PHA3032 Notes

Theme 2: Pharmacology of Mood and Behaviour

Lecture 5 Schizophrenia and Antipsychotic Drugs
Background
Schizophrenia is a relatively common disorder affecting about 1% of the
population at a flat rate. The onset of the disease commonly occurs between the
ages of 15 30. It is likely to have some component that allows for a genetic
transmission of the disorder, however environmental factors contribute greatly to
the extent and severity of the disease.
There are no definitive physiological or biochemical diagnostic tests, and the
disease is identified by symptomology: flat affect, bizarre delusions, prominent
hallucinations, functioning in work, social relations and self-care are diminished.
The symptoms are divided into three main modalities: positive, negative and
cognitive symptoms. Positive symptoms include delusions and auditory
hallucinations. Negative symptoms include social withdrawal, a lack of drive and
a blunting of emotions. Cognitive symptoms include lack of attention, deficits in
memory and problems with executive function.
Neurochemical Deficit
It is known that psychotic symptoms arise from cocaine and amphetamine use
(suggesting an elevation in dopamine). There are psychotic symptoms that arise
from NMDA channel blocker overuse as seen with PCP and ketamine. Finally
hallucinations can arise from LSD, the activation of 5-HT 2A receptors. As such,
schizophrenia probably involves a range of receptor classes.
However the most evidence for a neurochemical deficit in schizophrenia is that
there is an over activation of the dopaminergic system. It has been shown that
during a psychotic episode there is an increase in D2 receptor occupancy, and
post mortem studies show an increase in number of D2 receptors in the
schizophrenic brain.
The dopaminergic pathway that is most relevant in schizophrenia is the
mesocortical/mesolimbic pathway. The pathway arises in the ventral tegmental
area (VTA) where all the cell bodies are, and the axons leave this area to
innervate the nucleus accumbens and the prefrontal cortex. This pathway is
largely concerned with behaviour (agitation, psychosis, cognitive functions,
language and affect).

Drug Targets
Historically patients were
sedating using
antihistamines.
Chlorpromazine is a
prototypical agent still
used in schizophrenia
today, traditionally used
as a strong sedating agent
with mild antihistamine
action. Chlorpromazine
turned out to be a potent
antagonist at dopamine
receptors. All potent antipsychotic/neuroleptic agents are potent antagonists of
dopamine receptors, and clinical potency of most of these agents correlates with
the blockade of D2 dopamine receptor sites.
The inhibition of actions of dopamine acting through the mesolimbic pathway
include psychomotor slowing, emotional quietening, affective indifference and
inhibition of aggression. These are effect that we want to see in a dopamine
antagonist to combat the symptoms of schizophrenia. However, the other two
dopaminergic pathways (nigrostriatal and tuberohypophyseal) will also have their
actions blocked, which will give us unwanted effects. As such, most of the major
unwanted side effects are due to the extension of the pharmacological effects
following the blockade of D2 receptors at these other, unwanted sites.
Inhibition of the action of
dopamine acting through
the nigrostriatal pathway
result in extrapyramidal
symptoms (EPS) or motor
disturbances. Drug
induced Parkinsonism or
rigidity/bradykinesia can
be observed.
Inhibition of actions of
dopamine mediated
through the
tuberohypophyseal
dopaminergic pathway
lead to an increase in
prolactin release
(hyperprolactinaemia). This can cause gynacomastia and amenorrhea (in
females).

Antipsychotics/neuroleptics fall into several classes: classical antipsychotics (e.g.

chlorpromazide, haloperidol) and atypical/2nd generation antipsychotics (e.g.
clozapine). These are the three main drugs to remember.
Classical Antipsychotics
30% of schizophrenic patients respond completely to antipsychotic/neuroleptic
therapy. Many respond only partially. Classical antipsychotics work really well for
the positive symptoms of schizophrenia, but the negative and cognitive
symptoms tend to be resistant to these classical antipsychotics. While theyre
not curative, they certainly help reduce hospitalisation.
The current hypothesis for the mechanism of action of antipsychotics is that
there is an over activation of dopamine receptors in the nucleus accumbens. The
regulation of the mesolimbic pathway is important in many emotional behaviours
and contributes strongly to the positive symptoms of psychosis, and by blocking
D2 receptors you treat these positive symptoms.

If you look at the classical

antipsychotics more closely,
theyre not particularly tidy
drugs. Chlorpromazine blocks D2
receptors, as well as H1, M, 5-HT2,
and receptors. Most of the
classical antipsychotics resemble chlorpromazine. Interestingly haloperidol
only blocks D2 receptors (selective), and does not cause as many side effect.
Why is this?

This is because by only blocking D2

receptors, haloperidol does not
cause sedation, postural
hypotension, dry mouth/blurred
vision/constipation or weight gain.
These side effects are due to the
blockade of various other receptors
(left) which are only caused by
chlorpromazine.

If chlorpromazine produces more side-effects due to its non-selective blocking

mechanism, why is it preferred? It is because it produced less of the
Parkinsonism effects (EPS). It does this because dopamine neurons usually exert
a tonic inhibitory influence on cholinergic neurons within the striatum. A D2
blockade removes this inhibitory influence and intensifies the activity of the
cholinergic system (leading to EPS). The fact that chlorpromazine is also an M
receptor antagonist helps curb this side effect.
Atypical Antipsychotics
Though chlorpromazine is still used, nowadays the atypical antipsychotics are
more widely prescribed. This is because they treat a wider range of symptoms
atypical antipsychotics treat the negative AND positive symptoms well (variable
response with cognitive symptoms) c.f. classical antipsychotics which only treat
the positive symptoms.
Why is clozapine (an atypical
antipsychotic) so good? It shares a
similar pharmacological profile to
chlorpromazine with one exception:
it is a potent antagonist of 5-HT2C
receptors. It is due to this particular
blockade of 5-HT2C receptors that it is
able to treat a larger range of symptoms.

Where it is hypothesised that the overactivation of the mesolimbic pathway, in the

nucleus accumbens, is responsible for the
positive symptoms of psychosis, there is also
a hypothesis that there is a hypo-activation of
the mesocortical pathway, in the pre-frontal
cortex, which is responsible for the negative
and cognitive symptoms of psychosis.
So how do we increase the dopamine activity
of the mesocortical pathway?

In the prefrontal cortex there are no D2

receptors. So adding a D2 agonist will
not help. The receptors here are D1
dopaminergic neurons will release
dopamine and it will act on D1 receptors
in the prefrontal cortex. However,
dopaminergic neurons are negative
regulated by 5-HT that is, the
activation of 5-HT2A receptors cause a
decrease in the amount of dopamine
released. A potent atypical antipsychotic
that is strong at blocking 5-HT2A
receptors is able to remove this level of regulation and increase dopamine
release, changing the hypo-activation of the mesocortical pathway into a more
normal level of activation.

Drugs

 Chlorpromazine. Typical antipsychotic. Blocks D 2 receptors, as well as

H1, M, 5-HT2, and receptors. Used to treat schizophrenia. Because of
its anti-muscarinic properties, there are less EPS observed. Most
sedating, most likely to cause hypotension. Only treats positive
symptoms of schizophrenia.
Haloperidol. Typical antipsychotic. Only blocks D2 receptors, so less side
effects, but most likely to cause EPS. Only treats positive symptoms of
schizophrenia.
Clozapine. Atypical antipsychotic. Similar profile to chlorpromazine, but
it can also block 5-HT2C receptors so can treat a larger range of
symptoms. Treats negative and positive symptoms of schizophrenia.

Lecture 6 Anxiety and Anxiolytics, Sedatives and OCD

Background
Anxiety is a normal emotion experienced at some time by virtually all people. It
is characterised by an unsettling feeling of uncertainty and apprehension. It can
involve restlessness, agitation, tachycardia, sweating, GI disturbances, weeping
and sleep disturbances. This ensures survival, but in excess can cripple an
individual. Anxiety and panic disorders are often chronic illnesses in some
patients, this is characterised by remissions and exacerbations recurrence of
the illness can be due to situational stress.
The area of the CNS which controls the fear response is the amygdala. It recruits
different brain regions to experience feelings of fear/avoidance, endocrine output
of fear, autonomic output of fear and the re-experiencing of fear. As such, it is
important to look at the neurotransmitters that are present in the amygdala to
determine whats causing anxiety. Some of the transmitter systems that drive
amygdala activity include noradrenaline, GABA and 5-HT.
hSert is the human 5-HT transporter. The expression and activity of this
transported is regulated by a promoter called 5HTTLPR. This 5HTTLPR is only
present in humans and primates, and alleles are either identified as being
short (S) or long (L). It has been shown that the S variant results in lower
SERT expression and activity. Humans with the 5HTTLPR SS genotype have a
greater predisposition towards anxiety and depression related traits.
Benzodiazepines
Benzodiazepines have been the mainstay of treatment for anxiety, but
antidepressant drugs such as TCAs, MAOIs, RIMAs, SSRIs have been shown to be
effective in treating some forms of anxiety. Benzodiazepines act by enhancing
the actions of GABA at the GABAA site.
GABA is the major inhibitory neurotransmitter in the CNS. GABA A receptors are
ligand gated receptors (ionotropic), and are widely distributed among the CNS.

The activation of GABAA receptors results in increases in Cl- ion permeability and
entry of this ion into the cell, resulting in hyperpolarisation (and inhibition) of the
neuron. Benzodiazepines do not do anything on their own, they only augment
the effects of the endogenous neurotransmitter GABA.
The GABAA receptor is formed from a combination of 5 subunits forming the ion
channel receptor. You can get different GABA A receptors formed depending on
which subunits you combine. There is a family of GABA A receptors that arise from
the combinations of different subunits. Benzodiazepines will only respond to
GABAA receptors that are comprised of 1, 2, 3 and 5 subunits.
So it is the subunit that is essential for the modulation of the GABA A receptor
by BDZs (and contains the BDZ binding site). It is the subunit which determines
the affinity and efficacy of BDZ binding. As mentioned above, only GABAA
receptors that are 1, 2, 3 or 5 containing are sensitive to BDZs 4 or 6
containing GABAA
receptors DO NOT interact
with BDZs.
Benzodiazepines that work
on the 2 and 3
containing subunits are
usually responsible for the
anxiety-relieving effects. If
your benzodiazepine
causes sedation, then it
most likely targets 1containing GABAA
receptors. The 5 subunits
in the hippocampus are
associated with the
memory impairing effects of BDZs.

Choice of BDZ
All BDZs are relatively non-selective. They all reduce anxiety and aggression,
produce sedation and induce sleep, reduce muscle tone and co-ordination, and
have an anti-convulsant effect. Clinical efficacy for BDZs are the same i.e. they
are all targeting the same receptor, their pharmacodynamics dont change.
However, their pharmacokinetic characteristics vary considerably. The speed of
onset is determined by lipid solubility (access to CNS), duration of action is
dependent on metabolism, and longer durations BDZs usually form active
metabolites.

So diazepam is quite long lasting as it is metabolised into a range of active

metabolites before it is rendered inactive. Chlordiazepoxide is also long lasting.
Something like lorazepam is much shorter acting however, because there are not
secondary active metabolites, they are immediately metabolised and excreted.
Commonly Used BDZs
Flurazepam used for insomnia
1-2 hours life
Nitrazepam used for insomnia
20-30 hours life
Diazepam used for anxiety, panic
attacks 20-90 hours life

Using BDZs to Treat Anxiety

Treatment usually involved brief interrupted courses of 2-4 weeks duration with a
tapered withdrawal of drug. In panic disorder, continuous treatment for as long
as 6 months to a year may be necessary. Periodic breaks from treatment (and/or
dose reduction) are useful in determining whether continued drug use in
necessary. Withdrawal is similar to alcohol withdrawal.
BDZs are relatively safe in terms of overdosage compared with alcohol, and have
predictable side effects. These side effects include excessive sedation (fatigue,
poor concentration, confusion) as well as ataxia/muscle weakness. Some
tolerance develops to both these side effects, with little tolerance developing to
their anti-anxiety effects. There is also a decrease in REM sleep with a rebound
following discontinuing treatment. Additional side effects include disinhibition
(feelings of anger or irritability) as well as anterograde amnesia BDZs obliterate
memory of events experienced while under their influence. There is some
psychological dependence, and strong physical dependence.
BDZs in Insomnia
Short-term insomnia is best treated by a DBZ for 2 days to 1 week (if necessary).
Long-term insomnia usually requires that BDZs be used for a prolonged period.
These should be re-appraised within a month, and short-to-median life BDZs
are used e.g. temazepam, nitrazepam.
Zolpidem is a new selective BDZ for insomnia. It is technically not a
benzodiazepine, but it does target the same targets as BDZs (1 containing
receptors). It shows good sedative action, with little anticonvulsant or muscle
relaxing activity. It also has a rapid onset, and is short acting (3-6 hours).
5-HT and Anxiety
There are a multitude of 5-HT types, and they all serve various roles. For
example, 5-HT1C and 5-HT1D are associated with migraine, whereas 5-HT 2A
receptors are important in schizophrenia. Interestingly, all of the receptor

subtypes are also strongly linked with anxiety. So new therapies for anxiety
disorders dont have to just focus on GABAA receptors, but 5-HT receptors are
also a good candidate. This is why some antidepressants can be effective in
anxiety, as they also target 5-HT receptors.
Buspirone
Buspirone is a partial agonist at 5HT1A receptors. Paradoxically, through
activation of 5-HT1A receptors, it
inhibits 5-HT transmission.
Importantly, it has no action at BDZ
receptors. The benefits of using
buspirone over BDZs is that there is
less potential for sedation and
psychomotor impairment, as well as
less potential for abuse and
dependence. They have similar efficacy to BDZs in generalised anxiety, but are
less effective than BDZs in acute panic attacks. Buspirone also has a slower
onset of action than BDZs (weeks vs. days) improvement noted within 1-2
weeks, with further improvement noted over 4-6 weeks. Some of the side effects
though include dizziness, nausea, headache, some drowsiness/insomnia,
nervousness and fatigue.

Obsessive Compulsive Disorder (OCD)

OCD involves recurring obsessions and/or compulsions. They are excessive and
unreasonable, which cause marked distress and consume time, interfering with
normal life. The prevalence of OCD is approximately 1-5% - symptoms include
cleaning, washing, checking, arranging, counting, repeating and collecting. SSRIs
(antidepressants) and behavioural therapy is useful for moderate to severe OCD.

Drugs

Flurazepam. GABAA agonist at the BDZ site. Used for insomnia. 1-2 hours
life
Nitrazepam. GABAA agonist at the BDZ site Used for insomnia. 20-30 hours
life
Diazepam. GABAA agonist at the BDZ site Used for anxiety, panic attacks.
20-90 hours life, as it has a number of active metabolites.
Zolpidem. GABAA agonist at the BDZ site, though not structurally a BDZ.
Little anti-convulsant or muscle relaxing side effects. Used for insomnia. 36 hour half-life.

 Buspirone is a partial agonist at 5-HT1A receptors but inhibits 5-HT

transmission. Used for generalised anxiety disorder. Less potential for
sedation and psychomotor impairment, as well as less potential for abuse
and dependence. Slower onset of action vs. BDZ (weeks)

Lecture 7 Anti-depressant and Anti-manic Drugs

Background
The incidence of depression in the total population is about 5%. Only about 30%
of depressed individuals are in treatment, and up to 15% of severely depressed
individuals will commit suicide. It can be characterised by a depressed mood,
apathy, weight/appetite changes, sleep disturbances, psychomotor
agitation/retardation, and fatigue, feelings of guilt/worthlessness, executive
dysfunction and suicidal ideation. Depression is twice as likely in women, peak
onset is 20-40 years.
Biological Basis for Depression
The main hypothesis for the
biological basis of depression is the
monoamine hypothesis that there
is something wrong with
transmitters like noradrenaline or 5HT. This hypothesis was extended to
suggest that it was a lack of these
transmitters. Evidence in support of
this hypothesis was that be
depleting these transmitters,
depressive effects were seen. Also,
by augmenting the levels of these
neurotransmitters in individuals who
were depressed seemed to help.
Most of the drugs for depression work in a very simple way. They either target
the monoamine uptaker by blocking it, or by targeting the MAO and preventing it
from breaking down the neurotransmitter.
If this was the only factor that caused depression, then you would expect to see
an immediate increase in mood after using these drugs once the plasma levels
are recorded and the biochemical effect is accounted for. Instead, it actually
takes a long period of time before an improvement in mood is observed. This
suggest there is not just blocking of the uptake transporter or of MAO, but some
long-term process that is being targeted.
As such there is a modified hypothesis that takes into account monoamine
receptors. The evidence to support that it is not just neurotransmitter levels that

cause depression, is the observation that depression is associated with an

abnormal upregulation of monoamine receptors elevated 5-HT 2A receptors
observed in frontal cortex of depression suicides. This new modified hypothesis
suggests that antidepressant drugs act by elevating monoamine levels, which
then results in a down-regulation (normalisation) of monoamine neurotransmitter
receptors. Particularly implicated at 5-HT2, as well as and adrenoceptor
subtypes.
This is not the full story however, as there is some evidence to suggest that
depression is associated with neuronal loss in the hippocampus and frontal
cortex. It is also thought that depression is associated with a hyperactive hypopituitary axis increased cortisol levels cause cortisol-dependent stress related
atrophy of neurons within these regions, associated increased in glutamate
levels and potential for excitotoxic damage.

TCAs
Tricyclic antidepressants (TCAs) are
the original class of antidepressants.
Desipramine is the most well known
in this class. TCAs block the re-uptake
of NA and 5-HT to varying degrees,
though most usually favour blockade
of NA re-uptake.

All TCAs have at least 2 other actions:

blockade of muscarinic receptors (antiSLUD), blockade of H1 receptors (sedation)
or blockade of 1-adrenoceptors
(orthostatic hypotension).
TCAs are toxic. Overdose results in
atrial/ventricular extrasystoles, sudden
death ventricular fibrillation. This is due
to anti-muscarinic effect and blockade of
NA reuptake.

SSRIs
SSRIs are very selective and specifically block the re-uptake of 5-HT. A classic
example of an SSRI is fluoxetine. Increased 5-HT release in combination with
increased synaptic transmission ultimately results in a down-regulation of
postsynaptic 5-HT2A receptors.

SSRI side effects are generally acute

and are attenuated over time. The
side effects are attributed to the
intial increase in 5-HT stimulating a
whole range of receptors (5-HT2A, 5HT2C, 5-HT3 and 5-HT4) before there is
a down-regulation of 5-HT reuptake
transporters.
In terms of long-term side effects,
the is little sedation/insomnia, no
orthostatic hypotension, no
anticholinergic effects and no cardiac
toxicity (c.f. TCAs)
However, SSRIs should not be administered in conjunction with other MAOIs,
SSRIs, TCAs, St Johns Wort, Sumatriptan or ecstasy. Can cause serotonin
syndrome (excessive increase in synaptic 5-HT levels) characterised by:
agitation, confusion, sweating, shivering, tremor, diarrhoea, fever, incoordination.
Irreversible MAOIs
These include agents like
tranylcypromine. These prefer to target
(but dont always) MAOA which breaks
down NA and 5-HT. By inhibiting MAO, you
prevent a breakdown of NA and 5-HT, so
synaptic levels of these both increase.
These irreversible MAOIs tend to be nonselective and block MAOB as well, and
they bind to MAO and completely destroy
its function. Enzyme activity returns with
the resynthesis of new enzyme (2-3
weeks). Ultimately they increase
cytoplasmic and released levels of NA and 5-HT.
Side effect include insomnia, postural hypotension, atropine-like side effects
(though less than TCAs) and sexual dysfunction (loss of libido/impotence). There
is also an issue with the cheese reaction and irreversible MAOIs: they can inhibit
MAO present in gut and liver, which allows unmetabolised dietary monoamines
to have free access to body, which can overload NA and 5-HT stores in the
nerves leading to hypertensive crisis.
RIMAs
Reversible monoamine oxidase inhibitors (RIMAs) include moclobamide. RIMAs
bind reversibly to MAOA, they are selective for it, and will NOT lead to cheese
reaction. Can cause insomnia and nausea, but does not cause postural
hypotension or atropine like side-effects.

SARIs
Serotonin antagonist and reuptake inhibitors (SARIs) include nefazadone. SARIs
are a selective 5-HT reuptake inhibitor (less potent than either TCAs or SSRIs.
Predominantly, they are a selective antagonist for 5-HT 2A receptors reducing
the adverse effects associated with initial 5-HT receptor stimulation, so effective
in limiting anxiety that SSRIs tend to cause initially, also have a particular benefit
in sleep disturbances and less effect on sexual function.
Bipolar Disorder
Manic depression depression alternates with mania. Lithium stabilises mood
though the mechanism of action is largely unclear. It is possible that it permeates
the voltage depended Na+ channels and is not pumped out. This could allow it to
accumulate in excitable tissues, blocking the release of monamines, enhancing
their reuptake? Seriously, who knows? It works.

Drugs

Desipramine. Most well known TCA.

Theme 3: Hormones and Endocrine Mechanisms

Lecture 9 Hypothalamic-Pituitary Hormones
Background
The endocrine system regulates many body activities and consists of a variety of
organs that secrete substances directly into the blood which in turn affect the
function of target tissues. Why might we want to target the endocrine system?
As a replacement in hormone deficient states (e.g. thyroid hormone for
hypothyroidism), to modify malfunction of endocrine systems (e.g. carbimazole
for hyperthyroidism), to alter normal function where this is an inconvenience
(e.g. contraceptive pill), and to analyse the functional integrity of the endocrine
system (e.g. somatotrophin for GH release).
How can drug agents influence endocrine systems? They can mimic or block the
actions of endogenous hormones. Consider a partial agonist, it may act as an
agonist in the absence of endogenous hormones or an antagonist in the
presence of endogenous hormones by competing for the same sites.
Hypothalamic-pituitary axis
This is known as the co-ordination centre of the endocrine system and controls or
influences the activity of other endocrine organs. The pituitary gland is about the
size of a pea in a human brain and is responsible for the synthesis and release of
trophic hormones (trophic means to stimulate the activity of another endocrine
gland). Because it regulates the secretion of numerous hormones, it is known as

the master gland. In addition to releasing trophic hormones, it can also release
hormones which act directly on target tissues.
The pituitary gland has a connection with the hypothalamus, and is split into two
lobes. The anterior pituitary, or adenohypophysis, can release trophic hormones
which can act on the thyroid (to produce TSH), can act on the adrenal cortex to
release ACTH, as well as acting on the ovaries and testes to release FSH and
LH. In addition to releasing these trophic hormones, it can also release primary
hormones such as prolactin which can act on mammary glands, and growth
hormone (GH) for bone growth.
The posterior pituitary, or neurohypophysis, only releases primary hormones that
act directly on the tissue, and include oxytocin (can act on muscles of the
uterus) and antidiuretic hormone (ADH, acts on kidney tubules).

The Posterior Pituitary

The posterior pituitary consists largely of terminals of nerve cells which lie in
hypothalamic nuclei. So the hormones are synthesised in the hypothalamus, get
transported down the hypophyseal tract, where they reside in the posterior
pituitary i.e. peptides get synthesised in the hypothalamus, pass down along
axons into the posterior pituitary, then into the blood. The nerve endings are in
close association with the capillaries in the posterior pituitary, which is important
as the hormones are synthesised and then released into the blood vessels where
they can circulate around the body.

Vasopressin and oxytocin are structurally similar, so it

is no surprise that you can occasionally have them
bind to each others receptors. There are three types
of vasopressin receptors: V1A, V1B and V2. There is one
oxytocin receptor (OT).

Oxytocin
Oxytocin contracts the smooth muscle of the uterus
used to stimulate labour and to treat postpartum
haemorrhage. Oxytocin receptor antagonists can be
used as well to prevent the onset of labour (agents
include atosiban and barusiban), which although are
just as good as B2 agonists, they are far less effective
than nifedipine. In addition, oxytocin can be used to
cause milk release during lactation (it contracts the
myoepithelial cells surrounding mammary gland
alveoli). Oxytocin has also been linked to positive social interactions motherinfant bonding, love and pair bonding, sexual arousal and behaviour. It has been
shown to enhance social contact and promote social cohesion increases trust
and reduces fear, is calming.
Antidiuretic Hormone (ADH)
Arginine vasopressin (AVP) is involved in the control of body water, and is
released in response to an increase in blood osmolality (or decrease in blood
volume). Vasopressin activates various cell surface receptors such as V 1A on
blood vessels to cause vasoconstriction, V1B in the anterior pituitary to cause
ACTH release, and V2 in renal collecting tubules to cause an increase expression
of water channels and increased water reabsorption.
Diabetes Insipidus ADH deficiency
Patients have increased thirst; polydipsia, polyuria. This is due to either a
decrease in vasopressin being released (neurogenic DI) or a decreased response
to vasopressin (nephrogenic DI). Normally vasopressin will be released from the
posterior pituitary and act on V2 receptors on collecting ducts, causing increased
water channel expression and thus increased reuptake of water. In neurogenic DI,
there is a reduced amount of ADH being secreted from the posterior pituitary,
less receptor activation, less expression of water channels, less water
reabsorption. However in nephrogenic DI, the right amount of ADH is being
released from the posterior pituitary, but the V2 receptors are missing or
unresponsive, so less water channel expression and less reuptake.

Pituitary DI treat with vasopressin analogues. Vasopressin has a very short halflife, so treat with desmopressin (V2 selective, so treats problem in collecting
duct without causing hypertension or other issues if it was V non-selective).
SIADH ADH excess
Syndrome of Inappropriate ADH Secretion (SIADH) is caused by a small cell
carcinoma in the lung, causing ectopic vasopressin secretion, resulting in
hypertension and fluid retention. Treated with V receptor antagonists such as
demeclocycline.
The Anterior Pituitary
The anterior pituitary is composed of a heterogeneous collection of numerous
cell types. It is connected with the hypothalamus via the hypothalamic-pituitary
portal vascular system.

Hypothalamic-releasing factors (except

DA) are peptides, i.e. somatostatin,
TRH, GnRH, VIP.
Anterior pituitary hormones are
peptides/proteins, i.e. ACTH, PRL, GH,
TSH, FSH/LH
Posterior pituitary hormones are
peptide, i.e. oxytocin, vasopressin.
As such, none of them are orally
active.

Hypothalamic Control of Anterior

Pituitary and Regulation
Hormones get released from the
hypothalamus, travel down the
capillary bed, to affect the cells of the anterior pituitary. These releasing factors
act of specific GPCRs (to alter cAMP, IP3 or Ca+). Most of these hypothalamicreleasing factors are secreted in a cyclical or pulsatile manner. Their therapeutic
effects can vary depending on frequency and pattern of administration.
When the hypothalamus releases a hormone to act on the pituitary, it then
releases a trophic hormone which acts on an endocrine gland to release a
primary hormone. This primary
hormone then negatively feeds
back on the hypothalamus to
prevent it from continuing the
cycle.
An example of this is with
gonadotrophic releasing
hormone (GnRH) which is
released from the
hypothalamus to act on the
anterior pituitary, to release
FSH or LH. These hormones
then act on the ovaries to
regulate the amount of
oestrogen or progesterone
being released, and these
hormones in a negative
feedback fashion modulate both the hypothalamus and the anterior pituitary to
stop their production.
But what can go wrong? Sometime there can be too much or too little of the
primary hormone. This could be due to a number of abnormalities: dysfunction of
the primary endocrine organ (e.g. gonads, thyroid), dysfunction of regulatory

organs (e.g. hypothalamus, pituitary), or maybe the end (target) tissue is

unresponsive to the hormone.
Disorders of the Pituitary
Hyperpituitarism is generally caused by pituitary tumours and is characterised by
increased release of two or more pituitary hormones. Treatment involves surgery
or radiation therapy. In contrast, hypopituitarism may affect one or more
endocrine systems, and treatment involves the replacement of these primary
hormones.
Prolactin
Prolactin receptors are tyrosine kinase-linked receptors and are important for the
development and maintenance of lactation. Levels are increased during
pregnancy and breast feeding, at night and during stress. Dopamine exerts a
tonic inhibitory control over the release of prolactin (this occurs normally)
although when prolactin is released it is usually episodic. TRH, VIP and oxytocin
can enhance the release of prolactin.
Though there are no disorders caused by a lack of prolactin release, too much
can result in infertility disorders. Bromocriptine can be used as a dopamine
agonist to treat prolactin excess. Adverse effects include nausea and vomiting,
and a tolerance develops to these side effects but not to the therapeutic effects.
Though cabergoline is better tolerated and has better efficacy, bromocriptine
is older and we have more safety data for it.
Growth Hormone (Somatotrophin)
GH receptors are tyrosine kinase-kined. They stimulate linear body growth,
regulate cellular metabolism and have anabolic effects (also simulate lipolysis,
production of free fatty acids, increase blood glucose). GH is released
episodically and is stimulated by GHRH (somatorelin) while it is inhibited by GHIH
(somatostatin). GH can also be released by factors such as exercise, stress and
hypoglycaemia.

Lecture 10 & 11 Gonadal Hormones

Background
Steroids that are produced by the gonads mediate the endocrine functions of the
gonads. In the testes, the steroid there are androgens which make you feel like
superman. For ladies, the ovaries produce oestrogen and progesterone. The main
functions of the gonadal steroids are involved in sex differentiation and
differential expression of secondary sex characteristics, and control of fertility.
Gonadal steroids can be split into androgens, progestins and oestrogens. When
we think of male sex hormones we typically think of testosterone, and while it
certainly plays a key role in the effects we see, dihydrotestosterone is also
important bot are androgens. Progesterone is a progestin and is required for
the maintenance of pregnancy. The group of oestrogens are largely responsible
for feminising characteristics. All 3 steroid types are synthesised from
cholesterol.

Control of Sex Hormone Synthesis

The hypothalamus releases GnRH which stimulates the anterior pituitary to
release FSH and LH to then produce testosterone. There are two different types
of cells which can produce testosterone. In Leydig cells, LH increases
testosterone synthesis. In Sertoli cells, the FSH can lead to an increase in ABP
(androgen binding protein) which ultimately leads to an increase in testosterone.

Likewise in ovarian hormone synthesis, the hypothalamus releases GnRH to act

on the anterior pituitary, causing it to release FSH and LH, which then cause the
production of oestrogen and progesterone in the ovary. Oestrogen plays a key
role in the thickening of the endometrium, where LH is involved in the ovulation
or release of the egg. Sequence goes oestrogen increase first, then progesterone
increase. LH increases androgen synthesis in Thecal cells (increasing oestrogen)
and FSH increases aromatase in Granulosa cells which break down androgen into
oestrogen.

Gonadal Steroid Pharmacokinetics

All of these steroids are lipid soluble. This is important as they have to be able to
pass through the cell membrane to bind to intracellular receptors. Most are
subjected to extensive hepatic metabolic inactivation, so they cannot be given
orally and we must synthesis compounds that can avoid this process. In the
blood these hormones can bind to plasma proteins such as albumin, but they can
also bind to SHBG (sex hormone binding globulin), so if we change the amount of
SHBG levels in the blood we can change the amount of free steroid available.
There are separate receptors for each steroid hormone i.e. progesterone
receptors, androgen receptors, oestrogen receptors. There are some cross
reactivity observed, for example prolonged progestin levels can have androgenic
effect. There are some subtypes, mostly our knowledge is limited to oestrogen
receptor subtypes though. These nuclear receptors regulate gene expression.
Target cell activation can depend of blood levels of free hormone, the relative
numbers of the receptor for that hormone in the target cell, the affinity of the

bond between hormone and receptor, as well as the number of cofactors

recruited and their availability.
When we think about various drugs we typically think about them having an
agonist or an antagonist effect. However, there are selective steroid receptor
modulators that can have different effects at different tissues (ligand-specific
actions) due to the recruitment of different co-factors. For example SERMs
(selective oestrogen receptor modulators) which include tamoxifen and
raloxifen may be an antagonist for typical nuclear hormone receptors, they are
an agonist at certain GPCRs. There are also androgen-based modulators (SARMs)
as well as progesterone-based modulators (SPRMs)
Physiological Actions
Testosterone is involved in the development of the secondary sex characteristics,
increased muscle and fat distribution. DHT can also have a number of effects
such as increased facial hair, prostate etc.
Oestrogen has a number of different effects. It plays an important role in the
growth and differentiation of the uterus (to do with the endometrium), its also
involved in the growth of breast tissue. It also has other effects not related to the
sex organs: it has neuroprotective effects in various CNS disorders, plays an
important role in vasodilation, etc.
The actions of progesterones include metabolic changes (CHO and fat
metabolism), increase in body temperature, have a depressant/hypnotic effect
on the brain, mammary glandular development, and modulates action of
oestrogen on uterus. Is known as the hormone of pregnancy.
Replacing Hormones in Deficient States
Symptoms vary depending on age of onset, could be caused by hypogonadism
following ovariectomy/castration, menopause or andropause. In these cases the
aim is to replace the effects on peripheral tissue by perhaps adding hormones.
Reducing Innapropriate Growth of Hormone-dependent Tissues
Treatment aim is to inhibit the effect of oestrogen/dihydrotestosterone on these
tissues. We can do this by inhibiting the synthesis or activation of the receptor.
Here are three examples:
1. Some breast cancer cells express large amounts of oestrogen receptors,
which stimulate tumour growth. By using an oestrogen antagonist or an
agent that can decrease the rate of oestrogen synthesis, we can slow
tumour growth.
2. Likewise in BPH (benign prostate hyperplasia) and prostate cancer, in the
prostate the presence of testosterone can lead to prostate tissue growth
so we can use synthesis inhibitors and androgen receptor antagonists to
inhibit this growth.
3. Finally in endometriosis there is a benign ectopic growth of endometrial
tissue which grows and regresses with menstrual cycle. Because it is
oestrogen dependent, we can decrease oestrogen synthesis (by
decreasing GnRH).
Altering Normal Function Where This is Inconvenient
I.e. contraception. The treatment aim in this case is to upset hormonal control of
ovulation/spermatogenesis. By adding exogenous steroid hormone, you

negatively feedback on the anterior pituitary, which no longer produces FSH and
LH, so no spermatogenesis/ovulation occurs.
Restoring Dysfunction of the Hypothalamic-Pituitary-Reproductive Axis
1. Polycystic Ovarian Syndrome (PCOS)
This occurs as a result of an increase in serum androgen. Results in
abnormal ovulation, masculinisation, excess hair growth etc. Mechanism is
unclear, but the LH hypothesis suggests that and increase in LH causes an
increase in androstenedione. Insulin hypothesis: increased insulin =
decreased SHBG = Increased free testosterone. Ovarian hypothesis =
dysregulation of sex steroid synthesis in thecal cells leads to androgen
synthesis. Treatment involves oestrogen and/or antiandrogen.
Treatment Strategies
In constructing treatment strategies you can either affect the synthesis of certain
steroid hormones by stimulating or inhibiting these processes, you can block
their actions by using antagonists, or you can replace the hormones.
We can either increase FHS/LH leading to increased steroidogenesis, perhaps in
order to stimulate ovulation; or we can decrease FSH/LH (decreased
steroidogeneis) and directly inhibit steroid hormone synthesis perhaps for use in
endometriosis, prostate cancer or breast cancer.
Modulation of the Gonadotropin Axis
We can use GnRH agonists (e.g.
goserelin, nafarelin) which can be
released in a pulsatile manner (mimic
endogenous release to stimulate the
anterior pituitary) or in a continuous
manner (which inhibits the anterior
pituitary).

An example in PCOS, you can use

clomiphene (an antioestrogen
compound) which works by
targeting oestrogen receptors that
are located within the anterior
pituitary. By blocking these
receptors, you block the negative
feedback mechanism and thus
increase the amount of FSH and
LH.

In contrast danazol targets the

negative feedback loop, and by
targeting this it can drive down FSH
and LH and thus decrease
testosterone and oestrogen.

Gonadotrophins
Follitropin (recombinant FSH)
Lutropin (recombinant LH)
Human chorionic gonadotrophin (HCG) - acts as LH
Aromatase Inhibitors
Used in the treatment of metastatic breast cancer (oestrogen responsive).
Aromatase is the key enzyme involved in the conversion of testosterone to
oestrogen. Examples include aminogluethimide, anastrozole, exemestane.
Hormone Receptor Antagonists

Anti-androgens can be used to preococious puberty, benign prostatic

tumours, hirsuitism and acne.
o Flutamide, cyproterone, spirolactone all act to block the
androgen-receptor complex. Good to use in females as it still allows
testosterone to be produced and thus broken down into oestrogen.

SERMs (selective oestrogen receptor modulators) can be used for breast

cancer, anovulatory infertility, osteoporosis and menopausal treatment.
o Have agonist activity in bone, lipids, endometrium and coagulation.
Has antagonist activity in breast and pituitary.
Tamoxifen
Antioestrogenic mammary tissue. Oestrogenic in plasma lipids,
bone, endometrium. Used for treatment of breast cancer.
Clomiphene
Antagonist at pituitary oestrogen receptors. Pituitary
gonadotrophins induce ovulation. Partial agonist in ovaries. Used
for anovulatory infertility.

Raloxifene
Antioestrogenic in breast and endometrial tissue. Oestregenic in
bone. Used for treatment of osteoporosis.
Tibolone
Antioestrogenic in endometrial tissue. Oestrogenic in bone, breast
tissue. Used for treatment of osteoporosis and menopausal
symptoms.

Antiprogesterones
Progesterone is the key hormone in pregnancy and plays an important role in
getting the endometrial tissue ready for the fertilised egg. Menstruation occurs
with the withdrawal of progesterone. So if we antagonise progesterone we get
uterine bleeding. Pregnancy is also dependent on progesterone, and if we
antagonise progesterone you get an abortion.
Mifeprisone
Progesterone receptor antagonist. Used in pregnancy termination (RU486).
Emergency contraception in lower doses
Danazol
Weak progestational and androgenic activity. Inhibition of pituitary LH/FSH
secretion. Atrophic changes in endometrium. Use = endometriosis.
Therapeutic Uses of Oestrogens and Progestins
Can be used for ovulation suppression/menstrual disorders including
endometriosis, contraception, dysmenorrhoea, pre-menstrual tension. They can
also be used as replacement therapy in hypo-ovarian conditions e.g. postmenopausal hormone replacement.
Hormonal contraceptives can either be oestrogen only (just targeting the
negative feedback of the anterior pituitary) or oestrogen and progesterone
(targeting both negative feedback of anterior pituitary and the hypothalamus).
They act to inhibit ovulation, thicken cervical mucous to make it harder for sperm
to get through the cervix, and to reduce the receptivity of the endometrium.
Oestrogen also has adverse, systemic effects. It can increase the production of
liver proteins (bad), cause the growth and proliferation of breast tissue (risk
factor for cancer) as well as increase growth and differentiation of primary sex
organs (risk factor for endometrial cancer). These can be counter-balanced by
adding progesterone to counteract these effects.
Long-term use of oestrogen containing contraceptives confer a risk of deep vein
thrombosis and pulmonary embolism, which is related to dose of oestrogen and
type of progesterone (increased risk if >35 and smoker). Potential increased risk
of breast cancer. Increased risk of gallbladder disease. ALTHOUGH there is a
decreased risk of ovarian cancer, potentially due to the decreased amount of
circulating gonadotrophins.
Menopause
Decreased ovarian function. Signs include loss of periods, genital atrophy,
bladder overactivity, hot flashes, decreased libido, lack of energy, loss or

memory, mood swings and irritability. Long-term consequences of menopause

include increased risk of disease: increased bone loss (decreased density,
osteoporosis), increased risk of coronary heart disease (myocardial
infarction/fatal strokes) and potentially increased risk of Alzheimers disease.
Whilst there are
negative effects of
oestrogen, there are
also positive effects
which include
neuroprotective effects,
maintenance of bone
density and
cardioprotection. This
make hormone
replacement therapy a
good option to use in
menopause.

Theme 4:
Neuropharmacology of Neurodegenerative Diseases
and Epilepsy
Lecture 12 Excitotoxicity and Neurodegeneration
Background
It is important to know that in general, neurons of the CNS cannot divide (with a
few exceptions). Neurodegenerative diseases such as Parkinsons or Alzheimers
disease are progressive, and current therapy does not treat the underlying
cause, only the symptoms. It is important for us to understand the pathological
process to allow for the development of targets that can stop or reverse
neurodegeneration (neuroprotective agents/targets) or targets that are
applicable to other processes in the brain that lead to brain damage.
Neurodegeneration is the dysfunction and/or loss of neurons/synapses and there
are a number of pathological processes that are common including:
excitotoxicity, ageing/oxidative stress, neuroinflammatory processes,
mitochondrial dysfunction, changes to protein folding and aggregation.
Excitotoxicity
Excitotoxicity is the phenomenon that occurs when there is over-activation of the
excitatory glutamate system. Activation of NMDA receptors allows for the entry
of Na+ and Ca2+ ions, causing an increase in intracellular Ca 2+ and the activation
of Ca2+ dependent enzymes (kinases, lipases, proteases, NOS) ultimately
causing cell death.
Stroke is a good example of excitoxicity. It is associated with the loss of cellular
homeostasis (loss of transporter function). GLUT levels are tightly regulated by

EAATs, which work by sucking up

extracellular glutamate into the
cell to maintain levels, and so
when we get a loss of energy
(due to ischaemic or
haemorrhagic stroke) there is a
loss of energy, a loss of
transporter regulation and
reversal of EAATs. This causes
glutamine to be pumped into the
ECF, causing excessive ECF
glutamate concentration and
thus excessive NMDA receptor
activation.
Neurodegeneration involves a continuum of effects. The breakdown of cell
membrane integrity causes cell death through the process of necrosis. This
involves the depletion of glucose/ATP, failure of Na +, K+, ATPase and other ion
pumps, cellular swelling, run down of membrane potentials, further glutamate
release and stimulation of NMDA receptors, as well as the activation of Ca 2+
dependent enzymes.
Once these Ca2+ dependent enzymes are activated they can cause the activation
of proteases, the activation of lipases, activation of NOS, the activation of
endocucleases, the activation of oxygen-derived free radicals and the activation
of neuroinflammatory processes.
There is also an apoptosis component, a late stage response (hours to days). The
mitochondria are critical in the regulation of apoptosis and it involves alterations
in mitochondrial permeability, release of cytochrome C, activation of
mitochondrial pathway and the activation of caspases, all to cause apoptosis.
Oxidative Stress and Formation of ROS
Superoxide (O2) is probably the most common of the free radicals, it is
generated enzymatically by NOX (NADPH oxidase found in macrophages/reactive
microglia). Other free radicals include OH-, H2O2 and ONOO-. ROS attack key
molecules (such as enzymes, membrane lipids, DNA and mitochondria) hydroxyl
free radicals and peroxynitrite are the most destructive.
Defensive mechanisms against ROS include several antioxidant enzymes and
enzyme systems, including: SOD (superoxide dismutase), catalase and
glutathione peroxidase.
Amyotrophic lateral sclerosis (ALS) is a fatal motor
neuron disease causing death of neurons in the
spinal cord, brainstem and motor cortex. Prognosis
= progressive paralysis followed by death in 3-5
years. ALS may be sporadic or familiar 20% of all
ALS cases are heritable, and of these, 20-30% are
caused by gain-of-toxic function mutations in Cu, Zn-SOD (SOD1)
Oxidative Stress in Parkinsons Disease
To treat PD, often dopamine is given. However there is a consequence of this.

The metabolism of DA by MAOB can lead to the production of oxygen free

radicals. Because the DA-ergic terminals are sensitive to the elevated oxidative
stress, you get further cellular damage and tissue necrosis.
Apoptosis
Apoptosis is cell suicide, or programmed cell death. The cells are dismantled and
remains are removed by macrophages. It is a process that is essential in
embryogenesis and tissue homeostasis (i.e. shedding of intestinal lining,
regression of glands, pathophysiology of cancer, autoimmune diseases).
There are two main pathways by which apoptosis occurs: the death receptor
pathway (intrinsic pathway) and the mitochondrial pathway. The death receptor
pathway occurs by activation of tumour necrosis factor receptor family (TNFR),
which activate caspase-8, which can in turn activate caspase-3 (the key
executioner protein) for apoptosis. The mitochondrial pathway is activated by
DNA damage and withdrawal of cell survival factors. This DNA damage activates
the p53 pathway and the activation of pro-apoptotic factors. These pro-apoptotic
factors, such as Bax, promote the release of cytochrome C from the mitochondria
which activates caspase-9.
Neuroinflammation
Neuroinflammation is the first line of defence against injury and infection.
Excessive inflammatory response is a source of additional injury. Brain
inflammation occurs as a result of activation and recruitment to the areas affects
of glia (microglia)/astrocytes. These activated microglia/reactive astrocytes occur
in Alzheimers, Parkinsons, Multiple Sclerosis, AIDS, dementia, trauma and
stroke.
Activated microglia can generate reactive oxygen species causing oxidative
damage. Reactive astrocytes generate other reactive oxygen species via
myeloperoxidase (MPO). Activated microglia contribute to neuronal damage
(neurodegenerative diseases) via the release or production of cytokines such as
TNF (activation of apoptosis), stimulating the expression of other enzymes (e.g.
NOS and the generation of toxic levels of NO) as well as the recruitment of other
inflammatory cells to the area affected.
Drugs in Neuroprotection
Oxidative Stress use of free radical scavengers i.e. vitamin E
Neuroinflammation COX-2 inhibitors/anti-inflammatory steroids, ibuprofen,
inhibition of cytokines
Apoptosis caspase inhibitors

Lecture 13 Drugs for Parkinsons Disease and Huntingtons Disease

Parkinsons disease was first described in 187 by James Parkinson as essay of
the shaking palsy. Common disorder up to 1% (aged population over 60). PD
has a long latency/is progressive, and this makes early diagnosis impossible. In
the clinical phase there is difficulty walking, fatigue, limb discomfort, clumsiness.
70% show a resting tremor that is worsened by stress and decreases with action.

There is rigidity and bradykinesia, as well as impaired postural reflexes. Furth

signs include micrographia, difficulty swallowing, cognitive problems and the
presence of Lewy Bodies post-mortem.
The aetiology of Parkinsons
disease is questionable.
There are some evidence
that ageing/oxidative stress
is involved, potentially
environmental toxins, and
there is a minor genetic
susceptibility. We are left with
an idiopathic disease,
without one underlying
cause. The striatum (caudate
+ putamen) brain region in
those who have Parkinsons
shows a loss of dopamine.
This dopamine is lost
because there is a loss of cell
bodies which project from the substantia nigra into the striatum.
It is the nigrostriatal dopaminergic system which collects and integrates the
signals from the cortex as well as put a sequence to the movements to ensure
that the right muscles are moving at the right times. In this way, it prepares the
motor system for the next movement in a given sequence.
Why is there a latency to the disease? The
reason you do not observe symptoms until
the individual is in their 60s, 70s or 80s is
because there is quite a lot of adaptive
capacity within the nigrostriatal
dopaminergic system. It is possible to lose
up to 80% of dopaminergic neurons
without observing any symptoms, only
after further loss will you observe mild
symptoms getting increasingly worse. So
by the time the disease has been characterised, there is already a potential loss
of 80-90% of dopaminergic neurons. The reason why this adaptive capacity
exists is because DAergic neurons mediate their activity through D 2 receptors,
and symptoms dont occur until ~80% of neurons are lost because the D 2
receptors proliferate and increase in number to initially compensate for the loss
of dopamine.
Rational Therapy for PD
Because the pathology is so well understood, there are clear therapies to treat
the symptoms of PD. These include increasing synaptic concentrations of
dopamine (1), direct activation of dopamine receptors with dopamine agonists
(2), prevention of dopamine metabolism (3) and altering the efficacy of
interacting neurotransmitters (4).

1. Increasing Synaptic Dopamine

Increasing synaptic dopamine is key, and probably the most common

therapy. The conversion of DOPA to dopamine occurs via the enzyme
DOPA decarboxylase. We cant give individuals dopamine as it does not
cross the blood-brain barrier, so DOPA is used as replacement therapy
(levodopa). After adding this precursor, DOPA decarboxylase (DDC)
converts DOPA to dopamine in the remaining neurons. 80% of patients
show improvement in function, and 20% are restored to normal function
with this therapy.
There are some issues with levodopa though, it doesnt last very long
(plasma life of 2hrs). Another issue is that while DDC is present in the
CNS, it is also present in the periphery more than 90% of levodopa is
converted to DA in the periphery by peripheral DDC so less than 1%
enters the brain for conversion to DA in the CNS.
As such, to optimise levodopa therapy it is usually combined with
inhibitors of DDC that are unable to cross the BBB. This allows for a
greater proportion of levodopa to reach the CNS, and allows
concentrations in the plasma to be higher for longer. Some of the DDC
inhibitors that are supplied in combination with levodopa include
carbidopa and benserazide.
One of the main side effects of levodopa therapy include dyskinesia
(abnormal involuntary movements) caused by too much dopamine and
dopamine receptor activation, potentially due to fluctuations in plasma
levels owing to the difficulty of giving the proper dose.
2. Direct Activation of Dopamine Receptors
Forget about dopamine, lets use a D2 receptor agonist. Using a DA agonist
means that you do not require the CNS for metabolism and storage, there
is increased reliability in dose by dose effects, and many DA agonists have
a longer life than levodopa. Potentially less likely to result in
dyskinesias for some reason. All of these agents that promote a clear cut

improvement in PD symptomology are D2 agonists, and include

apomorphine, bromocriptine and pergolide.
Side effects from these agents are due to peripheral and central DA
receptor stimulation. Nausea, vomiting and hypotension are observed
(peripheral effects) these occur when DA activates the chemoreceptor
trigger zone (CTZ) and can be treated with domperidone which is a
useful peripheral DA antagonist.
There are also some psychological side effects such as delusions, mania
and anxiety hallucinations due to excessive DA stimulation of the
mesocortical pathways (see schizophrenia).

3. Prevention of Dopamine Metabolism

When dopamine is released it is taken back up by the nerves, so there is a

degree of recycling. MAO is the enzyme that breaks down dopamine.
There are two types of this enzyme, and the one we want to target is MAO B
which is the type that is most common in the brain.
One compound that is a very selective MAO B inhibitor is selegiline. It can
be used alone or in combination with other agents for PD. Can be given
without restriction (i.e. no cheese reaction). Minor side effects include
insomnia/headache.
What happens when you inhibit MAOB and/or DDC is that other enzyme
systems start to become more relevant. An inhibition of DDC is associated
with an increase in other pathways for levodopa metabolism. COMT
metabolism results in production of 3-methyl-dopa. This competes with
levodopa for transport across the BBB and is associated with a poor
response to levodopa. COMT inhibitors include tolcapone and
entacapone.

4. Altering the Efficacy of Interacting Neurotransmitters

Dopamine neurons usually exert a tonic inhibitory influence on cholinergic
neurons within the striatum. PD removes this inhibitory influence and
intensifies the activity of the cholinergic system, so one strategy is to
diminish this level of activity.
Muscarinic antagonists provide mild relief in the early stage of PD 25% of
patients are adequately controlled with muscarinic antagonists.
Benzotropine is such an agent. All of these agents are centrally active,
uncharged, and able to cross the BBB. As they are anti-muscarinic agents
their side effects are predictable: dry mouth, constipation, urinary
retention, mental confusion.

Parkinsons Disease Polypharmacy

When treating PD, you can use a whole
range of drugs. For example selegeline
can be combined with levodopa, or
combined with DA agonists or muscarinic
antagonists.

Huntingtons Disease
HD is an inherited neurodegenerative disorder which is autosomal dominant and
largely displays 100% penetrance. The age of onset is 35-45 years, and affects
approximately 4-10 individuals per 100,000 (relatively rare). Death occurs 10-15
years after symptoms are observed, so by this stage the gene is potentially
passed on to offspring.
The symptoms of HD are quite the opposite to what is observed in PD. It is
characterised by chorea (irregular, unpredictable, purposeless, rapid
movements), impaired voluntary movement, jerks, cognitive deficits and severe
rigidity in late stages.
HD actually affects GABA, completely different transmitter. In this disease there
is a selective loss of GABA neurons within the striatum. GABAergic neurons exert
an inhibitory influence on DA within the striatum. This loss, leads to DA
hyperactivity, which accounts for the motor hyperactivity. Most drugs are poorly
effective or only effective in the short term. It is possible to use DA antagonists
(such as chlorpromazine), GABA agonists (such as baclofen) or
tetrabenazine (depletes dopamine within the brain).

Lecture 13 Epilepsy and Anti-Epileptic Drugs

Background
Epilepsy and seizures are two different things. A seizure is a clinical
manifestation of abnormal/excessive synchronous excitation of a population of
cortical neurons. Epilepsy is defined as 2 or more recurrent, unprovoked seizures.
Epilepsy affects 0.5-1% of the population, and drugs are affective in 70% of
cases (though 20% do not respond at all to drugs).
Partial seizures begin locally and remain localised, with symptoms depending on
brain regions involved. Simple partial seizures show motor signs, sensory
symptoms and autonomic symptoms. Complex partial seizures show impaired
consciousness and various clinical manifestations that vary with origin and
spread of seizure temporal lobe epilepsy most common.
Generalised seizures involve the whole brain and are associated with a loss of
consciousness. Toni-clonic seizures show strong contraction of musculature (rigid
extensor spasm)/involuntary vocalisation. Absence/petit mal seizures are
common in children and are characterised by stopping current action and vacant
stares with little or no motor disturbances.

Epilepsy can be acquired due to physical injury to the brain from things such as
tumours, strokes, CNS infections etc. 50% of patients with head trauma develop
a seizure disorder. An initial seizure can lead to pathological events which can
lead to future vulnerability. Genetic epilepsy involves mutations in structural
elements of the brain such as receptors or ion channels.
The main mechanism of action of all anti-epileptic drugs is to target the neuronal
excitability. It is still unclear whether there is too much neuronal excitation
occurring, or whether there is too little neuronal inhibition. To model epilepsy, a
number of different methods can be used. Convulsants such as bicuculline and
picrotoxin inhibit GABAA receptor activation. To model complex partial seizures,
kainic acid can be used as an agonist at glutamate receptors which results in

seizure activity with systemic/IV administration. Also, repeated stimulation to a

group of neurons can result in a sustained enhanced excitability of the neurons
which can initiate seizure activity weeks after the stimulus.
GABAergic Transmission as a Target
Most of the anti-epileptic agents in use seek to enhance GABA function, not so
much block glutamate activity. GABA is metabolised by the enzyme GABA-T
(GABA transaminase). The inhibition of this enzyme leads to substantial
increases in neuronal and extra-neuronal levels of GABA enhanced levels of
neuronal inhibition/quiescence. Alternatively, as GABA is removed from its site of
action by reuptake through a specific transporter, blocking this transporter leads
to increases in extra-neuronal levels of GABA and enhanced neuronal inhibition.
So here are potentially to mechanisms to target. Valproate and vigabatrin
target GABA-T, whereas tiagabine targets GABA reuptake transporter.

Another key target in epilepsy is the

GABA receptor itself. Benzodiazepines
and barbiturates tend to be used
which target the allosteric site and
potentiate the effects of GABA.
Diazepam and phenobarbitone are
used in epilepsy.

Na+ Channels as Targets

If we want to stop electrical activity (the action potential) we must affect Na +
ions and their movement. Action potentials are an all-or-none depolarisation of
the cell membrane, once propagated it spreads to all parts of the cell. During
seizures there are neurons firing at a high frequency. To effectively target Na+
channels in epilepsy, we need to utilise a use-dependent blockade of Na +
channels, that is preferentially block neurons that are firing at high frequency
without interfering with the firing of neurons which are in a normal state.
Ca2+ Channels as Targets
Absence seizures are exclusively associated with T-type Ca 2+ channel activation.
The T-type Ca2+ channels within the thalamus provide a pacemaker current
that produces bursting intrinsic firing, leading to absence seizures.
Ethosuximide specifically blocks these T-type Ca2+ (low voltage activated)
channels.
Gabapentin also works through Ca2+ channels, but a different type, known as
the high voltage activated (HVA) Ca2+ channel. Some partial seizures are
associated with HVA Ca2+ channel activation.
Comparative Unwanted Effects of Major Anti-Epileptic Drugs and Drug
Interactions
Sedation and confusion are common, as are skin rashes. Phenytoin also

produces gum hyperplasia, acne and hiruitism ,and it shown zero order kinetics
(narrow safety margin).
The cytochrome P450 enzyme system in the liver is responsible for the
metabolism of many drugs. These enzymes have broad specificity and several
enzymes can metabolise a drug. The enzyme activity within this system can be
induced or inhibited. An example of an inducer of CYP450 is phenobartbitol and
phenytoin, whereas valproate is an inhibitor of CYP450.
Some anti-epileptic drugs can cause miscarriage and foetal abnormalities.
Phenytoin affects palate/heart, and valproate causes spinal bifida.

Lecture 15 Alzheimers Disease and Dementia

Background
Dementia is a significant loss of intellectual abilities severe enough to interfere
with social or occupational functioning. Mild cognitive impairment is significant
memory loss without the loss of other cognitive functions. Forgetfulness is a
common symptom associated with ageing. Many things can cause or lead to
dementia, with neurodegenerative disorders being the most common. Currently
1 in 4 people over the age of 85 are affected by dementia, and it is the third
leading cause of death in Australia after heart disease and stroke. The most
common condition resulting in dementia is Alzheimers disease.
Neuropathy of Alzheimers Disease
AD is the most common neurodegenerative disease, affecting more than
20million people worldwide. Familial AD <10% of cases, much more prevalent is
late onset AD (>90%, age related). AD is characterised by a shrinkage of the
temporal cortex/frontal lobe by as much as 20%. The two hallmarks which allow
us to identify AD are the presence of amyloid plaques and neurofibrillary tangles.
Amyloid plaques are formed outside of neurons
and are composed of -amyloid (A). When A is
in its soluble form it is toxic to neurons when it is
taken up by the neurons, and when it is in its
insoluble form they clump together outside
neurons to form plaques which release oxygenderived free radicals, disrupt potassium and
calcium channels, and cause vasoconstriction and
blood vessel injury.
Neurofibrillary tangles form inside neurons and
occur as a result of production of abnormal form of
tau. Tau normally forms cross bridges between
microtubules and keeps them in stable configurations. Microtubules collapse, and
tau proteins clump together to form neurofibrillary tangles.
Diagnosis of Alzheimers Disease
Diagnosing is problematic, and involves post-mortem confirmation. Cognitive
tests such as a Mini Mental State Examination (MMSE) can be performed, but
they are subjective. Biomarkers in CSF, looking for A and tau are invasive and

unreliable. Neuroimaging is expensive, but MRI can look for hippocampal

atrophy, and a PET tracer compound can bind to A plaques. Cognitive
symptoms of AD include
impairment in
memory/concentration,
disorientation, alterations in
personality, aphasia, apraxia,
agnosia.
Cholinergic Hypothesis
It has been identified that
there is a selective loss of
cholinergic neurons arising
from the basal forebrain in AD.
Typically there is a 70% loss of
choline acetyl transferase
(ChAT), causing decreased ACh release. Treatment for this is largely focused on
replacing ACh: increasing ACh synthesis, adding choline as a precursor,
augmenting the release, stimulating post-synaptic receptors, and reducing the
degradation of ACh by inhibiting AChE or BuChE.

Drug Treatments

Synthetic
precursors
choline is not
effective at driving
ACh production
Cholinesterase
inhibitors AChE
inhibitors do have
beneficial effects on
the cognitive and
behavioural
symptoms of AD
Direct activation
of cholinergic
receptors agonists poorly effective

Tacrine is a reversible cholinesterase inhibitor, but is not used very often due to
high liver toxicity (25%). The most widely prescribed reversible cholinesterase
inhibitor is donepezil which is highly selective for AChE and has a long life.
Mematine was approved by the FDA in 2008. It is an antagonist for NMDA
receptors and shows moderate affinity. The rationale for its use in AD is that the
overactivation of NMDA receptors has been implicated in many
neurodegenerative states. However, it only treats symptoms and it not thought
to affect the pathology.

Other targets for AD include cognitive enhancers that treat the symptoms,
disease modifying therapies such as A therapies, kinase inhibtors to block tau
hyperphosphorylation and anti-aggregation therapies.
A Drug Therapies

Rosiglitazone supresses -secretase activity. Phase III clinical trial, but

the FDA has warned of cardiac risk as an adverse event.
Semegacestat inhibits A production by inhibiting -secretase at the
active site. Phase III clinical trial halted as it failed to slow disease
progression and increased risk of skin cancer.
Tramiprosate is a glucosaminoglucan mimetic which prevents A fibril
formation and aggregation, currently in Phase III clinical trials

A Immunization Therapies
Active Immunization
AN-1972 Anti- A vaccine. Patients developed significant A antibody titres.
Stopped because aseptic meningo encephalitis in some patients, attributed to
cytotoxic T cells/immune reactions.
Passive Immunization
Bapineuzumab is a humanised anti-A monoclonal antibody 18 month
treatment no significant effect on cognitive measures
Solanezumab is a monoclonal antibody that binds specifically to soluble A,
promotes A clearance from brain through the blood

Tau-based Therapies
There are two main therapeutic approaches:
1. Modulation of tau-phosphorylating kinases
- Protein phosphatase 2A inibitors

2. Inhibition of tau aggregation and/or promote aggregate disassembly

- Methylthioninium chloride widely used histology dye, tau antiaggregant

Lecture 16 The Immune Response as a Drug Target in Stroke

Background
Stroke is the second largest cause of death in Australia (after heart attack) and
the major cause of disability. One in five people having a first-ever stroke die
within one month, one in three die within a year. There are two types of strokes:
ischaemic (85-90%) and haemorrhagic (10-15%). Neurons have very high energy
demands but they cannot store ATP it is the boring lecture. So I will come back
to it.

Theme 5: Hormones and Endocrine Mechanisms

Lecture 17 Agents That Affect Bone Mineral Homeostasis
Background
Bone provides structure and support, a space for
haemopoiesis, as well as a storage site for calcium (and
phosphate). There is approximately 1000g of calcium
stored in the body, 99% of that is within the bone in
crystalline form. The bone is the site of calcium
deposition and reabsorption it is a source of calcium
when plasma levels fall, and is a storage site for
calcium when plasma levels are too high.
Bone is made up of two major types: cortical bone
which is the typical long, hard and dense bone you
think of, and trabecular bone which is spongy and has a
honeycomb-like structure to absorb force. The
proportion of these two types of bone varies in different skeletal sites.

Bone Homeostasis
In order for bone to maintain its strength, it must undergo a continuous process
of reformation. Bone is constantly being broken down in areas where it may be
damaged, absorbed into the circulation as free calcium, and new bone is laid
down in its place. Bone homeostasis and remodelling occurs particularly in
response to mechanical stress. It is known that trabecular bone has a faster
turnover rate than cortical bone. This homeostasis is a balance between the
activity of osteoblasts (which cause bone deposition) and osteoclasts (which
cause bone resorption).

Osteoclasts are in a precursor form that is inactive, and they get activated by
osteoblasts. When there is stimulation and differentiation of osteoclasts, they
turn into a multinucleated cell that sits down on top of the bone which release
enzymes to break down the bone. As they start to break down the bone you get
the release of free calcium and phosphate, as well as some cytokines, and when
theyre released they stimulate the activity of osteoblasts to lay down new bone
matter.

The way that osteoblasts activate osteoblasts is via the RANK/RANK-L system.
Osteoclast progenitors express RANK on their cell surface. Osteoblasts express
the RANK ligand, so when they come into contact with osteoclasts they activate
them into multinucleated osteoclast which resorbs bone. Osteoblasts also
produce osteoprotegerin (OPG) which is like a soluble form of the RANK. This
allows them to bind to RANKL and prevent binding to osteoclasts, preventing
excessive osteoclast activation and bone resorption.

Parathyroid hormone (PTH) released in response to low calcium levels, tries

to increase again, does this by recruiting and activating osteoclasts. At high
concentrations it can inhibit osteoblast activity. All of this promotes the calcium
going back into the plasma.
Vitamin D vitamin D levels go up in response to low calcium levels. Promotes
the maturation of osteoclasts & indirectly stimulates their activity. Promotes the
calcium going back into the plasma.
Calcitonin Opposite. Inhibits osteoclast activity.
Calcitriol increases expression of the RANKL more osteoclast activity.
Glucocorticoids at physiological levels stimulate osteoblast activity. At
increased (pharmacological) levels stimulate osteoclast activity.
Oestrogens decrease osteoclast activity (increases OPG), opposes PTH. Works
to slow bone turnover and bone loss
Osteoporosis
Peak bone mass occurs around age 30, and is determined by genetic factors,
endogenous factors (hormones) and exogenous factors (diet, drugs, physical
activity). Bone loss occurs with age of 0.5-1.0% per year. Osteoporosis is a
reduced bone mass/density due to greater resorption happening than deposition.
As you would imagine some factors that can contribute to osteoporosis include
decreased oestrogen, TSH, calcium/VitD, OPG, as well as increased PTH and
RANKL.
As trabecular bone has a faster turnover rate than cortical bone and is generally
responsible for weight bearing, its not surprising that when this imbalance
occurs the bones that are most affected are those that have high trabecular
content i.e. hip, spine, wrist.
Pharmacological treatments for osteoporosis are considered when people with
presence of history of osteoporotic fracture, or when their bone density is >2.5
SD below young mean value. Drug treatments aim to decrease bone resorption
in order to maintain calcium levels and prevent fractures. They can be classified
as either antiresorptive agents that inhibit the bone resorption, or as bone
anabolic agents which stimulate bone formation.
Calcium and/or Vitamin D
Used as a preventative treatment. Meta-analysis shows a reduction in fracture
rates. May reduce bone loss if there is low dietary calcium intake. Treatment
though is less effective than other treatments when used as a sole therapy, so
recommended to take with other anti-resorptive agents.
Colecalciferol/ergocalciferol
Vitamin D precursor, evidence to suggest it can increase bone mineral density
and reduce falls in older people.
HRT e.g. oestrone and/or progesterone
Only really appropriate if high risk of osteoporosis but with no other risk factors,

due to the increased risk of endometrial cancer, breast cancer, cardiovascular

disease. Can decrease loss in bone density
SERMS e.g. raloxifene
Oestrogenic activity in bone. Can increase bone density and decrease risk of
vertebral fractures in postmenopausal women. Antioestrogenic activity in breast,
so will not promote breast cancer. Still retains adverse cardiovascular effects.
Calcitonin
Reduced bone resorption by inhibiting osteoclast activity. Not really more
effective than raloxifene
Bisphosphonates
Analogues of pyrophosphate, are concentrated in bone and incorporated into the
mineralised matrix. They work to decrease the resorption of bone by inhibiting
the formation and activity of osteoclasts. Leads to increased BMD and strength,
and a decrease in fractures. Serves as a 1st line management for
postmenopausal osteoporosis. As they are embedded in the bone matrix, when
osteoclasts attach to and degrade the bone they release these bisphosphonates
which are toxic to the osteoclasts, decreasing their activity. Issue with patient
compliance however. Adverse events include atypical fractures (rare) and
osteonecrosis of jaw (very rare)
Denosumab
A new monoclonal Ab against RANKL. It causes the number and function of
osteoclasts to be reduced. Mops up the RANKL before it can activate and
differentiate osteoclasts. Increased BMD, decreased resorption. Approved for the
treatment of osteoporosis in postmenopausal women.
PTH/PTH fragments e.g. teriapartide
Paradoxically anabolic effect if given intermittently at low doses. Causes bone
anabolism due to the stimulation of osteoblast development and activity.
Increased BMD and decreased risk of vertebral fractures in postmenopausal
women with established osteoporosis. Treatment restricted to 18 months as
animal studies show increased incidence of osteosarcoma.
Strontium ranelate
2 molecules of strontium combined with organic ranelic acid. Inhibits bone
resorption and stimulates bone formation. Decreases RANKL and increased OPG.

Lecture 18 Pancreatic Hormones and Antidiabetic Drugs

Background
Diabetes mellitus is the term given when a patient has chronic hyperglycaemia.
It is a metabolic disorder affective 1.7 million Australians. Signs and symptoms
include excessive thirst, excessive urination, glucose in urine, loss of weight (in
children) and tiredness. These symptoms occur because the kidneys have a
certain threshold for the reabsorption of glucose. If that is exceeded, then
glucose spills into the urine. This causes the kidney to produce more urine to fix
this gradient (osmotic diuresis), and the frequent urination leads to thirst and
dehydration.
Type 1 Diabetes
Also known as juvenile-onset or insulin-dependent diabetes. In this disease,
the cells in the pancreas that produce insulin are destroyed by autoimmune
response. This can occur following infection (virus) where the cells are
attacked, antibodies are produces and an autoimmune response develops.
Sometimes the symptoms may not appear for a few years as 90% of cells must
be wiped out before symptoms are seen. Happens in the young population and
treatment involves insulin injections and diet modification.
Type 2 Diabetes
Also known as mature onset or non-insulin dependent diabetes. In this case,
the cells are usually functioning pretty well and producing insulin, but what
happens is that there is resistance to the effects of the insulin. This happens
slowly over time, usually developing in middle/late life. Many who have type 2
diabetes are overweight. Majority have this form (85-90%). Treatment involves
change in diet/exercise, oral hypoglycaemics and insulin. There is a strong
genetic component, involving a resistance to circulating insulin, a reduction in
receptor numbers and/or an altered release mechanism.
Insulin
In the pancreas there are , and cells. It is the cells which generate and
secrete insulin. How is insulin released? Ingesting food and nutrients causes the
release of glucose from the liver into the blood, which causes the cells to
release insulin. Parasympathetic nerves stimulate cells to produce insulin.
There is a continual basal release on insulin, but a surge when feeding. Out of all
the insulin that is generated, about 50% that reaches the liver via the portal vein
is destroyed and never reaches general circulation. When insulin binds to its
receptor, the receptor gets translocated internally within the cell. In type 2
diabetes, after having such high levels of circulating insulin chronically, the
receptors mostly get internalised so there are no longer enough receptors on the
cell surface to respond to circulating insulin. Insulin stimulates glucose uptake in
skeletal muscle, amino acid uptake and facilitates protein synthesis. It preserves
fat stores in adipose tissue, and inhibits glycogenolysis and gluconeogenesis.
Glucagon
The hormone of the fasting state. Released by the cells of the pancreas.
Provides fuel between meals. Secretion is stimulated by amino acids, stress and

hypoglycaemia. Glucagon acts predominantly on the liver to increase blood

glucose to provide energy. As such, promotes the breakdown of glycogen stores
into glucose, as well as gluconeogenesis.
Despite effective treatment, diabetic complications can include: large blood
vessel disease (atherosclerosis) kidney disease (nephropathy), nerve damage
(neuropathy) and eye damage/blindness (retinopathy).
A more sensitive measure to test for diabetes is glycosylated haemoglobin,
rather than simply testing blood glucose levels. Glycosyated haemoglobin means
sugar molecules attached to haemoglobin, and though blood glucose levels are a
current snapshot, this is a more long-term accurate measurement.
Treatment
For Type 1 diabetes, insulin is injected as well as dietary modifications. End of
story.

For type 2 diabetes, after dietary modifications, insulin sensitizers can be give
(such as metformin and glitazones) or drugs that increase insulin secretion
(such as sulfonylureas and glitinides).
Metformin is the first line choice against type 2 diabetes, because it combats
the insulin resistance and makes the target tissues more sensitive to insulin and
will facilitate glucose uptake. Not sure how it works. Does NOT stimulate insulin
release. Has a very low risk of causing hypoglycaemia, and can be used in
combination with sulphonylureas and insulin. Side effects include weight loss,
nausea and diarrhoea.
Glitazones increase tissue sensitivity to insulin. Promote increased glucose
transporters? Inhibit hepatic gluconeogenesis. Bind to nuclear receptor PPAR .

Less efficacious than metformin/sulphonylureas. Slow onset (weeks?). Low risk

hypoglycaemia. Can be used in combination. Side effects include weight gain.
Sulphonylureas stimulate insulin release from the pancreas. Require
functioning cells. Block ATP-sensitive K+ channels (depolarisation). Useful in
early stages of diabetes. High protein binding (90-95%), can cause
hypoglycaemia and weight gain.
Stil 2 lectures in this theme to come back to. But boring so move on.

Theme 6: Pain and Addiction

Lecture 21 Pain Systems and Analgesic Agents
Background
Pain is a subjective experience which is usually a direct response to things such
as tissue damage, inflammation or cancer etc. There is acute pain and chronic
pain. Acute pain you would describe as a really excessive, noxious stimuli.
Chronic pain is usually just a change in the physiological perception of pain so
you may detect pain for a relatively mild stimuli. Pain perception is via
nociceptive afferent neurons. Their nerve terminals at are various sites in the
periphery, which project back to the spinal cord.
So if you have an injury, youll have these nociceptive afferent neurons being
stimulated. These nerve terminals in the periphery are stimulated by
endogenous mediators that are released in response to tissue damage:
bradykinin, 5-HT, prostaglandin, ATP, H +, etc.

How do the neurons transmit their signal? By depolarisation of Na + channels. If

you look at prostaglandins for example, when they are released to local tissue in
response to injury they act on receptors which can lead to the opening of
voltage-gated Na+ channels, causing an influx of Na+ ions into the cell,
depolarisation and excitation and transmission of signal. Some patients can have

a mutation in this sodium channel meaning they do not feel pain. Thats why
blocking these channels pharmacologically is an effective way of blocking
transmission and inhibiting the pain response.

Prostaglandins are synthesised by arachidonic acid by cyclooxygenase (COX) and

are released during inflammation. They do not directly cause pain but can
enhance the effects of pain producing events. They work by facilitating the
opening of voltage gated Na+ channels. PGE2 is the one that increases sensitivity
to pain. When we use NSAIDs, we inhibit COX and so stop the production of PGE 2,
causing analgesic and anti-inflammatory effects for mild-moderate pain.
Excitation of these pain neurons is not just by excitation of sodium channels,
there is also a type of channel present in these neurons called TRP channels.
Activation of TRP channels leads to a large influx of Na + and Ca2+. These
channels can be activated by a number of different ways: by bradykinin
phosphorylating them, and directly by capsaicin (chili), high temperatures.
Caspaicin results in a large influx of Ca 2+ ions by targeting the VR1 receptor.
Alternatively, can also release substance P and cause propagation of pain
transmission. When capsaicin activates the neuron it causes a really large
increase in Ca2+ initially (and sever pain) which is enough to cause the nerve
terminals to degenerate (weeks to recover). Potential future target for pain
relief?
When the afferent neurons transmit their signal, which neurotransmitters are
released at the level of the spinal cord? This could be an important target in
analgesia. Substance P is abundant in nociceptive primary afferent neurons
(produced and released), looks like it is a pain transmitter in the periphery. Its
actions are mediated via NK1 receptors. Glutamine is also an important cotransmitter.
Opioids and Opioid Receptors
Opioids are endogenous or synthetic compounds that produce morphine-like
effects. They produce a mixture of euphoric/dysphoric and depressant effects.

Opioids are agonists at their receptor systems. Opioids have actions in the
periphery, the spinal cord, and in the CNS, and they will have an analgesic effect
at each of these sites.
Morphine mimics the effects of endogenous opioids such as endorphins and
enkephalins. Endogenous opioids are small peptides (a neuropeptide transmitter)
that are released from nearby neurons. In the CNS and periphery they are
involved in the modulation of pain. There are three different types of opioid
receptors: -receptors, -receptors and -receptors. It is the -receptors which
mediate most of the analgesic effects of opioid (as well as some of the adverse
events).

Opioid receptors are G-protein coupled

receptors which when activated target a
G inhibitory subunit, causing a decrease
in cAMP. In addition what this receptor
activation does is it opens K+ channels
causing hyperpolarisation, decreasing
neuronal excitability. It also inhibits Ca2+
ion entry. In total causes decreased
neuronal excitability and decreased
neurotransmitter release.

Opioids, Pain and Analgesia

Fast pain better treated with NSAID, slow/dull pain good for opioids.