Pharmacology and Physiology,

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Pharmacology and Physiology, Pharmacology
Lectures BIOL243 / BMSC 213
Dr Paul Teesdale-Spittle School of Biological
Sciences KK713 Phone 6094
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Case Study Adrenoceptor agonists and
antagonists and control of cardiac
function   Adrenoceptors The receptors for
adrenaline (epinephrine) and noradrenaline
(norepinephrine). Also called adrenergic
receptors. Widely distributed, being responsible
for control of the stimulation and relaxation of
muscle, including the heart. Adrenoceptors
mediate the control of cardiac function by the
sympathetic nervous system the parasympathetic
nervous system control is mediated by muscarinic
acetylcholine receptors.
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Route of the biosynthesis of epinephrine and
norepinephrine
Dont panic I do not expect you to learn the
structures!!
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• Adrenoceptors are divided into 5, or possibly 6
  types ?1, ?2, ?1, ?2, ?3, and potentially ?4.
• They are all G-protein coupled receptors.
• The secondary messengers for the ?1 adrenoceptors
  are inositol triphosphate and diacylglycerol.
• All other adrenoceptors have cAMP as their
  principal secondary messenger.
• Remember that cytoplasmic Ca2 regulates the
  development of tension in muscles, such as the
  heart.
• The activation of ? and ? adrenoceptors usually
  elicits opposing responses
• ? receptor activation leads to constriction of
  veins and arterioles.
• ? receptor activation leads to dilation of veins
  and arterioles.

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• Presence and function of adrenoceptors and the
  heart and vascular system.
• Epinephrine administered rapidly intravenously
  has a number of simultaneous effects that
  contribute to a rapid rise in blood pressure on
  its administration.
• A rise in the strength of ventricular
  contraction (a positive inotropic action)
• The heart rate is increased (a positive
  chronotropic action)
• Blood vessels become constricted.
• Noting the opposing roles of ? and ? receptors,
  it may be no surprise to discover that
  administration regimes other than rapidly
  intravenous injection can have quite different
  effects.

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?1-Adrenoceptors These are less abundant than
?-adrenoceptors. They couple to phospholipases C
and D, to certain Ca2 channels, and a number of
ion channels allowing modification of cellular
cation content, including K and Na. Stimulation
of ?1-adrenoceptors does not lead to elevated
cAMP levels within the cell, and may even reduce
cAMP levels. ?1-Adrenoceptor stimulation leads to
formation of 1,4,5-inositoltriphosphate and
diacylglycerol. Inositoltriphosphate releases
Ca2 from intracellular stores, and this may
explain the observed increase in force of
contraction upon ?1-adrenoceptor
activation. Their activation leads to
constriction of vascular smooth muscle.
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?2-Adrenoceptors Present in only very low
levels in the heart. Their activation leads to
constriction of vascular smooth muscle. ?1 and
?2-Adrenoceptors The ratio of ?1 to
?2-Adrenoceptors is about 6535 in the atria, and
around 7525 in the ventricles. These receptors
both lead to increases of cAMP following
stimulation. This in turn activates protein
kinase A, which can phosphorylate, amongst other
proteins, certain Ca2 channels, leading to an
influx of Ca2 ions, and so enhances
contraction. ?-Adrenoceptor agonists also
increase heart rate.
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Only the ?1 receptor is thought to be involved in
the exercise-induced increase in heart rate
bought about by noradrenaline. Adrenaline, on the
other hand, may function primarily through the
?2-adrenoceptors. ?2-adrenoceptor activation also
leads to relaxation of vascular smooth
muscle. ?3, and potentially ?4-Adrenoceptors
The presence of these in the heart is not fully
established, and their role, if present, is even
more uncertain.
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Adrenoceptor agonists ?1-Adrenoceptor agonists
These can be used to treat hypotension through
vasoconstriction, leading to increased blood
pressure and cardiac arrhythmias through
activation of vagal reflexes. Also valuable
adjuncts to local anaesthetics, as
vasoconstriction can slow the systemic dispersal
of the anaesthetic. Drugs in this class include
phenylephrine and methoxamine.   ?2-Adrenoceptor
agonists Despite the tendency of ?-adrenoceptor
agonists to cause vasoconstriction, these can be
used to treat hypertension. This unexpected
activity occurs through action at the CNS,
reducing signal to the heart and so lowering
cardiac activity and constriction of the
peripheral vasculature. Drugs in this class
include methyldopa and clonidine. Clonidine can
also be used in protection against migrane.
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?-Adrenoceptor agonists These can be used to
treat hypotension, cardiac arrhythmias and
cardiac failure. They stimulate the rate and
force of cardiac contraction. Simultaneously,
they lead to a drop in peripheral vascular
resistance. These combined effects can result in
palpitations, sinus tachycardia and serious
arrhythmias. Drugs in this class include
xamoterol and dobutamine. ?2-Adrenoceptor
agonists lead to muscle relaxation and so find
use in treatment of asthma (salbutamol) and delay
in the onset of labour. (ritodrine).
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Adrenoceptor antagonists ?1-Adrenoceptor
antgonists Antagonism (or blockade) of
?1-adrenoceptors inhibits the action of
endogenous vasoconstrictors, resulting in
vasodilation of both arteries and veins, and thus
reduction of blood pressure. These drugs are,
therefore, useful in the treatment of
hypertension and cardiac failure. Prazosin and
indoramin fall into this class of compounds.
?2-Adrenoceptor antagonists Just as
?2-adrenoceptor agonists unexpectedly reduce
vasoconstriction and lower cardiac activity,
their antagonists cause a rise in blood pressure
through reversal of these effects. Yohimbine is
an ?2-adrenoceptor antagonist.
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?-Adrenoceptor antagonists These can be used to
treat hypertension, angina, cardiac arrhythmias
and ischemic heart disease. The effects of
?-adrenoceptor antagonists (?-blockers) are
only evident when the heart is under stress or
increased workload. Under these circumstances,
they preclude or attenuate increases in the rate
and force of cardiac contraction. They also cause
an increase in peripheral resistance to blood
flow, although this effect is reversed on
prolonged administration. Drugs in this class
include propanolol and metoprelol.
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Introduction What is pharmacology History Drug
action Drug targets Receptors Enzymes Nucleic
acids Mechanisms and Specificity of Drug
Binding Covalent bonds Van der Waals
forces Electrostatic forces Hydrogen bonds The
Hydrophobic interaction Conformation
effects Configuration effects Dynamics
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Selectivity, toxicity and therapeutic
index Agonists antagonists Activity Concn vs
response curves Quantised data Continuous
data Some Physical Chemistry Agonist
binding Competitive Antagonists Bioassays Clinical
trials Drug administration Enteral
administration Parenteral administration
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Absorption, distribution elimination Bioavailabi
lity and crossing membranes pH effects Drug
distribution Fat Plasma proteins Body fluid
compartments Elimination Metabolism Excretion Phar
macokinetics Single compartment model Effect of
dosing regimes
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Case StudyAdrenoceptor agonists and antagonists
and control of cardiac function Adrenoceptors Pres
ence and function of adrenoceptors and the heart
and vascular system Adrenoceptor
agonists Adrenoceptor antagonists