L16 - L Flashcards
Alcohol
- fat & water soluble, readily diffuses across all cell membranes
blood alc conc.
- grams of alcohol in 100ml of blood
- 80mg alc in 100ml blood = 0.08%
> 0.15% = significant impairment
0.30& = loss of consciousness
- alcohol agonises GABA receptor , sending inhibitory neurotransmission
- increases influx of chlorine ions (a CNS depressant) that reduces action potential
- causes activity in different neuronal systems (glutamate , dopamine)
Alcohol Excess in Effect
- Wernicke’s & Korsakoff Diseases
- alcohol excess inhibits thiamine conversion to thiamine pyrophosphate in small intestine
- interrupts thiamine liver storage. causing deficiency
- thiamine peripheral neuropathy and dementia
also sleep disturbances , malnourishment , confusion
Alcohol Metabolism
- acetaldehyde
- alcohol becomes acetaldehyde by alcohol dehydrogenase
- acetaldehyde has negative effects : nausea , vomiting , headache - Acetaldehyde is further converted into Acetic acid by aldehyde dehydrogenase
- women have 50% less alcohol dehydrogenase than men.
- women have higher fat:muscle ratio meaning more alcohol in blood
Treating Alcohol Withdrawal
- mainly use BDZ’s
they have similar effect to alcohol
- BDZ’s and alcohol increase GABA transmission
chlordiazepoxide used for 7 day reducing dose daily
Diazepam used for 6 month detox
- 30mg daily reduced by 2mg fortnightly
Disulfiram
- Irreversibly inhibits aldehyde dehydrogenase
inhibiting aldehyde dehydrogenase
- causes acetaldehyde accumulation
- this will cause nausea , vomiting , headache
- taking disulfiram will help prevent patient drinking alcohol
Drug Dependence Mechanism
- ventral tegmental and substantia nigra
- dopamine signalling from Ventral Tegmental area to Nucleus Accumbens is increased by drug action
- glutamate from Nucleus Accumbens causes prefrontal cortex to “remember” the behaviours leading to dopamine flood
- excess glutamate neurons in PFC stimulates the Nucleus accumbens into dependence cycle
Dependence Vs. Addiction
-
Dependence : physical need the body develops towards a substance
- mediated by dopamine release with certain substances
Addiction : altered behaviour resulting from psychological need for substance
Stimulant Drug Dependence
- lose dopamine sensitisation over time
- cocaine , nicotine
cocaine - inhibits dopamine reuptake transporters
nicotine - stimulates ACh receptor neurons to stimulate dopamine receptor neurons
causes dopamine flood in the brain
Depressants Drug Dependence
- increase sensitivity over time
- BDZ’s , alcohol , barbituates
BDZ’s
- CNS develops tolerance to BDZ’s sedation over time
- leads to withdrawal
Alcohol + Barbituates
- increase GABA receptor leading to GABA hypersensitivity
Opioids Drug Dependence
- morphine
- morphine blocks cAMP 2nd messenger production
- neurons try to change cAMP imbalance so produces more cAMP
- when morphine is absent too much cAMP will be generated by neurons inducing withdrawal symptoms
Cannabis Drug Dependence
- THC , CBD , CBN
acts on cannabinoid receptors CB1, CB2 in brain
- peripherally bind signalling molecules , causing dopamine release
- leads to dopamine sensitisation and eventually becomes tolerant
- will have to take more drug to have same effect
5 Sleep Stages
- 5-10min : transition from awake to sleep (loss of muscle tone)
- 20min : light sleep, HR & temp drop
- 30min waves : deep restorative sleep
- REM : 25% of total time (rapid eye movement), inc. brain activity
Neurotransmitters in Sleep Cycle
- cholinergic
- dopaminergic
- noradrenaline
- GABA
- Melatonin
- Orexins
Cholinergic - slows during non-REM but maintains alertness
Dopaminergic - involved in arousal , rises in the morning signalling brain to awaken
Noradrenaline - associated with awakeness
GABA – inhibitory nt in brain. calms neuronal activity, promoting sleep
Melatonin - released from pineal gland (regulates circadian rhythm)
Orexins- from hypothalmus - promotes wakefulness and regulates arousal
Sleep Disorders
- Insomnia
- can be from psychiatric disorder
insomnia is a symptom
- affects quality and quantity of sleep
Transient Insomnia
- in people who normally sleep well but having trouble from stimulus (noise)
- use very short term Z-hypnotics
Short-term Insomnia
- related to emotional problem or medical
- Z-hypnotic given for up to 3 weeks
Chronic
- underlying complaint must be treated
- hypnotics have little effects
Treatments for Sleep Disorders
sleep hygiene : dont eat before bed , turn off devices an hour before sleep, block all light , no caffeine late in the day
cognitive therapies : CBT
Drugs : inc. brain inhibition via GABA
- or dec. excitement from 5-HT/histamine
Drug Intervention in Sleep Disorders
- BDZ’s
- inc. time in stage 2 but suppresses stage 3 and decreases REM sleep
Mechanisms of Action in Both
- Binds to GABAa receptor , enhncing inhibitory effects
- activating GABAa allows Cl_ ions into neuron , reducing excitability
- short term use
- affects driving ability
Drug Intervention in Sleep Disorders
- Hypnotics
- decreases stage 1, inc. time in stage 2 , little effects on stage 3 or REM
Hypnotics
- same MOA as BDZ’s (inc GABA)
- nitrazepam has half-life of 26hrs so longer acting
S/E: headache, confusion
- nitrazepam causes residual hangover effect
- respiratory depression if given IV
Drug Intervention in Sleep Disorders
- Z-Drugs : zopiclone , zolpidem
an alternative to BDZ’s
- lower risk of dependence + tolerance
- agonises GABA . increasing Cl- influx into cells , slowing transmission
- rapid onset + short duration
Drug Intervention in Sleep Disorders
- antihistamines
- only use ones that cross BBB
- these drugs antagonise H1 causing sedation
- promethazine 5-10mg at night
- diphenhydramine 25-50mg at night (affects cognitive function)
Stages of Dementia
- cognitive impairment
Mild : memory loss noticeable (could be normal ageing at this point)
Moderate : memory lapse and confusion
- personality changes
Severe : memory and personality deteriorate further.
- impaired ability to communicate
Dementia Associated Diseases
Vascular Dementia - CT or MRI scan. reduced blood flow to brain
Dementia w/ Lewy Body’s
- SPECT scan (more sensitive than CT/MRI)
- neuronal deposits of d-synuclein
Frontotemporal Dementia
- usually 45-64 yr olds
- CT/MRI to assess damage in frontal + temporal lobes
Causes of Dementia
Alzheimer’s Disease
- progressive decline in cognitive ability
- plaques around neurons (extracellular) made from amyloid beta protein
- tangles within neurons (intracellular) made from tau protein
Amyloid : causes angiogenesis , tumour suppression & aids recovery
Tau : promotes myelination , insulin signalling , protects DNA
Alzheimer’s Disease Cuase
- Amyloid incorrect cleaving
- Tau hyperphosphorylation
Amyloid precursor protein (APP) is cleaved incorrectly by secratases
- beta amyloid plaques extracellularly can inhibit neurotransmitter transport
- reduces angiogenesis , tumour suppression etc
Hyperphosphorylation of Tau
- not usually phosphorylated
- tau helps make microtubules but when hyperphosphorylated , the tubules break
- this will disrupt nt transport
- helps cause AD + dementia
Parkinson’s Disease
- umbrella term for loss of structure/function in neurons over time
includes Alzheimer’s , parkinsons , huntingtons
AD = beta amyloid plaque formation and hyperphosphorylated tau tangling up
PD = lewy bodies near nucleus of cells found with toxic alpha synuclein aggregates
- also caused from oxidative stress neuroinflammatory effects
- mitochondrial dysfunction from warped gene
Alzheimer’s Disease Treatment
- Memantine
- affinity for NMDA receptors
SEVERE Dementia
- NMDA receptor blocked by memantine
- too much NT acting on NMDA allows calcium ions in , causing cell death
- in AD there is inc. glutamate causing the calcium entering. leads to apoptosis
- memantine blocks NMDA receptor at rest (-70mV) and at pathological conditions (-50mV)
- magnesium only blocks NMDA at rest
Alzheimer’s Disease Treatment
- AChE Inhibitors
- donepezil
Mild/Moderate Dementia
AChE inhibitors : stop breakdown of ACh
- donepezil - 5mg before bed
- increase weekly max 20mg
- AChE inhibitors increase ACh conc. by inhibiting ACh Esterases
- dementia has been shown to degrade ACh pathways cholinergic receptors
Parkinson’s Symptoms
- PD , Vascular parkinsons , lewy body dementia , fronto-temporal dementia
bradykinesia - slow movement
tremor at rest
postural instability
hypokinesia
How Parkinson’s Disease Develops
- nigra-striatal dopaminergic pathway leads to muscle coordination loss
- treated with Levodopa
- substantia nigra and stratum have dopaminergic transmission between them
- this controls motor functions. over time substantia nigra cells die
- this stops dopaminergic pathway, limiting motor ability
Factors Triggering Parkinsons
- Normal dopamine metabolism
- environmental factors
- genetic
Normal Dopamine Metabolism
- generates reactive oxygen species that damages mitochondria
- damaged mitochondria produce more ROS causing oxidative stress
Environmental Factors
- toxins
- pyridine related compounds
Genetic Variants
- genes that are inherited
- unchecked inflammation leads to neurotoxic factors
Levodopa Overview
- given as Sinemet (co-careldopa) a dopamine reuptake inhibitor to stop it being degraded before it reaches target
- acts on dopamine receptor
- dopamine doesn’t cross BBB so uses a dopamine transporter
- can be metabolised by MAO , COMT , AADC
- dont want it to be released too early as it can cause peripheral side effects
- so it is formulated as co-beneldopa or co-careldopa
L-dopa Combo Treatments
- prolong the action of L-dopa
Dopamine Agonists
- rotigitone patch , apamorphine sc injection
MAO-B Inhibitors
- selegiline
- blocks L-dopa metabolism
COMT Inhibitors
- entacapone
- blocks metabolism of L-dopa
Acute Care of Parkinsons
- if patient is nil by mouth
- dizziness and falls
- nausea and vomiting
Nil By Mouth
- use sc apomorphine + rotigitone patch
Dizziness
- likely in PD and Elderly
- avoid drugs that cause hypotension
Nausea + Vomiting
- use domperidone oral 10mg every 8hrs
- max 1 week due to cardiac tissue
- cyclizine 50mg every 8 days (25mg in elderly)
Principles for Prescribing in Elderly
less body water = higher conc. of water-soluble drugs
less lean body mass = lower binding and inc. plasma conc. of muscle bound drugs
shrinkage in kidneys = less blood filtration and excretion
Alzheimer’s Disease
- loss of neurons + neurotransmitters causing dementia and alzhiemer’s
cholinergic hypothesis
- cognitive deterioration is due to progressive loss of cholinergic neurons , decreasing ACh
AVOID : drugs that block a1 adrenoceptors (because it will decrease ACh release)
- drugs with anticholinergic s/e
- drugs that are sedating
Dangers of Counterfeit Medicine
inc. drug resistance especially in antibiotics
undermines public confidence
may not have same efficacy
incorrect additives can cause adverse reactions
it may not work causing the persons condition to deteriorate
Methods of Counterfeiting
- recycled meds
- imported meds
- false relabelling
- stolen meds
- online pharm
Recycled - pooled and sold back to supplier danger it can be out of date
Imported : not made with same regulations which can be bad for quality assurance
Relabelling : masks unauthorised suppliers
Stolen : lack of supply chain control
Online : hard to regulate , no px required , patient could fake details to get drugs
