DRUG
USE
MOA
SE
SPECIAL
PSYCHOTROPIC DRUGS:
1. ANTIDEPRESSANTS:
SSRI
related
chain
-
Selective serotonin reuptake inhibitors
SAR
Dimethylaminoethyl or propyl analogues of ring systems containing electron withdrawing groups (CF3 or CN [both electron withdrawing])
Lower cardiotoxicity than TCAs
Dual (multimodal) actions but more selective as SERT inhibitors
o Lower concentrations inhibit SERT while higher inhibit SERT & NET
Serotonin syndrome occurs when used with MOAIs (^ 5HT levels lead to rigidity, hyperthermia, muscle twitches and changes to mental status)
Citalopram (SSRI) and talopram (NRI) are structurally
they have the same phthane skeleton and aminopropyl
differ in 4 subunits
Cyano (CN) group: ↑ SERT activity (remove ↑AD activity)
Dimethyl group: ↓ SERT activity
Fluorine & N-methyl substituents are less important for
SERT
No CN or dimethyl ↑ NET activity
S-enantiomer has been shown to be responsible for
essentially all the SSRI activity & non clinical
antidepressant activity (27-170 fold more than R)
R-enantiomer counteracts the activity of the Senantiomer: R citalopram may alter BBB penetration rate of citalopram at a site other than the serotonin transporter; modulate pcol activity of scitapolram at a site other than the SERT; modulate effect of S-citalopram at the SERT level
Two sites on the transporter: high and low affinity site (that modulate the binding of ligands at the primary site)
-
-
-
-
Fluoxetine is a 3-phenoxy-3-phenylpropylamine
o Selective for SERT
o Chiral canter is not important for activity (equipotent R&S)
Nisoxetine is selective for NET
Subtle differences lead to marked selectivity
o CF3 in para position is necessary for SERT
o Introducting OMe in ortho position introduces NET activity
o Removal of CF3 from para position eliminates SERT but retains NET
o Thus phenoxy group determines selectivity
Changes in phenyl group (like replacing with thien-2-yl group leads to SNRI activity even if the CF3 is in the para position
o Thien-2-yl is not acting as a biostere oof phenyl but increases interactions with NET
Citalopram
(is the most selective
for the SERT)
Escitalopram
Sertraline
Fluvoxamine
Paroxetine
Fluoxetine
Major depression
Anxiety disorders –
panic disorder, OCD
Bulimia nervosa
Premenstrual
dysphoric disorder
Selectively inhibit the
presynaptic reuptake of
serotonin (5HT)
Asthenia, diarrhoea, nausea, anxiety,
dizziness, insomnia, nervousness, tremor,
somnolence – mostly short term effects
Drugs with serotonergic
action that may contribute
to Serotonin toxicity:
SSRI, MAOI (moclobemide),
TCAs, mianserin,
mirtazapine, duloxetine,
Sexual dysfunction & ^ GI bleeding w NSAIDs
Discontinuation syndrome:
Dizziness, nausea, anxiety, headache
Serotonin toxicity: hyponatraemia
Steady state is reached in ~ 1
wk
Reduce dose slowly to
prevent withdrawal
Washout 2-4 days (unless to
another SSRI)
Paroxetine more likely to
have withdrawal
Requires washout of 10-14
days
SSRIs do not interact
with alcohol w low CV
effects and OD effects
desvenlafaxine, venlafaxine,
pethidine, tramadol,
dextromethorphan,
phentermine, sibutramine,
sumatriptan, naratriptan,
zolmitriptan, selegeline,
buspirone, lithium and
linezolid.
TRICYCLIC ANTIDEPRESSANTS
SAR
-
Mainly dimethylamino groups (not always) with
different tricyclics ring systems
2-3 carbon spacer before dimethylamino group
‘A-shape’ or ‘Butterfly shape’
Distal protonated amine
Metabolised in lever to N-desmethyl analogues
ad metabolites are active
See binding to homology model (MC)
Abdominal cramps, agitation, diarrhoea,
myoclonus, tremulousness, coma,
tachycardia, hypotention/hypertension,
confusion, disorientation, profuse sweating,
hyperpyrexia
Long t1/2 + active metabolite
thus tapering not required (no
likely withdrawal)
TCA (1st GEN)
Amytriptyline
(metabolite of older
drug)
Clomipramine
(metabolite of older
drug)
Major depression
Anxiety Disorders
Depression associated
with schizophrenia
Nocturnal enuresis,
urge incontinence
Adjunct in pain
management
ADHD (third-line
treatment)
Migraine prophylaxis
Dothiepin
Doxepin
Imipramine
Trimipramine
Do not produce
euphoria
Have no discernible
effects in nondepressed
Have no reinforcing
effects (dependence)
In depressed
individuals they :
↑ mood
↑physical activity
↑appetite
↓ morbid
preoccupation
TCAs inhibit reuptake of
noradrenaline and serotonin
into presynaptic terminals.
Although unrelated to the
therapeutic effects of the
TCAs, they also block
cholinergic, histaminergic,
alpha1-adrenergic and
serotonergic receptors.
Clomipramine has a greater
effect on serotonin transport
than other TCAs.
Long term: down regulate
postsynaptic NA & 5HT
receptors (↓binding sites, ↓
in agonist response)
↑ activity/sensitivity of post
synaptic 5HT1 receptors in
hippocampus
↓ activity sensitivity of
presynaptic alpha2
adrenoceptors and 5HT1
receptors (inhibitory) to
facilitate MOA release
Anticholinergic effects:
Blurred vision, dry mouth, constipation,
sweating, urinary retention
Cardiovascular effects:
Hypotension, tachycardia, arrhythmias
CNS effects:
Confusion, anxiety, restlessness, insomnia,
drowsiness
Gastrointestinal effects:
Nausea, vomiting, anorexia, diarrhoea
Endocrine effects:
Disturbances of libido and potency
Relative potency* (>1
show greater
selectivity for NA over
5HT)
1
0.2*
Contraindications:
MAOIs, SSRIs/SNRIs,
MI and heart disease,
Epilepsy, Glaucoma,
Urinary retention.
Washout – 2-4 days
for all TCAs
1*
3*
TCAs strongly
potentiate ALCOHOL
effects (combination
can cause death from
respiratory depression)
OD:
CNS effects:
excitement, delirium,
convulsions,
drowsiness,
respiratory depression,
coma & death
Cardiotoxicity: cardiac
depression,
arrhythmias,
hypotension
MIRTAZEPINE & MIANSERIN
Mirtazepine
Major depression
Mianserin
*neutropenia &
agranulocytosis =
rare significant ADR
Block presynaptic alpha2-adrenoceptors,
increasing adrenergic transmission &
indirectly enhancing seretonergic
transmission. Additionally presynaptic
5HT2/3 receptor blockade ↓
seretonergic SE.
Mianserin is also an antagonist at H1histaminergic receptors
Low anti-cholinergic effect
Marked sedation, increased
appetite, weight gain,
weakness & peripheral
oedema
Orthostatic hypotension and
occasional hypertension
2-4 day washout
Moclobemide competitively and
reversibly inhibits monoamine oxidase
(MAO); it is relatively selective for type A
(MAO-A). Synaptic concentrations of
serotonin, noradrenaline and dopamine
are increased.
RIMAs (meclobeminde)
Nausea, headache, dizziness,
insomnia, anxiety, agitation, dry
mouth, constipation, diarrhoea
(but few Ach effects)
Take in morning to minimise risks
of insomnia
Washout 1-2 days
Interactions with
tyramine containing
foods: (cheese effect)
but unlikely at
recommended doses as
MAO-B is still functional
Relatively free of CV risk and
sexual ADR + low lethality OD
eTG table 3 (p13) for
cheese effect
(ie significant
hypertension from the
accumulation of
endogenous
catecholamines)
Contraindication: TCAs & SSRIs –
Wait 14 days after
2-4 day washout
Show fewer anticholineric &
CV effects
MAO Inhibitors
Moclobemide
(reversible MAOA)
Major depression 2nd
line after phenelzine
Atypical depression
(irreversibles)
(panic disorder, social
phobia (irreversibles)
Anorexia and bulimia
nervosa
No interaction with
alcohol.
Full activiy of the MOA-A enzyme is
restored 24-48 hr after cesation
MAOI long term effects: down regulation
of postsynaptic NA, 5HT1/2 receptors
Irreversible non-
Immediate ↑ in motor
Decreases the activity/sensitivity of
presynaptic alpha2 adrenoceptors and
5HT1A receptors (autoreceptors)
facillitating MA release
Short term: binds covalently to MAOA & B
selective:
Phenelzine
Tranylcypromine
Irreversible MAOA:
Clorgyline
Irreversible MAOB
Selegiline (trials)
activity innondepressed individuals
Euphoria and
excitement develop
over a few days
Similar to TCAs in
depressed people
Preventing breakdown of NA, 5HT & DA
Increases cytoplasmic pool of
monoamines & increases leakage of MA
into synapse/extracellular space
causes hypertension, excitement
& convulsions, hyperpyretic crisis
and death
Pethidine – hyperpyrexia,
hypotension, restlessness &
coma
Selegiline (don’t take with RIMAs
Liver disease (irreversible)
Acute confusional states
Other MAOIs
cessation before eating
tyramine rich foods to
avoid the risk of the
cheese effect.
Required dose 10-25mg
tyramine & a throbbing
headache (occipital) is the 1st
sign
Avoid pethidine and
tramadol
See parkinsons drugs (neuro)
SNRI
Reboxetine
(selective NA
reuptake)
Venlafaxine
Desvenlafaxine
Duloxetine
(selective NA/5HT
reuptake)
Major depression
Major depression
Generalised anxiety
disorder
Painful diabetic
peripheral neuropathy
Highly selective blockade of presynaptic
NA reuptake  ↑release of NA  ↑ NA
levels
Dose range is narrow compared to most
other antidepressants
As for TCAs without affinity for
adrenergic, histaminergic or cholinergic
receptors
Dry mouth, constipation,
impotence, dizziness, hypotension,
insomnia, sewating, anxiety,
paraesthesia, headache,
tachycardia.
Fatal doses are rare
↑ serum cholesterol, nausea,
constipation, anorexia, sexual
disturbances
Suicide risk: (all
ADepressants)
Studies showed
increased suicide risk
in persons takeing
antidepressants
Suicide OD may be
attempted
No immediate
reversal
Common in younger
patients
Bipolar Disorder:
LITHIUM
Lithium
Bipolar disorder
Prevention of manic or
depressive episodes in
bipolar disorder
Treatment of acute
mania
Schizoaffective
MOA not fully understood 
Its actions include inhibition of
dopamine release, enhancement of
serotonin release and decreased
formation of intracellular second
messengers. Lithium has little or no
psychotropic effect in normal
Narrow therapeutic index
Weight gain, hand tremor,
inverted T-wave of ECG,
impairs thyroid function,
antagonises ADH (nephrogenic
dieresis)
Monitor for thyroid, renal and CNS
effects recommended.
- TSH
- UECs
(clinical hypothyroidism and
euthyroid goitre)
disorder and chronic
schizophrenia
individuals
1st line therapy in
acute mania and
prophylaxis in
bipolar disorder
Intoxication: confusion,
unsteadiness, nausea,
diarrhoea, worsening tremor
DO NOT STOP TAKING LITHIUM
ABRUPTLY OR TREAT
INTERMITTENTLY ULESS
TOXICITY PRESENTS
Monitor serum lithium and plasma
concentrations 0.6-0.8mmol/L
Can inhibit responses of
vasopressin in distal nephron
(treat with thiazide)
Contraindications:
Toxicity: ataxia, vomiting, coarse tremor, disorientation, dysarthria, muscle twitches, impaired consciousness, acute renal failure, death (or irreversible
brain damage)
Causes: 1. Interactions 2. Dehydration 3. Fluid loss 4. Deliberate/accidental
Lithium toxicity treatment:
1. sufficient fluid replacement (IV) to ensure dieresis
2. Haemodialysis ↑ Li clearance (if GFR < 60ml/min, Li > 2.5 – delirium; seizures, coma,
persistent clinical effects in spite of fluids)
ADR profile:
o Thyroid
o hypothyroidism (up to 10%) especially in females
o euthyroid goitre (4-12%) [enlargement of thyroid]
o Renal
o inhibits response to ADH (15-30%): polyuria, polydipsia; UECs; e-GFR
o CNS
o fine tremor, muscular weakness, EPS (rare)
o cognitive difficulties: memory problems, EEG changes, “generalised slowing” –
“curbs creativity”
Antiepileptics for bipolar:
Carbamazepine
Sodium Valproate
Lamotrigine
Approved for acute
mania & maintenance
Approved for acute
mania; used as
alternative to Li for
maintenance
Prevention of bipolar
depressive disorders
(not unipolar)
Prevents repetitive firing action
potentials in depolarised neurones
through the blockade of sodium
channels
Potentiates GABA (action related to
effects on protein kinase C)
Stabilises presynaptic neuronal
membranes by bloackade of voltagedependant sodium channels,
preventing the release of excitatory
neurotransmitters, particularly
glutamate and aspartate
Sedation, headache, ataxia,
dizziness, nausea, diplopia.
Reversible mild Leucopenia
Vasopressin like actions 
hyponatraemia
Hair loss, tremor, sedation,
appetite stimulation + weight gain.
GI – anorexia, nausea & vomiting
Alters platelet function
(thrombocytopenia)
Rash! Varying severity
(maculapapular associated with
fever, arthralgia & eosinophilia)
ADR primarily CNS related –
dizziness, diplopia, ataxia, blurred
vision, somnolence, insomnia
Can induce its own
metabolism
Monitoring (TDM): FBC, LFT,
hyponatraemia
TDM: FBC (thrombocytopenia)
Idiosyncratic hepatotoxicity +
pancreatitis (can be fatal :S)
Dose should be gradually
increased over 6-8 weeks and
further graduation in
combination with sodium
valproate
SGA - Antipsychotics for bipolar: See antipsychotics SGAs (new)
Olanzepine
Approved for acute
mania & prevention of
relapse in Bipolar 1
disorder
Risperidone
Approved for
continuation for six
months following
acute treatment of
mania
(also new for bipolar = asenapine)
Wide range of receptor affinities.
Weight gain, dyslipidaemia,
diabetes
Monitoring: BGL, lipids
Orthostatic hypotension,
hyperprolactinaemia
Monitoring: BGL, lipids
HYPNOTICS AND SEDATIVES:
Benzodiazepines:
Diazepam
Alprazolam
Bromazepam
Clobazam
Clonazepam
Flunitrazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam
Anxiety
Panic disoder
Sleep disorders
Seizures
Acute behavioural
disturbance
Acute alcohol,
barbiturate, benzo
withdrawal
Muscle spasm
Premedication and
sedation for
intensive care
proceedures
Potentiate the action of GABA at
the GABAa receptor resulting in
neuronal inhibition (positive
allosteric modulation)
High therapeutic index but
combination may be dangerous
Anterograde amnesia
Dependence
Drowsiness
Over sedation
impaired psyhomotor and memory
functions
dry mouth
blurred vision.
Ataxia
light-headedness
slurred speech
solnambulance
Dependence
Can affect performance and
impair judgement
Withdrawal symptoms
Tolerance to sedative effects
For short term use
(2-4weeks)
Insomnia: max
duration of 1 month
including tapering
off
Anxiety: as short as
possible, but no
longer than 23months including
tapering off
Benzos have high affinity binding
between an alpha subunit and the
gamma-2L subunit
Contrindications:
Respiratory depression
Hepatic impairment
Myasthenia gravis (muscle
relaxant properties)
others
Non Benzodiazepine hypnotics:
Z
Zolpidem
Zopiclone
Selective for alpha1
containing GABAa receptors
(with gamma-2L subunits
Sonambulance: black box
warning - May be associated
with potentially dangerous
complex sleep related
behaviours
B
Buspirone
Not for panic or severe
anxiety
5HT1A partial agonist
No memory impairment or
dependence
Delayed therapeutic effect
ANTIPSYCHOTIC - Schizophrenia
FGA: ‘Typical’
-
Ameliorate positive symptoms of schizophrenia but have little effect on negative and cognitive symptoms
Phenothiazines
Chlorpromazine
Thioridazine
Fluphenazine
Trifluoperazine
Pericyazine
Acute and
chronic
psychoses (eg.
Schizophrenia)
Lower EPSE
Acute mania
and
maintenance of
bipolar disorder
Higher EPSE
Higher EPSE
Higher EPSE
Lower EPSE
Butyrophenones
Haloperidol
Droperidol
Pimozide
Higher EPSE
Thioxanthines
Flupenthixol
Zuclopenthixol
Organic
psychoses (eg
dementia
associated
agitation)
The short term goal is to ↓ +ve symptoms
The long term goal is to prevent relapse
~30% achieved good recovery
~30% demonstrated partial improvement
~30% resistant to treatment
SGA: 1st Line!!
-
ameliorate both positive and negative symptoms of schizophrenia (within 6-12months)
greater therapeutic efficacy compared to typical antipsychotics
o fewer SE
o effective in treatment-resistant patients
Amisulpride
Aripiprazole
Clozapine
Severe
behavioural
disorders in
children
Same as typical EXCEPT:
1. ↓ EPSE
2. ↓ elevated prolactin
Prologation of QTc interval  arrhythmias
Tourette’s
syndrome and
other choreas
Metabolic syndrome weight gain,
hyperglycaemia, ↑ TGs etc.
Olanzapine
Paliperidone
Quetiapine
Resperidone
Ziprasidone
ANTI CHOLINERGIC ANTIPARKINSONIAN MEDICATIONS
DRUGS OF ABUSE + TREATMENTS
No hyperglycaemia
CYP2D6 & 3A4
Used for treatment
resistant
patients due to risks
CYP1A2
Agranulocytosis (TDM)
Myocardis/Cardiomyopathy
CYP1A2
Dyslipiaemia
Hyperprolactinaemia risk
Treatments
-
drug addiction involves a cycle of drug seeking, use, withdrawal and further use
Acamprosate
*Alcohol
Disulfiram
(antabuse)
*Alcohol
Naltrexone
*Alcohol
*Opioids
Decreases distress of
protracted
withdrawal by
stabilising persistent
neurobiological
abnormalities
(glut/NMDA/GABA)
↓ relief craving and
the need to drink
due to withdrawal.
Produces an
unpleasant reaction
when alcohol is
ingested; used to
deter alcoholics from
drinking
Naltrexone blocks
the pleasurable
effects from alcohol
and reduces the
craving for alcohol
Inhibits excitatory neurotransmission
(blocks glutamatergic processes) and
stimulates inhibitory
neurotransmission (promotes
GABAergic processes)
Safe, well tolerated, does not cause
dependence
Interferes with the breakdown of
acetylaldehyde, a toxic by-product of
alcohol metabolism
Ethanol  acetylaldehyde  acetate
Ethanol reaction: skin flushing,
sweating, tachycardia (rapid pulse),
hypotension (↓ Bp), nausea,
vomiting, extreme physical
discomfort, has resulted in death : S
Long acting opioid receptor
antagonist. Opioid receptors modulate
dopamine neurotransmission.
Safe, no reported abuse potential
Nausea within the 1st week but self
limiting
Blocks DA release in mesolimbic and
mesocortical pathways associated
with reward centre n.acc. ↓ cravings
Several studies have shown
beneficial effects
Nausea and vomiting at high doses
May accelerate the loss of
tolerance with abstinence of
opioids
Disulfiram was found to be
no better than placebo in
helping patients remain
abstinent. A subset of
relapsed patients drnk less
frequently
Non-adherence problems
Effective only under
supervision.
Several studies have
suggested beneficial effects
Best to combine with
psychosocial treatment
Methadone
*Opioid
Buprenorphine
*Opioid
Opioid substitution
therapy is the most
effective approach.
Long term
substitution for
heroin and other
opioids used as a
maintenance
therapy after opioid
withdrawal
Used in the
treatment of opioid
dependence
Full mu opioid agonist
High oral bioavailability
Partial opioid agonist
With high receptor affinity
Typical opioid effects :sedation
Increased risk of prolonged QTc
inverval
Requires supervision, widespread
diversion and methadone related
deaths.
Opioid toxicity: sedation,
respiratory depression, death
Medical therapy is generally
unsatisfactory unless
another opiate is given: 50%
fail to complete treatment
Typical opioid effects such as
sedation, nausea,
Lower OD risk & physical
dependence than
methadone
Naloxone is included to
prevent euphoric effects
upon injection and to reduce
OD – required higher doses
due to partial agonist
properties
CYP3A4
Lead to a recurrence in pain &
Precipitates withdrawal when
injected in opioid dependent
individuals
No clinical effect orally/
sublingually
Effects are seen upon
injection (discourage
diversion)
Does not compromise
buprenorphine kinetics
– 30% nausea as SE
Reports of suicide ideation and
Longer = better
Best results seen with
Antagonist when other opioids are
present
Ceiling effect on euphoric effects and
respiratory depression
Naloxone
*Opioid
Varenicline
(champix)
Discourage diversion
Treatment of opioid
over dose
Used to reverse
sedation and
respiratory
depression after OD
Smoking cessation
Lower reinforcing potential = less
abuse liability & reducd severity of
dependence
Acts as a competitive antagonist at mu
opioid receptors preventing the
binding of other opioids.
Nicotinic acetylcholine-receptor
partial agonist with agonist activity
CYP 3A4 1A2 & 2D6
*Nicotine
1st line
alone and antagonistic effects in the
prescence of nicotine. Thought to
work by reducing craving and
withdrawal symptoms
aggression
Insomnia
Drowsiness, dizziness &
exacerbation of psychiatric illness
Some effects of nicotine
withdrawal may be mistaken as SE
Combination with NRT: increased
risk nausea, headache, dyspepsia,
fatigue, dizziness
NRT
*Nicotine
1st line
Bupropion
*Nicotine
1st line
Patch: skin irritation & Sleep
disturbances – vivid dreams
An antidepressant that inhibits
neuronal reuptake of dopamine and
noradrenaline, and is a noncompetitive nicotine antagonist at
nicotine cholinergic receptors
Gum: dyspepsia
Tablet: sore throat, dry mouth,
burning sensation, coughing,
headache, hiccups, nausea
Minimal SE
Safe
Nausea, rashes, facial swelling,
insomnia, dry mouth
Can precipitate mania in bipolar
disorder.
Nortriptylline
TCAs
counselling program
Should titrate dose (eTG
p34)
Reduce dose in renal
impairment
Combining varenicline and
NRT is valid and effective
Not all patients to well on
varenicline /alone.
Delayed response of > 2 wks
Contraindicated with severe
CVD and in pregnancy (not
1st line for heavy smokers)
Consider risks or ADR against
risks smoking
Excellent outcomes (same as
NRT)
Cost effective
Should be 1st line
Shown to be at least as
effective as NRT
Should be used along with
behavioural therapy
Commencement while the
person is still smoking
Shown to have similar
efficacy to bupropion
Not approved in au
Serotonergic drugs * alcohol:
-
SSRIs – some positive studies but mainly intitial transient benefits or in those with a family history
5HT receptor antagonists (more specific) – ondansatron (5HT3) has modest efficacy
Drug
Alcohol
Type of dependence
Psychological &
Physical:
Extreme withdrawal
syndrome
Tolerance?
MOA
LOA
Acute tolerance
Cellular
tolerance
PK tolerance
(severe
alcoholism)
CNS depressant
Frontal cortex
Reticular formation
Cannabis
Psychological only
9
Δtetrahydrocannabinol
Nicotine
Psychological only
Caffeine
Psychological only
Craving, fatigue,
irritability,
headache
Heroin (diamorphine)
Psychological &
Physical:
Withdrawal:
Papillary dilation,
Receptor action:
CB1 (CNS & Periphery); Mainly
presynaptic; Gi/o coupled receptors
that inhibit Ca2+ and adenylate
cyclase
Acute tolerance
Cellular
tolerance (to
+ve effects)
PK tolerance
Cellular after
chronic use
Little tolerance
to
psychostimulant
effects
Cellular type to
euphoric effects
Euphoria, paranoia/anxiety, sedation,
cognitive impairment, appetite
increase, rare hallucinations
Mild psychostimulant
Stimulation of nicotine acetylcholine
receptors at probably a variety of
subtypes
Psychstimulant effects
CNS depressant:
Act on mu, (kappa, delta) opioid
receptors
Special:
Endogenous ligands =
anandamide, 2arachidonyl glycerol
(2-AG)
(retrograde
messengers)
N.acc
Hippocampus
Ventral tegmental area
(VTA)
Reticular formation
n.acc
reticular formation
Users to don’t seek to
↑ ‘high’ by ↑
concnentration
PAG
Area prosterma
n.acc
VTA
Endogenous ligands:
B-endorpine, leucine –
enkephalin, methioneenkephalins
sweating,
piloerection,
tachycardia,
vomiting, diarrhoea,
hypertension,
yawning, fever,
weight changes,
anxiety insomnia,
craving, dysphoric
mood, restless,
irritable increased
sensitivity to pain,
cramps, nausea,
muscle aches
Dexamphetamines
MDMA (ecstacy)
Psychological only
Cellular type
rapidly develops
Tolerance to
euphoria 
psychosis
↑ Bp effects are
diminished over
time
Nausea vomiting, analgesia, cough
suppression, respiratory depression,
sedation, constipation, papillary
constriction
Reticular formation
Psychomotor stimulant:
1. stimulate release of catecholamines
2. inhibit their recapture by DA uptake
transporters
3. inhibit MAO
Euphoria, energy, physical
performance, suppress appetite
n. acc
hypothalamus
reticular formation
(alertness)
Works by elevating brain 5HT levels
- ↑ 5HT release
- block reuptake of 5HT
1. Euphoria, confidence, mental &
emotional clarity, ↑ energy,
↓appetite and thirst,
2. insomnia, ↑ anxiety, impulsivity,,
involuntary teeth clenching, chills &
sweat, hypertension, tremors,
seizures
More potent than
morphine
MDMA Neurotoxicity:
In axons and dendrites
of 5HT releasing
neurons
Related to
hyperthermia
5HT depletion may
explaine ↑
impulsivity,
depression,
memoryoss with
heavy use
LSD (lysergic acid
diethylamide
Cocaine
Rapid tolerance
Psychological only
Chronic use can lead
to: 1. Psychotic
episodes 2. Damage
to the heart  HF
Binds to various subtypes of 5HT1,2A
& 2C as well as DA receptors and
alpha adrenergic receptors
2A – hallucinogenic (LSD = partial
agonist) similar structure to serotonin.
Ie ↑activity & ↓ intrinsic activity at
2A than serotonin.
Synesthesias, subjective time, loss of
boundaries, labile mood, anxiety,
hallucintions
Blocks MA uptake (transporter)
n.acc
increasing synaptic DA & NA & 5HT
hypothalamus
levels. Does not cause direct
reticular formation
stimulation of psychomotor release
Short lived euphoria, ↑ HR & Bp, ↑
motor activity, LA actions, OD:
tremors, convulsions, followed by
respiratory depression
MIGRAINE
Tryptans
Sumatriptan
Treatment of
migraine
Naratriptan
Zolmitriptan
Ergotamine
An ergot alkaloid
with marked arterial
vasoconstrictor
activity
Selective serotonin agonists, acting
at 5HT1 receptors
1. contracts vascular smooth muscle
- intracranial vasoconstriction
- coronary vasoconstriction
2. trigeminal axon reflex
- ↓release of neurogenic
inflammatory peptides from
trigeminal peripheral afferents
- possible via 5HT 1B/1D receptors
Are generally minor and include
dizziness, fatigue, drowsiness,
heaviness or tightness of upper body
(chest pressure), warmth/tingling,
severe chest pain, cardiac ischaemia
Contraindicated with IHD, angina and
hypertension
Problem: headache returns within
24hrs in 30% cases
Rapid incomplete oral
absorption with low
bioavailability (first pass)
Subcutaneous formulations
peak at 30 min with higher
bioavailability
Improved oral bioavailability
Slower onset of action &
longer elimination t1/2
Improved oral bioavailability
Antimigraine efficacy:
1. intracranial vasoconstriction
- ↓ release of neurogenic
inflammatory peptides
- calcitonin gene related peptide
(GCRP)
- substance P
Triptans give the highest
proportion of individual s
pain-free at 2hrs post dose
1. contracts vascular smooth muscle
- direct: 5HT 1/2 , alpha
adrenoceptors
- indirect: prostanoid release, non
specific sensitisation to other
vasoconstrictors
2. Trigeminal axon reflex
- ↓ release of neurogenic
inflammatory peptides from
Concomitant use has
resulted with macrolide
antibiotics has resulted in
ergot toxicity – ergotamine
and triptans should not be
taken within 24hrs of each
other
Good self management is
required to optimise
treatment
Nausea vomiting, diarrhoea,
paresthaesis of fingers and toes,
muscle cramps, and muscle pain.
RARE: Cyanosis of fingers and toes
intermittent claudication,
retroperitoneal, pericardial & cadiac
vulvular fibroses
Dihydroergotamine
Less vasoconstrictor
activity than
ergotamine
Methysergide
Semi-synthetic ergot
derivative
For acute migraine
prophylaxis
Pizotifen
trigeminal peripheral afferents
- ? via 5HT 1B/1D receptors?
Hydrogenated ergotamine
Potent serotonin antagonist
ergotism
Caution: venous vasoconstrictor
contraindicated with DVT
Similar ADR to ergotamine – nausea
diarrhoea vomiting and muscle pain
Nausea vomiting, abdominal
discomfort, acute leg pain,
drowsiness, dizziness
Long term use: retroperitoneal,
pericardial & cadiac vulvular fibroses
reduced with intermittent use
Non-ergo derivative
Antagonist at both histamine
H1 and serotonin receptors
Drowsiness, increased
appetite, weight gain,
nausea, dizziness
Migraine prophylaxis
Precise mechanism
unknown.
Appear to be equally
effective prophylaxis
Bronchospasm, lethargy,
depression, aggravation of
raynaud’s phenomenon,
intermittent claudication,
HF,decreased exercise
intolerance, vivid dreams
Gradually taper over 1 week
Beta blockers
Propanolol
Metoprolol
Atenolol
Selectivity decreases with
increasing dose
Contraindicated in asthma
and severe peripheral
arterial disease
Other: Analgesics:
Paracetamol (1st line)
NSAIDS + Aspirin (1st line) [indomethacin ineffective! May precipitate migraine]
Opioids: codeine, tramadol, dextropropoxyphene (Avoid) [see nps news: can worsen symptoms of nausea and vomiting and impede absorption of other
meds]