PY365 - Substance Misuse Case

Ali AlAttar 20800061
L1) Substance Misuse Introduction:

Prescription drug addiction
e.g., regarding prescription opioids
What do you think of when we

say substance misuse?
Consider the
duration, dose,
history of the
patient and
preventing addiction
https://www.theguardian.com/uk-news/2019/sep/10/addictive-medication-nhs-opioid-crisis-government-study-england
Alcohol is the biggest substance misuse in the UK & then nicotine
where Acceptable alcohol intake is 14 units in a week according
Physical health causing a strain in PY365 Substance Misuse 3 and Introduction to case
the cardiac system
to NICE guidelines, that’s the target but zero alcohol is the goal
What are Mental health and emotional well-
the being either acutely or chronically

as the damage is accumulating
impacts of Due to the

acidic nature
substance Relationships and social functioning

regarding the e.g., care
misuse?
Society as a whole
Harmful Drinking and Alcohol3 and

PY365 Substance Misuse
Dependence
Introduction to case
PY365 Substance Misuse 3 and Introduction to case
More than 10% drinking

>14 units a week
The Chief Medical Officer

(CMO) published new alcohol
guidelines
Harmful Drinking and Alcohol

Dependence
CMO supported by a new review
from the Committee on
Carcinogenicity (CoC) on alcohol
and cancer risk.
Guidance and regulation

1. Alcohol use screening tests, Guidance 1 June 2017 Public Health
England
2. Alcohol consumption: advice on low risk drinking, Guidance 25
August 2016 Department of Health and Social Care
3. NDTMS: community alcohol and drug treatment business
definitions, Guidance 3 July 2020 Public Health England
4. Mutual aid toolkit for alcohol and drug misuse treatment,
Guidance 10 April 2018 Public Health England
5. Parental alcohol and drug use: understanding the problem,
Guidance 22 May 2018 Public Health England
1
increase
e.g., atrial cardiovascular
damage risk and strokes
breaking skin barrier
hence high risk of
hepatitis and HIV,
Dual Diagnosis
Dual diagnosis refers to people with a severe mental
illness (including schizophrenia, schizotypal and
delusional disorders, bipolar affective disorder and
severe depressive episodes with or without psychotic
episodes) - combined with misuse of substances (the use
of legal or illicit drugs, including alcohol and medicine, in
a way that causes mental or physical damage).
NICE. https://www.nice.org.uk/guidance/ng58/documents/evidence-review
Recent studies have estimated prevalence rates of 20-37% in
secondary mental health services and 6-15% in substance
misuse settings, Substance misuse is ALWAYS linked with
mental health issue
2
Society as a whole The extent of the

problem in the UK
With rehab, the dose is reduced as the body is already

used to it hence it’s a slow process
Government Strategy
PY365 Substance Misuse 2017
3 and Introduction to case PY365 Substance Misuse 3 and Introduction to case
Reduce Restrict
demand supply
Global What are treatments for drug addiction?

Build action to • Behavioural counselling.
• Medication.
recovery reduce • Medical devices and applications used to treat withdrawal
supply symptoms or deliver skills training.
• Evaluation and treatment for co-occurring mental health issues such
as depression and anxiety.
• Long-term follow-up to prevent relapse.
As a pharmacist what
can
3 and Introduction to case
you do?
Know the law on Controlled Drugs
• A big part of your coursework will be appraising CD
prescriptions for legality, clinical appropriateness
and nonpharmacological interventions.
• During the workshop we will discuss these, but you
need to spend a substantial amount of time fully
internalising control drug laws because they will be
assessed during the coursework, OSCEs and the
pre-Reg exam.
PY365 Substance Misuse 3

3 and Introduction to case
- FP10 prescription is green, what found in

it is the patient’s name, date of birth (not
legally required, only when the patient is
under 12), address of the patient, name of
the drug, its frequency & administration
instructions, dose of the medication, the
prescriber, when it’s prescribed\date of
issue, signature of the issuing doctor and
their name and their unique number (unique
code which links them to a practice) and
their address – all form legality of the prescription.
- It’s valid for 6 months if it was a standard prescription.
- FP10CPD is the prescription for controlled drugs (private
prescriptions for Schedule 2 & 3 CDs) – pink coloured.
- FP10 MDA forms can only provide a maximum of 14 days' supply,
the prescriber must specify the number of instalments to be
dispensed and the interval between each instalment e.g.,
Methadone.
Introduction to the patient - “Clean needles” technique is

A female, who has recently moved to Brighton from provided when it’s a case of
London to live with friends. She comes to see you to
collect “clean needles” from your pharmacy, but she is substance misuse and an important
desperate for help in stopping her heroin
public health initiative that reduces
dependence.
the spread of blood borne viruses including HIV and hepatitis C among
people who inject drugs and the wider community. It works by using clean
needles to prevent transmission of infections e.g., HIV where it’s like a
menu on different types of needles e.g., red and blue needles.
4
- For example, there are needles for steroids (intramuscular - have to be

robust and be able to penetrate a big muscle for the drug to be delivered)
and there are needles for heroin injected as a thin needle to penetrate the
skin where the muscle is flat as it goes through the vein quick into the
system.
- Alcohol swabs are also provided to clean the area before injection, spoon to
prepare the drug, a diluent for mixing, citric acid & vitamin C. A yellow bin is
also provided to discard needles or available in a pharmacy.
- The toxins in needles will eventually build up at the site where injected,
leading to dark-coloured needle marks hence a marker of SM.
Questions to ask
• Age – childbearing age, is she pregnant or could conceive (exposes
dangers to the baby)?
• History/Duration – how long used as e.g., risk assessment in terms
Q to ask & Poss Solutions:
of for example cardiovascular risk or any health issues/screening • What other meds?
e.g., HIV or any STI & choice/impact of treatment which will affect • Blue Rx - drug and
how easy or difficult to withdraw • How are you in alcohol service
• Medical history - events (long history of substance misuse = more general? • Substance Misuse
risks e.g., of MI, stroke, heart attacks and cancers) • How long have you service e.g., needles
• Drug history – compound? Single substances e.g., just heroin or been on heroin?
double intake of it with alcohol etc. where Naloxone/opiate
antagonist can be used for overdose treatment • Intentions to stop?
• Rx meds e.g., antidepressants and antipsychotics • Substance?
• Family history – seeing a parent engaging in such, suspected dead
from SM etc.
• Trauma/Mental health issues – neglect, abuse, rape, depression,
heart break (hence SM for seeking relief) therefore mental health
service could be approached
• Environment – in terms of friends engaging in SM, homeless? PY365 Substance Misuse 3 and Introduction to case
SAQ -
Name two of the main aims that a Needle Exchange
Programme delivered by a community pharmacy is
set out to achieve (2 marks). Outline how you would
ensure that one of these aims is delivered (2 marks).
Hint: Needle and syringe programmes Public health guideline

[PH52]Published date: 26 March 2014
https://www.nice.org.uk/guidance/ph52
Help patients to stop their misuse and to stop any

infections or risk of contamination

5
NOTES FROM EXTRA READING:

- Controlled Drug (CD) prescription writing requirements: length of
treatment, prescription validity, owings, repeat dispensing, instalment
dispensing & amending typographical errors on paper prescriptions.
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L2) Physiology of Reward Circuit:

Substance misuse is having a drug good for
Introduction treatment e.g., Morphine used instead of a
painkiller but for recreational use
• Substance misuse is a major global risk factors for disability and
premature loss of life. Illicit substances include alcohol,
amphetamines, cocaine, benzodiazepines, heroin and other
opioids. E.g., the ancient Sumerians and Assyrians used opium
(natural source of morphine and codeine) about 4000 BCE.
• In England and Wales in 2021:

• Approximately 1 in 11 adults (9.4%) aged 16 to 59 years had taken
a drug (3.2 million people)
• From the 4,859 drug poisoning deaths, 3,060 were identified as
drug misuse/overdose (63% of drug poisonings)
• The recurrent use of –illegal- drugs and substances for the
purposes not indicated within the legal and medical guidelines is
termed as substance misuse
• Understanding the physiology of brain’s reward circuit is the key
factor to understand the pathophysiology of substance misuse and 1
accordingly understanding the therapeutic strategies
Reward circuit
• The brain’s reward circuitry was first discovered by James Olds in Canada and Peter Milner at
McGill University in 1954 (https://www.youtube.com/watch?v=uofQPLuLV9A)
• They found that animals would repeatedly return to an area of the laboratory in which they
had received mild electrical stimulation of subcortical structures anatomically associated with
the medial forebrain bundle
• Animals would avidly perform hard and painful tasks in order to receive such brain stimulation
• Mapping studies were conducted to identify the brain reward pathways
• Translational studies transform animal findings to human body
• Our brains developed a reward circuit to motivate performing behaviours and tasks including
eating and drinking tasty food and beverages, having sex, taking psychoactive drugs
• Such activities induces a behavioral-reward feedback: positive reinforcement
• A classic example would be giving a treat to kids when performing good tasks, or food to a pet
as a reward for doing what you tell them to do
• Such experimental studies have elucidated the brain areas involved in positive reinforcement
and hence revealing reward circuit that includes
1. Mesocortical pathway
1
2. Mesolimbic pathway
11
Reward pathways
• Ventral tegmental area (VTA) receives information from
several brain regions responsible for processing
information on fundamental needs such as the
hypothalamus, and more importantly how human needs
are being satisfied
• The VTA functional diversity is partly reflected by its
cellular and circuit heterogeneities. The VTA is composed
of ∼60% dopaminergic neurons (DA neurons), ∼35%
GABAergic neurons (GABA neurons), and ∼5% glutamate
neurons (glutamate neurons)
• The common things between the pathways is the brain,
Ventral tegmental area/VTA & the dopaminergic neurons
(yellow lines)
• The hypothalamus functions as being connected to
pituitary gland controlling the release of hormones,
maintaining daily physiological cycles, controlling
appetite, managing sexual behaviour, regulating
emotional responses & regulating body temperature.
- Gamma-aminobutyric acid (GABA) is an amino acid that serves as the

primary inhibitory neurotransmitter in the brain and a major inhibitory
neurotransmitter in the spinal cord. It exerts its primary function in the
synapse between neurons by binding to post-synaptic GABA receptors
which modulate ion channels, hyperpolarizing the cell and inhibiting the
transmission of an action potential. It acts by binding to two types of GABA
receptors of pre- and postsynaptic neurons, an ionotropic receptor, GABAA,
and a metabotropic receptor, GABAB.
- Glutamate is the most abundant excitatory neurotransmitter released by
nerve cells in the brain where it plays a major role in learning and memory.
For the brain to function properly, Glutamate needs to be present in the
right concentration in the right places at the right time. Glutamate is
released from the presynaptic neuron and interacts with its receptors on
the cell membrane of the postsynaptic neuron.
12
Reward pathways:
mesolimbic pathway
• Mesolimbic pathway: Ventral tegmental area (VTA) and Nucleus accumbens (Nac)
• The dopaminergic pathways runs from VTA of the midbrain through medial
forebrain bundle to reach Nac and the limbic regions
• The dopaminergic neurons connecting VTA to Nac receive information from other
parts of brain such as cortex, hippocampus, thalamus, amygdala, and raphe
nuclei, to modify the reward feeling and hence contributing to reward-associated
learning DA
DA:
• Dopaminergic neurons activate GABAergic neurons in the Nac that project to
Dopamine
multiple regions, including the VTA
• This pathways is responsible for regulating emotional expression by relaxing the
brain, learning, reinforcement and hedonic capacity
• Clinical and preclinical studies revealed the involvement of other
neurotransmitters such as GABA and glutamate when they blocked Dopamine as
it’s the predominant but not the only way
Reward pathways:
Mesocortical pathway
• The dopaminergic pathways runs from
ventral tegmental (VTA) of the midbrain
through medial forebrain bundle to reach When PFC gets stimulated, it will
the prefrontal cortex (behind the release glutamate and GABA.
eyebrows)
• Dopaminergic neurons activate
glutaminergic neurons in the PFC that DA
project to multiple regions, including the
Nac releasing glutamate
• The activation of this pathway is involved
in regulating motivation, concentration,
and executive cognitive functions DA: Dopamine
• Clinical and preclinical studies revealed the
involvement of other neurotransmitters
such as GABA and glutamate
Mesocorticolimbic pathways
Reward pathways
(Dopamine) – two pathways linked
DA
DA
Mesolimbic pathway Amy: Amygdala Mesocortical pathway

OFC: Orbitofrontal cortex
DA: Dopamine 1
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Mesocorticolimbic pathways (GABA)

• γ-amino butyric acid (known as GABA, involved in both pathways)
binds to its postsynaptic GABA receptor to exert inhibitory effects in the
mature mammalian CNS and hence decreasing neuronal excitability of
many neural circuits
DA
• GABA neurons of the VTA receive inhibitory, excitatory, and
neuromodulatory inputs from throughout the brain
• VTA GABA neurons synapse onto VTA DA neurons and hence inhibiting
the dopamine firing from dopaminergic neurons DA
• GABA autoreceptors (GABAB) are found on GABA neurons to inhibit –
through negative feedback- the release of GABA and hence inhibit the
inhibitory effect of GABA (disinhibition)
• GABA is released from different brain areas including:
1. VTA interneurons Having a positive charge inside the
2. Nac shell cells = action potential = activating
3. Ventral pallidum (VP) calcium channels = excitation q
GABA B efflux more positive charges to stop the system.

GABA GABA A influx more negative charge stopping the system.
• GABA receptors are:
1. Fast acting ionotropic GABA-A receptor: composed of 5 receptor
subunits
qEach of the 5 subunits is one of 3 predominant subtypes: α, β, or γ
qReceptor activation requires the simultaneous binding of two GABA
molecules to the receptor, one to each of the two binding sites at the
interface of the α and β subunits
2. Slow-acting metabotropic GABA-B receptors: G-protein couple
receptors that activate potassium channels to mediate the efflux of
potassium and hence inhibiting the cell excitation (autoreceptors)
3. Fast-acting ionotropic GABA-C receptors
• The GABAA and GABAC receptors are Cl– channels that mediate fast
synaptic inhibition
• Both GABAA and GABAC receptors are members of a superfamily of
transmitter-gated ion channels that includes the nicotinic
acetylcholine, strychnine-sensitive glycine and 5HT3 receptors
1
Channels activated by GABAA influxes a negative charge in the form of chloride ions to bring down AP whereas
GABAB by efflux of potassium ions by effluxing positive charge out making the cell hyperpolarize/more negative
Mesocorticolimbic pathways (GABA and Overall network of major afferents and efferents of VTA GABA neurons.
Abbreviations: BNST, bed nucleus of the stria terminalis; CeA, central amygdala; DRN, dorsal raphe
dopaminergic neurons) nucleus; LHb, lateral habenula; LH, lateral hypothalamus; NAc, nucleus accumbens; PAG,
periaqueductal gray; PFC, prefrontal cortex; SC, superior colliculus; VP, ventral pallidum; VTA, ventral
tegmental area.
DON’T MEMORIZE
• Constant GABA = no dopamine = depression.

• GABA is the negative feedback to shut down the system
stopping dopamine release to Nac.
• If GABA release is more than needed it will lead to depression.
1
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Mesocorticolimbic pathways (Glutamate)

• Dopamine firing is stimulated by glutamate
• Glutamate is released from different brain areas
including:
1. The PFC has been shown to send glutamatergic DA
afferents to the VTA to control burst firing
2. VTA receives a number of excitatory inputs including
glutamate from subcortical brain structures (such as
amygdala) that may be relevant to the integration of DA
environmental stimuli
3. Orbitofrontal cortex (OFC), a key region for the
encoding of reward value and prediction error
4. VTA glutamate neurons can drive positive
reinforcement by releasing glutamate in the Nac even
in the absence of DA release
Glutamate
1
• Glutamate is synthesized/produced through α-ketoglutarate –a byproduct from

Krebs cycle- transaminated to glutamate in CNS nerve terminals releasing GABA
• Glutamate is released in the synaptic cleft via calcium-dependent exocytosis, to
bind:
v Excitatory postsynaptic ionotropic receptors (NMDA, AMPA or Kainate)
v Modulatory metabotropic receptors (mGluRs) that change the excitation rate of
postsynaptic ion channels leading to either inhibition or excitation
• Glutamate signal is terminated by
1. Reuptake into the presynaptic nerve by Na+-dependent transporters
• The blue symbol is
2. Diffusion away from the cleft the ion channel
3. Receptor desensitisation (loss of sensitivity to neurotransmitter) (ionotropic - faster)
• The one next to it
• In glial cells, the enzyme glutamine synthetase converts glutamate to is G protein
glutamine, which is recycled into adjacent nerve terminals for conversion back
coupled receptor
to glutamate (by glutaminase) or enters the Krebs cycle and oxidised to α-
ketoglutarate that enters neurons to resynthesise glutamate (metabotropic –
slower & is more
• Increased glutamate in the synaptic cleft leads to a positive feedback cycle that sensitive)
increase intracellular Ca2+ levels leading to further glutamate release and
excessive excitation causing hyperalgesia, seizures, neurodegenerative diseases
e.g., Alzheimer’s and stroke 1
Overall network of major afferents and efferents of VTA Glutamate neurons.

Abbreviations: DH, dorsal hippocampus; LHb, lateral habenula; NAcc, nucleus accumbens; PFC,
prefrontal cortex; VP, ventral pallidum; VTA, ventral tegmental area.
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A crucial brain reward Dopamine Phenylalanine

neurotransmitter activated by Hydroxylase
• Dopamine (DA) is synthesised from
addictive drugs like opioids is food/amino acids:
L-Tyrosine
dopamine, specifically in the ventral 1. Tyrosine (mainly obtained from diet) [Major] L-Phenylalanine
Tyrosine
tegmental area to nucleus 2. Phenylalanine (from the liver) [Minor] 1st
step
Hydroxylase
• Tyrosine is the precursor amino acid in
accumbens link in the brain’s catecholamines synthesis
reward circuitry • DA is synthesised from L-tyrosine in the
cytoplasm of the neurons
• DA is then transported into secretory vesicles
L-Dopa
for storage and release
Aromatic amino
• The insertion of DA into vesicles is achieved acid (Dopa)
y.shamsaldeen@brighton.ac.uk through pumps: 1 decarboxylase
1. Proton ATPase pumps that facilitate H+
influx into the vesicle Transporters
2. Proton antiporter: vesicular monoamine
transporter (VMAT) that works as
dopamine/H+ exchanger Dopamine
1
Dopamine receptors and reward circuit

• Dopamine receptors are G-protein coupled receptors (GPCR)
• Dopamine projection pathways act on D1-like (excitatory) or D2-like
(inhibitory) receptors
q D1-like receptors: D1 (mainly in the brain) and D5 (Increase cAMP and
PKA)
q D1: on the postsynaptic neurons has a moderate stimulatory effect on
locomotor activities and critical roles in learning and memory
mechanisms, such as working memory, that are mediated primarily by
the prefrontal cortex in addition to reward and reinforcement
mechanisms
q D4&5 functions: minimal learning and cognitive roles?
v D2-like receptors: D2,D3 and D4 (decrease cAMP and PKA)
v D2 functions: on the postsynaptic neurons has a moderate stimulatory
effect on locomotor activities and critical roles in learning and memory
mechanisms, such as working memory, that are mediated primarily by
the prefrontal cortex in addition to reward and reinforcement
mechanisms. May contribute to negative feedback as autoreceptors
v D3 functions: May contribute to negative feedback as autoreceptors
minimal learning and cognitive roles?
1
v D2,D3 and D4 have an inhibitory effect.
Dopamine synaptic transmission

1. After the synthesis, DA is stored in the vesicle
2. As action potential arrives, voltage-gated calcium channels open
leading to influx of calcium ions that bind to loaded synaptic vesicles
3. Vesicles translocated and docked with the membrane of the nerve,
leading to the release of DA in the synaptic cleft
4. DA binds to DA-receptors in the postsynaptic affected organ/tissue
leading to excitatory or inhibitory postsynaptic action
5. DA binds to DA-autoreceptors in the presynaptic affected
organ/tissue leading to inhibitory effect (negative feedback)
6. From the cleft DA is
• Transported from the cleft back into the presynaptic cell by a 12-
transmembrane domain protein, the highly selective dopamine-
sodium co-transporter (DAT) to either recycled in the vesicle, or
metabolised by mitochondrial monoamine oxidase (MAOA or MAOB)
• Metabolised by cleft catecholamine-O-methyltransferase (COMT)
7. Homovanillic acid (HVA) is the major metabolite of DA, which is
excreted in the urine
1
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Short-term synaptic plasticity (rule of 20 ms)

• If the presynaptic neuron is stimulated twice it may lead to:
• Paired-pulse depression: when longer interstimulus intervals
(200 ms) are applied, it leads to a transient depletion of the Postsynaptic neuron
release-ready pool of vesicles docked at the presynaptic Pre: Firing of AP firing AP
terminal (↓ excitatory postsynaptic potential: EPSP) (Na+ and Ca+2 influx)
• Many synapses exhibit paired-pulse facilitation at shorter
interstimulus intervals (20 ms) mainly because of the residual
Ca2+ left from the invasion of the first action potential Pre: Firing after 20 ms Postsynaptic neuron
contributes to additional release during the second from the 1st AP firing AP is depressed
stimulation, together with additional mechanisms (↑ EPSP) (neurotransmitter (Ca+2 ions returned to
(NT) depletion) baseline)
qLonger-lasting forms of plasticity are observed following
repetitive or tetanic stimulation of synapses when prolonged
(200 ms to 5 s) trains of stimulation applied
qRepeated pairing of postsynaptic spiking within 20 ms after
presynaptic activation leads to long-term potentiation (LTP) Pre: Firing within 20 Postsynaptic neuron
qPostsynaptic spiking within 20 ms before presynaptic ms of 1st AP (excessive firing AP is enhanced
activation leads to long-term depression (LTD), as it will lead release of NT due to (due to accumulation
to inactivation of Na+ and Ca2+ channels in the postsynaptic residual cytoplasmic of Ca2+ from the 1st
neuron and hence leading to lack of response Ca+2) AP) 1
Long-term synaptic plasticity Orexin neurons regulate various

• Long term potentiation (LTP): mainly involves upregulation of physiological phenomena such
either presynaptic and/or postsynaptic receptors. When
Glutamate is released and binds to AMPA, it enhances Ca2+ influx as wakefulness, feeding, reward, and
that leads to Mg+2 liberation from NMDA receptors that become thermogenesis. The body energy level
active and hence more Ca2+ entry leads to increase CaMKII
activity (calcium calmodulin kinase II) leading to more AMPA influences orexin neuronal activity to
calcium membrane docking and hence amplifying glutamate-
induced excitation (AMPA has higher acceptance of calcium the coordinate arousal and energy homeostasis.
NMDA). Orexin-A signals through both OX1R and
• Long-term depression (LTD): mainly involves downregulation of
OX2R, whereas orexin-B signals mainly
either presynaptic and/or postsynaptic receptors and/or cascade
components. When Glutamate is released and binds to NMDA, a through OX2R. Intracellular cascades
lower threshold Ca2+ current is generated that leads to increase
calcineurin and protein phosphatases 1 (PP1) leading to AMPS mediated by G proteins increase intracellular
dephosphorylation and internalization thereby depressing calcium and activate the sodium/calcium
glutamate-induced excitation (so, released glutamate that binds
to NMDA with a low calcium, will bind to phosphatases and will exchanger, which depolarizes target neurons.
dephosphorylate the phosphate receptors to cause LTD)
qLet us apply these principles to VTA and reward pathway induced
by food/arousal (Orexin effect)
1
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Summary
• The brain’s reward circuit is comprised of mesocortical and mesolimbic pathways
(mesocorticolimbic pathways)
• The main neurotransmitter in brain’s reward circuit is dopamine
• The activity of dopaminergic neurons in reward circuit is mainly controlled by three
neurotransmitters
1. Dopamine
2. GABA
3. Glutamate
• A crucial brain reward neurotransmitter activated by addictive drugs is dopamine, specifically
in the ventral tegmental area to nucleus accumbens link in the brain’s reward circuitry
• Synaptic plasticity is the capacity of the neurons to exert physical and biochemical changes
and hence changing neural activity caused by an experience leading to modification of neural
circuit function and thereby modifying subsequent thoughts, feelings and behaviour
1
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L3) Quality Issues Associated with Recreational Drugs:

Substance Misuse: Case Synopsis and Introduction Recreational drug
qStacey, 26 year old moved from London to Brighton. Recreation
qComes to pharmacy to collect “clean needles” n. “The process or means of refreshing or entertaining
qDesperate to stop heroin dependence but needs help oneself after a period of work by some pleasurable activity”
qHas been using for 2 years, has damaged veins due to
Oxford English Dictionary
poor hygiene and quality.
qUses heroin, cannabis and cigarettes but also alcohol.
Takes diazepam for anxiety Drug
n. “A substance that acts on the nervous system e.g., a
Disease narcotic or stimulant, especially one causing addiction”
ê
Therapy Oxford English Dictionary
ê
Science Can addiction or self-injury be a pleasure?
Quality
PCQ = purity,
PY365•– Advanced Pharmacyconsistency
1 and quality the foundation
3.3 Substance Misuse 1
The 3 most commonly used
PY365 – Advanced Pharmacy 1 drugsMisuse
3.3 Substance are: 1
of good and safe medicines’ production – expected • Alcohol (most abused)

for pharmaceuticals • Nicotine
• Caffeine
• Is there any such thing as quality control when drug
formulations are made up by layperson • All are legal, all are psycho-active (have
(responsibility free) with no interest in PCQ? influence on the CNS)
Heroin doesn’t dissolve well hence why it’s heated
when taken in the form of spoon from a needle
How illicit drugs are taken
Depends on its solubility IV-intravenously
• PY365 by injection
– Advanced Pharmacy 1 (“shoot-up”:
3.3 heroin,
Substancetemazepam)
Misuse 1
PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 • Subcutaneous depot by injection (“popping”: heroin) - not used
often but taken for an immediate effect)
• Inhalation (smoking: heroin, crack-cocaine, marajuana)
• Insufflation (“snorting”: amphetamine, cocaine) – taken by nose
• Orally (pills: MDMA, barbiturates; micro-dots, bombs,
POMs/prescription only medicines)
• Rectally (“bombs”, “plugging”: heroin)
• Intra-vaginally (“bombs”: heroin)
When all their veins are “shot through”/damaged seasoned
heroin addicts then are forced to look for easily viewed “last
ditch” veins and so inject into their perineum and genitalia
Common recreational (illegal) drugs are PY365 – Drug

Advanced Pharmacy
Common recreational (legal) drugs are
1 3.3 Substance Misuse 1
Euphemism Active Risk lethal
PY365 – Drug
Advanced Euphemism/synonym
Pharmacy 1 Active 3.3 Substance
Risk Misuse
lethal 1
Restoril Mazzies, jellies, benzo Temazepam Addiction, years
Heroin Smack, junk, horse, H, brown, scag Diacetylmorphine Blood, HIV, HepB years DVT on injection
Cocaine Coke, Charlie, Columbian marching Benzoylmethylecgonine Cardiac arrest, years Mogadon Moggies Nitrazepam Addiction years
powder, coca, C, snow arrhythmias
Cannabis Ganj, hash, blow, smoke, grass, dope, D-9 Tetra Psychosis, cancer years Valium Mummy’s helper, housewife’s Diazepam Addiction years
mash, puff, THC, resin, skunk Hydrocannabinol friend
Co-codamol Co-codamol: Tramadol, zydol Codeine+paracetamol Addiction years
Amphetamine Whizz, Billy, sulphate, speed, 1-phenyl-2- Cardiac arrest years
(codeine),
sulphate Adderall aminopropane
Vicodin Vicodin; fluff, scratch, V- Hydrocodone+paracetamol
MDMA Ecstasy, E, Ebeneezer, XTC, Molly 3,4-methylenedioxy-N- Psychosis years (hydrocodone) Itamin, vike , hydros
methylamphetamine Cardiac arrest Amyl nitrate Poppers, fuzzies, cyanide 1-nitrooxypentane Vision, erection unknown
GHB Liquid heaven, GBH g-hydroxybutyrate Cardiac arrest years antidote problems
Tobacco Fags, cigs, smokes, tabs, snuff Nicotine Many cancers years
Psilocybe Magic mushroom, shroom, pixies hat Psilocybin Psychosis unknown
(Paan/betel nut)
fungus
Alcohol Booze, drink, sauce, hooch Ethanol Cancer, cirrhosis years
a- Krokodil, crocodile, liquid (Dr) death, Desomorphine Abscess, months,
Chlorococide super-heroin, bite, Russian pleasure, amputation, year max Rohypnol Date-rape drug, roofies Flunitrazepam (ADHD) Coma unknown
(oxidised flesh-eater, zombie gangrene,
codeine) septicemia Legal “highs” Nutmeg, khat (Virola Yupo), Hallucinogens Psychiatric unknown
(unregulated) kava, bhank, BZP, AMT, Spice disorders
LSD Smileys, tabs, Lucy, acid, trips, Alice, Lysergic acid Permanent unknown
Food 1. Mucor, Ergot fungus 1. Ergotamine Psychosis, liver 3 months
Hawk, LSD-25 diethylamide psychosis
derivatives 2. Delerians 2. Solanaceae cancer
Other “traded” illegals include : phencyclidine (PCP), methadone, nandrolone, ketamine, barbiturates, etc…. Other legals include POMs, Pro-Plus, etc….
PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1
19
•
Regulatory comparison
The difference between ‘street’ and approved drugs
Quality the cost of supply
Drug R&D Animal Clinical Regulatory Product Route to • NHS prescription cost (£8)+ [Govt. subsidy (general 26-86%) +
screening and testing scrutiny licence recipient pharmaceutical cost, approx. £5 (Ergotamine) but 100% - for some £525
safety models
(Faslodex, BRCA/injection)]
POM Yes Yes Yes FDA Driven by Through • Illicit drug costs
OTC MHRA SAFETY controlled
Preformulation ca. 12 years tests EMEA supply chain – Heroin ~ £3 wrap 0.2g (habit costs about £15/day) purity 4-71% (usual
Extensive
Specific
per each new
drug SQE +++
SmPC
CTD
then via
pharmacy
30-50%), US, UK, Australia 1971-present
informed Full GMP PCQ
Full QA Policed by • Black-tar variety very crude
Full QC SQE pharmacist,
dentist, medic – Cocaine (habit costs about >£70/day)
or QP‡
Heroin NIL NIL NIL No SQE NIL Smuggled†
• Powder ~£50/g
Cocaine
Ecstasy
No GMP
No QA
Driven by
profit
Dealer • Crack ~£16/0.2g (per rock)
Cannabis
etc …
“rudimentary”
QC (+/-)
– Cannabis Quality comes at a cost but
• Leaf ~£9-15/sixteenth ounce (0.175g) that means safe!!
‡ 90% of tests and policy undertaken by graduates, licensed professionals and
• Resin ~£7/sixteenth ounce (0.175g) Dirt cheap means ‘dirt!’
doctorates; †60-100% by personnel with no scientific training or higher than
secondary school education – Pills e.g., Ecstasy vs Vycodin ~£6-10 to 50p
The supply chain PY365 – Advanced Pharmacy 1 Hygiene 3.3 Substance Misuse 1
• Profit vs safety • The following microbes are routinely found in recreational drugs
but never in ‘sold’ commercial medicines
• 12-40% of drug shipments are intercepted • Bacterial
• 2014: It costs £1,500 in Columbia to make 1kg of – Bacillus cereus [soil]
cocaine but sells for £67,000 in UK – Clostridium botulinum (C. bot.) C. novyi, C. perfringens, C. sardellii
[soil]
• 2014: An Afghan farmer is paid £90 for 1 kg of heroin, – Streptococcus spp. cause of necrotising faciitis [faeces]
the Afghan wholesaler pays £3000 but the UK street – Staphylococcus spp. [poor hygiene]
value of this heroin (diluted to 40% w/v) is £290,000. – E. coli [poor hygiene, faecal bacterium]
– Bacillis anthracis (anthrax) [soil]
Case study 1 - Heroin • Fungi
– Serratia liquifaciens [soil, rodent gut]
• In Europe/UK, heroin is the 4th most used type of – Geotrichum spp. [soil, faeces]
recreational drug after cannabis (1st), cocaine (2nd) and – Trichosporon spp. [soil] Cocaine manufacture
“amphetamine class” (3rd) • Viruses
• Heroin use is responsible for a disproportionate number of – Polioviruses, Coxsackie viruses and Echoviruses [soil; human,
recreational drug deaths ca. 30-50% despite usage being domestic animal and rodent gut]
PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1
more than 20x less than amphetamines, which are used 4x Case study 1 - Heroin
less than cannabis
• The greatest user of cannabis in Europe is Spain (3%) • Everyone knows about the HIV risk of self-
• A heroin “hit” lasts 4-6 hours, intense craving then follows injectors but why is that?
Injectors test they’ve “hit a vein” by
aspirating their own blood. This gives a
Lipophilic, better proof that the hit won’t be lost but since
penetrating in the system
about 9% of IV heroin abusers are HIV+
(50% don’t know this), this means the
syringe is then contaminated and despite
Case study 1 - Heroin being prepped in a hot mug of water no
• Opium poppy sap exudate mixed with CaO (lime), ammonium chloride,
assurance of STERILITY
acetic anhydride, HCl, activated charcoal, ammonia, acetone Afghanistan, Mexico, etc
• Impurities in heroin come from opium derivatisation and components are: PY365 – Advanced Pharmacy 1
Cooking up The nod
– Diacetylmorphine (aka diamorphine, heroin) ca. 75% - indicates the
brown colour
– Monoacetylmorphine 8%
– Morphine 2% ‘Chasing the dragon’
– Acetyl codeine 5% Interception

(Azerbaijan) Shooting up
Dignified place to
take drug and
– Narcotine 6% pass out?
– Papaverine 1%
– Noscapine 1% Heroin
– Plus metals and materials (~2%) carried over from the crude processing • Heroin is dissolved by mixing with vinegar, lemon juice, Overdose, coma
citric acid or battery acid; boiling, cooling, filtration,
• 17 kg opium ® 1 kg heroin Heroin forms
aspirating, cooling then injection
and death
• It can also be inhaled and smoked

“Golden brown”
• Can be mixed with other drugs e.g., cocaine (speed-
• Methadone - Laevo-a-methadol (a prescribed heroin replacement, balling)
levomethadone) is sometimes illegally traded by addicts – for this reason • Potency varies 4-70%, overdose and dose misjudgement
its often needed to be seen taken in the pharmacy is common. Purity and cutting agents vary.
20
Case study 2 – Coca leaf
Death
Cocaine and amphetamines Line of coke Tissue loss
• Pulped coca leaf (2% cocaine) mixed with CaO, NaOH,

H2SO4, KMnO4, Ammonia, bicarbonate of soda, automobile
fuel (car petrol) - traces of these substances are found as Snorting
Crack pipe
impurities in the powder Smuggling
• Cocaine causes heart irregularities, as one of its actions is in

modifying heart rate and the ion-pump mechanism
• 20-50% of cocaine users culminate in irreversible Mules carry Cocaine Erosion of
septum
the drug via •Cocaine is manufactured by using lye (NaOH) and diesel/petrol
arrhythmias or fatal heart attack their gut
•It can also be insufflated (by nose) and smoked
•Can be mixed with other drugs e.g., LSD (a blotter)
Amphetamine Crystal meth •Potency varies 10-70%. Purity and cutting agents vary.
MDMA/Ecstasy •Degrades the tissues – very serious damage
1
1 PY365 – Advanced Pharmacy 1 3.3 Substance Misuse
Active
PY365 – Advanced Pharmacy 1 3.3 Substance Misuse
Euphoria turns tragic Hardwood
Ecstasy tablets
tree used in
Various forms
Seizure
the clubbing
culture
Safrole or sassafras oil
Suck a (carcinogenic Safrole oil is
lollipop
natural pesticide in hardwood harvested from
to avoid
Doing a line of speed the roots of
“Gurning” tree roots) is used to make Cambodian
MDMA (Ecstasy). jungle hardwoods
Schoolgirl – Leah Betts,
1kg oil (£100) makes 95g
• “Coming down” crises, depression coma and death MDMA
• Over-heating common ≈ 1000-5000 pills
• Judgement of self, risk distorted = £20,000-100,000
PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 MDA (hallucinogen) is a

common CNS toxin impurity
Tissue decay
present with bathtub prep
Drug den causing degradation of CNS
and hallucinations Can be done in the kitchen, saves cost for laboratories
Case study 3 - Krokodil

• Oxidation of codeine
• Purity 15-40% at best (85% sold falsely) – product is made “at home”
Krokodil Flesh decay
Pre-cursor Reagent Reagent Reagent Solvent
OTC Codeine Paint thinner Li watch battery Toilet cleaner Gasoline
Reptilian skin appearance Acetone, ethylbenzene, Cadmium Hydrochloric acid Octane, benzene, ethanal
Brain, liver and xylene, butanol, Thionyl Chloride
methylethyl ketone
kidney tissue death
starts from the first OTC Codeine- Match heads Iodised floor Lighter fuel
paracetamol Red phosphorus,
cleaner
injection potassium chlorate,
sulphur, atimony Iodine, iodophor
Butane
sulphate povidone
• Self-made desomorphine is very impure
Cutting agents (diluents)

•
•
Tissue decay at injection site as noxious cocktail is also corrosive (pH ~3)
Four times as powerful and two times as addictive as heroin. Effect short-
lasting (1-2h). User needs an immediate fix.
• Mannitol • Plaster of Paris (calcium sulphate, • Death typically 1 year after first use
gypsum)
•
•
Creatine
Inositol • Urea
Contents of “standard”
Case study 4 - Cannabis
• Pectin • Caffeine Diamorphine HCl Tablets 10mg • Harmless? Urban myth?
• Glucose • Boric acid (insecticide) Ø Lactose BP
Ø Magnesium stearate BP • Psychosis and psychiatric ill-health
• Lactose • Quinine Ø Talc BP
Ø Povidone USP is common immediately or several
• Maltodextrin • Ammonium nitrate Ø Microcrystalline cellulose EP
years after use, particularly with
• Saccharin • NaCl Ø Starch BP
Ø Calcium phosphate BP current form of the drug e.g.,
• Baking soda • Talc Ø Eudragit S100 coating
Ø Food colour (E171, E172) “skunk”. This has 90% more THC
• Flour • Sodium carbonate
• Silica, fine sand • ALL active/excipients need a
than the “ganja” of yesteryear.
• Milk powder certificate of analysis and are
• Brick-dust • White food colour, titanium dioxide part of GRAS listings (clinical • 40% of users show signs clinical
testing). From a licensed
• Borax/disodium tetraborate - supplier depression and anxiety disorder 10 Cannabis sativa
• Chalk
cleaner e.g., Vim, washing soda years after routine use

21 1
Hallucinogens: psilocybin, LSD, etc.

Cannabis
Joint-spliff
Leaf and buds

Cookie
Acid tab (LSD)
• Cattle excrement is found

quite commonly in resin Magic mushrooms
• Fungal and bacterial Acid pill
Resin contamination is common
Dosage is difficult : Problems:
Adulteration of illicit drugs • LSD 30-100 µg dose (microdot – very tine dose,
tinnier than salt) causes a “trip”
Flashbacks - hallucination
Psychosis
• Adulterants for bulking, disguise, weight boosting, flavour change and MP modification Schizophrenia
PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 • Psilocybin “mushroom tea” - impossible to predict Case of Sid Barrett et al.
Heroin Adulterant Cocaine Adulterant Amphet. Adulterant Cannabis Adulterant
China Strychnine* Lidocaine MDMA Ketamine† Leaf Calamus

white Titanium dioxide Benzocaine palm ** PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1
Caffeine
Aspirin
Caffeine
Aspirin
MDMA Ephedrine Leaf Dactura
plant*/**
UK Quality and Penalty Laws
Quinine Phenacetin MDMA Methylphenidate† Resin Beeswax
Clenbuterol Levamizole‡ Amphetamine Lead nitrate Resin Pine resin**

• Dangerous Drugs Act 1920 (mods 1964, 1967)
Scopolamine Tetramisole‡ Shoe polish**
Phenobarbital Atropine Amphetamine Benzodiazepines† Lead dust **
• The Drugs (Prevention of Misuse) Act 1964
Black tar Soil, silt, clay** Milk Amphetamine Naphyrone / Ground • The Misuse of Drugs Act 1971
powder** NRG-1† glass**
Brown Brick dust** Crack Bicarb, chalk Amphetamine Plaster of Paris** Resin Soil** • The Medicines Act 1968
• A plethora of regulations
Borax(cleaner)** Ketamine† Amphetamine Vitamin B1/B6† Resin Droppings
Danger C. Botulinum Danger Coma, cardiac Danger Coma, cardiac Danger Bacteria,
Faecal Strep arrest arrest fungi,
Anthrax Paralysis Paralysis pesticide
Fungal spores Psychosis Psychosis
* - Toxic, ** - non-pharmaceutical drug or excipient, ‡- dog worming tablets, † - psychoactive. What’s the difference between
MDMA is 3,4-methylenedioxy-N-methylamphetamine
a manufactured medicine and a
Russian Roulette
drug (illegal)?
Death common Ê
• –The
PY365 difference
Advanced Pharmacybetween
1 the manufacturer
3.3 Substanceof a drug1
Misuse
q Do you know [illicit] and a medicine, is in terms of "intent." A
Dependency ®
what this is?

Nicotine Cocaine Heroin medicine is beneficial, bespoke or purposeful, a drug
q Krokodil
Cannabis
is hedonistic and purely for self-gratification. The
LSD
Alcohol
former takes a lot of care, knowledge and altruism.
Ecstasy The latter involves significant disregard for others,
Amyl nitrate
indifference or malice

Physical harm ®

Specimen questions
Questions:
PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 • What is missing from recreational drugs in terms of quality?
PY365PCQ
Answer: – Advanced Pharmacy
- purity, consistency 1
and quality 3.3 Substance Misuse 1
Chalk and Cheese Quality control
• Why use cutting agents (heroin, cocaine, ecstasy and amphetamines –mostly)?
• Answer: Dilution of active and profit – active is impure but also may count for as little as 4% by weight
• Why is Krokodil so deadly?
Drug dealer Pharmaceutical
industry and health Answer: Lack of purity, addictiveness/intoxification, corrosiveness/lack of biocompatibility, “bathtub”
and supplier science professions Bespoke technology synthesis, mixed starting materials, poor reproducibility of synthesis
custom-built facility
• What makes ‘street grade’ heroin such a risk to the drug taker?
1. PCQ NO YES • Answer: The drug (diacetylmorphine), a white powder, is mixed or “cut” with diluents powder; this means a
threefold risk, firstly – potency is uncertain possibly leading to misjudgement and overdose and secondly –
2. Specialised NO YES the modus operandi of (administration and) solvation using mineral acid and “cooking” the preparation is
apparatus
variable and thirdly - the cutting excipients are or various and dubious safety e.g. ranging from glucose,
3. Inspected NO YES lactose, chalk, talc, flour, cornstarch, powdered milk, acetaminophen, etc to plaster, brick dust, abrasive
facility kitchen cleaner e.g. Vim. Black-tar heroin is sometimes mixed with soil. Deadly!
University graduate
4. Educated NO YES Professional licence • How much heroin does a user take?
workforce
• Answer: Users become “desensitised”, a 200-400mg dose of heroin could kill a novice, BUT a chronic user
5. Professionals NO YES may take 1800mg without ill-effects
CPD, professionlal
register • How is heroin made?
6. Bespoke NO YES • Answer: The process of making diacetylmorphine or heroin from opium varies, depending on the methods
supplier used, and the facility for making it. These range from state-of-the-art legitimate laboratories run by fully
Licensed outlet qualified chemists, to clandestine labs run by illicit drug manufacturers, to makeshift processes using old oil
drums and outdoor fires, run by local growers with little or no education in pharmaceutical chemistry.
22
L4) Systemic Drug Delivery Via the Nose:

Why nasal delivery? Lateral view of nasal cavity
• Local effects – year 1
• Systemic effects Lateral view of nasal cavity:
• Main nasal passage –
• Where oral route not available
turbinates and meatuses
– Destroyed in GI fluids
(air spaces 0.5 – 1.0 mm).
– Metabolized in gut wall
• Ciliated columnar
– Extensive biotransformation by liver during first
passage around circulation
epithelium. Convolutions
» Peptides, vaccines, hormones
increase surface area.
• Nasal mucosa highly
• Vaccines
Lateral view of nasal cavity
• Delivery to brain – direct route
vascularized. Important in
modification of inspired air
PY365 Advanced Pharmacy 1 3.3 Substance Misuse

- Particles deposited on turbinates are
IMMEDIATELY available for clearance – but
this is best area for absorption, reduces how
TURBINATES long the drug needs to be absorbed.
- Particles deposited anterior to turbinates
not immediately available for clearance
5 Advanced Pharmacy 1 (dragged on3.3mucus through

Substance Misuse cavity) but not best absorption site.
- Particles deposited in nasopharyngeal region cleared immediately by

Lateral viewswallowing.
of nasal cavity
Applied Physiology
NASOPHARYNX
• Air conditioning • Filtration
• Main function of the • Vibrissae (> 10 µm)
human nose • Mucociliary clearance
Advanced Pharmacy 1 3.3 Substance Misuse • Temperature – (5 – 10 µm) & hair of
• Warming from 23oC the nose
to ~32oC
• Olfaction (the sense of
• Humidity smell)
• 40% - 98%
Structure of nose allows for intimate contact
between inspired air and mucosal surfaces.
23Advanced Pharmacy 1
PY365 3.3 Substance Misuse
some secrete Direction of

Mucus Transport Mucociliary clearance
mucous where Secreted Mucus
mucous gels
are in the cilia
that are beating
continuously Periciliary Fluid
and as they Deposition

move forward
Dissolution
mucous is also
if necessary Absorption
moved
Ciliated Cells Mucin Secreting

Goblet Cell
Where we Moves
want it for into
absorption turbinate
Deposition and
Intranasal administration clearance from a
and deposition (gamma scintigraphy) nasal spray
Gamma scintigraphy showing deposition
which reflects area for absorption. Disappears
into throat
Drug
Systemic drug delivery

Front of PY365 Advanced Pharmacy 1 3.3 Substance Misuse
• Metered-dose device, insert
the nose
into nostrils and depress
device while inhaling.
• Avoids filtration by vibrissae. Where the drug is delivered to one site acting
• 10-20 minute window before in a different site of the body and is related to
most cleared by mucociliary
clearance. transportation through the bloodstream
Deposition and clearance of

PY365 Advanced Pharmacy 1 a nasalMisuse
3.3 Substance spray What is difference between local and
from the nasal cavity systemic delivery?
Local is given where we want to act directly
Which requires absorption?

The spray goes from turbinates and
slowly goes to the nasopharynx area

Need drug to cross the mucosa into the
bloodstream hence systemic drug
PY365 Advanced Pharmacy 1
delivery Misuse
3.3 Substance
Factors affecting nasal absorption

Surface area of the nose
30 Patient factors
minutes
PY365
Charge Advanced Pharmacy 1 3.3 Substance Misuse
MW
PY365 Advanced Pharmacy 1 3.3 Substance Misuse Lipophilicity
What factors affect nasal absorption

(directly or indirectly)? Drug factors Nasal absorption
Anatomical and
Physiological factors
Surface area of the nasal cavity, concentration of

drug applied due to absorption being passively Deposition
Mucociliary clearance
pH
diffused, size affects pre-absorption especially Osmolarity
Formulation factors
Permeability
Viscosity Enzymatic degradation
the weight, nature of the drug in terms of Concentration Surface area
lipophilicity and log P Volume

Dosage form
PY365 Advanced Pharmacy 1 24

3.3 Substance Misuse
Anatomical/structure and physiological/behave

factors affecting nasal absorption – things that
are normally happening in the body
Advantages Disadvantages
• Large surface area • Mucociliary clearance
(~160 cm2) • ↓ Contact time
• Turbinates, microvilli
• Metabolic activity
• Highly vascularized • Cytochrome P450
• Avoids first pass hepatic • Peptidases
metabolism • P-glycoprotein
• Immunological clearance in terms

of antibodies production
neutralizing the drugs making
them ineffective
• Mucus barrier & Epithelial barrier Absorption routes and mechanisms
– affects blood entry
• Transcellular (across the
cell)
• Passive diffusion
• Active mechanisms like
transporters
• Endocytosis
• Paracellular (between the

cell)
– Tight junctions that are
joining the epithelial cells
• Passive diffusion
Drug factors affecting nasal absorption

• Molecular weight (h’philic, polar molecules) Cocaine – recreational
PY365 Advanced Pharmacy 1 drugMisuse
3.3 Substance
• Absorption decreases sharply when MW >1000 Da

• Limited diffusion of molecules > 3.6 Angstroms • Commonly snorted
• Negligible diffusion if molecules > 15 Angstroms • Molecular mass: 303 g/mol
• Lipophilicity • Log P: 2.3 hence cross the mucous
• Absorption increases with increased lipophilicity membrane easy ending up in the
• Charge bloodstream to eventually cross
• Absorption best if molecules unionized the BBB (blood brain barrier)
Most drugs given In are less than 1000 Da and are lipophilic. But • Onset of action: seconds to minute
for hydrophilic/ polar drugs that are transported via paracellular
route. MW is an important determinant to rate and degree of in the brain
transport drug where large MW = decreased absorption
A sudden and brief flare-up of pain from a chronic
condition like arthritis or cancer. Can be as a consequence
Breakthrough pain
Breakthrough pain of dressings, movement,
bed changes etc.
A liquid is traditionally is given orally for those peaks

Increasing the dose can lead to drowsiness,
but it’s not fast due to being oral sleepiness, laziness and worsen the condition etc.
PY365 Advanced Pharmacy 1 3.3 Substance Misuse PY365 Advanced Pharmacy 1 3.3 Substance Misuse
25
Breakthrough pain Fentanyl

• Fentanyl citrate
• Useful for breakthrough pain
• Mwt 336.5
• Log P 4.05
• Intranasal bioavailability 70 – 89 %
• Instanyl (50, 100 and 200 mcg/spray)

– Sodium dihydrogen phosphate dehydrate
– Sodium phosphate dehydrate
– Purified water
Hence nasal drug delivery is used • Tmax 12-15 minutes (works quick)
PecFent®
What is function of each excipient?
PY365 Advanced Pharmacy 1 PecFent® 3.3 Substance Misuse
• Fentanyl citrate (100 and 400 mcg/spray)

• More effective than placebo in reducing pain 30 min
– Pectin (E440) – polysaccharide after use in 83 cancer patients
– Mannitol (E421) – for tonicity - Reduced by 6.6 compared to 4.5 points
– Phenylethyl alcohol – preservative due to it being an aqueous solution
– Propyl parahydroxybenzoate (E216) – a parabens used as a
preservative • Patients ‘satisfied’ or ‘very satisfied’ with PecFent for
– Sucrose – for tonicity 90% of breakthrough pain episodes
– Hydrochloric acid (0.36%) or sodium hydroxide - to adjust the pH
making it neutral
– Purified water
• Pectin – in situ gelling with calcium ions
• Tmax 15 – 21 minutes
Accidental overdose3.3of
opioid
Substance Misuse
• Drug overdose deaths, driven largely by prescription

drug overdoses, are now the leading cause of injury
death e.g., in car accidents in the United States
• Treatment
• IV & IM naloxone, also IN naloxone
Naloxone
• M wt. 327.4
• Log P 2.09
• After intranasal (IN) administration, naloxone
exhibits opiate antagonist effects almost as rapidly as
the IV route with bioavailability approaching 100%.
Hence sometimes needs a repeated dose as opioids can

replace them due to vast production

26
Naloxone nasal spray (Narcan) Naloxone Nasal Spray (Nyxoid)

• Narcan approved by FDA 18th
November 2015 • MA issued by EMA 10th November 2017
• Drug overdose deaths, driven largely by prescription drug
overdoses, are now the leading cause of injury death in the • ‘Hybrid’ medicine
United States
• Single dose container (1.8 mg/0.1 mL)
• Many first responders and primary caregivers, however,
feel a nasal spray formulation of naloxone is easier to • 38 healthy volunteers 2 mg IN similar to 0.4 mg IM
deliver as administering the drug as IV could be risky as
needs a personal hence IN is more efficient, and eliminates https://www.nyxoid.com/uk/hcp/about
the risk of a contaminated needle stick -
https://www.narcan.com/ - it’s imp. to contact a health People likely to witness an
carer because it has a short duration of action & the opioid
can still re-bind to the receptor therefore signs and opioid overdose
symptoms can re-occur
• People at risk of an opioid overdose, their friends
and families would witness them
Why would a nasal spray be better
PY365 Advanced Pharmacy 1 3.3 Substance Misuse • People whose work brings them into contact with
than an injection? PY365people who
Advanced overdose
Pharmacy 1 (health-care workers, police,
• It doesn’t need a train person to do it like injections emergency service workers, people providing
accommodation to people who use drugs, peer
and to avoid injuries caused by needles or prevent
education and outreach workers).
contamination of STIs
What would be effect of mucociliary

clearance on absorption of naloxone?
• It’s rapidly absorbed due to emergency situations
and a have a high bioavailability.
• Mucociliary clearance affects the drug in terms of
removing it, it approx. takes 20-30 minutes therefore
it isn’t needed due to immediate absorption of the
drug by IN hence it’s irrelevant due to the right
physiochemical properties and it being in the
bloodstream in minutes having its effects
Desmopressin, DDAVP PY365 Advanced Pharmacy 1 3.3 Substance Misuse
• Peptide - can’t be given orally

PY365 Advanced Pharmacy 1 3.3 Substance Misuse Formulation factors affecting
• log P (-4.0 to -5.0) – very low & very nasal absorption
hydrophilic
• Large/massive drug • pH
• Molecular mass = 1,069 – the molecular • Osmolarity
size is related to diffusion in tissues and • Viscosity
Year 1 – all apply for
absorption across biological membranes • Concentration Passive systemic and local
diffusion
• Volume = 768 Angstroms3 • Volume
• Oral bioavailability = 0.08 – 0.16% as it’s • Dosage form
a peptide hence given by IN
• Penetration enhancers – we don’t put it in local
• Nasal bioavailability ~ 10% (go with it
even though it’s low) hence for this administration but used for systemic
molecule mucociliary clearance is
relevant as it’ll take time
27
Penetration enhancer - chitosan Comparison of IV (10 mg), oral (15 mg) and
nasal (15 mg) delivery of morphine
• Polysaccharide (deacetylation of chitin)
• MW ~250,000 Da 285 g/mol
Log P 0.9
• Cationic Small, and is
• Increases absorption of polar molecules/hydrophilic not lipophilic
• Acts as bio adhesive making the drug sticky in the

membrane
• Transiently opens tight junction increasing the
absorption of polar molecules/hydrophilic ones
letting them through
Better absorption than nasal morphine alone
PY365 Advanced Pharmacy 1 Therapeutic areas suitable

3.3 Substance Misuse PY365 Advanced Pharmacy 1 for IN
administration
• Common theme(s)
• Breakthrough cancer pain (fentanyl, morphine, alfentanil)
• Migraine and cluster headaches (sumatriptan, zolmitriptan)
• Anticholinesterase inhibitors for Alzheimer’s disease (galantamine)
• Insulin for Alzheimer’s disease (autism) (nose to brain route
directly)
• Apomorphine for erectile dysfunction
• Anti-nausea and motion sickness medicines (scopolamine) – when
it’s not able to be taken orally
• Emergency situation medicines
» Naloxone for opioid overdose
» Benzodiazepines for seizures
» Glucagon for insulin-induced hypoglycaemia
Patient factors affecting nasal

absorption
• Acceptable to patient
• Non-invasive – comfort and compliance
• Simple dosage form – drops and sprays
• Variability of dosing (largely due to mucociliary
clearance)
• High MWt vs. low MWt
• Disease
• Inflammation
• Common cold
Deposition and clearance of

nasal spray in patients with Nose is blocked
cold exhibiting symptoms of hence increased
profuse nasal discharge (drug absorption
is lost due to not much
absorption hence not ideal as
it’s runny)
Nasal Spray
PY365 Advanced Pharmacy 1 3.3 Substance Misuse PY365 Advanced Pharmacy 1 3.3 Substance Misuse
28
29
L5) Controlled Drug Requirements for Substitute Prescribing (Legal Aspects):

What is a Controlled Drug? Difference between them
and POM is there might Classification of CDs -
be a misuse associated
§ The Misuse of Drugs Act 1971 defines CDs as with control drugs There are 5 schedules
“dangerous or otherwise harmful drugs” and
categorises them into three distinct classes – A, B & Class A those considered Schedule 1 (CD Lic POM) – less relevant
most harmful – ecstasy,
C LSD, diamorphine § Virtually no therapeutic use
§ So how can these be used in medicine? (Heroin) § No requirements
Class B includes
§ The Misuse of Drugs Regulations 2001 – stipulates cannabis, § Social problems through misuse
how CDs may be prescribed, handled, stored and amphetemines,
§ A license is required from Home Secretary to produce,
methylphenidate &
supplied by pharmacists. pholcodeine possess or supply.
With classes Class C painkillers, GHB
With schedules (Penalty for
possession Examples include LSD, ecstasy and cannabis e.g., Sativex is an exception to the
(Medicinal use)
or supply) rules and does not require a licence, it is a schedule 4 drug
Schedule 2 (CD POM) Substance Misuse Schedule 3Pharmacy

(CDPractice
No Reg POM) 1
§ Strict control § Reduced control e.g., no record keeping in register

§ Invoices, however, must be retained
§ Drugs of great therapeutic value
§ Witnessed destruction not legal requirement but good practice
§ All sch 2s are subject to full prescription control, safe
custody, witnessed destruction and record keeping § Most sch 3s require prescription requirements and safe custody
(except midazolam, tramadol, pregabalin and gabapentin)
Examples opiates, major stimulants -amphetamines. Ketamine

Examples: temazepam, buprenorphine, midazolam, phenobarbitone
products for medicinal use, epidyolex(cannabis oil)
Recent additions (October 2018): Pregabalin and gabapentin
Schedule 4 (CD Benz POM) and Schedule 5

(CD Anab POM)
§ Few restrictions Substance Misuse (CD InvPharmacy
POM or CD Inv P)
Practice 1
§ No safe custody, witnessed destruction or prescription § Only requirement is that invoices must be
Substance Misuse Pharmacy Practice 1
requirements but validity of prescription is 28 days (true for retained for 2 years
schedules 2,3 & 4)
§ Good practice – 30 days clinical needed for supplement (true § Dilute preparations of schedule 2 drugs
for schedules 2,3 & 4) – chosen due to being enough for § Prescription validity 6 months
getting patients through where if we have more in stock =
more awareness from public which can enhance addiction? § Some available OTC
Examples CD Benz- most benzodiazepines and sativex

CD Anab – anabolic and androgenic steroids plus growth hormones Sativex
(cannabis oil spray) – less likely to find them Examples codeine, pholcoldine & low strength morphine
Prescribing drugs to help with addiction Substance Misuse CD prescription requirements

1
Schedule 2 & 3 CDs
Pharmacy Practice
• Diamorphine (heroin), dipipanone, Cocaine

– Can only be prescribed in addiction by prescribers who have Prescription requirements
a special home office licence (BNF guidance on prescribing, • Prescriptions for Controlled Drugs that are subject to
controlled drugs and drug dependence) prescription requirements must be indelible, and must
• Substitute prescribing (in which both are opioids) be signed by the prescriber, be dated, and specify the
Methadone, buprenorphine (BNF section 4.10.3) prescriber's address. The prescription must always state:
CD prescription requirements
CD prescription requirements Schedule 2 & 3 CDs
Prescription requirements Important to avoid forgery
Schedule 2&3 CDs The prescription must always state
in prescriptions
Prescription requirements (continued) The total quantity in words and figures
The prescription must always state • for liquids, the total volume in millilitres (in both words and
• the name and address of the patient; figures) of the preparation to be supplied; for dosage units, the
number (in both words and figures) of dosage units to be
• in the case of a preparation, the form and where appropriate
supplied; in any other case, the total quantity (in both words
the strength of the preparation;
and figures) of the Controlled Drug to be supplied;
30
CD prescription requirements What a pharmacist must check

Schedule 2 & 3 CDs before dispensing a CD (2 & 3)
Prescription requirements • The prescription complies with the requirements as
The prescription must always state set out above
• the dose; (‘as directed’/’when required’ not acceptable • The pharmacist must know the prescriber's signature
but ‘one as directed’/’one when required’ is) and have no reason to suspect a forgery OR the
• the words ‘for dental treatment only’ if issued by a pharmacist has taken reasonably sufficient steps to
dentist. satisfy himself that it is genuine
NHS CD prescriptions
Substance Misuse
Pharmacist’s checks continued….
Pharmacy Practice 1
§ Within 28 days of appropriate date – (2,3 & 4) – this
Substance Misuse ‘Normal’ NHSPharmacy Practice 1
includes any owings
prescription –
§ Marked, at the time of supply, with the date on which the send by the end
drug was supplied (2&3) of each month,
§ Not over 30 days supply – recommended (2, 3 & 4) can have CD
written on it
§ The prescriber's address is in the UK
Private CD prescriptions • With most private prescriptions you don’t

have to send them to the NHS business
Schedule 2 & 3 services agency at the end of each month,
along with the NHS prescriptions.
Substance Misuse
• However, with private controlled drug Pharmacy Practice
Specialised
Substance Misuse
form, which, prescriptions for schedules 2 & 3 you do 1
Pharmacy Practice
unlike private have to send them in – this is to keep a Technical errors on schedules 2&3 drugs
prescriptions for register to see what prescribers are A pharmacist can supply a prescription if:
Non-CDs is sent actually prescribing. § The drug is spelt wrongly
to the NHSBSA § Either the words or figures (but not both) of the total
at the end of quantity is missing
each month 6-digit number which identifies that
the prescriber is legally eligible to PROVIDED:
prescribe CDs as not all are eligible Prescription is genuine & supply is made according to
e.g., those who have sanction prescriber’s intention.
Amendments are made in ink and pharmacist dates and
signs prescription
If there’s no age,
then assume
Mrs M Smith
Mrs M Smith
5 West road
5 West road
they’re over 12 Mediton Mediton
456789
456789
• Spelling incorrect
Morphagesic 60mg SR
Capsules (Morphgesic) – pharmacist Zolpidem Tablets
¨CD Benz POM (Schedule 4)
can still dispense 28
One at night ¨Strength required
One twice a day
• Words and figures – ¨Only valid for 28 days
60 pharmacist can add if one
¨Check signature
missing – not both
N Chance N Chance
Dr N. Chance 567483
12/10/2020
• Check signature Dr N. Chance 567483
11/10/2020
The Surgery The Surgery
High Street High Street
Mediton Mediton
01942 768554 01942 768554
I.Makewell M.B. Ch. B. MRCGP

Substance Misuse
The Surgery • Prescription
Pharmacy Practice form OK – Substance Misuse
1
Pharmacy
Mrs M Smith
5 West road
Practice 1
Acacia Place
Mediton
Schedule 4, – allowed to be Mediton
456789
prescribed in private ¨Which strength

Rx
prescriptions (also 3) MST tablets
1 twice a day
100 one hundred
Diazepam 5mg Tablets • No Town ¨High quantity
• Should be for 30 days or
One to be taken three times a day
120
less supply – good practice ¨Check signature
I. Makewell – not illegal
• Check signature & identity N Chance 12/10/2020
12/10/2020 Dr N. Chance 675982

The Surgery
High Street
Mediton
Mr Wilber Force 01942 768554
15 West Street
Substance Misuse Pharmacy Practice

31
Collection of Dispensed Sch 2 CDs

• Good practice for person
• Need to establish if it is the patient, the patient’s collecting Sch2 & Sch3 CD to
representative or a health care professional collecting. sign space on reverse of
• Proof of identity not always required prescription form
• Can still supply if not signed
• If proof not established, the pharmacist decides whether to subject to professional
supply a controlled drug judgement of pharmacist
• Where the person collecting is a health care professional, the • Representative can sign (can
ask for ID)
pharmacist must also obtain their name and address.
• Signing the back of the prescription
Substance Misuse Controlled Drug

Pharmacy PracticeRegisters must 1
Substance Misuse CD REGISTERS Pharmacy Practice 1
• Be chronological Drug Class________________________ Brand_____________________________ Strength______________
Form_____________________________
• Be made on the day of the transaction or the

Date Obtained Supplied Balance
Name & Amount Name & Authority to Person collecting Was proof of Was proof of Amount
address of obtained address of possess – Sch 2 CD & if identity identity of person supplied
person or firm person or firm prescriber or healthcare requested of collecting
next day
from whom supplied licence professional, patient/patient’s provided?
obtained holder details name & address rep? (Yes/No)
(Yes/No)
• NOT be cancelled, obliterated or altered but

corrected by dated marginal notes or footnotes
on the page
• Corrections must be in ink or indelible, signed
and named
• Can be electronic
• Have a running balance

Substance MisuseDrug Class__M o rp h in e__________ Pharmacy Practice
Brand____________M ST ___________ Strength__1 0m g ____ 1
Form______T a b l ets ______________
Date Obtained Supplied Balance

Name & Amount Name & address of Authority to Person Was proof of Wss proof of Amount
address of obtained person or firm possess – collecting Sch identity identity of supplied
person or firm
from whom
obtained
supplied prescriber or
licence holder
details
2 CD & if
healthcare
professional,
requested of
patient/patient’s
rep?
person
collecting
provided?
Is what’s
left in stock
Instalment prescribing
name & (Yes/No) (Yes/No)
address
1 / 1 0/ 1 5 AAB 60 --------- -------------- --------------- -------------- -------- 60
w h o l es a l ers
l td ,
B rig h to n
R oad,
Lo n d o n
4 / 1 0/ 1 5 M rs J o a n N HS Pa tien t Y es Y es 30 30
Sm ith Pres crip tio n ( p a s s p o rt)
1 2 D en ew a y Dr H .
Pa l o o o k a v il l e Sh ip m a n
1 23231
Control of daily supply Dispensing MDA prescriptions

Instalment
Substance •Misuse Prescriptions
Pharmacy Practice 1
• Valid 28 days from date / start date
– Allow daily supply of substitute
• Sign and ID on first visit – representative could collect
– Lives are already chaotic
with prior agreement and letter for each collection
– Avoids temptation to overdose on first day
• Supervised consumption • Dispensing fee for each collection (If patient pays it’s
– Greater levels of control as the patient take it Infront of the Ph.
only one prescription charge costing a pound)
• Should write a contract between the pharmacy and the On the left is the
main prescription
service user e.g., methadone has a 24-hour half-life,
privacy as it’s tempting to take the drug Infront of a que
Relationship with prescriber Substance Misuse Pharmacy Practice
• Most people on substitution programs will be under the

care of a substance misuse clinic
• Should have a good relationship with their ‘key worker’
32
How instalment prescriptions work
Request to
supply on a Record of
particular date daily supply
and the
amount
ce Misuse Pharmacy Practice 1

Single missed doses
• Problem, particularly as it normally happens at weekends or bank holidays.
Recording supply • Best to have agreement beforehand
• Prescribers can put a specified form of words to help in this situation.
• Many pharmacies have a separate CD register for
substitution therapy. Multiple missed doses
• Must be done on day of supply or the next day. • Missing a single dose quite frequently
– May be a good reason
– May indicate chaotic lifestyle
– Contact key worker
• Missing multiple days at a time
– Danger that opiate tolerance will reduce, so when previous dose resumes it may
be toxic (dose might be effective today, next time won’t = needs a higher dose)
– Contact key worker
e Misuse Pharmacy Practice 1
33
L6) Substance Misuse Pathophysiology, Treatment & Pharmacology Pt.1:

Introduction Tolerance
• The recurrent use of –illegal- drugs and substances for
the purposes not indicated within the legal and medical occurs when a
guidelines is termed as substance misuse
• In England and Wales in 2021:
substance gradually
• Approximately 1 in 11 adults (9.4%) aged 16 to 59 years loses its effectiveness
had taken a drug (3.2 million people)
• From the 4,859 drug poisoning deaths, 3,060 were over time. This means
identified as drug misuse (63% of drug poisonings)
• Over half of all adults (51%) received treatment for that a person needs a
problems with opiates. A further 21% had problems
with other drugs, and over a quarter (28%) had higher dosage to
problems with alcohol only.
• We will apply our physiology principles about the brain’s experience the same
reward circuit to understand the pathophysiology of
substance misuse and accordingly understanding the effects.
rational of therapeutic strategies
1
Tolerance
• Drugs of abuse may elicit certain forms of synaptic
plasticity (LTP) in specific circuits while simultaneously
impairing plasticity (LTD) in other circuits
• The term tolerance is sometimes used rather loosely to
refer either to very short or long-term loss of agonist
efficacy
• Tolerance is mainly attributed to LTD –within the reward
circuit-
• Preclinical studies have shown that acute tolerance can
be observed rapidly (seconds to minutes) during the
course of a single episode of opioid intoxication
• Long-term tolerance is more substantial, and it emerges
after days to weeks of substance misuse
• Tolerance results from adaptive mechanisms at the level
of the drug target receptors (desensitisation and/or
internalisation), as well as at the cellular, synaptic and
network levels (downregulation of signalling
components)
• Adaptations due to homeostatic mechanisms tend to
restore normal function in spite of the continued
perturbations produced agonist 1
- In downregulation, when the cell is targeted by a drug e.g., agonists on the endogenous
ligand e.g., Dopamine or Adrenaline etc. potentiating its action it’ll reduce the receptors
or keeps them but if that’s the case those receptors are not sending the instruction to
the cell where both of these will return the cell back to a normal condition and it will
cause a short term over excitation where with time it’ll go back to normal therefore the
dose might be increased. It can also desensitise the signal.
- In upregulation, the antagonist will start to compete with the endogenous ligands
increasing amount of the receptors or bind to lots of the G-protein coupled receptor
(sensitisation) making the cell more sensitive to a normal binding bringing it back to
normal condition in which the body is assuming that where it’s still pathological
therefore this is why the dose of antagonist needs to be increased e.g., beta blockers
34
and CCB to supress it. When we block them, the cell will misunderstand that not all
receptors are functioning hence adds more receptors to bring itself back to normal
condition therefore will increase the number of signals.
Dependence and addiction (not always =) Dependence on opioids =

addiction unlike other drugs
• Dependence: compulsive craving that develops as a result of
repeated administration of a substance of misuse mainly due to
the positive reinforcing action (reward)
• Drug addiction: an uncontrolled craving for a substance and is
manifested in drug-seeking behaviours
• The most well-established key site of action of addictive drugs is
the mesocorticolimbic dopamine system
• Plasticity of VTA dopaminergic synapses plays an important role

in mediating behavioural consequences
• Substance misuse is mainly attributed to two main factors:
1. Positive reinforcement (reward circuit)
2. Avoiding negative effects (withdrawal)
• Dependence and addiction are associated with tolerance
1
Drug-related harms
qDespite causing positive reinforcement, substance
misuse can lead to a wide range of drug-related
harms:
• Damaging quality of life (social impact)
• Liver damage
• Neuropathy/neurotoxicity
• Respiratory complications
• Cardiovascular complications
• Infection
• Money and the associated criminal risk (survival)
ü That is why, it is very important to treat substance
misuse
1
Receptor/signalling
The principle component

activation
Time LTD
Short- Long-
term term
Primary targeted Negative-

Misused receptor/signalling Positive-
reinforcement
substance cascade component reinforcement
(withdrawal
will either be: (reward)
syndrome)
Excitation Downregulation
Short- Long-
term term
Receptor/signalling
component Time LTP
blockade/inhibition
1
35
Alcohol ethanol: pathophysiology

• Ethanol mainly acts via activating GABA
receptors
• Activating GABA receptors lead to overall
inhibitory effect including inhibiting
GABAergic neurons
• Inhibiting GABAergic neurons lead to less
GABA production
• Less GABA production means less inhibition to
dopaminergic neurons (Disinhibition:
inhibiting the inhibitory pathway)
• Therefore, increase dopaminergic neuron
excitation
• Ethanol leads to synaptic plasticity for 3 main transmitters in the brain = GABA,
dopaminergic and GABAergic neurons dopamine & glutamate
• Tolerance is induced Each neuron have different receptors where
GABA, dopamine & glutamate receptors are
• Dependence and addiction start found on all neurons mentioned
GABA
GABA/Alcohol
inhibits GABA
release
Short-term effect
R (Disinhibition) GABA
BA inhibits
GA DA
GABA GABA release
GABAergic neuron
R
BA
EtOH can GA
induce DA
release
Et DA
DA DA
OH
Dopaminergic neuron
DA
DA
DA
DA 1
Reward pathway
- When we intake Ethanol it’ll release Dopamine where if Dopamine is

released from the neuron, it exerts an action (e.g., happiness) and at the
same time will bind to its Dopamine receptor on GABA neurons to stimulate
it to release GABA and find a receptor on Dopamine neuron as it’s inhibitory
it will inhibit Dopamine release hence won't be euphoric due to shutting
down the system hence still in balance.
- But with Ethanol, its main action is activating GABA receptors hence will go
all the way to bind to GABA receptors and facilitate the autoregulation of
GABA back to its GABA receptor hence GABA will inhibit GABA neurons
causing disinhibition of the pathway as GABA is inhibitory therefore no
36
more GABA release therefore lots of Dopamine will be released hence why
we have more Dopamine when using alcohol.
- Glutamate has GABA receptors; hence one GABA is stimulated so no more
release of it due to its receptor not being activated then Glutamate is
released where activation of the receptor will lead to downregulation due
to the neurons being constantly activated hence low amount of receptors
due to Ethanol therefore the patient need to take Ethanol, or if they’re left
with GABA as high levels of it activate GABA receptors directly but we still
have basal GABA receptors hence the patient will still be taking Ethanol to
suffice the crave of withdrawal symptoms (this is what happens when GABA
is inhibited as it binds to its own receptor leading to lots of Dopamine out).
What is the problem with alcohol misuse?
Euphoria
Caused by (positive
alcohol and no reinforcement)
GABA released
Disinhibition Time
(chronic)
DA
v Potentiated dopamine and Dependence

More drug needed ↓ GABAAR on
glutamate and
(to compensate) dopamine glutamate
v The depressed GABA Addiction
↑ Boost GABA neurons (LTD)
receptors are not able to or/and Leading to
inhibit the dopaminergic and ↓ Dopamine and ↑ Dopaminergic and
glutamatergic neurons Stopping the drug? glutamate glutamate pathways
v Psychosis, hallucination and ü Tolerance (LTP)
seizures develop due to
excess release of glutamate
v (Withdrawal symptoms) High doses/combining different substances 1
- GABA receptors are activated by alcohol and by the time we keep activating
them the number of receptors will go down (downregulation) on the
amount of Dopamine in the neuron hence the neuron will be inhibited
where if we stop taking Ethanol and because it already downregulated the
GABA receptors on Dopamine neurons – this will lead to Dopamine not
being inhibited as it used to and be excessively released leading to
psychosis and same happens with Glutamate leading to seizures after long
term of addiction with Alcohol. So, to overcome it, the dose will be
37
increased, or another drug is added like an opioid to fill the gap to activate
the residual amount of GABA receptors.
Withdrawal effect – in alcoholism - Due to excessive

glutamate production
• Withdrawal effects are mainly attributed to synaptic plasticity
• In alcohol syndrome, GABAergic receptors on dopaminergic and
glutamatergic neurons are directly activated by high dose of
alcohol, this –initially- leads to supressing dopamine and
glutamate release
• Accordingly, LTP occurs in these supressed neuronal synapses
• Prolonged alcohol use leads to the development of tolerance
and physical dependence, which may result from compensatory
functional changes by downregulation of GABA receptors and
increased expression of NMDA receptors with production of
more glutamate to maintain central nervous system transmitter
homeostasis
• Therefore, alcohol is administered to calm and counteract the
overexcited excitatory neurons
• However, in the absence of alcohol, withdrawal effects evolve by
overstimulated potentiated and overstimulated dopaminergic
and glutamatergic neurons leading to a wide range of symptoms
such as delirium and seizures due to excitation of motor nerves 1
Major alcohol-related harms Ethanol is converted by ALDH

to acetaldehyde that is
• Liver damage - Accumulated acetaldehyde leads to: converted to acetate that is
1. Increase fatty acid and lipogenesis and hence fatty liver released to the blood going to
2. The formation of free radicals and reactive oxygen species such as H2O2 that tissues and muscles and is
induce Ang II synthesis increasing BP hence develop it and hence the production of converted to CO2 and H2O
pro-inflammatory mediator leading to liver fibrosis (Cirrhosis) where acetaldehyde stimulate
• Respiratory depression: potentiating and mimicking GABA action leading to lots of reactions like Ang II
inhibitory effects on respiratory centres and hence respiratory failure
• Cardiovascular complications: causing hypertension, stroke, arrhythmia,
cardiomyopathy and cardiac hypertrophy
• Nervous system: depressing the vital centres in the central nervous system.
Additionally, Alcohol and its metabolite acetaldehyde are neurotoxic, and associated
with nutritional deficiencies such as thiamine deficiency that leads to Wernicke’s
encephalopathy (mental confusion, paralysis of the nerves that move the eyes:
oculomotor disturbances and ataxia) and Korsakoff’s psychosis (behavioural
abnormalities and memory impairments) [Wernicke–Korsakoff syndrome], as well as
cerebellar degeneration
• Infection: Alcohol reduces key pulmonary defences against infection such as
reducing mucociliary clearance of the respiratory system where the cilia will be
disrupted hence induce cough when particles are inhaled triggering a nerve in the
medulla, macrophage mobilisation, killing and clearance; and phospholipid
metabolism
- In the nervous system, Ethanol causes vitamin B1 deficiency by either inhibiting the
absorption from the GIT or inhibiting the transporter from the GIT to the blood or
inhibiting the utilisation/the reuptake of B1 from the circulation to the tissue or
inhibiting the utilisation within the tissue so vitamin B1 will not be processed.
38
- Vitamin B1 is not synthesised within the body where the main source of vitamin
B1/thiamine is by ingestion, by food. So, if someone is in a chronic ethanol, they will
experience vitamin B1 deficiency.
Alcohol ethanol: treatment and pharmacology

• Disulfiram – used for alcohol misuse: Irreversible inactivation of liver ALDH and hence
increasing acetaldehyde concentration leading to disulfiram-alcohol reaction (DAR) in
addition to inhibiting tissues’ (cardiovascular) dopamine-beta-hydroxylase (which
converts dopamine and noradrenaline) thereby reducing alcohol-induced cardiovascular
complications. Causes N&V hence alcohol is avoided due to acetaldehyde accumulation.
• Acamprosate: similar structure to that of amino acid neuromediators, such as GABA
(without WD symptoms). It stimulates GABAergic inhibitory neurotransmission and
antagonising excitatory amino-acids, particularly glutamate where it behaves like ethanol.
• Naltrexone: Long-acting specific opioid antagonist. It is a non-aversive therapy and does
not cause reactions when alcohol is ingested, therefore not causing disulfiram-like
reaction. It reduces the risk of a full relapse after having consumed a limited amount of
alcohol (due to blocking the narcotic receptors that induce euphoria). Naltrexone
hydrochloride reduces the desire for alcohol (“craving”) during abstinence and after
alcohol ingestion.
• Benzodiazepines (to reduce withdrawal effect, only in emergencies): increases the
inhibitory effects of GABA, hence reducing neuronal excitability.
• Thiamine (B1 vitamins) why? To top up the vitamin B1 treating vitamin B1 deficiency
caused by alcohol reducing neurotoxicity.
1
Actions of disulfiram Disulphiram acts to inhibits the
conversion of acetaldehyde into acetate.
Aldehyde dehydrogenase (ALDH)
H2O
Acetald
EtOH Acetate +
Alcohol dehydrogenase (ADH) ehyde Aldehyde dehydrogenase (ALDH) In other tissue
CO2
Phenylalanine Tyrosine
Hydroxylase Hydroxylase
L-Dopa
Aromatic amino
L-Phenylalanine L-Tyrosine DA β-hydroxylase acid (Dopa)
decarboxylase
DA β-
PNMT hydroxylase
Adrenaline Noradrenaline Dopamine

1
y.shamsaldeen@brighton.ac.uk
Methanol
Alcohol: methanol
• Methanol exerts similar CNS actions as ADH
Fomepizole
ADH
ethanol but is a cheap quality alcohol
• Methanol exerts major health problem
due to the metabolic product
formaldehyde Formaldehyde
• Formaldehyde is toxic to the retinal and AL
optic nerve causing permanent/complete DH
blindness by giving a 10g of methanol
• Treatment of methanol toxicity involves
either: Formic acid
1. Ethanol Vit.
B9
2. Fomepizole: inhibitor of ADH/alcohol
dehydrogenase (in emergencies) CO2 + H2O 1
39
BDZ and BARBs: pathophysiology

• Benzodiazepines (BDZ) and barbiturates (BARBs) are sedative and
hypnotic agents and CNS depressants
• Benzodiazepines such as diazepam are prescribed for management of
anxiety (anxiolytics), insomnia (and what?)
• Barbiturates such as phenobarbital are used for the management of
severe epilepsy
• In addition to euphoric feeling, anxiolytic and tension-reducing properties
are the main contributors for self-administration and misuse that may
lead to lethal intoxication
• BDZ and BARBs are GABAergic drugs
• Chronic use can induce of GABAergic pathways (plasticity) leading to
tolerance and withdrawal symptoms
• BDZ are less likely to cause death, however, co-administration with other
CNS suppressants such as alcohol may increase mortality incidence
• Z-drugs: Zolpidem, zopiclone, and zaleplon are non-BDZ: similar
mechanism and different structure 1
- Activates GABA receptors leading to disinhibition inhibiting the release of

GABA itself hence Dopamine neuron won't be inhibited therefore lots of
Dopamine and Glutamate therefore the person will feel euphoric. So, by
time the GABA receptors on the Dopamine and Glutamate will go down as
they keep being activated therefore once the person stops misusing this
drug there will be lots of Dopamine and Glutamate leading to seizures and
epilepsy and all the psychotic effects.
Combined with alcohol

What is the problem with BDZ misuse? opens GABA receptors
increasing risk of respiratory
Euphoria depression and death
(positive
reinforcement)
Disinhibition Time
(chronic)
DA
Dependence
v Potentiated dopamine and More drug needed ↓ GABAAR on
and
glutamate (to compensate) dopamine &
Addiction
v The depressed GABA ↑ Boost GABA glutamate neurons
receptors are not able to or/and (LTD)
inhibit the dopaminergic and ↓ Dopamine and Leading to
Stopping the drug? glutamate
glutamatergic neurons ↑ Dopaminergic and
v Psychosis, hallucination and ü Tolerance glutamate pathways
seizures develop (LTP)
40
There is no disulphiram-like drug for benzodiazepines to

treat misuse hence symptomatic treatment.
BDZ: treatment and pharmacology
• There is no MHRA, EMA or FDA-
Fluma
approved treatment for BDZ misuse zenil
(October, 2022)
• Supportive therapies might be

implemented such as
1. Behavioural therapy
2. Inpatient and outpatient treatments Acts as an antagonist
• Flumazenil is an antidote for BDZ
toxicity AR
BDZ GABA
BA
• Flumazenil acts as an BDZ receptors GA
GABA
antagonist that is used to treat BDZ
Inhibitory effect
overdose but not approved for
substance misuse therapy Neuron
1
Gabapentin & Pregabalin: pathophysiology

• Gabapentin and pregabalin bind at α2δ (delta) subunit-specific
voltage-gated (VGA) calcium channels blocking them in the CNS and
hence reducing the excitation of nerve cells as there’s no firing AP
leading to euphoria, relaxation and calmness due to upregulation
• α2δ-2 distribution of was found to correlate partially with
GABAergic neurons
• Gabapentin and pregabalin are believed to inhibit GABA release
(disinhibition) & glutamate and increase dopamine (= happiness).
After time, GABA receptors will increase/be up-regulated on
dopamine and lots of GABA will be released leading to dopamine
inhibition therefore depression and on GABA itself million channels
hence lots of AP increasing GABA
• Gabapentin and pregabalin increase the euphoric and some
harmful effects of other drugs: opioids
• The Home Office has placed pregabalin and gabapentin to Schedule
3 of the Misuse of Drug Regulations 2001 since 1 April 2019 1
- In order to activate any neuron, we need to fire an AP leading to influx of calcium

leading to release of neurotransmitters where there are special types of calcium
channels of special subunits called Alpha-2 delta that have gates that regulates the
function of calcium channels where these drugs will block the calcium channel.
- Generally, Glutamate will tense the muscles exciting them & GABA inhibits where both
have the same calcium channel unlike Dopamine which doesn’t have this channel as
much as the others hence when it’s inhibited, we have less GABA & Glutamate release
as no calcium is going in and no vesicles therefore when people take these drugs they
feel their muscles relaxed and at the same time we inhibit GABA we are freeing
Dopamine from the inhibitory effect hence lots of Dopamine is getting out therefore
when it’s misused the person receives an euphoric effect.
41
- By the time when the person stops taking them there’s no inhibitory effect hence lots of
calcium channels in the GABA hence lots of GABA released inhibiting Dopamine leading
to severe depression. Same with Glutamate where the Glutamate neuron will lead to
lots of Glutamate released due to lots of calcium expressed leading to seizures.
What is the problem with Gabapentin and

pregabalin misuse? Euphoria
(positive
Disinhibition reinforcement)
+ Time
glutamate (chronic)
inhibition
DA
Dependence
v Potentiated GABA & More drug needed
and
glutamate (to compensate)
Addiction ↑ GABA and Glutamate
v Lead to depressing ↓ GABA & glutamate
calcium channels
dopamine (by GABA) and or/and
(LTP) increasing its
exciting glutamatergic ↑ Dopamine and
Stopping the drug? influx into the neuron
neurons glutamate
v Depression, anxiety and ü Tolerance
seizures develop
Gabapentin and pregabalin: treatment and

pharmacology
• There is no MHRA, EMA or
FDA-approved treatment for
amphetamine misuse (October, 2022)
implemented such as
2. Inpatient and outpatient
treatments (symptomatic)
Marijuana or cannabis: pathophysiology

• Endocannabinoids are neurotransmitters that can indirectly
y.shamsaldeen@brighton.ac.uk 1
affect dopamine signals by modifying the activity of other

neurotransmitters such as GABA
• These molecules bind to cannabinoid receptors (type 1) on the
adjacent GABA neuron reducing the amount of GABA it releases
(disinhibition) due to no action potential firing
• Inhibiting GABA neurons in this way boost the dopamine signal
in the reward synapse hence are euphoric (eye contact found but
the mind is somewhere else due to being not conscious)
• Endocannabinoid and other mechanisms that regulate dopamine
activity help the brain develop, learn, adapt, and navigate a
complex world.
1
42
- CB1 = cannabinoid type 1 receptor where it works by causing an efflux of potassium ions
inhibiting the action potential where if we activate GABA neuron, GABA won’t be
released as there’s no AP firing, same with Glutamate. Therefore, those who misuse it
are euphoric due to no GABA release and to Dopamine being very high where they have
their mind somewhere else despite direct eye contact due to Glutamate not being
released hence they’re not conscious whereby time, we have less CB1 due to it being
constantly activated.
- Stopping taking it (CB) = continuously fire AP = lots of GABA released shutting down
Dopamine leading to depression = lots of Glutamate release due to receptor
deactivation leading to seizures and convulsions by affecting motor neurons.
Inhibiting glutamate is the

What is the problem with marijuana use? reason why lots of drugs are
used for epilepsy as it’s a
Euphoria genetic marijuana derivative
hence inhibiting only the
(positive
Of GABA glutamate and not GABA
reinforcement)
Disinhibition
+ Time
glutamate (chronic)
inhibition DA
Dependence
More drug needed
and
v Potentiated GABA and (to compensate)
Addiction By the time
glutamate pathways ↑ CB pathway
v The depressed dopamine activation
release ↓ GABA neurons ↓ CB1 receptor (LTD)
Stopping the drug? ↓ Glutamate release ↑ GABA release
v Depression, anxiety, seizures
vivid dreams develop ↑ Dopamine ↑ Glutamate release
v (Withdrawal symptoms) ↓Dopamine release
High doses/combining different substances 1
Cannabis: treatment and pharmacology

cannabis (marijuana) misuse
(October, 2022)

implemented such as
treatments
43
L7) Situational Diagnostic Tests (Related to the New Driving Laws):

“Driving Under the Influence” Laws UK Drug Driving: Testing
• The first drink driving law arrived in 1872 and another in • It is illegal to drive if you:
1925 – Are either unfit to do so because you’re on legal or illegal
• Road Traffic Act 1962, provided for the first-time analytical drugs
tests on the presence of alcohol in bodily fluids – Have certain amounts of illegal drugs in your blood (even if
• Road Safety Act 1967 made it illegal to drive or be in charge they haven’t affected your driving)
of a vehicle after consuming so much alcohol that the – Legal drugs are prescription or over-the-counter (OTC)
proportion of it in the blood, breath, or urine exceeds the medicines. If you are not sure if you should drive, talk to any
'prescribed limit'. The prescribed limits were set at: healthcare professional
– 35 mg of alcohol in 100 ml of breath – The police can stop you and make you do a ‘field impairment
– 80 mg of alcohol in 100 ml of blood assessment’ (sobriety test) if they think you are on drugs.
They can also use a roadside drug kit (roadside chemical test)
– 107 mg of alcohol in 100 ml of urine to screen for cannabis and cocaine (and others)
• The Crime and Courts Act 2013 created a new limits-based – If they think you are unfit to drive because of taking drugs,
offence of drug-driving by inserting a new section 5A in the you will be arrested and will have to take a blood or urine test
Road Traffic Act 1988. Under the Act, a driver can be at a police station
convicted if the amount of drug proportion of the drug in – You could be charged with a crime if the test shows you’ve
their blood or urine exceeds the specified limit taken drugs
PY365 – Advanced Pharmacy 1 1

PY365 3.3 Substance Misuse
– Advanced Pharmacy 1 “Drug Driving”
In 2012, the UK government announced a new offence in regard to driving with
“Drug Driving” a specific controlled drug in the body above that drug’s accepted limit.
Following a report from a panel of experts and a consultation the government
standpoint is:
In 2012, the UK government announced a new offence in regard to driving with a specific q a zero-tolerance approach to 8 illegal drugs
controlled drug in the body above that drug’s accepted limit.
Following a report from a panel of experts and a consultation the government standpoint
q a road safety risk-based approach to 8 drugs for medical uses
is: In 2019 any reference to q a separate approach to amphetamine that balances its legitimate use for
q a zero tolerance approach to 8 illegal drugs medical purposes against its abuse
q “roadside tests”
a road safety risk only refers
based approach tofor–medical
to 8 drugs ROADSIDE
uses CHEMICAL
q TESTING (RCT)toand
a separate approach not simply
amphetamine the itsantiquated
that balances sobriety
legitimate use for medical In March 2014 Road Safety Minister - Robert Goodwill said:
purposes against its abuse
tests (STs)
“The results of the consultation is sending the strongest possible message that
RCTRoad
In March 2014 tests areMinister
Safety often based
- Robert on specific
Goodwill said: antibodies or
you cannot take illegal drugs and drive. This new offence will make our roads
electrochemical methods
“The results of the consultation is sending the strongest possible message that you safer for everyone by making it easier for the police to tackle those who drive
cannot take illegal drugs and STsdrive.
are This
used newtooffence
support RCTour roads safer for
will make after taking illegal drugs. It will also clarify the limits for those who take
everyone by making it easier for the police to tackle those who drive after taking illegal medication.”
drugs. It will also clarify the limits for those who take medication.”
Drug Driving Guidelines
The “New” Drug Driving Regulations PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1
Table of drugs and limits
The recommended limits for 16 different drugs have now Amounts of dosage would equate to being over the specified limits are not
been approved following 2 government consultations indicated but healthcare professionals should be able to advise (There are too
many variables, such as physical characteristics, where each person will
On 2 March 2015, 8 generally prescription and 8 illicit drugs metabolise the drug at different rates. Eating or drinking will also have an effect
on the blood concentration)
were added into new regulations that came into force in
England and Wales. Regulations on amphetamine came into Information for healthcare professionals
force on 14 April 2015. The Department for Transport published guidance and reference documents for
healthcare professionals. Their purpose is to make sure people taking
Some Statistics prescription and over-the-counter drugs understand the new offence and their
• Drug driving was a factor in 81 fatal road crashes in the UK in responsibility not to drive whilst impaired
2016 alone with cocaine and cannabis featuring most Road Traffic Act 1988
prominently The illicit drug limits are as follows:-
Ref: https://www.gov.uk/government/collections/drug-driving
• 2015-2018 in the UK there were 8300 cases of arrests for q Benzoylecgonine (Cocaine metabolite), >
cocaine drug-driving 50 µg/L
PY365 – Advanced Pharmacy 1 and 3000 arrests for cannabis drug- Misuse
3.3 Substance 1
driving – based on RCT q Cocaine, > 10 µg/L
q Delta–9–Tetrahydrocannabinol (Cannabis Pupil dilation
DRUG-DRIVING IN ENGLAND & WALES PY365 – Advanced and Cannabinol),
Pharmacy 1> 2 µg/L 3.3 Substance Misuse 1
9000
10,200
q Ketamine, > 20 µg/L
8000 q Lysergic Acid Diethylamide (LSD), > 1 µg/L
Positive drug tests
7000
q Methylamphetamine, > 10 µg/L
q Methylenedioxymethaphetamine “Drunk” test
(MDMA – Ecstasy), > 10 µg/L
900
q 6-Monoacetylmorphine (6-MAM –
2015-2016 2016-2017
Year
2017-2018 2018- (Jan to August)
Heroin and Morphine), > 5 µg/L

44
Road Traffic Act 1988 Drug Detection

The general prescription drug limits are as follows:- RCT: Cocaine detected in sweat and saliva using a low-cost chip and surface-
q Clonazepam (e.g., Rivotril), > 50 µg/L enhanced Raman spectroscopy (SERS). Detection <25ng/mL
q Diazepam (e.g., Valium), > 550 µg/L Gao J et al (2018) Small Methods, May 2018: at https://doi.org/10.1002/smtd.201800045
q Flunitrazepam (e.g., Rohypnol), > 300 µg/L
q Lorazepam (e.g., Ativan), > 100 µg/L
q Methadone (e.g., Dolophine) Class A, > 500 µg/L
Tired or taking drugs?
q Morphine (e.g., Mscontin) Class A, > 80 µg/L
q Oxazepam (e.g., Alepam), > 300 µg/L
q Temazepam (e.g., Restoril), > 1000 µg/L
q Amphetamine (e.g.. Adderall) Class B > 250 µg/L and

selegiline (used to alleviate amphetamine) – to be Arrested
discussed with pharmacist as this may influence driving. drugged
Amphetamine – is used to treat ADHD or narcolepsy. driver Article on cocaine detection in sweat: i-Weekend Sat/Sun 23/24 Sept 2017: No. 2132, p28.
PY365 – Advanced Pharmacy 1 Sober or not? 3.3 Substance Misuse 1

Sobriety Tests and RCT
PY365 – Advanced
Chemical Pharmacy
tests are now1 very specific and accurate
3.3 Substance low LOD 1
with aMisuse
Since 2017 sobriety tests linked to quantifiable chemical tests
(RCT) form the basis of legal action. Sobriety plus chemistry
provides a strong argument
q Sobriety tests cover
q Verbal incoherency
q Walk-the-line
q Touch-the-nose
q Stand still, stand on one leg
q Response to posed questions, simple calculations
q Breath test
q Gaze and pupil dilation
UK Drug Driving: Penalties

PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 These form the basis of an inability the handle the vehicle
Ø Behaviour linked to precise chemical concentration
Penalties for drug driving (or working)
• If you’re convicted of drug driving you’ll get:
– A professional FTP ban Drug Driving Law: What
PY365 – Advanced Pharmacy 1
to Expect1
– a minimum 1 year driving ban

– an unlimited fine • The police will use a drug screening device (DSD) to establish
– up to 6 months in prison the presence of drugs. These can test up to 6 drugs in a single
– a criminal record test of a person’s saliva.
– Your driving licence will also show you’ve been convicted for
drug driving. This will last for 11 years.
– The penalty for causing death by dangerous driving under the • 2019: The DSDs are now ~100% accurate and therefore can
influence of drugs is a prison sentence of up to 14 years
be used as evidence in a court case. They have been
• These have devastating consequences on employability
constituted to avoid false readings both positive and negative
Exceptions to Drug Driving Tests and are unaffected by eating and drinking prior to the test
• There are NO LONGER a number of concerns about whether

PY365 – Advanced Pharmacy 1
speeds at which the1
the limits accurately reflect the different Diagnostics – At the Roadside
drug breaks down in the blood No, I just think it’d be Sir, I’d like you to step out of
funny. I can see if your car, stand on one foot,
• Some prescribed drugs could give positive results for illicit Why? Do you
think I’m off you are driving touch your nose, count
backwards from one hundred…
drugs e.g. dexamphetamine which is used to treat ADHD my head?
PY365 – Advanced Pharmacy 1 illegally with my RCT
3.3
andSubstance Misuse
then do this test 1
suffers or Sativex (Therapeutic THC) which is used to treat MS
suffers. Both drugs could give positive results for
amphetamine or cannabis. However, a defence has been
introduced under S5 A(3) Road traffic Act 1988 which states
that if a drug is prescribed for medical or dental reasons and
taken in accordance with any directions by the physician or
dentist and also the manufacturers instructions
“Roadside” tests really mean CHEMICAL or chemistry-based diagnostic tests performed in situ
• NB: The drugs must also be being used legally i.e., not
prescribed to another PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1
45
Diagnostics – At the Roadside Diagnostics – Back at the Station

• SalivaConfirm4®: 4 Drug Screen – Saliva test • 8 Panel Drug Test with Integrated Cup – urine test
Easy-to-read drug test kit that uses saliva for the sample. What is it: This is a multi-drug test kit that has all you need to get result
Evidence of the following illicit drugs at and above the in less than 10 minutes. Testing is carried out using a urine sample.
stated levels: What drugs does it test for: This eight-panel drug test detects the
presence of:
– AMP Amphetamines (>50 ng/ml)
– Amphetamines (Speed)
– COC Cocaine (>20 ng/ml) – Benzodiazepines(Valium)
– MOR Heroin/Opiate/Morphine (>40 ng/ml) – Buprenorphine (Subutex)
– THC (Cannabis >10 ng/ml) – Cannabis (Marijuana)
– Cocaine (Crack)
1 nanogram/ml saliva is the same as 1 part per billion (normal healthy school children
have approx. 5ng/ml Mercury and 130 ng/ml Copper in their saliva) – EDDP (Methadone)
– Metamphetamines (Crystal Meth or Ice)
Police Drugalyser – Opiates (Heroin)
• Police
PY365 havePharmacy
– Advanced been granted
1 new powers 3.3
allowing them
Substance to use a1 PY365 – Advanced Pharmacy 1
Misuse 3.3 Substance Misuse 1
Drugalyser to test drivers for illegal substances. Selected police Portable Police Drugalyser
forces throughout England and Wales will be issued with
cannabis testing kits prior to the introduction of a new drug
• Cannabis
driving law.
• Alcohol
• Heroin
• The new law in March 2015 allowed the police to perform
• Cocaine
roadside drug testing using a roadside oral saliva drug testing
kits called DrugWipe. A positive result will result in the driver
Matrix Diagnostics technology can detect cannabis
being taken to the police station for a blood test. The drugs that 14-20 hours after intake (effects last <5 hours)
will be tested for under the new law include Cannabis, Cocaine,
Ecstasy and Ketamine & Benzodiazepines
Dräger SSK 5000® sampler
• Sampling of drugs
PY365 – Advanced Pharmacy 1 DrugWipe® 3.3 Substance Misuse 1
from surfaces
• The detection limit of the active substance Δ9-THC in saliva is now PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1
10 ng/ml.
• All results remain valid for 10 minutes after the test is completed.
• Easy, quick and hygienic handling with lowest sampling volume and Dräger Drug Test® 5000
colour indicator.
• Cannabis
• DrugWipe® S saliva test is robust. The test cassette is designed for
• Alcohol
a safe transport
• Heroin
• Cocaine
• Ecstasy
• Ketamine
Saliva • Benzodiazepines
Reader device Sweat/skin Surface
Rapid Detection Systems

PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 Test spots
• Range of 6-10 drugs Rapid Detection Systems

Cocaine,
RangePharmacy
PY365 –•Advanced of 6-101 drugs detected3.3 Substance Misuse 1
Amphetamine,
Methamphetamine,
Cannabis,
Methadone,
MDMA (Ecstasy)
Benzodiazepines,
Buphrenorphine
Ketamine
Opiates (Heroin)
Drug identification sampling kit Urine test strips Test strips
PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 46

How Drug Kits Work 1. We deposit some body fluid at the

“Heavy/slow” “Light/quick”
Antibody coated nanobead sample pad.
D
D D
Bank
Migration 2. At the sample pad, there are latex
D
Start line Positive line Control line beads that are tagged with antibodies
• Spectrometry
– Colour evolution based of chromatography (using antibody coated that detect specific drugs.
beads) or multiple redox reactions (similar to pregnancy or ovulation test
kits) 3. When the antibodies detect the
– Use of specific enzymes to promote a response: colour, loss of colour or
produce fluorescence/luminescence
• Electrochemical response
drug, they bind to it, making them
– Based on redox reactions that may involve an enzyme (similar to blood
sugar kits) liberating electrons and producing a measurable current larger and heavier.
4. As a result, they travel slower down the length of the test strip, and you
end up with a positive line.
5. The empty latex beads travel the furthest because they are lighter
(control). Urban Myths
How Drug Kits Work • Sucking a copper coin defeats the alcohol
breathalyser
• If I handled bank notes† there may be traces of
cocaine on them and that’s why its on my skin
• Sucking a mint or menthol sweet or eating food with
vinegar will produce errors on a drugalyser
• If I smoke cannabis tonight it’ll be undetectable
tomorrow
• I could test positive if I have been in a room with
people taking drugs‡
• Drug-driving – RCT kits aren’t accurate anyway!
Health and Safety at Work Act 1974 † Crude testing has indicated that up to 11% of Bank of England notes in circulation in the UK may be
PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 contaminated with traces of cocaine (from the rolling and snorting process). Concentration median
• Duty of care to all employees average <<1.4 µg/note; that’s the same as 0.6 grams (half a paperclip) on an entire football pitch! This
• Inappropriate behaviour becomes an untenable argument.
• Risk ‡ Limits are set that preclude such miniscule concentrations
Shock!
Food for Thought • 2011 urine/saliva data show >3% of tests on range of workers
• Common in the USA for many professions. A typical US employer multi-drug (pharmacists to porters) positive for either illicit drugs (cannabis>
screen of employees will consist of a test for: opiates>cocaine; 2-0.5%) and unreported P/OTC (codeine,
– Amphetamine (AMP) benzodiazepines, etc.). Data set: 1,668,330 drug tests by Concateno labs
– Barbiturates (BAR)(Phenobarbital, Secobarbitol, Butalbital)
on behalf of 856 UK employers over 5-year period
– Benzodiazepines(BZO)(Valium, Xanax, Librium, Serax, Rohypnol) – 2011 volume represents a ~40% increase from a baseline in 2007
– Cocaine (COC)
– Drug tests conducted as random or pre-employment NHS programmes
– Cannabis/Marijuana (THC)
– Methylenedioxymethamphetamine (MDMA)(Ecstasy) • Estimated 1 in 30 employees have drugs in their system at any point in
– Opiates (OPI) time
– Oxycodone (OXY) • Manifestations of this fitness-to-work issue:
– Phencyclidine (PCP) – Death at work
– Propoxyphene (PPX)(Darvon compounds)
– Safety and injuries at work
– Tricyclic Antidepressants (TCA)
– Impaired ability to undertake tasks
• Employers also include the following: Hydrocodone (Lortab, Vicodin),
Methaqualone (Quaaludes), Methadone, Ethanol (Alcohol), Buphrenorphine – Clerical and role-related mistakes: dispensing error
(Subutex) – Pilfering and criminality
47
L8) Public Health Aspects of Harm Reduction:
What is Public Health? History of Public Health

• Public health is the science and art of preventing • 17th to 19th century public health was focused on
disease, prolonging life and promoting health through eliminating infectious disease such as bubonic
the organised efforts of society (Acheson, 1988) plague, smallpox and cholera where the main effort
was to isolate infection people therefore decreasing
spread
• Public health deals with health from the perspective of
• In 19th century, with urbanization, public health
populations, not individuals. became focused on environmental issues such as
sanitation and clean water
• The epidemiological shift during the 20th century saw
more deaths from chronic illness – focus more on
personal health and lifestyle factors
Today we see more recognition of the role
of wider social factors and health
Case 3 – Harm Reduction PY365 Substance Misuse
PY365 Substance Misuse Case 3 – Harm Reduction
disparities

The Bio-Psycho-Social model of health
What does it look like in England? PY365 Substance Misuse Case 3 – Harm Reduction
• Used to be the domain of Public Health England

• Now called the Office for Health Improvement and
Disparities
Their job is to look what are

people dying from

Why is substance misuse a public health issue?

48

Approaches in Public Health
PY365 Substance Misuse Primary isCase 3 – Harm
preventing Reduction
people
• Centre on prevention from starting & using addictive
– Primary substances in the first place,
secondary is preventing people
– Secondary from continuing and tertiary is
– Tertiary preventing unnecessary
harm/suffering & death
• Are multi-disciplinary
– Housing, education, medicine, legal system,
policy..
• Cross the life-span
From prevention to abstinence to
PY365 Substance Misuse Case 3 – Harm Reduction harm reduction
• Primary prevention – stop people from using

addictive substances in the first place
• Abstinence – encourage absolute cessation of
substance use
• Harm reduction – reduce the harm that
people do to themselves or others from their
drug use.
What does it look like in relation to
substance misuse inCase
pharmacy?
3 – Harm Reduction
• Clean needle exchange
What is harm reduction? • Naloxone for overdose
• Counseling in general e.g., in OTC products that are
“Harm reduction refers to policies and practices that try available for all
to reduce the harm that people do to themselves or
others from their drug use. It can be contrasted with • Methadone – done in the pharmacy (involves
primary prevention which tries to prevent people using observation)
drugs in the first place, or to stop them using once • Rehab suggestion/substitution therapy
they’ve started” • Nicotine patches
Main points
• Public health moves from a focus on the individual to
a focus on the population PY365 Substance Misuse Case 3 – Harm Reduction
• Involves multiple systems and approaches
• Prevention at different stages can be successful
49
L9) Public Health Aspects of Harm Reduction - Blood Borne Viruses Including
the Patient Perspective:
- Why do we do harm reduction? Harm reduction focuses on ‘safer’ drug use

and has also been developed as a way of educating young people about
drug use, rather than telling them to ‘Just Say No’. There have been
arguments over the morality of harm reduction where some people say
that it condones or promotes drug use, but people who support it say it is
realistic, helps keep drug users safe and respects individual choices and
freedoms. Harm reduction strategies
Not first goal, as just trying to get
Pharmacy-harm reduction strategies people to detox doesn’t always work
• Needle Exchange – high risk of STDs due to e.g., needle

used between people and prostitution hence it’s a
programme to encourage people reduce transmissions
and spread awareness
• Supervised Consumption (e.g., of opioid treatment)
• Dispensing services - to manage comorbidities e.g.,
mental health and starting a new medication
• Health & Well being advice e.g., bad hygiene
Injection drug use
Harm reduction advice on different qMain goal is to reduce patient need for injection but try
formulations of misused drugs to minimize the use
qInjection drug use and other high-risk behaviours are the
1. Injecting /Case
Slamming /
3 – Harm Reduction cause of significant morbidity and mortality. Therefore, it
Shooting / Banging up has been the focus of many health promotion strategies
• Never share ANY injecting equipment qPharmacists are recognized as one of the most accessible
• Never re-use a needle health care professionals for the general population and
• Visit your local needle exchange are in an ideal position to reach injection drug users
• Injecting any drug is an extremely (IDUs)
high-risk practice – best avoided! qCommunity pharmacies are acknowledged as important,
• Always dispose of equipment safely – underutilized resources in preventing the spread of HIV
in a sharps bin hence disposing is and other blood-borne infections such as: Hepatitis B &
imp. hepatitis C and bacterial infections
• Use with other people that you know
Harm reduction advice on different Harm reduction advice on
PY365 Substance Misuse different
Case 3 – Harm Reduction
formulations of misused drugs formulations of misused drugs

3. Swallowing / Dropping / Eating
2. Snorting / Tooting / Sniffing / Inhaling
• Break pills into ½ or ¼ & wait up to 3
• Alternate nostrils causing bleeding due to hours before re-dosing.
caused damage • The drug has to pass through your
• Rinse nose with water before and after digestive system so this method is less
snorting intense but more long-lasting than some
• If you get nosebleeds or headaches you’re others
using too much! • Eat a light meal a few hours before to
• Use a clean straw & not a bank note: money reduce stomach aches, nausea or
carries lots of germs vomiting
• Don’t share rolled bank notes or straws: you • Regular use can give you stomach ulcers
risk getting a blood-borne viral infection (like & other digestive problems like
Hepatitis C / BBV) constipation and can cause RD
50
Harm reduction advice on different If the program is offered

formulations of misused drugs by a pharmacy, it’ll be
indicated outside, green
clean needles whereas red
4. Smoking / Chuffing / Inhaling / Toking
are dirty ones
• Don’t hold your breath after inhaling,
Pharmacy services
this causes more damage to the lungs
• Generally, results in a shorter, more NEEDLE EXCHANGE PROGRAMME
intense experience
• Regular smoking of any drug can cause Needle exchange service
Aim
PY365 - to provide
Substance Misusedrug
users with the appropriate
Case 3help and
– Harm Reduction
respiratory problems like bronchitis and
support to remain healthy until they are ready and willing to stop
even cancer injecting and achieve drug-free life
• Choose a non-toxic pipe (e.g., a water
bong) & avoid plastic or metal Objectives:
• Promote safer injecting practices
Why Needle Exchange?
PY365 Substance Misuse Case 3 – Harm Reduction • Reduce the risk of sharing and high risk injecting behaviour
• Provide sterile injecting equipment
• Needle Exchanges were set up in the 1980s • Ensure safe disposal of used equipment- prevent the spread of
• This was in response to the sharp increase in the BBV’s
• Increase access to pharmacy-Provide and reinforce harm
spread of Blood Bourne Viruses (BBVs) – Hepatitis B, reduction messages including advice on overdose prevention
Hepatitis C and HIV amongst injecting drug users (e.g., risks of poly-drug use and alcohol use) via relevant
• Providing injecting equipment has proven to be one of publications and materials.
the most effective ways in reducing the spread of BBVs’ • Signpost to services - support individual to engage in recovery
from substance misuse
The groups of people likely to use
a needle exchange
Needle exchange is not just for people who inject Heroin,
Crack or Amphetamine
PY365 The service

Substance may also:
Misuse Case 3 – Harm Reduction Citric acid is for heroin as it helps dissolving
it as it acts as an acidic environment
• Performance or image enhancing drugs (PIEDs) such as
anabolic steroids (to enhance physical appearance or
strength), cadambine etc.
• Psychoactive compounds, chemicals, plants or medicines
• Ketamine
Misuse of Drugs Act 1971 2003:changes to section 9A MDA
PY365Section
Substance 9a was
drafted to enable prosecution
Misuse of drug
1971 made it legal to supply -
dealers who sell complete 'kits' of drug and implements
to take them, and/or are raided and although not found • Swabs
to be in possession of drugs, do have all the • Utensils for preparation of control drugs
paraphernalia needed to take them. • Citric acid/ascorbic acid
• Filters
• 1998 – Pharmacist wrote a letter to the PJ questioning • Sterile Water ampules up to 2ml
the legality of pharmacists selling citric acid to potential
misusers NICE public health guidance 52
• Pharmacists stop supplying citric acid
A pharmacist may supply specified drug
• Misusers turned to lemon juice and vinegar for acid –
paraphernalia to illicit drug
users.
with reports of eyesight issues and blindness from
candida infection
51 PY365 Substance Misuse Case 3 – Harm Reduction

Needle Exchange…
The Pharmacy
• All staff need to be trained on the scheme
• Need to be Hepatitis B vaccinated
• Specific SOP/Protocol in Place
• Area of the pharmacy for storage not accessible
for general public
• Record keeping
The Practicalities-process
Needle Exchange… • SMS run training and authorise pharmacy
The Client • Substance
PY365 Pharmacy orders stock from SMS Case 3 – Harm Reduction
Misuse
• Need to know how to access the scheme where • PCO collects sharps bins
they have a number to allow access • Colleagues do not touch returned sharps
• Need privacy and confidentiality
• Need clean full packs to take quickly and easily as • Client comes in, places sharps in bin and picks up
they might be dirty new pack.
• Needs to respect pharmacy environment • Payment – Locally commissioned service
REDUCING HARM THROUGH Respiratory depression

MANAGING OVERDOSE = no longer breathe =
use naloxone
Naloxone
NALOXONE Case 3 – Harm Reduction
ANTIDOTE FOR OPIOID OVERDOSE CAN ADMINISTER PARENTERAL/NASAL

WHERE COMA OR BRADYPNEA IS NALOXONE HYDROCHLORIDE FOR LIFE-
PRESENT SAVING IN AN EMERGENCY
OPIATE SUBSTITUTION THERAPY

PY365 Substance Misuse Case 3 – Harm(OST)
Reduction
Enrolment & assessment
Road to Abstinence… • Once they make an informed decision about
Enrolment & Assessment treatment then
Buprenorphine works in • Pharmacist will get them to fill the relevant referral
a different way to
methadone and other forms to enrol them at drug treatment programme
opioids and gives you • Receive an appointment for formal assessment covers:
less of a “high”. This
means you are less likely -drug use ( past and present)
to have withdrawal Titration at SMS Clinic
effects or become -health (mental & physical)
dependent on it. -employment
-social history
Maintenance and eventual withdrawal

52
Treatment of addiction Methadone & Buprenorphine

§ It is important that all aspects of patients life are Opioid replacement
addressed-rarely drug use is the only problem § Treatment choice depends largely on patient factors & their
§ Identify their aims and expectation from the treatment- level of illicit drug use
will help to take full part in their treatment § The dose is titrated until symptoms of withdrawal are prevented
- SMS clinics
The overall outcome = abstinence from both illicit and prescribed
First aim of the treatment: medications
To control drug use with substitute prescribing & support
that will lead to a stable lifestyle which enable other issues Where does the community pharmacist fit into all of this? They
such as: mental health, childcare etc. talk to the patient as first point of contact & discuss practical issues
The Community Pharmacist The Community Pharmacist

In order for community pharmacist to supervise
SUPERVISED CONSUMPTON consumption they:
PY365•Substance
• Must have a private area
PatientMisuse
is titrated at the SMS clinic Case 3 – Harm Reduction
• Have sufficient capacity for new patient
• Agreement is made with SMS, Client and Pharmacist
• Ability to confirm Rx/prescription and if the
for the supervised consumption
prescriber is genuine
• Supervision is taken over by community pharmacy to • Understanding of SMS service and client needs-
view adherence and such referral to other health and social care professionals
Why Community Pharmacist? when appropriate
• Undertake training
• Can legally dispense CD2 medication
• Convenience for client – increases compliance PY365 Substance Misuse Case 3 – Harm Reduction
• Long opening hours

PY365 Substance Misuse Case 3 – Harm Reduction FP10MDA
• Healthcare Professional on the high street
• Cost effective
Sharing information… • Installment
prescribing for
Shared care policy - between prescriber, patient and controlled drugs used
in substance misuse
pharmacist: treatment
• When patient misses scheduled pick-ups or
MDA =
supervision consumption for e.g., 3 consecutive misuse of
PY365 Substance Case
Misusethey will not get another
days missed 3 – Harm Reduction
prescription drug act
as the tolerance depleted
• Concerns about a patient’s health or well-being
DISCLOSING
CONFIDENTIAL
• Patient attends intoxicated-none adherent
INFORMATION –
MEP (book used in workshop)
• Decisions about disclosing confidential information
PY365 Substance Misuse Case 3 – Harm Reduction can be complex. In most situations you do not have to
disclose information immediately.
• However, there will be limited situations where to
delay is not practical, for example if this may cause risk
to another person.
• You should take the necessary steps to satisfy yourself
that any disclosure sought is appropriate and meets
the legal requirements covering confidentiality.

53
L10) Whistleblowing & Misuse Among Pharmacists:

A scenario Definition of Whistle-Blowing
• You are working in the hospital, and you see another Ø One who reveals wrong-doing within an
pharmacist take a pot of patient returns for a CD and organization to the public or to those in positions of
put them in his pocket? authority.
• What should you do? WHISTLE BLOW as they can Ø This wrong-doing relates to information about
give it to someone else, give it to a black market etc. misconduct in their workplace that they feel
as it’s illegal either way. violates the law or endangers the welfare of others.
Ø The individual who whistle blows is protected by
the law.
Why do people not whistle blow?
Types of Whistle-Blowing
• Fear – repercussions from management and
Internal Whistle-Blowing External Whistle-Blowing colleagues
PY365 Case Number 3 – Substance Misuse
ü When an individual ü When an individual PY365 • Time – workload Case Number 3 – Substance Misuse
raises concerns within raises concerns outside • Not mandatory but is part of the GPhC standard
inside the organisation. the organisation. • Thinking someone else will report it
• Lack of knowledge about whistle blowing
Possible effects of whistleblowing
Mild Impact Moderate Impact Severe Impact • Not promoted by organisation’s culture
Deskilled, Difficult • Feeling isolated and lacking support & advice
PROFESSIONAL Insecure Unemployable
to Get Work
Reputation
Public Interest Disclosure Act 1998 (PIDA)
REPUTATIONAL Stigma Spurned by Others
Destroyed
it works in terms of ‘protecting whistle-blowers from
Use Most of PY365 Case Number 3 – Substance Misuse
FINANCIAL Strain
Savings
Have to Sell Home detrimental treatment by their employer when making
a disclosure in the public interest’
PY365 Death (illness,
Case Number 3 – Substance Misuse
HEALTH Minor Complaints Major Illness suicide) • Qualifying disclosures:
i. someone’s health and safety is in danger
EMOTIONAL Anxious Depressed Suicidal ii. damage to the environment
SOCIAL Isolated Marginalised Ostracised iii. a criminal offence
Divorce, No iv. the organisation is not obeying the law
FAMILY LIFE Disrupted Major Strains Contact with
Children
v. failure to comply with a legal obligation
vi. miscarriages of justice
PY365 Ethics of whistleblowing
vii.a deliberate attempt to cover up wrongdoing
• You must be prepared to challenge the judgement of
your colleagues and other professionals if you have PY365 What can you do? Steps to 3consider
Case Number – Substance Misuse
reason to believe that their decisions could affect the • Record concerns, evidence
safety or care of others. • Get advice
• Internal disclosure
Pharmacy professionals – supervisor
must speak up when they – safeguarding teams
have concerns or when • External disclosure
things go wrong • Regulators
– CQC
– GPhC
What sanction would be • MPs and Councillors
appropriate? • Media
1. Issue a warning
2. Impose conditions on the Registrant’s continued
PY365
Some facts
registration
• 46% of pharmacists use prescription drugs without a
3. Suspend the Registrant
4. Order the removal of his or her name from the prescription
Register (pretty difficult to get back on) • 62% of pharmacy students surveyed had used a
prescription drug with no prescription
What does this tell us?
• Fitness to practise sanctions are NOT punishments • 11 to 15 % of pharmacists are confronted with
• Mitigating factors are taken into account alcohol/dependency problems at some time in their
• INSIGHT is a really important part of mitigating careers
54
PY365 Case Number 3 – Substance Misuse

Pharmacist Support Drugs – legal ones

Pharmacist Support is an independent charity Cognitive enhancers – Modafinil
for pharmacists and their families,
preregistration trainees and pharmacy students
in need.
The Charity has provided a lifeline for
pharmacists who, through circumstances often
beyond their control – personal illness, disability
or other life changing events - have required
much needed help and assistance. This has been
provided in many formats on a short or long-
term basis and is specifically tailored to the
individual’s circumstances and needs.
PY365 Consider….
Case Number 3 – Substance Misuse Legally
• Buying off the internet – what are you getting? • Buying modafinil for personal own use is NOT illegal
• Supplying modafinil is illegal
• Pharmacological effects – variable
• Once the product is brought into the UK and exposed
• “We found that whilst most studies employing basic for onward sale or supply, UK medicines legislation
testing paradigms show that modafinil intake enhances will apply
executive function, only half show improvements in
attention and learning and memory, and a few even report
Ethically
Justifications for personal use
impairments in divergent creative thinking. In contrast,
when more complex assessments are used, modafinil • What’s the harm?
appears to consistently engender enhancement of • It’s the same as caffeine really
attention, executive functions, and learning.” • It’s not illegal
• Everybody’s doing it
Using cognitive enhancers
PY365 Case Number 3 – Substance Misuse Fairness
B does not take B takes modafinil
When you are assessed, what are we measuring? Your
modafinil
ability or your enhanced ability?
A does Honest, fair and equal A at an academic
not take disadvantage to B “Students could face compulsory drug tests as rising
modafinil numbers turn to 'cognitive enhancers' to boost
A takes A at an academic Dishonest but fair concentration and exam marks”
modafinil advantage over B and equal The Independent
or accept cognitive enhancers, what next?
Use this to idealize the question and get rid of “In doping, the war is never won”
issues like loyalty, will they break my kneecaps, etc. Juan Antonio Samaranch former IOC president
PY365 Case Number 3 – Substance Misuse PY365 Case Number 3 – Substance Misuse
55
L11) Substance Misuse Pathophysiology, Treatment & Pharmacology Pt. 2:

Amphetamines: pathophysiology
• They block the reuptake of monoamines,
especially dopamine and noradrenaline
transporters
• Therapeutically, they are used to treat ADHD and
narcolepsy
• It can be used to override tiredness or for weight
management, for example as an appetite
suppressant
• A common misused amphetamines is ecstasy
(MDMA)
• What are the expected pathological
consequences of misusing amphetamines? and
why?
• Withdrawal effects?: depression, sleeping..?
- From the diagram is the way Dopamine is released, calcium ions get in & binds to the
vesicle releasing Dopamine hence have a reward effect thus a rewarded & euphoric
feeling. Also, the drug acts on Noradrenaline neuron where after the neurotransmitter
is released, it binds to a receptor and then the action is terminated due to being
metabolized in the cleft or transported where Amphetamines work by blocking the re-
uptake of the neurotransmitter increasing its concentration in the synaptic cleft
prolonging the action of Dopamine & Noradrenaline.
- The problem with ADHD is not the HD part (hyperactivity) but the AD/attention defect
part where the patient is hyperactive and not paying attention therefore, we increase
attention by increasing Dopamine and Noradrenaline (mainly).
- One of the side effects of this abuse drug e.g., Ecstasy is tachycardia drug to high
adrenergic effect from inhibiting the reuptake of Noradrenaline increasing its action.
56
What is the problem with amphetamines misuse?

Euphoria
(positive
reinforcement)
Inhibiting the
uptake of Time
monoamines (chronic)
DA
Dependence
and
v There is not enough Addiction
dopamine/dopamine More drug needed
↓ Dopaminergic
receptors to normalise the (to compensate)
receptors (LTD)
situation ↑ Boost dopamine
Stopping the drug?
v Depression, bradycardia and
lethargy occurs
v (Withdrawal symptoms)
- In the long term, the patient will experience high release of Dopamine
leading to a euphoric effect, by the time due to Dopamine keep binding to
its receptor; the receptor will become downregulated therefore the person
increases the dose/use of Amphetamines to increase the amount of
Dopamine in the cleft to compensate such reduction in the receptors
(tolerance). By the time, due to the increased dose the body, reduces
Dopamine receptors hence experiencing depression (WD symptoms) due to
binding to only one receptor hence the cycle of dependance start as it’s not
enough to boost the mood of the person therefore they take the drug.
Amphetamines: treatment and pharmacology

amphetamine misuse (October, 2022)
implemented such as
treatments (symptomatic
treatment)
57
Cocaine: pathophysiology
• Cocaine can be snorted, swallowed, injected, or
smoked
• Cocaine blocks the reuptake of monoamines:
dopamine, serotonin and noradrenaline
• Increasing dopamine in the synaptic cleft,
increases the dopaminergic output in reward
circuit and hence leading to euphoria commonly
experienced immediately after taking the drug
• What are the expected pathological consequences
of misusing amphetamines? and why?
• Withdrawal effects?: depression, sleeping..?
Acts as the same way as amphetamine
inhibiting the reuptake of noradrenaline, largely
serotonin (extra step) and dopamine where it
works by increasing its concentration in the
clefts increasing the binding of dopamine to its
receptors leading to LTD which causes
depression of dopamine receptors 1
What is the problem with cocaine misuse?
Dopamine receptors are being less as seen in red where at that time the patient develops
tolerance increasing the dose of cocaine having dependence as there’s not much of dopamine
receptors activated hence leads to cycle of dependence
Cocaine: treatment and pharmacology

• There is no MHRA, EMA or FDA-approved treatment for cocaine misuse
(October, 2022)
• Supportive therapies might be implemented such as
• Symptomatic treatment should be conducted
• Cardiovascular toxicity and agitation may be treated with
benzodiazepines
• NDHP CCB may reduce hypertension reliably
• DHP CCB should be avoided
• Alpha-blocker can treat alpha-mediated hypertension but not tachycardia
• Nitric oxide donors are effective at lowering blood pressure
• The mixed beta/alpha blocker has been shown to be safe and effective for
treating concomitant cocaine-induced hypertension and tachycardia,
without any “unopposed alpha-stimulation” adverse events recorded
58
- Hypertension is one of the outcomes that occurs due to an increased Noradrenaline

action but WHY don’t we give the patient drugs like alpha blockers, dihydropyridines,
beta blockers and nitric oxide donors despite them working to reduce BP?
- Because increasing Noradrenaline (which can cause vasoconstriction) increases the
heartbeat leading to ‘tachycardia’ and through the activity of nitric oxide donors and
alpha blockers we can induce vasodilation and enhance reflex tachycardia thus the
patient will experience excessive tachycardia because of this action. Therefore, the best
drug choice for cocaine overdose (NOT MISUSE) is to mix beta and alpha blockers. They
work by inhibiting alpha 1 receptor which will inhibit vasoconstriction causing
vasodilation therefore it’s mixed to induce vasodilation and block the reflex tachycardia
through beta 1 receptors protecting the heart and vasoconstriction which can lead to
high blood pressure.
Opioids
• Opioids (morphine-like molecules) exert their actions through 3 main receptors:
1. Mu (μ) receptors (MOP): main target for most opioids providing analgesia, euphoria and respiratory
depression (responsible for most of the CNS actions)
2. Kappa (κ) receptors (KOP): spinal analgesia and dysphoria without inducing dependence
3. Delta (δ) receptors (DOP): peripheral analgesic receptors
• These receptors are GPCR that interact with the reward circuit through disinhibition:
1. Inhibiting adenylate cyclase (AC) and hence reducing AMP synthesis
2. Opening potassium channels Opiates is the natural source (in plants)
3. Inhibiting the opening of voltage-gated calcium channels e.g., morphine, but opioids is both the
natural and synthetic hence used as
• Some drugs may exert different pharmacological properties
general term
• Morphine is a potent agonist for all the three receptors
• Buprenorphine is a partial agonist for MOP while acting as an antagonist to KOP and of weak (not exerting)
activity toward DOP
• Methadone is a potent agonist for MOP and of weak (not exerting) activity toward KOP and DOP (more
towards mu receptors) – blocks agonist binding
• Naltrexone and naloxone are antagonists to all MOP, KOP and DOP, with more affinity to MOP
- It works by activating G protein coupled receptors which is the form of its receptors,
and its action is through inhibiting the excitation of the cell inhibiting the release of
neurotransmitter (specifically GABA) hence causes disinhibition causing euphoric effect.
- A partial agonist activates the receptor partially as it has a subthreshold effect whereas
a full agonist exerts 100% efficacy. In the presence of a full agonist, the partial agonist
will compete with it acting as an antagonist whereas in the absence of full agonist the
partial agonist will act as a partial semi-full agonist (half-effect) which avoids the
development of negative effects
59
Opioids: pathophysiology
• Tolerance and addiction arise from the upregulation of the
cellular components (LTP): adenylyl cyclase (AC), cAMP and
PKA, which were initially supressed by opioids
• LTP of AC, cAMP and PKA in addition to dynorphin (cAMP
downstream cascade component) leads to severe withdrawal
symptoms upon abrupt drug abstinence such as dysphoria and
diarrhoea
• Respiratory depression (OIRD – opioid induced):
1. MOP activation supresses locus coeruleus’ noradrenaline
neurons and hence supressing medullary centres leading and
respiratory rhythm
2. The type I glomus cells in the carotid body are the body’s
main sensors for hypoxia and hypercapnia. MOP activation
inhibits carotid body activity through inhibiting dopaminergic
and purinergic neurons and hence leading to slowly
progressing hypoventilation and death
1
- Main problem with opioids is tolerance that leads to addiction leading to certain side
effects e.g., constipation, respiratory depression & some cardiovascular issues.
- OIRD (opioid-induced respiratory depression) – when the person takes the drug, both the
VTA & the reward cycle will activate activating the nucleus accumbens activating the
mesolimbic system leading to a feeling of reward. One of the signalling molecules e.g.,
Dynorphin (a neuropeptide involved in pain, addiction, and mood regulation) will inhibit
the Dopamine neuron leading to a feeling of withdrawal or tolerance and so the patient
starts to increase the dose to feel more euphoric.
- RD is caused by the brain stem which contains the pons and medulla where they’re
communicating with each other through adrenergic and noradrenergic neurons. In the
pons, there’s a neuron that releases Noradrenaline to the medulla which accepts it
making the breathing rhythm goes on & on where when a mu receptor is activated on
the noradrenergic neuron it’ll inhibit the release of Noradrenaline inhibiting the medulla
so the rhythm will go down.
- In the carotid arteries, we have peripheral chemoreceptors which sense the reduction
in O2 and the increase in CO2 hence Dopamine and an ATP go to the medulla to
compensate a deep force breathing as the person could die (involuntary process,
controlled by the brain stem). However, the mu receptor activated from opioids inhibits
these receptors hence someone using opioids will have their centrals inhibited hence
the body doesn’t response and they’ll accumulate hypoxia (low levels of oxygen) due to
60
a drop in blood concentration and hypercapnia leading to death in sleep where

hypoxia causes symptoms like confusion, restlessness, difficulty breathing, rapid heart
rate, and bluish skin.
- Hypercapnia is when we have too much carbon dioxide (CO2) in the bloodstream. It
usually happens as a result of hypoventilation, or not being able to breathe properly and
get oxygen into the lungs. When the body isn’t getting enough fresh oxygen or getting
rid of CO2, we might need to gasp or suddenly inhale a lot of air to balance the levels of
oxygen and CO2. Additionally, a carbon monoxide goes to the RBC, and it will compete
with O2, and it has high binding affinity with the RBC/haemoglobin, and it will not be
able to bind to the RBC so it will not lead to oxygen delivery,
- In 2015, the MHRA inhibited the use of codeine-based drugs to those under 12
(sometimes below 18) as codeine is a prodrug that gets converted to its active form
where it’ll go all the way from the GIT to the liver and get converted to Morphine from
CYP2D6 enzyme. In children, this enzyme is not mature where lots of Morphine will form
inside their body. Even though their cough centre will be inhibited (no dry cough), kids
will die to the accumulation of Morphine which will inhibit the respiratory and
peripheral chemo centres so when the kid sleeps = death.
Opioids: pathophysiology (cardiovascular)

• The QT interval is defined as the time between the start
of the Q wave and the end of the T wave which is the
electrical presentation of ventricular depolarization and
repolarization in ECG
• Prolongation of QT occurs due to delayed repolarisation
due to blocked or loss of function of the cardiac rapid-
rectifying K+ channel (KCNH2 or hERG: this channel is
encoded by human-ether-a-go-go gene)
• Opioids block hERG channels leading to TdP: Torsades de
pointes and arrhythmia
• In addition to prolonging QT interval, morphine and
hydromorphone are related to various cardiac side
effects such as histamine release, which leads to
bradycardia, vasodilatation and hypotension, decreasing
cardiac output especially when used in combination with
benzodiazepines
- Sodium gets in = depolarization, potassium getting out and calcium getting in at the
same time = plateau, voltage-gated calcium channel shut down and potassium keeps
leaving the cell = repolarization and relaxation of the heart muscle. For example, Opioids
can bind to mu receptors and certain types of potassium channels e.g., hERG where they
61
block the efflux of potassium prolonging the QT interval (the period from depolarization
to repolarization is prolonging) leading to arrythmia.
Mechanism of action of ventricular action potential

In presence of opioids
Na Na
Ca Ca
Opioids
K K
K K
1
- In normal conditions, sodium gets in leading to excitation of the ventricular myocyte

causing depolarization, the potassium leaves for a transient repolarization and at the
same time we have calcium channels being activated = plateau phase and with time they
shut down and potassium channels are still open leading to phase 4 (repolarization).
- In the presence of opioids, depolarization takes place but at the same time potassium
leaves and we have calcium getting in but at that moment opioids will block the
potassium hence no more of it are leaving the cells = prolonging the action of the QT
interval for arrhythmia.
Opioids: pathophysiology (constipation: OIC)

1. Decrease motility: Excitatory motor neurons release
acetylcholine (Ach) and tachykinins (e.g., substance
P), which evoke longitudinal smooth muscle
contraction. MOPR activation inhibits the release of
Ach and other peristaltic neurotransmitters leading
to decrease in the normal propulsive activity
2. Decrease fluid secretion: opioids bind to receptors
on secretomotor neurons in the submucosa of the GI
tract and suppress Ach and vasoactive intestinal
peptide (VIP) release, resulting in a decrease in
chloride and water secretion into the lumen
3. Increase sphincter tone: Opioid-induced dysfunction
of anorectal function leading to increased
contraction of the internal anal sphincter which
causes straining, haemorrhoids and/or a sense of
incomplete evacuation
1
62
- When we have constipation, the factors above mainly involve Acetylcholine or the
parasympathetic nervous system activity.
- The mu receptors due to its inhibitory effect will inhibit the release of Ach hence it will
not induce the peristaltic movement – so, the GIT won’t squeeze and move forward
which will lead to constipation. Also, due to Ach release being inhibited this will inhibit
the release of the GIT fluids making it dry leading to constipation. Finally, it can increase
the sphincter and by the end of the GIT the anal canal will become constricted hence the
patient won't find it easy to pass stools where the more stools = the more absorption of
water = becomes dry = severe constipation.
- When we have Dopamine being released from the VTA to activate the reward circuit,
it’ll bind to the Dopamine receptors (D1 which is excitatory) on the GABA neuron located
in Nac leading to activation of the G protein/alpha-s subunit of the G protein which will
be phosphorylated and then will be translocated from the receptor site all the way to an
enzyme located in the membrane called adenyl cyclase which converts cellular ATP to
cAMP (cyclic adenosine monophosphate) which will activate protein kinase A activating
calcium channels which will open leading to calcium coming in/influx leading to
neurotransmitter release which is GABA which will shut down the system hence there’s
no euphoria.
- With Morphine, it binds to an inhibitory G protein which will translocate from the
receptor site to deactivate adenyl cyclase resulting in ATP not being converted to
cAMP hence calcium can’t come in therefore accumulated ATP which phosphorylate the
63
channels that activate potassium channels leading to efflux of potassium leading to the
action potential to go down due to positive charges leaving hence no neurotransmitter
released (GABA not released = Dopamine is not suppressed and is released = euphoria).
Opioids and reward circuit

M • Disinhibition
Morphine ↑ Postsynaptic
on mu
O Inhibiting
P Glutamate release release of
Less Neuro dopamine
transmitter ↑ Glut
release
Inhibiting GABA • Disinhibition

release ↑ Postsynaptic
release of ↑ Dopamine
Affects GABA more than glutamate due to mu dopamine
receptors being more expressed in the
mesolimbic compared to the PFC hence we have y.shamsaldeen@brighton.ac.uk 1
more response on the GABA neurons there.
What is the problem with opioids misuse?

Reduction ↑ Dopamine: Due to reduction in
of the Euphoria GABA release
activity of (positive
AC/adenyl reinforcement)
cyclase of
µ-receptors GABA Time:
Disinhibition
activation Neuron chronic
Dependence
↑ Adenylate cyclase and
↑ cAMP Addiction
More drug needed ↑ Adenylate cyclase
↑ GABA release (to compensate) (AC) - LTP
↓ Dopamine Supress AC ↑ GABA release
↓ Glutamate Stopping the drug?
v Depression, craving, anxiety
and hypertension
Opioid misuse: treatment and pharmacology

Buprenorphine: Methadone:
• It is a potent but partial agonist (competes with • Is a potent MOP receptor full agonist
whatever we have of morphine) of MOP receptor • Characterised by high extravascular
showing a high affinity, but low intrinsic activity compartments binding leading to slow release
hence won’t induce euphoria as much as morphine from extravascular reservoir into the circulation
reducing SE of morphine
• High potency and slow off rate (half-life of • Increase duration
association/dissociation is 2–5 hours) • Less withdrawal
• The ceiling effect due to partial agonism • Not euphoric
• Less dependence • Less risk of developing dependence and
• Less respiratory depression addiction and consequently the rest of the
opioids misuse complications
• Less cardiovascular depression
• Less Constipation
• Mainly (70%) excreted through enterohepatic
circulation
64
Mu receptor More potent

activated in term of
binding but
less
consequences
Inhibits the side
effects evolving
Less risk of these SE
Opioids major harms

Bupre M
O Activating reward
norphi Neuro Tolerance, withdrawal and addiction
P circuit
ne transmitter
release
More potent (binds much better) = not full

intrinsic activity = less neurotransmitter
released = less inhibition = less activation of
reward circuit = less complications
The main therapeutic strategy:

1. Reduce addiction and Respiratory
overdosing Cardiovascular depression
complications Constipation
2. Prevent withdrawal
symptoms
Opioid antidotes Compete with the opioids on the mu receptors to

treat an overdose in the case of opioids
Naloxone Naltrexone
• A potent antagonist of opioid receptors • Oral antidote of opioids (PO)
• Naloxone is used to reverse the action of • Longer duration of action
opioids (antidote) • Longer duration: up to approximately 24
• IV hours
• Rapid onset
• Rapid hepatic metabolism
• Short duration: 2-4 hence requires repetitive
dosing because the action of Morphine is higher
Because if we treat opioid misuse with naloxone or naltrexone, we will induce withdrawal
symptoms hence mimic stopping the drug leading to the symptoms
65
Nicotine: pathophysiology
• Nicotine is obtained from the leaves of tobacco (Nicotiana
tabacum), is being used for centuries for its pleasurable
effect
• Different routes of administration
• Activating presynaptic nAch receptors leading to activation of
VTA dopaminergic pathway
• Exceptionally, nicotine induces nicotinic receptors
upregulation
• Nicotine due to being on the most presynaptic receptors it
has a wide spectrum of activity where it stimulates
presynaptic receptors and hence mediating the release of
almost all neurotransmitters leading to a wide range of side
effects and mix of feelings & euphoria. Hence as a person
keeps on smoking, more dopamine released, more reward
circuit. But nicotinic receptors upregulate (more number),
and their efficacy downregulate leading to upregulation and
desensitization hence not as good of a response
1
What is the problem with nicotine?

Positive
reinforcement
Stimulates
Time
nAch receptors
(chronic)
DA
Dependence
and
More nicotine needed ↑ nAch receptors
v There is not enough nicotine Addiction
(to occupy the (LTP)
to activate nAch receptors to receptors and & Decrease in response
stimulate dopamine release compensate) to (LTD of downstream
v Depression, anxiety and Stopping the drug? ↑ Boost dopamine cascade)
lethargy occurs
Nicotine: treatment and pharmacology

• NRT/nicotine replacement therapy is a

medication that provides a low level of
nicotine, without the tar, carbon monoxide
and other poisonous chemicals present in
tobacco smoke and preventing withdrawal
symptoms, complications and craving.
Summary
• Substance misuse enhances reward circuit for short term and then
tolerance develops leading to dependence and addiction due to synaptic
plasticity and withdrawal syndrome in the form of increasing the dose
• Tolerance and addiction leads to dose increase and hence complications
based on targeting other central and peripheral tissues in addition to
withdrawal syndrome
66

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Ali AlAttar 20800061

L1) Substance Misuse Introduction:

e.g., regarding prescription opioids

What do you think of when we

What are Mental health and emotional well-

the being either acutely or chronically

impacts of Due to the

substance Relationships and social functioning

Harmful Drinking and Alcohol3 and

More than 10% drinking

The Chief Medical Officer

Harmful Drinking and Alcohol

Guidance and regulation

PY365 Substance Misuse 3 and Introduction to case

PY365 Substance Misuse 3 and Introduction to case

PY365 Substance Misuse 3 and Introduction to case

Society as a whole The extent of the

With rehab, the dose is reduced as the body is already

PY365 Substance Misuse 3 and Introduction to case

Global What are treatments for drug addiction?

PY365 Substance Misuse 3

- FP10 prescription is green, what found in

Introduction to the patient - “Clean needles” technique is

PY365 Substance Misuse 3 and Introduction to case

- For example, there are needles for steroids (intramuscular - have to be

Hint: Needle and syringe programmes Public health guideline

Help patients to stop their misuse and to stop any

PY365 Substance Misuse 3 and Introduction to case

NOTES FROM EXTRA READING:

L2) Physiology of Reward Circuit:

• In England and Wales in 2021:

- Gamma-aminobutyric acid (GABA) is an amino acid that serves as the

Mesolimbic pathway Amy: Amygdala Mesocortical pathway

Mesocorticolimbic pathways (GABA)

GABA B efflux more positive charges to stop the system.

• Constant GABA = no dopamine = depression.

Mesocorticolimbic pathways (Glutamate)

• Glutamate is synthesized/produced through α-ketoglutarate –a byproduct from

Overall network of major afferents and efferents of VTA Glutamate neurons.

A crucial brain reward Dopamine Phenylalanine

Dopamine receptors and reward circuit

Dopamine synaptic transmission

Short-term synaptic plasticity (rule of 20 ms)

Long-term synaptic plasticity Orexin neurons regulate various

L3) Quality Issues Associated with Recreational Drugs:

of good and safe medicines’ production – expected • Alcohol (most abused)

Common recreational (illegal) drugs are PY365 – Drug

– Acetyl codeine 5% Interception

• It can also be inhaled and smoked

PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1

Case study 2 – Coca leaf

Cocaine and amphetamines Line of coke Tissue loss

• Pulped coca leaf (2% cocaine) mixed with CaO, NaOH,

• Cocaine causes heart irregularities, as one of its actions is in

PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1 MDA (hallucinogen) is a

Case study 3 - Krokodil

• Self-made desomorphine is very impure

Cutting agents (diluents)

PY365 – Advanced Pharmacy 1 3.3 Substance Misuse 1

Hallucinogens: psilocybin, LSD, etc.

Leaf and buds

• Cattle excrement is found

China Strychnine* Lidocaine MDMA Ketamine† Leaf Calamus

what this is?