therapeutic profile of drugs of abuse and other CNS disorders Flashcards
Therapeutic potential of cannabis
cannabis doesn’t have as much harm to others as alcohol does
Classes based on harm (to self and others)
Very difficult to OD on nicotine from smoking (most nicotine overdoses are from exposure to pesticides), but it has proven health risks
Jouanjus et al., 2014 details that chronic cannabis use can lead to cardiovascular problems
quite prevelant
Medical indications:
↓N/V in chemotherapy patients
Alleviates chronic pain
Neurological problems
↑appetite in HIV patients
PTSD
used for management of vomiting in chemo patients
manages neurological conditions like epilepsy and MS
some reports show efficacy of medical cannabis that increase appetite
Describe emesis/vomiting
Vomiting centre co-ordinates complex events
Vomiting centre – nucleus tractus solitarius (NTS)
NTS, nerve impulses:
Cranial nerves (upper GI tract)
Spinal nerves to diaphragm & abdominal muscles
Reverse peristalsis
Begins at ileum → duodenum → stomach
Closure of epiglottis over trachea
Oesophagus and gastric sphincter relax
Abdominal muscles contract
Gastric contents ejected
emesis has a protective physiological role to get rid of harmful substances
some chemo agents used for cancer are cytotoxic, inducing vomiting- undesired side effect
one centre is chemoreceptor trigger zone and the vomiting centre (NTS)
these send signals to diaphragm to contract (via cranial and spinal nerves), pushing stomach downwards and pushing food upwards
also sends signals for reverse peristalsis- ileum, dudenum and stomach to contract
food is ejected upwards
Vomiting centre is in the lateral reticular formation of the medulla. It receives signals from the NTS and send signals to the NTS to initiate vomiting
Pathophysiology of emesis
4 factors can act on the vomiting centre in the medulla
1)cancer chemotherapy opioids work via Chemoreceptor Trigger Zone (CTZ)
via
Dopamine D2
5 HT3,,d Opioid Receptors, CB1, NK1
2)anticipatory emesis (smell, sight etc)
3)chemo and radiotherapy+gastroenteritis can act from pharynx and GIT
4)vestibular nuclei, Muscarinic Histaminic H1
through motion sickness
act on vomiting centre in the medulla
these all act on the vomiting centre in the medulla (Muscarinic, 5 HT3 & Histaminic H1, m opioid, NK1)
how can cannabis help in chemo induced vomiting
Cannabis shown to be effective
In fact, more effective than some conventional anti-emetics!
However, side effects
Induced n/v is known as cannabinoid hyperemesis syndrome.
medical cannabis for chronic pain
opioids have side effects, pregablin and gabapentin used, NSAIDS not that effective
should medicinal cannabis be used? is it safe for chronic pain?
Lynch and Campbell have shown efficacy in the management of chronic pain
we still have safety concerns
Lynch et al., indicate that the benefits of cannabis use outweigh the risks
Martin-Sanchez et al., unclear if benefits outweigh the risks
Whiting et al., indicates that they are effective in alleviating chronic pain
Carter et al., indicates that cannabinoids are safer than opiates in palliative care
Two systematic reviews – one for (Deshpande) and one against (Andreae) for use in chronic pain. Note: Andreae do say it may be useful in short term, but in the long term, risks outweigh benefits, and efficacy is quetioned
does cannabis help with neurological problems?
Koppel et al., report low efficacy
Patients report efficacy, but this has not been reliably measured
The power of placebo!?!?
CBD to manage seizures
in last 5/6 years
CBD has no psychoactive effect
reports show that there is some efficacy in the management of seizures- but not a lot of data to confirm this, and we don’t understand the mechanism
can cocaine be used for nasal surgery?
cocaine blocks monoamine transporters- DAT/ SERT/ NET reuptake blockade
class A
increases anxiety, panic, and due to noradrenergic effect, increases heart rate, BP
chronic use will deplete brain of monoamines causing depression
cocaine has been used in nasal surgery-
Vasoconstriction
Blockade of voltage-gated Na+ channels
vasoconstrictive (because it increases noradrenaline) and anaesthetic property
snorting of cocaine can cause vasconstriction in the nasal cavity to the extent that the nasal septum becomes necrotic
this is attractive for surgeons because vasoconstriction causes bleeding
blockade of VG Na channels can help to block pain
now replaced with lignocaine
Glutamate- what effect do NMDA agonists have?
Antiepileptic
Schizophrenia
Loss memory
Agonists: epilepsy Antipsychotic antidepressant Cognitive enhancer ADHD
sodium and calcium can get into channel, glutamate allwos positively charged ions to get in
inlvolved in neuroplasticitiy, long term potentiation
can induce amnesic effects
NMDA colocalised with AMPA receptors. Highly permeable to Ca2+ but at resting potential channel blocked with Mg2+, only when cell is depolarised (e.g. activation of AMPA receptor) Mg2+ moves out and allows Ca2+ to flow in. Also needs glycine to bind (glycine thought of as an inhibitory transmitter) therefore glycine antagonists can inhibit glutamate action. Some anaesthetics (ketamine) and psychotomimetics (phencyclidine) block the NMDA channel. Glycine site may be important as may have fewer side effects – results from clinical trials so far have not been conclusive
Medical indications of ketamine
Medical indications:
Anaesthetic
Treatment-resistant depression
Pain
ketamine does not induce halucinogenic effects in children (because they hallucinate anyway)
so the anaesthetic is only used in children
ketamine does not suppress breathing- advanatge over opioids
also it stimulates circulatory system
people who suffer traumatic shock have risk of blood loss and lowers blood loss; ketamine stimulates
Anaesthetic
Children, but not (usually) adults
However, it can be a drug of choice
Ketamine does not suppress breathing
Traumatic shock increases risk of hypotension; ketamine stimulates the circulatory system
Problems with current antidepressant pharmacotherapy
SSRIs eg fluoxetine block the serotonin transporters
causing serotinin to build up in synapse
first line of drug for management of depression
soemtimes clinican prescribes tricyclic antidepressnts (TCAs)
induce antidepresseant effects by blocking boht serotinin and NA transporters
only used for severe depression
monoamine oxidase inhibitors are only used in rare cases of severe depression
they block the enzyme that breaks down NA and serotonin
Problems with current antidepressants: Side effects (especially insomnia=>relapse)
Toxic with overdose
Delayed effects
Non responsive in certain people (30-40% fail to improve with drug treatment)
SSRIs are quite safe but they do have side effects such as sexual dysnfunction or insomnia
monoamine ox inhibitors have some mroe severe side effects like cardiovascular effects (cardiotoxic at high doeses)
in overdose, can be toxic
plus they have delayed effects- can take 4-6 weeks to have any beneficial effects- can be too late if you’re suffering from severe depression
30-40% are resistant to treatment with anti-depressants
Treatment resistant depression- can ketamine be used to help?
Given at MUCH lower doses than that used to induce analgesia
Rapid onset (within 2 hours)
But…cause dissociative symptoms, abuse potential
BUT ketamine can treat resistant depression
much lower doses than that needed for analgesia can be used
onset in 2 hours
rapid onsent with low dose
high effiacy in depression suppression
but side effects are psychosis, and potential for abuse
study for those with major depressive disorder- current medication not effective
ECT is an electric shock to your brain
comaprison between ketamine and ECT
studies used BDI scores (depression scores) following giving ECT or ket
red is ket, blue is ECThigher the BDI higher the depression
you don’t need high doses of ketamine for antidepressant effects,
moderate doses of ketamine give anaesthetic effect
high overdose can cause death
long term use of ketamine will cause necrosis of the bladder
will cause poeple to use a bag for a bladder
How can ketamine be used to manage chronic pain
chornic pain is difficult to manage- problems w opioids
papers show ketamine has efficacy for management of chronic pain
how pain is transmitted from periphery via dorsal horn of spinal cord to sensory cortex for pain to be sensed:
pain is sensed as a mechanical or chemical stimulation by nociceptors in periphery
sense pain signal via action potential in afferent neruones which project to the dorsal horn of the spinal cord
afferent neurones release glutamate
bind to nmda receptor in neighbouring neurone
produce substance P
in chronic pain, transmission of info from periphery to brain gets hyperstimulated
to extent that sometimes you don’t even need a stimulus
continuous triggering of train pathway and constant release of glutamate from neurones in dorsal horn andconstant activation of nmda receptor
sends action potential to sensory cortex for pain to be sensed
so anything that blocks this pathway can be an analgesic
ketamine can work by blocking nmda receptor
no substance P produced, no signal to sensory cortex
blockage of signal from periphery to brain overall
medical implications of amphetamine
ADHD Anti-Depressant Stroke Narcolepsy Appetite supressant
amphetamine to help with ADHD
Attention deficit hyperactivity disorder (Ritalin)
Abnormal brain structure/function can be resolved upon chronic amphetamine administration
Relatively safe at the dose prescribed
ritalin
adderal
chronic amphetamine administration can help people suffering from adhd
particularly with hyperactivity in the frontal cortex and anterior cingulate cortex (lack of concentration)+ abnormalities in the basal ganglia (movement problems)
amphetamine can reverse some of these abnormalities
people predicted there would be problems w people getting addicted to other addictions later in life with ritalin and adderall
side effects- insomnia, reduced appetite, high blood pressure
amphetamines as anti depressants
Increase serotonin, noradrenaline, dopamine
ssris and amphetamines work the same way to increase monoamines so makes sense how they both help with treating both severe depression and treatment resistant depression
