02 Noradrenergic pharmacology

Question 1

2.01 β2-RECEPTOR AGONIST

Short-acting: salbutamol (albuterol), terbutaline - actions

Answer 1

bronchodilation
(minimal action on heart: ↑rate and force)
relaxes uterine smooth muscle

Question 2

2.01 β2-RECEPTOR AGONIST

Short-acting: salbutamol (albuterol), terbutaline - MOA

Answer 2

↓calcium-mediated contraction in bronchioles
↑cAMP which activates protein kinase A (PKA)
PKA inhibits myosin light chain kinase (MLCK) - the mediator of contraction

Question 3

2.01 β2-RECEPTOR AGONIST

Short-acting: salbutamol (albuterol), terbutaline - abs/distrib/elim

Answer 3

given as required by inhalation for asthma
salbutamol, terbutaline: fast onset, short-acting (3-5h)
can also be given IV for severe airway disease or premature labour

Question 4

2.01 β2-RECEPTOR AGONIST

Short-acting: salbutamol (albuterol), terbutaline - clinical use

Answer 4

asthma and obstructive airway disease (main use)
salbutamol and terbutaline for rapid relief of the acute attack
treatment of pre­mature labour, and hyperkalaemia

Question 5

2.01 β2-RECEPTOR AGONIST

Short-acting: salbutamol (albuterol), terbutaline - adverse effects

Answer 5

tremors, tachycardia (sometimes dysrhythmias), nervousness, some peripheral dilatation
high-dose nebulised salbutamol drives potassium into cells and causes hypokalaemia - this is used for emergency management of hyperkalaemia

Question 6

2.02 β1-RECEPTOR ANTAGONIST

Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - actions

Answer 6

reduces BP in hypertensive patients by:
↓cardiac output
↓renin release
↓CNS-mediated sympathetic activity
in angina, slows heart rate and reduces metabolic demand

Question 7

2.02 β1-RECEPTOR ANTAGONIST

Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - MOA

Answer 7

blocks the action of endogenous and exogenous agonists on β1 receptors

Question 8

2.02 β1-RECEPTOR ANTAGONIST

Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - abs/distrib/elim

Answer 8

absorbed orally, with rapid onset of action
mainly metabolised in liver

Question 9

2.02 β1-RECEPTOR ANTAGONIST

Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - clinical use

Answer 9

ischaemic heart disease
congestive cardiac failure
cardiac arrhythmias
hypertension
migraine prophylaxis (propranolol)

Question 10

2.02 β1-RECEPTOR ANTAGONIST

Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - adverse effects

Answer 10

dangerous: bronchconstriction in asthma
potential heart block or worsening heart failure in patients with unstable cardiac conditions
decreased sympathetic warning to hypoglycaemia in diabetes
inconvenient: cold extremities, fatigue

Question 11

2.03 α- AND β-RECEPTOR AGONISTS

Epinephrine (adrenaline) - actions

Answer 11

α1: vasoconstriction (thus ↑BP); contraction of uterus, GIT sphincters, bladder sphincter, radial iris muscle
α2: inhibits lipolysis, inhibits NA release
β1: increased heart rate
β2: bronchodilation, vasodilation (decrease in diastolic BP)

Question 12

2.03 α- AND β-RECEPTOR AGONISTS

Epinephrine (adrenaline) - MOA

Answer 12

α1: activation of phospholipase C with generation of IP3 (which increases intracellular calcium and thus force of contraction)
β2: ↑cAMP activates protein kinase A (PKA); in smooth muscle, PKA reduces the contractile action; in cardiac muscle, PKA increases intracellular calcium and thus force of contraction

Question 13

2.03 α- AND β-RECEPTOR AGONISTS

Epinephrine (adrenaline) - abs/distrib/elim

Answer 13

given IM or SC
plasma half-life 2min
metabolised by MOA and COMT

Question 14

2.03 α- AND β-RECEPTOR AGONISTS

Epinephrine (adrenaline) - clinical use

Answer 14

anaphylactic shock
also added to local anaesthetic solutions to prolong activity of the anaesthetic

Question 15

2.03 α- AND β-RECEPTOR AGONISTS

Epinephrine (adrenaline) - adverse effects

Answer 15

tachycardia, raised BP, anxiety

Question 16

2.03 α- AND β-RECEPTOR AGONISTS

Epinephrine (adrenaline) - special points

Answer 16

phenylephrine and oxymetazoline are similar drugs except that they are α1-selective

Question 17

2.04 α1-RECEPTOR ANTAGONIST

Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - actions

Answer 17

vasodilation (thus ↓BP)
↑heart rate (a reflex β-receptor response to the ↓BP)
↓bladder sphincter tone
inhibits hypertrophy of smooth muscle of bladder neck and prostate capsule

Question 18

2.04 α1-RECEPTOR ANTAGONIST

Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - MOA

Answer 18

blocks the action of endogenous and exogenous agonists on α1 receptors
tamsulosin is an α1A-receptor antagonist that is “uro-selective”
phenoxybenzamine is a non-selective, irreversible inhibitor

Question 19

2.04 α1-RECEPTOR ANTAGONIST

Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - abs/distrib/elim

Answer 19

selective agents are absorbed orally and metabolised by liver
prazosin has a shorter half-life of 3-4h (others are longer acting)

Question 20

2.04 α1-RECEPTOR ANTAGONIST

Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - clinical use

Answer 20

for severe hypertension: prazosin, doxazosin (in combination with other agents)
for benign prostatic hypertrophy: doxazosin, tamsulosin
for phaechromocytoma: phenoxybenzamine

Question 21

2.04 α1-RECEPTOR ANTAGONIST

Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - adverse effects

Answer 21

orthostatic hypotension, dizziness
hypersensitivity reactions
insomnia
sometimes priapism
tamsulosin can cause abnormal ejaculation and back pain

Question 22

2.05 β1-RECEPTOR AGONIST

Dobutamine - actions

Answer 22

cardiac stimulant: increases contractility and thus cardiac output
it has less effect on heart rate and there is little vasoconstriction

Question 23

2.05 β1-RECEPTOR AGONIST

Dobutamine - MOA

Answer 23

acts mainly on β1 receptors causing G protein-mediated increase of cAMP, which increases calcium influx in the cardiac myocytes
minimal effect on β2 receptors

Question 24

2.05 β1-RECEPTOR AGONIST

Dobutamine - abs/distrib/elim

Answer 24

given IV
plasma half-life 2min
inactivated by MAO and COMT

Question 25

2.05 β1-RECEPTOR AGONIST Dobutamine - clinical use

Answer 25

cardiogenic shock low cardiac output hypoperfusion (dopamine is a related drug used in these situations)

Question 26

2.05 β1-RECEPTOR AGONIST Dobutamine - adverse effects

Answer 26

dysrhythmias

Question 27

2.06 α1-RECEPTOR AGONIST Phenylephrine, xylometazoline, etc. - actions

Answer 27

vasoconstriction nasal decongestion pupil dilation without effect on accommodation

Question 28

2.06 α1-RECEPTOR AGONIST Phenylephrine, xylometazoline, etc. - MOA

Answer 28

causes release of calcium from the sarcoplasmic reticulum the increased calcium activates the contractile mechanism

Question 29

2.06 α1-RECEPTOR AGONIST Phenylephrine, xylometazoline, etc. - abs/distrib/elim

Answer 29

given intranasally or topically in the eye plasma half-life 3h (longer in the elderly)

Question 30

2.06 α1-RECEPTOR AGONIST Phenylephrine, xylometazoline, etc. - clinical use

Answer 30

as nasal decongestant for opthalmoscopy

Question 31

2.06 α1-RECEPTOR AGONIST Phenylephrine, xylometazoline, etc. - adverse effects

Answer 31

hypertension, reflex bradycardia

Question 32

2.07 DRUGS THAT RELEASE NORADRENALINE Amfetamine, methylphenidate, atomoxetine - actions

Answer 32

indirectly acting sympathomimetics release NA from the varicosity, therefore has similar actions to NA and epinephrine, but weaker: α1: vasoconstriction (thus ↑BP) β1: increased heart rate β2: bronchodilation also a potent CNS stimulant

Question 33

2.07 DRUGS THAT RELEASE NORADRENALINE Amfetamine, methylphenidate, atomoxetine - MOA

Answer 33

taken up by Uptake 1 into the varicosity, then into the vesicle by exchange with NA the NA, now loose in the cytoplasm, is then released by exchange with amfetamine at Uptake 1

Question 34

2.07 DRUGS THAT RELEASE NORADRENALINE Amfetamine, methylphenidate, atomoxetine - abs/distrib/elim

Answer 34

absorbed orally plasma half-life ~12h excreted unchanged in urine

Question 35

2.07 DRUGS THAT RELEASE NORADRENALINE Amfetamine, methylphenidate, atomoxetine - clinical use

Answer 35

stimulant effects in narcolepsy treatment of ADHD

Question 36

2.07 DRUGS THAT RELEASE NORADRENALINE Amfetamine, methylphenidate, atomoxetine - adverse effects

Answer 36

increased BP, tachycardia insomnia psychosis with excessive doses

Question 37

2.08 SELECTIVE β3-ADRENOCEPTOR AGONIST Mirabegron - actions and MOA

Answer 37

stimulates relaxation of bladder smooth muscle through increased cAMP concentrations

Question 38

2.08 SELECTIVE β3-ADRENOCEPTOR AGONIST Mirabegron - abs/distrib/elim

Answer 38

given orally with peak plasma concentrations at 3-4h metabolised and eliminated through multiple pathways, including renal and hepatic

Question 39

2.08 SELECTIVE β3-ADRENOCEPTOR AGONIST Mirabegron - clinical use

Answer 39

urgency, frequency and/or incontinence in overactive bladder syndrome

Question 40

2.08 SELECTIVE β3-ADRENOCEPTOR AGONIST Mirabegron - adverse effects

Answer 40

tachycardia urinary tract infections

Question 41

2.09 α2-AGONIST PRODRUG Methyldopa - actions

Answer 41

reduces release of NA lowers blood pressure

Question 42

2.09 α2-AGONIST PRODRUG Methyldopa - MOA

Answer 42

acts mainly in the CNS is taken up into adrenergic neurons and converted into false transmitter methylnoradrenaline (methylnorepinephrine) this is released and acts on the α2 adrenoceptors, decreasing the release of NA

Question 43

2.09 α2-AGONIST PRODRUG Methyldopa - abs/distrib/elim

Answer 43

given orally actively transported into CNS neurons plasma half-life ~2h duration of action ~24h

Question 44

2.09 α2-AGONIST PRODRUG Methyldopa - clinical use

Answer 44

hypertension

Question 45

2.09 α2-AGONIST PRODRUG Methyldopa - adverse effects

Answer 45

hypotension transient sedation dry mouth diarrhoea hypersensitivity reactions

Question 46

2.10 DOPA DECARBOXYLASE INHIBITOR Carbidopa, benserazide - actions and MOA

Answer 46

levodopa is used to treat parkinsonism, but in the GIT and periphery it is metabolised by DOPA decarboxylase this reduces the amount available to the CNS the resulting GI and peripheral dopamine causes nausea and hypotension carbidopa inhibits DOPA decarboxylase, thus increasing the availability of levodopa to the CNS and reducing the dopamine-mediated side effects

Question 47

2.10 DOPA DECARBOXYLASE INHIBITOR Carbidopa, benserazide - abs/distrib/elim

Answer 47

usually given in combination with levodopa to treat parkinsonism carbidopa cannot cross the blood-brain barrier so it affects only the peripheral metabolism of levodopa

Question 48

2.10 DOPA DECARBOXYLASE INHIBITOR Carbidopa, benserazide - clinical use

Answer 48

an adjunct in treatment of parkinsonism

Question 49

2.10 DOPA DECARBOXYLASE INHIBITOR Carbidopa, benserazide - adverse effects

Answer 49

hypotension transient sedation dry mouth diarrhoea hypersensitivity reactions