02 Noradrenergic pharmacology Flashcards
2.01 β2-RECEPTOR AGONIST
Short-acting: salbutamol (albuterol), terbutaline - actions
bronchodilation
(minimal action on heart: ↑rate and force)
relaxes uterine smooth muscle
2.01 β2-RECEPTOR AGONIST
Short-acting: salbutamol (albuterol), terbutaline - MOA
↓calcium-mediated contraction in bronchioles
↑cAMP which activates protein kinase A (PKA)
PKA inhibits myosin light chain kinase (MLCK) - the mediator of contraction
2.01 β2-RECEPTOR AGONIST
Short-acting: salbutamol (albuterol), terbutaline - abs/distrib/elim
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
2.01 β2-RECEPTOR AGONIST
Short-acting: salbutamol (albuterol), terbutaline - clinical use
asthma and obstructive airway disease (main use)
salbutamol and terbutaline for rapid relief of the acute attack
treatment of premature labour, and hyperkalaemia
2.01 β2-RECEPTOR AGONIST
Short-acting: salbutamol (albuterol), terbutaline - adverse effects
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
2.02 β1-RECEPTOR ANTAGONIST
Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - actions
reduces BP in hypertensive patients by:
↓cardiac output
↓renin release
↓CNS-mediated sympathetic activity
in angina, slows heart rate and reduces metabolic demand
2.02 β1-RECEPTOR ANTAGONIST
Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - MOA
blocks the action of endogenous and exogenous agonists on β1 receptors
2.02 β1-RECEPTOR ANTAGONIST
Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - abs/distrib/elim
absorbed orally, with rapid onset of action
mainly metabolised in liver
2.02 β1-RECEPTOR ANTAGONIST
Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - clinical use
ischaemic heart disease
congestive cardiac failure
cardiac arrhythmias
hypertension
migraine prophylaxis (propranolol)
2.02 β1-RECEPTOR ANTAGONIST
Selective: atenolol, bisoprolol, etc.; non-selective: propranolol; mixed α/β: labetalol, etc. - adverse effects
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
2.03 α- AND β-RECEPTOR AGONISTS
Epinephrine (adrenaline) - actions
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)
2.03 α- AND β-RECEPTOR AGONISTS
Epinephrine (adrenaline) - MOA
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
2.03 α- AND β-RECEPTOR AGONISTS
Epinephrine (adrenaline) - abs/distrib/elim
given IM or SC
plasma half-life 2min
metabolised by MOA and COMT
2.03 α- AND β-RECEPTOR AGONISTS
Epinephrine (adrenaline) - clinical use
anaphylactic shock
also added to local anaesthetic solutions to prolong activity of the anaesthetic
2.03 α- AND β-RECEPTOR AGONISTS
Epinephrine (adrenaline) - adverse effects
tachycardia, raised BP, anxiety
2.03 α- AND β-RECEPTOR AGONISTS
Epinephrine (adrenaline) - special points
phenylephrine and oxymetazoline are similar drugs except that they are α1-selective
2.04 α1-RECEPTOR ANTAGONIST
Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - actions
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
2.04 α1-RECEPTOR ANTAGONIST
Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - MOA
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
2.04 α1-RECEPTOR ANTAGONIST
Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - abs/distrib/elim
selective agents are absorbed orally and metabolised by liver
prazosin has a shorter half-life of 3-4h (others are longer acting)
2.04 α1-RECEPTOR ANTAGONIST
Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - clinical use
for severe hypertension: prazosin, doxazosin (in combination with other agents)
for benign prostatic hypertrophy: doxazosin, tamsulosin
for phaechromocytoma: phenoxybenzamine
2.04 α1-RECEPTOR ANTAGONIST
Selective: prazosin, doxazosin, tamsulosin; non-selective: phenoxybenzamine - adverse effects
orthostatic hypotension, dizziness
hypersensitivity reactions
insomnia
sometimes priapism
tamsulosin can cause abnormal ejaculation and back pain
2.05 β1-RECEPTOR AGONIST
Dobutamine - actions
cardiac stimulant: increases contractility and thus cardiac output
it has less effect on heart rate and there is little vasoconstriction
2.05 β1-RECEPTOR AGONIST
Dobutamine - MOA
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
2.05 β1-RECEPTOR AGONIST
Dobutamine - abs/distrib/elim
given IV
plasma half-life 2min
inactivated by MAO and COMT
2.05 β1-RECEPTOR AGONIST
Dobutamine - clinical use
cardiogenic shock
low cardiac output hypoperfusion
(dopamine is a related drug used in these situations)
2.05 β1-RECEPTOR AGONIST
Dobutamine - adverse effects
dysrhythmias
2.06 α1-RECEPTOR AGONIST
Phenylephrine, xylometazoline, etc. - actions
vasoconstriction
nasal decongestion
pupil dilation without effect on accommodation
2.06 α1-RECEPTOR AGONIST
Phenylephrine, xylometazoline, etc. - MOA
causes release of calcium from the sarcoplasmic reticulum
the increased calcium activates the contractile mechanism
2.06 α1-RECEPTOR AGONIST
Phenylephrine, xylometazoline, etc. - abs/distrib/elim
given intranasally or topically in the eye
plasma half-life 3h (longer in the elderly)
2.06 α1-RECEPTOR AGONIST
Phenylephrine, xylometazoline, etc. - clinical use
as nasal decongestant
for opthalmoscopy
2.06 α1-RECEPTOR AGONIST
Phenylephrine, xylometazoline, etc. - adverse effects
hypertension, reflex bradycardia
2.07 DRUGS THAT RELEASE NORADRENALINE
Amfetamine, methylphenidate, atomoxetine - actions
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
2.07 DRUGS THAT RELEASE NORADRENALINE
Amfetamine, methylphenidate, atomoxetine - MOA
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
2.07 DRUGS THAT RELEASE NORADRENALINE
Amfetamine, methylphenidate, atomoxetine - abs/distrib/elim
absorbed orally
plasma half-life ~12h
excreted unchanged in urine
2.07 DRUGS THAT RELEASE NORADRENALINE
Amfetamine, methylphenidate, atomoxetine - clinical use
stimulant effects in narcolepsy
treatment of ADHD
2.07 DRUGS THAT RELEASE NORADRENALINE
Amfetamine, methylphenidate, atomoxetine - adverse effects
increased BP, tachycardia
insomnia
psychosis with excessive doses
2.08 SELECTIVE β3-ADRENOCEPTOR AGONIST
Mirabegron - actions and MOA
stimulates relaxation of bladder smooth muscle through increased cAMP concentrations
2.08 SELECTIVE β3-ADRENOCEPTOR AGONIST
Mirabegron - abs/distrib/elim
given orally with peak plasma concentrations at 3-4h
metabolised and eliminated through multiple pathways, including renal and hepatic
2.08 SELECTIVE β3-ADRENOCEPTOR AGONIST
Mirabegron - clinical use
urgency, frequency and/or incontinence in overactive bladder syndrome
2.08 SELECTIVE β3-ADRENOCEPTOR AGONIST
Mirabegron - adverse effects
tachycardia
urinary tract infections
2.09 α2-AGONIST PRODRUG
Methyldopa - actions
reduces release of NA
lowers blood pressure
2.09 α2-AGONIST PRODRUG
Methyldopa - MOA
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
2.09 α2-AGONIST PRODRUG
Methyldopa - abs/distrib/elim
given orally
actively transported into CNS neurons
plasma half-life ~2h
duration of action ~24h
2.09 α2-AGONIST PRODRUG
Methyldopa - clinical use
hypertension
2.09 α2-AGONIST PRODRUG
Methyldopa - adverse effects
hypotension
transient sedation
dry mouth
diarrhoea
hypersensitivity reactions
2.10 DOPA DECARBOXYLASE INHIBITOR
Carbidopa, benserazide - actions and MOA
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
2.10 DOPA DECARBOXYLASE INHIBITOR
Carbidopa, benserazide - abs/distrib/elim
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
2.10 DOPA DECARBOXYLASE INHIBITOR
Carbidopa, benserazide - clinical use
an adjunct in treatment of parkinsonism
2.10 DOPA DECARBOXYLASE INHIBITOR
Carbidopa, benserazide - adverse effects
hypotension
transient sedation
dry mouth
diarrhoea
hypersensitivity reactions
