What is the major difference in the ways that noradrenaline and adrenaline work?
Adrenaline acts as a hormone (it is released from the adrenal medulla in response to stressful stimuli), whereas Noradrenaline acts as a neurotransmitter.
Name three different ways of classifying sympathomimetic drugs.
1. Direct acting vs. Indirect acting 2. Catecholamines vs. Non-catecholamines 3. Natural vs. Synthetic
Name the three naturally-occurring catecholamines
Adrenaline, Noradrenaline, Dopamine
Describe two different ways that indirect-acting sympathomimetic drugs can work, with examples.
1. To displace stored catecholamines from the adrenergic nerve ending (e.g. amphetamine, tyramine) 2. To inhibit reuptake of catecholamines (e.g. cocaine)
What type of receptor is an adrenoceptor?
G-protein linked receptor.
What are the names of the subunits of a G-protein linked receptor, and which subunit is the one that varies between different types of G-protein linked receptor?
Alpha, Beta, and Gamma subunits. The alpha subunit is the one that varies.
Describe the intracellular signalling pathway of Alpha-1-adrenoceptors?
G-protein linked to phospholipase C --> IP3 + DAG --> release of intracellular stores of Ca2+ --> activates calcium-dependent protein kinases. (Just like that picture from Campbell-Reece :)
Describe the intracellular signalling pathway of Alpha-2-adrenoceptors?
G-protein linked --> Inhibition of adenylyl cyclase --> reduced intracellular cAMP
What are the second-messengers of all ß-adrenoceptors?
G-protein linked --> Stimulation of adenylyl cyclase -> increased intracellular cAMP
Briefly explain how ß-adrenoceptors can become desensitized? What are two other words for desensitization?
With repeated exposure to agonists, ß-adrenoceptors become phosphorolated, which enhances their affinity for binding a protein called ß-arrestin, which promotes degradation of the receptor by lysosomes. Desensitization is also called tachyphylaxis or tolerance.
What is homologous desensitization?
Homologous densensitization refers to loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by an agonist. e.g. phosphorylation of the beta-adrenoceptor that is repeatedly stimulated --> homologous desensitization.
What is heterologous desensitization?
Heterologous desensitization refers to the process by which desensitization of one receptor by its agonists also results in desensitization of another receptor that has not been directly activated by the agonist in question.
What is the main way in which noradrenaline is removed after its release into the synaptic cleft?
NET (norepinephrine transporter), which is a membrane transporter in the presynaptic membrane.
How does cocaine exert its effects in the body?
It blocks NET, thereby blocking the reuptake of noradrenaline in the synaptic cleft.
What is a monoamine ? Give a few common examples of monoamines.
A monoamine is a naturally-occurring substance that contains a single amino group linked to a benzine ring by -CH2-CH2-
Some examples: Adrenaline, Noradrenaline, Dopamine, Serotonin, Melatonin, Histamine.
How does amphetamine exert its effect on the body?
It travels through the NET (noradrenaline transporter for reuptake into the presynaptic cell), and then triggers release of reuptaken noradrenaline back into the synaptic cleft.
What is COMT?
COMT is catechol-O-methyltransferase, found in the gut and the liver, and catalyzes metabolism of catecholamines. COMT is the reason why catecholamines are not active orally.
Name as many tissues that contain alpha-1-adrenoceptors as you can (up to 5), and the effect of their agonists.
Vascular smooth muscle - Contraction
Pupillary dilator muscle - Contraction (dilates pupil)
Pilomotor smooth muscle - Piloerection
Prostate - Contraction
Heart - Positive inotropy
Name two tissues where you would find ß1-adrenoceptors. What effect does the agonist have?
Heart - Positive inotropy + chronotropy
Juxtaglomerular cells - Renin release
Name up to 3 tissues that contain ß2-adrenoceptors. What effect does the agonist have?
The smooth muscle of Respitary, Uterine and Vascular tissues. Agonists promote smooth muscle relaxation.
Name 1 tissue that contains ß3-adrenoceptors. What effect does the agonist have?
Fat cells - Activates lipolysis.
How does the administration of an alpha-adrenoceptor agonist cause an increase in BP?
Because it causes systemic vascular smooth muscle contraction, which increases peripheral vascular resistance.
The administration of an alpha-adrenoceptor agonist causes an increase in BP. What is the cause of the subsequent drop in HR?
In the smooth muscle, what do alpha-adrenoceptor agonists promote? And beta-adrenoceptor agonists?
Alpha-agonists: Contraction of smooth muscle.
Beta-agonists: Relaxation of smooth muscle.
Note that the adrenoceptors present in different tissues varies, e.g. the vessels in the skin have predominantly alpha-adrenoceptors.
What are two mechanisms by which ß1-adrenoceptor agonists trigger increased HR?
1. By direct activation of the sinus node.
2. By causing increased calcium influx in cardiac cells, causing pacemaker cells to have more frequent action potentials, and a reduced refractory period.
What is the effect of dopamine on the kidneys?
Promotes renal blood flow by dilating renal blood vessels.
Which adrenoceptor type is responsible for bronchodilation?
ß2-adrenoceptors in bronchial smooth muscle.
What kind of adrenoceptors are in the bladder, prostate and urethral sphincter? What is the effect of agonists? What if the agonists are in excess?
Alpha-1-adrenoceptors. Agonists promote contraction and therefore promote urinary continence. Excessive agonist concentration can cause urinary retention.
Do catecholamines cross the blood brain barrier?
No, not unless they are given at the highest rates of infusion.
Parkinson's disease is caused by a deficiency of ________ in the _______.
Parkinson's disease is caused by a deficiency of _dopamine_ in the _basal ganglia_.
Name a few indirect-acting sympathomimetic drugs.
1. Amphetamines, Methamphetamines
3. Catecholamine reuptake inhibitors (e.g. cocaine)
What category of drug is Levodopa?
A dopamine agonist, useful in the treatment of Parkinson's disease.
Why is adrenaline given together with local anaesthetics? Which adrenoceptor does it bind to in this case?
Because it causes vasoconstriction --> reduced local blood flow --> promotes haemostasis. It thereby prolongs the duration of infiltration nerve block, lowering the required dose of anaesthetic. Alpha-adrenoceptors are activated, which are abundant in skin vessels.
Name two important therapeutic applications of sympathomimetic drugs, in cardiovascular conditions.
1. Treatment of Acute Hypotension (e.g. noradrenaline)
2. Treatment of Chronic Orthostatic Hypotension (e.g. Midodrine, which is an alpha-1-adrenoceptor agonist, causing peripheral vasoconstriction)
How long does it take for desensitization of adrenoceptors to occur?
Sometimes it happens within minutes, sometimes it takes days.
What is the difference between the intracellular signalling pathways of Beta-adrenoceptor stimulation and Alpha-2-adrenoceptor stimulation?
They are both G-protein linked, but Beta-adrenoceptor stimulation causes stimulation of adenylyl cyclase (and thus increased production of cAMP), but Alpha-2-adrenoceptor stimulation causes inhibition of adenylyl cyclase (and thus decreased production of cAMP)
Adrenalin and Noradrenaline - explain the differences in their affinity for alpha-1-adrenoceptors, alpha-2-adrenoceptors, beta-1-adrenoceptors and beta-2-adrenoceptors
Adrenalin is non-selective, alpha-1 = alpha-2, beta-1 = beta-2
Noradrenalin: alpha-1 = alpha-2, beta-1 >>> beta-2
Name two synthetic catecholamines.
Name three non-catecholamines that are sympathomimetic.
Amphetamine, Ephedrine, Phenylephrine.
Isoprenaline: Describe its affinity for alpha and beta adrenoceptors.
Isoprenaline is a selective beta-agonist. Its affinity for beta-adrenoceptors >>> alpha-adrenoceptors. B1 = B2
Dobutamine: Describe its affinity for alpha / beta adrenoceptors
Dobutamine is a beta-1 selective agonist. It is a racemic mixture:
The positive isomer is a B1 agonist and A1 antagonist
The negative isomer is a A1 agonist
Salbutamol and Terbutaline - describe their affinity for different adrenoceptors.
Both are B2 >> B1 >>>> A
What is the difference between adrenaline and noradrenaline with regard to their effect on total peripheral resistance?
Noradrenaline has less effect on B2 receptors than adrenaline. B2 receptor agonism in the peripheral vasculature causes relaxation and vasodilation. This means that adrenaline can reduce TPR (and diastolic BP), and noradrenaline can increase TPR (and diastolic BP).
What is the effect of dopamine on peripheral blood vessels?
Vasodilation (and reduced TPR). Importantly, this includes renal afferent arteriole vasodilation.
Dobutamine acts on which receptor? What is the cardiovascular effect from this?
Beta-1-adrenoceptors. This causes positive inotropy in the heart.
List the clinical uses of adrenaline.
Shock / Low cardiac output.
Asthma / Croup.
Local vasoconstriction + prolongation of action of local anaesthetic.
What are the infusion rates of adrenaline?
1-20 mcg / kg / min
List the clinical uses of noradrenaline.
List the clinical uses of isoprenaline.
Complete heart block.
Low cardiac output. (as an inotrope and chronotrope)
List the clinical uses of dopamine.
Low cardiac output.
Impending renal failure.
Prevention of hepatorenal failure.
List the clinical uses of dobutamine.
Short-term treatment of heart failure.
Name one key difference in the distribution to tissues of catecholamines vs non-catecholamines.
Non-catecholamines penetrate CNS (e.g. amphetamine). Catecholamines do not.