediating contraction from response to NA and A

Vasoconstriction in skin, lungs, kidneys, blood vessels leading to increased arterial pressure

Activation of beta2 receptor lead to relaxation

What physiological effects occur when alpha1 adrenoceptors are active? (Where are they found in the body)

Alpha1 receptors are “excitatory”

Constriction: blood vessels, bronchi, uterus, iris (radial muscle), bladder and GI sphincters

Relaxation: GI tract

Causes glycogenolysis in the liver

What physiological effects occur from alpha2 receptors?

Cause blood vessels to either constrict or dilate.

GI tract relaxes

Decrease insulin secretion

What are the physiological effects from beta1 receptors when active?

Increased heart rate (+ve chronotropy), increased force of contraction (+ve inotropy)

What are the physiological effects from the activation of beta2 receptors?

Relaxation/dilation: blood vessels, bronchi, GI tract, uterus

Increased heart rate (+ve chronotropy) and increased force of contraction (+ve inotropy).

Increased tremor and speed of contraction of skeletal muscle with glycogenolysis.

Liver carrying out glycogenolysis

At the adrenergic and cholinergic effector nerve terminals, is there an increase or decrease in release of neurotransmitter upon activation of different adrenoceptors?

Alpha2 receptors reduce release in both adrenergic and cholinergic terminals

Beta2 receptors increase release in adrenergic terminals

What are the effects on the lungs from adrenergic compounds? (Give example drug type involved)

Beta2 mediated- bronchodilation (Selective Beta2 agonists are good anti-asthmatic drugs such as Salbutamol)

Alpha1 mediated- vasoconstriction

What are the effects on skeletal muscle from adrenergic compounds?

Adrenaline (alpha/beta agonist)- vasodilation, muscle tremors, glycogenolysis (mostly beta2 effect)

What are the effects on the eye from adrenergic compounds?

Dilation by stimulating alpha1 adrenoceptors

Beta receptors increase production of aqueous humor therefore its antagonists is used in treating glaucoma

What are the effects in the liver from adrenergic compounds?

Increasing glycogenolysis (beta2 effect)

IMPORTANT: What are the sympathetic effects in the liver, muscle and fat?

Liver: Increase of breakdown of glycogen into glucose. Glycogen undergoes phosphorylase treatment to form glucose-1-phosphate and the glucose-6-phosphate before forming glucose with phosphatase.

Fat: Increased fatty acids production from triglycerides with lipase activity.

Muscle: Increased glycogen breakdown in the mechanism pathway similar to the liver but also involving the citric acid cycle to form ATP for energy release.

What are the clinical uses for non-selective adrenergic receptor agonists (adrenaline and noradrenaline)? Both with affinity for alpha and beta receptors

Adrenaline: used for cardiac arrest, anaphylaxis (bronchodilation, vasoconstriction, histamine inhibition)

Noradrenaline: for hypotension and shock (Increases BP)

What are some indirect acting sympathomimetrics and role? (Indirect adrenergic receptor agonists)

Drugs that increase catecholamine synthesis and increase the release of catecholamine stores.

Examples include amphetamine, ephedrine and tyramine

Cocaine inhibit the re-uptake of NA by its transporters to prolong in the synaptic cleft

What are the effects of indirect acting sympathomimetrics?

Drugs with low, weak actions on adrenoceptors.

Actions can include bronchodilation, increase arterial pressure, vasoconstriction, increase heart rate (+ve chronotropy) and greater force of contraction (+ve inotropy).

What is the role of amphetamine in the axon terminal?

Amphetamine enters nerve terminal with a NA transporter (norepinephrine transporter). It then enters synaptic vesicles with a vesicular monoamine transporter in place of NA. This results in increase of NA concentrations in synapse.

It also blocks NA transporters to prevent re-uptake

What effects does cocaine have on adrenergic receptors and release of catecholamines?

Blocks all catecholamine transporters to inhibit re-uptake. Cocaine with HIGH AFFINITY for the dopamine transporter

This leads to enhanced sympathetic transmission causing tachycardia and arterial pressure.

Prolonged effects of euphoria and excitement. Cocaine enhances experiences of reward and pleasure before levels deplete leading to a crash

What are MAO inhibitors and an example drug (With uses)?

Involved in inhibiting the activity of monoamine oxidase enzyme that metabolizes catecholamines such as NA.

Phenelzine- a non-specific MAO inhibitor that is clinically used as an anti-depressant.

What are adrenergic antagonists and clinical uses?

Many indirect and direct adrenergic antagonists have been developed to treat clinical disorders involving deregulation of the sympathetic nervous system such as hyperactivity or sensitivity.

What are directly acting adrenoceptors antagonists and what are they dependent on?

Block activity of catecholamines in stimulating the sympathetic nervous system. Therefore sympathetic effects.

Effect of drug is dependent on:

Concentration of agonist and antagonist at receptor site (target tissue)

Relative affinities of these agonists and antagonists for the target receptor

Level of expression of the receptor in the target tissue

How are adrenergic receptor antagonists classified?

It’s selectivity (which type of adrenergic receptor)

Mechanisms of action: direct v indirect and reversible v irreversible

Directly acting antagonists with greater selectivity, therefore fewer toxicities

Where are alpha adrenergic receptors found?

Alpha1- heart, veins, pancreas, liver and smooth muscle

Alpha2- predominantly pre-synaptic

What is an example drug that is an irreversible non-selective alpha-adrenergic receptor antagonist? How does it work?

Phenoxybenzamine- related to nitrogen mustards, used in WW1 as a nerve gas

The drug binds covalently (irreversibly) to alpha-adrenergic receptors.

What are the differences between direct and indirectly acting antagonists?

Give an example of an indirect acting antagonist.

Direct acting antagonists bind to adrenergic receptors to prevent catecholamine binding to reduce sympathetic effects. Indirect acting antagonist Act as adrenergic antagonist target catecholamine storage, release and synthesis for reduction of the presence of these catecholamines.

Reserpine- inhibits NA uptake into vesicles, leaving NA to be deaminated by MAO.

What is guanethidine, its effects?

Gunaethidine is a competitor of NA at the NA transporter (the NET), therefore blocking re-uptake that leads to eventual depletion of NA in the sympathetic nerve terminals.

This promotes the deamination and therefore the metabolism of NA by MAO.

Effects include drop in BP, bradycardia

What is a false transmitter?

A compound with no intrinsic activity, acts as an antagonist.