Scenario 31 Flashcards
Where is 5-HT released?
Alla round the brain incl cerebellum from raphe nuclei
How is 5-HT synthesised?
Tryptophan (diet)→5-hydroxytryptophan→ 5-hydroxytryptamine
How is 5-HT stored?
Vesicle in presynaptic terminal, uses proton gradient- requires ATP (VMAT)
How is 5-HT released?
Calcium dependent vesicular release at the end terminal
What 5-HT receptors are there?
Ligand gates ion channels and GPCRs
How is 5-HT reuptaken?
Diffuses round end terminal and is reutaken by SERT co transporting with Cl and Na
How is 5-HT degraded?
5-hydroxytryptamine→ 5-hydroxyinolealdehyde→5-hydroxyindeoleacetic acid
What drugs interfere with 5-HT synthesis and storage?
P–chlorophenyalanine and reserpine
What drugs interfere with 5-ht release?
MDMA
What drugs interfere with 5-HT receptors?
- Full agonists- 5-HT, sumitiptan
- Partial agonists- buspirone
- Antagonists- ondansetron, ketanserin
What drugs interfere with 5-HT reuptake?
SSRI (citalopram), TCAs, MDMA
What drugs interfere with 5-HT degradation?
MAOI- Phenelzine
What recreational drugs interfere with 5-HT?
MDMA, LSD, mescaline, magic muschrooms
What diseases are related to 5-ht?
Depression, anxiety, migraine, hallucinations
Where is NA released?
Very few neurons, post ganglionic symp nerves, retina and almost everywhere in brain (incl cerebellum)- associated with mood
How is NA synthesised?
Tyrosine–>DOPA–>Dopamine–>NA (by beta-hydroxylase)
How is NA stored?
In vesicles filled using a proton pump using ATP (transported in as dopamine then converted)
How is NA released?
Calcium dependent vesicular release at end teminal and en passant varicosities (Co-released with ATP)
What NA receptors are there?
All GPCRs (ligand gated so no fast firing)
How is NA reuptaken?
Diffuses round end teminal and taken up by NET whihc requires Cl and Na -uptake 1
Also taken up by glia also using NET
How is NA degraded?
Diff pathways involving MAO and COMT resulting in VMA which can be measured in urine
What drugs interfere with NA synthesis?
alpha-methyltyrosine
What drugs interfere with NA storage?
resepine, tyramine
What drugs interfere with NA release?
guanethidine
What drugs interfere with NA receptors?
- Full agonists- NA, adrenaline, salbutamol
- Parial Agonists- clonidine, ergotamine
- Antagonists- propanolo, atenolol, prazosin, yohimbine
What drugs interfere with NA reuptake?
NSRI (reboxetine), TCAs (imipramine), amphetamine, cocaine
What drugs interfere with NA degradation?
MAO inhibitors- phenelzine
What recreational drugs intefere with NA?
cocaine, amphetamines
What diseases are related to NA?
Drug dependence, depression, hypertension
What is drug dependence defined as?
Repeated compulsive use of a drug to receive its chemical rewarding effect or to avoid withdrawal
What is the molecular target of opiods?
opiod receptors
What is the molecular target of amphetamines?
Dopamine transporter
What is the molecular target of cocaine
Dopamine transporter
What is the molecular target of nicotine?
Ach receptors
What is the molecular target of alcohol?
GABA receptors?
What is the molecular target of ecstasy?
5-HT transporter
What is psychological dependence?
Taking the drug primarily for the pleasurable rewarding effects
How do drugs produce pleasurable effcts?
Reward pathways in the brain are hijacked by the drug causing DA transmission in mesolimbic DA pathway (particulary nucleus accumbens- strenthens association between stimuli and response)
What is the development of psychological dependence affected by?
Pharmacokinetics- more rapid onset more rewarding
Ritual and environment- can positively reinforce further
What is physiological dependence?
Taking the drug to avoid unpleasant effects
Why do we become tolerant of drugs?
Pharmacokinetics- blood levels not maintained (new enzymes)
Pharmacodynamics- reduced effect of drug despite maintained blood levels (eg opiod tolerance- can tolerate a dose usually lethal)
Why does pharmacodynamic tolerance happen?
Receptors are upregulated and homeostatic changes- when stopped left upregulated and withdrawal response
How is drug dependence treated?
Reducing withdrawal discomfort, reduce rewarding effects of the drug, treat co-morbidities, diminish cravings
What are typical symptoms of psychoses?
Dellusions, halluinations
What is organic psychosis?
Caused by almost any physical disturbance to the brain and its environment (sometimes impaired consciousness) eg. dementias, endocrine, toxic (drugs), traumatic injury, neoplastic
What is functional psychosis?
No functional distrubance to the brain, happens in clear consciousness eg. schizophrenia, delusional disorder, acute and transient disorders, depression, manic
What is the life time risk of schizophrenia (SC)
0.9%
What is the world wide prevalence of SC
1%
What is the annual incidence of SC
10-15 pr 100,0000 adults
What is the ave age of onset of SC?
28 in men, 32 in women
What are the biological causes of SC?
MZ twins- 40-50%
First degree relatives 10%
Brain lesions during neurodevelopment
Cannabis use
What are the social causes of SC?
Lower socio economic group
What are the psychological causes of SC?
Cognitive decline? critical comments (relapse) stress
What is the pathogenesis in SC?
increased ventricle:brain ratio
disruption of hippocampal pyramidal cells and cell loss in amygdala and enterohinal corted
Smaller neurons and reduced density in prefrontal cortex
What neurotransmitter changes take place in SC?
Serotonin- sleep disturbance
NA
Increased limbic dopamine- positive symptoms, thought disorder
Ach/ GABA- cognitive impairment
What drugs are used to manage SC?
Antipsychotic- highly effective against positive symptoms but s/e such as extrapyramidal syndrome and hyperprolactinaemia, metabolic syndrome, sexual dysfunction
WHat other therapies can be used?
Psychological (family therapy, cognitive)
What are the common outcomes of SC patients
20% highly dependent, 50% relatively independent 30% fully independent
What are some common symptoms of anxiety?
sleep disturbance, muscle tension, sweating, tachycardia
What is the pathology of anxiety?
reduced GABA- agonists reduce anxiety (benzodiazipines), antagonists produce anxiety
reduced 5-ht- agonists reduce anxiety (buspirone)
NA- overactivity in locus coeruleus
How do you diagnose depression?
Need 2 of- low mood, low interest and enjoyment, reduced energy
Need 3 of- reduced self-esteem, guilty, pessimism, self-harm, reduced concentration, seep disturbance, reduced appetite
For 2 weeks
What is the genetic factor in depression?
60% concordance in MZ twins
What is the biolofical factor in depression?
HPA axis overactivity
What is the psychological factor in depression?
Negative bias, loss/ abuse in childhood
WHat is the social factor in depression?
Vulnerability- lack of support, life event onset brought forward
What are the NT changes in depression?
Decreased 5-HT (low mood, sleep disturbance), NA (decreased motivation), DA (anhedonia), increased cholinergic activity (memory and sleep)
What are the neuroendocrine changes in depression?
Increased CRH secretion (HPA activity, hypercortisolaemia), TRH/TSH (sub-clinial hypothyroid), GH/somatostatin (increased day time GH, reduced SST)
What is the lifetime risk of suicide?
1%
What is ETC?
Generate seizure activity in brain- unilateral electric shock
What drugs are available to treat depression?
Enzyme inhibitors- MAOI, RIMA
Uptake inhibiroes- TCA, SNRI, SSRI, NSRI
Presynaptic receptor antagonists- atypical
What enzymes do MAOIs and RIMAs inhibit? and what adverse reactions do they have?
Degrative enzynes for 5-HT and NA- diet interactions (more for MAOIs) because tyramine from diet can displace NA and increase symp drive to the heart increasing BP
What is an example of a MAOI?
Phenelzine
What is an example of a RIMA?
Moclobemide
What is an example of TCAs?
amitriptyline, clomipramine, imipramine
What is the function of TCAs?
Block 5-HT and NA reuptake
What is the cons of TCAs?
Many s/e and toxic in OD
How do SSRIs work and example?
Citalopram and block 5-HT reuptake
What is an exaple of a NSRI and what do they do?
Reboxetine and block NA reuptake
What is a s/e of NSRI
insomnia
What do atypicals so and example?
Mitrazapine and block NA or 5-HT presynaptic receptors
Adverse effect of atypicals?
Weight gain
What is the monoamine hypothesis?
Depression is caused by a functional defecit of MA transmitters, mania is a functional excess
What evidence is there to support the MAH?
Show genetic linkage- biochemical basis
Drugs that increase functional availability treat and opposite causes depression
Some drugs that reduce NA synthesis can mimic depression
What evidence is there against the MAH?
Therapeutic lag, no clear evidence of mechanism of ECT and psychology, cocain and amphetamine increase NA but nnot anti depressant
Some people dont respond to drug treatment and other systems involved
What drugs are used anxiolytics?
CNS acting or PNS acting
What CNS anxiolytics are there?
Benzodiazepines, GABAa receptor agonists (sedation, impaired coordination), buspirone (5-HT partial agonist), Autoreceptor modualtion (nausea, lag, restlessness)
What PNS anxiolytics are there?
Beta blockers for anxiety symptoms (bronchospasm, baradycardia, fatigue)
