Katzung 12th ed - Chapter 9 - Sympathomimetic Drugs (1)

Question 1

What is the major difference in the ways that noradrenaline and adrenaline work?

Answer 1

Adrenaline acts as a hormone (it is released from the adrenal medulla in response to stressful stimuli), whereas Noradrenaline acts as a neurotransmitter.

Question 2

Name three different ways of classifying sympathomimetic drugs.

Answer 2

1. Direct acting vs. Indirect acting 2. Catecholamines vs. Non-catecholamines 3. Natural vs. Synthetic

Question 3

Name the three naturally-occurring catecholamines

Answer 3

Adrenaline, Noradrenaline, Dopamine

Question 4

Describe two different ways that indirect-acting sympathomimetic drugs can work, with examples.

Answer 4

1. To displace stored catecholamines from the adrenergic nerve ending (e.g. amphetamine, tyramine) 2. To inhibit reuptake of catecholamines (e.g. cocaine)

Question 5

What type of receptor is an adrenoceptor?

Answer 5

G-protein linked receptor.

Question 6

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?

Answer 6

Alpha, Beta, and Gamma subunits. The alpha subunit is the one that varies.

Question 7

Describe the intracellular signalling pathway of Alpha-1-adrenoceptors?

Answer 7

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 :)

Question 8

Describe the intracellular signalling pathway of Alpha-2-adrenoceptors?

Answer 8

G-protein linked –> Inhibition of adenylyl cyclase –> reduced intracellular cAMP

Question 9

What are the second-messengers of all ß-adrenoceptors?

Answer 9

G-protein linked –> Stimulation of adenylyl cyclase -> increased intracellular cAMP

Question 10

Briefly explain how ß-adrenoceptors can become desensitized? What are two other words for desensitization?

Answer 10

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.

Question 11

What is homologous desensitization?

Answer 11

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.

Question 12

What is **heterologous **desensitization?

Answer 12

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.

Question 13

What is the main way in which noradrenaline is removed after its release into the synaptic cleft?

Answer 13

NET (norepinephrine transporter), which is a membrane transporter in the presynaptic membrane.

Question 14

How does cocaine exert its effects in the body?

Answer 14

It blocks NET, thereby blocking the reuptake of noradrenaline in the synaptic cleft.

Question 15

What is a **monoamine **? Give a few common examples of monoamines.

Answer 15

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.

Question 16

How does amphetamine exert its effect on the body?

Answer 16

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.

Question 17

What is COMT?

Answer 17

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.

Question 18

Name as many tissues that contain alpha-1-adrenoceptors as you can (up to 5), and the effect of their agonists.

Answer 18

Vascular smooth muscle - Contraction

Pupillary dilator muscle - Contraction (dilates pupil)

Pilomotor smooth muscle - Piloerection

Prostate - Contraction

Heart - Positive inotropy

Question 19

Name two tissues where you would find ß1-adrenoceptors. What effect does the agonist have?

Answer 19

Heart - Positive inotropy + chronotropy

Juxtaglomerular cells - Renin release

Question 20

Name up to 3 tissues that contain ß2-adrenoceptors. What effect does the agonist have?

Answer 20

The smooth muscle of Respitary, Uterine and Vascular tissues. Agonists promote smooth muscle relaxation.

Question 21

Name 1 tissue that contains ß3-adrenoceptors. What effect does the agonist have?

Answer 21

Fat cells - Activates lipolysis.

Question 22

How does the administration of an alpha-adrenoceptor agonist cause an increase in BP?

Answer 22

Because it causes systemic vascular smooth muscle contraction, which increases peripheral vascular resistance.

Question 23

The administration of an alpha-adrenoceptor agonist causes an increase in BP. What is the cause of the subsequent drop in HR?

Answer 23

Baroreceptor reflex.

Question 24

In the smooth muscle, what do alpha-adrenoceptor agonists promote? And beta-adrenoceptor agonists?

Answer 24

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.

Question 25

What are two mechanisms by which ß1-adrenoceptor agonists trigger increased HR?

Answer 25

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.

Question 26

What is the effect of dopamine on the kidneys?

Answer 26

Promotes renal blood flow by dilating renal blood vessels.

Question 27

Which adrenoceptor type is responsible for bronchodilation?

Answer 27

ß2-adrenoceptors in bronchial smooth muscle.

Question 28

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?

Answer 28

Alpha-1-adrenoceptors. Agonists promote contraction and therefore promote urinary continence. Excessive agonist concentration can cause urinary retention.

Question 29

Do catecholamines cross the blood brain barrier?

Answer 29

No, not unless they are given at the highest rates of infusion.

Question 30

Parkinson’s disease is caused by a deficiency of ________ in the _______.

Answer 30

Parkinson’s disease is caused by a deficiency of _dopamine_ in the _basal ganglia_.

Question 31

Name a few indirect-acting sympathomimetic drugs.

Answer 31

1. Amphetamines, Methamphetamines
2. Tyramine
3. Catecholamine reuptake inhibitors (e.g. cocaine)

Question 32

What category of drug is Levodopa?

Answer 32

A dopamine agonist, useful in the treatment of Parkinson’s disease.

Question 33

Why is adrenaline given together with local anaesthetics? Which adrenoceptor does it bind to in this case?

Answer 33

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.

Question 34

Name two important therapeutic applications of sympathomimetic drugs, in cardiovascular conditions.

Answer 34

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)

Question 35

How long does it take for desensitization of adrenoceptors to occur?

Answer 35

Sometimes it happens within minutes, sometimes it takes days.

Question 36

What is the difference between the intracellular signalling pathways of Beta-adrenoceptor stimulation and Alpha-2-adrenoceptor stimulation?

Answer 36

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)

Question 37

Adrenalin and Noradrenaline - explain the differences in their affinity for alpha-1-adrenoceptors, alpha-2-adrenoceptors, beta-1-adrenoceptors and beta-2-adrenoceptors

Answer 37

Adrenalin is non-selective, alpha-1 = alpha-2, beta-1 = beta-2

Noradrenalin: alpha-1 = alpha-2, beta-1 >>> beta-2

Question 38

Name two synthetic catecholamines.

Answer 38

Isoprenaline. Dobutamine.

Question 39

Name three non-catecholamines that are sympathomimetic.

Answer 39

Amphetamine, Ephedrine, Phenylephrine.

Question 40

Isoprenaline: Describe its affinity for alpha and beta adrenoceptors.

Answer 40

Isoprenaline is a selective beta-agonist. Its affinity for beta-adrenoceptors >>> alpha-adrenoceptors. B1 = B2

Question 41

Dobutamine: Describe its affinity for alpha / beta adrenoceptors

Answer 41

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

Question 42

Salbutamol and Terbutaline - describe their affinity for different adrenoceptors.

Answer 42

Both are B2 >> B1 >>>> A

Question 43

What is the difference between adrenaline and noradrenaline with regard to their effect on total peripheral resistance?

Answer 43

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).

Question 44

What is the effect of dopamine on peripheral blood vessels?

Answer 44

Vasodilation (and reduced TPR). Importantly, this includes renal afferent arteriole vasodilation.

Question 45

Dobutamine acts on which receptor? What is the cardiovascular effect from this?

Answer 45

Beta-1-adrenoceptors. This causes positive inotropy in the heart.

Question 46

List the clinical uses of adrenaline.

Answer 46

Anaphylaxis.

Asystole.

Shock / Low cardiac output.

Asthma / Croup.

Glaucoma.

Local vasoconstriction + prolongation of action of local anaesthetic.

Question 47

What are the infusion rates of adrenaline?

Answer 47

1-20 mcg / kg / min

Question 48

List the clinical uses of noradrenaline.

Answer 48

Hypotension.

Question 49

List the clinical uses of isoprenaline.

Answer 49

Complete heart block.

Low cardiac output. (as an inotrope and chronotrope)

Asthma.

Question 50

List the clinical uses of dopamine.

Answer 50

Low cardiac output.

Septic shock.

Impending renal failure.

Prevention of hepatorenal failure.

Question 51

List the clinical uses of dobutamine.

Answer 51

Short-term treatment of heart failure.

Question 52

Name one key difference in the distribution to tissues of catecholamines vs non-catecholamines.

Answer 52

Non-catecholamines penetrate CNS (e.g. amphetamine). Catecholamines do not.