Lectures 17-24 Flashcards
What are the 3 different types of cannabinoids and what are they?
o Phytocannabinoids- cannabinoids derived from plants
C21 terpenophenolic compounds
• e.g. THC, CBD, CBG, CBDV, THCV, CBC, CBN and THCVA
140 different phytocannabinoids
o Synthetic cannabinoids (from the lab)
Mostly CB1 agonists
• e.g. Nabilone, HU-210, AB-PINACA, JWH-018
Abused in society and potentially quite toxics
• Many synthetic cannabinoids are full agonists of cannabinoid receptors
o Endocannabinoids (in the brain and body)
Neuromodulatory lipids
• E.g. anandamide, 2-AG, noladin ether
How many cannabinoids are there in a plant? How many molecules in cannabis? How many cannabis strains?
• There are more than 100 cannabinoids in the plant- the vast majority are not intoxicating
o Each has its own therapeutic potential
o 500 molecules in cannabis, some of which are bioactive such as the terpenoids and flavonoids, which might also be considered in the actions of new cannabis based medicines
o Different cannabis strains (more than 2000) have different cannabinoid profiles
Describe the composition of street cannabis
o Street cannabis has high amounts of THC (14.9%) and low CBD (<0.1%)
What is the acid precursor to THC? How are they used?
o THC-A is the acid precursor to THC
In the biosynthesis of the plant, you have enzymes like THC-acid synthase and CBD-acid synthase that create acid precursors-> those are then decarboxylated with exposure to light and heat into the neutral forms (THC and CBD)
Why is CBD better than THC?
• CBD might make cannabis more healthy
o Cannatonic- more balanced strain of cannabis (1:1 THC:CBD)
o Industrial hemp: high CBD: low THC
o CBD is not psychoactive
o CBD could be a good anxyolitic compound
What percentage of cannabis is used for pain in Australia?
• Cannabis and its uses in Australia- o Pain (34%)
What percentage of cannabis is used for anxiety disorders in Australia?
o Anxiety disorder (15%)
What percentage of cannabis is used for depression in Australia?
o Depression (11%)
What percentage of cannabis is used for sleep disorders in Australia?
o Sleep disorder (7%)
What percentage of cannabis is used for PTSD in Australia?
o PTSD (6%)
What percentage of cannabis is used for epilepsy/seizure disorders in Australia?
o Epilepsy/seizure disorder (5%)
What percentage of cannnabis is used for cancer in Australia?
o Cancer (4%)
What percentage of cannabis is used for gastro-intestinal disorders in Australia?
o Gastro-intestinal disorder (4%)
What percentage of cannabis is used for attention deficit disorders in Australia?
o Attention deficit disorder (3%)
What percentage of cannabis is used for spinal cord injury in Australia?
o Spinal cord injury (2%)
What is the role of endocannabinoid in homeostasis and how does it do so?
• Endocannabinoid (endCBs) system maintains homeostasis
o EndoCBs comprise a homeostatic regulatory system and subserves normal physiological functions
o EndoCBs synthesised on demand to maintain balance
o EndoCBs activate receptors in a lock and key fashion which regulate cell function in different organs of the body
o Levels of endoCBs are tightly regulated by synthetic and catabolic enzymes
o The optimal function of the endoCB system maintains health
What does THC mimic and activate?
o Δ9-THC mimics endocannabinoids and activates CB1 cannabinoid receptors
Where are CB1 cannabinoid receptors mainly expressed? What are these areas responsible for/ why are they expressed in those areas?
o CB1 cannabinoid receptors are highly expressed in the cortex, amygdala, the hippocampus, throughout the striatum, ventral midbrain and cerebellum, but lowly expressed in the brainstem Motor related regions of the brain • THC can shut down motor functions Memory related (hippocampus) Planning (prefrontal cortex) Anxiety (amygdala) Low expression of brainstem • Hard to overdose on cannabis- has no ability to shut down respiratory/cardiovascular system
Where are CB2 receptors found in the brain?
o CB2 found in the brain and microglia- neuronal expression is controversial
Might help reduce neuroinflammation
What fat molecules activate cannabinoid receptors and what do cannabinoid receptors tend to be coupled with?
o 2-AG (fat molecules) activate cannabinoids receptors
Cannabinoids receptors- tend to be coupled to inhibitory Gi proteins (G-protein coupled)
What are the functions of endocannabinoid signalling in cells?
o Functions:
Activates inwardly rectifying potassium channels: leaks potassium out of cell
• Causes cell hyperpolarisation-less likely that the cell will fire
Inhibit calcium channels
• Inhibits neurotransmitter release and have neuromodulatory function
Affect different enzymatic cascades in cells
• Inhibit adenylate cyclase-> inhibits protein kinase A cascade and changes cellular function
Are endocannabinoids retrograde or anterograde messengers?
o Endocannabinoids are retrograde messengers
CB1 receptors are largely presynaptic
Endocannabinoids are synthesised on-demand from lipids
Travel backwards from post-synaptic to presynaptic
What is the process of endocannabinoid messaging and when does it occur?
Process-
• Calcium influx into excitatory pyramidal neurons causes neurotransmitters (e.g. glutamate) to traverse across the synapse to activate post-synaptic receptors
o Feedforward
• Dysfunction of glutamate release (too much)
o Can lead to epilepsy, brain hyperexcitability and neuronal death
• Dysfunction triggers mechanism to synthesise 2-AG, liberate it from the post-synaptic membrane and then travel backwards to activate pre-synaptically located CB1 receptors
o CB1 blocks calcium channels, stops calcium influx which impedes ability of further neurotransmitter release
What does the endocannabinoid system act on to perform its function?
Endocannabinoid system is involved to act on presynapse and block the release of glutamate
• Has neuroprotective applications
On what types of cells can the endocannabinoid system be expressed on?
Can be expressed on excitatory GABAergic neurons and inhibitory GABAergic interneurons
How does 2-AG and AEA travel across synapses in the endocannabinoid signalling system and where to?
Fatty acid binding protein 5 (FABP5)
• Transports 2-AG from the post-synapse to pre-synapse
• Transports N-arachidonoylethanolamine (AEA) intracellularly to ER, where Fatty acid amide hydrolase (FAAH) lives, for degradation
What are synthetic endocannabinoid enzymes and what do they synthesise?
Synthetic enzymes
• DAGL (synthesises 2-AG)
• NAPE-PLD (synthesises AEA)
What are degradative endocannabinoid enzymes and what do they synthesise?
Degradative enzymes
• MAGL (degrades 2-AG)
• FAAH (degrades AEA)
Describe the process of the synthesis and degradation of 2-AG
o Synthesis and degradation of 2-AG
Phosphatidylinositol 4,5 bisphosphate -> diacylglycerol (DAG) by phospholipase C (PLC) action-> 2-Arachidonoyl glycerol (2-AG) by diacylglycerol lipase (DAGL) action-> arachidonic acid by monoacylglycerol lipase (MAGL) action-> prostaglandin H2 by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) action-> prostacyclin, thromboxanes and prostaglandin E2
Describe the process of the synthesis and degradation of AEA
o Synthesis and degradation of AEA
Phosphatidylethanolamine-> N-arachidonoylphosphatidyl ethanolamine (NAPE) by N-acetyltransferase (NAT) action-> Palmitoyl ethanolamide (PEA), Oleoyl ethanolamide (OEA) and arachidonoyl ethanolamide (AEA) through NAPE-Phospholipase D (NAPE-PLD) action-> arachidonic acid through fatty acid amide hydrolase (FAAH) action-> -> prostaglandin H2 by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) action-> prostacyclin, thromboxanes and prostaglandin E2
What are the system functions of the endocannabinoid?
• Endocannabinoid system functions o Sleep and circadian rhythms o Analgesia (by cannabinoid boost) o Positive mood (by cannabinoid boost) o Energy balance o Stress coping
Where are CB receptors found in the pain pathways
o Endocannabinoids and CB receptors are found at all levels of pain pathways
Spinal cord- CB2
Brainstem and brain-CB1
How do CB1 antagonists have antinociceptive effects (how do they act)
CB1R- inhibition of ascending nociceptive transmission, modification of emotional and cognitive manifestations and activation of descending inhibitory pathways at the level of the brain (which gives analgesic effect)
How do CB2 antagonists have antinociceptive effects (how do they act)
CB2R- inhibition of ascending nociceptive transmission and inhibition of neuronal sensitization at the level of the spinal cord
Describe the psychological effects of lowered AEA
o Lowered AEA (anandamides) lead to: Higher anxiety Higher HPA axis Lower neurogenesis Lower fear extinction and anhedonia Higher memory consolidation
Describe the psychological effects of increased 2-AG
o Increased 2-AG lead to: HPA response termination HPA axis habituation Modulates synaptic plasticity Lower memory retrieval Lower pain
How are endocannabinoids related to PTSD? Describe a relevant stufy
• Endocannabinoid deficiency in PTSD
o Study examined patients who developed PTSD following world trade center attacks of 9/11
Found they had lowered levels of 2-AG
Having less 2-AG being released puts less of a break on the HPA axis
• Less 2-AG means that this stress response is not being terminated
o Suggests plasma endocannabinoids deficiency ii PTSD
What are the current pharmacological strategies for boosting endocannabinoid levels and how do they do so?
• JZL184- MAGL inhibitor
o Boosts levels of endocannabinoids in tissues
• PF-3845- FAAH inhibitor
o Boosts levels of endocannabinoids in tissues
• Paracetamol and NSAIDs increase endocannaboids
o Inhibitors of FAAH which degrade anandamide
May by why there is an analgesic effect
What are examples of current medical cannabis and what are they used to treat?
Medicinal cannabis, Sativex, epidiolex • Sativex: 1:1 THC:CBD formulation o Administered as oral mucosal spray o Approved to treat spasticity (as in MS) o Neuropathic pain (but evidence less convincing) • Epidiolex: purified CBD o Drug in US, EU and Australia o Treating childhood epilepsy
What is synthetic THC used for and how does it act?
THC: CB1 and CB2 orthosteric agonist
• Synthetic THC- treats chemotherapy induced nausea and vomiting
What is CBD and how does it act?
CBD: increases endocannabinoid levels but also a CB1 receptor negative allosteric modulatory effect
• Inhibits fatty acid binding protein 5- activates cannabinoid receptors
What is JNJ-42165279 and what is it used for?
JNJ-42165279: FAAH inhibitor
• Phase II trial social anxiety disorder underway
What is ABX-1431 and what is it used for?
ABX-1431: MAGL inhibitor
• Phase 1b neuropathic pain
What are the positive and negative effects of CB1 and CB2 positive allosteric modulators?
CB1 and CB2 positive allosteric modulators
• CB1 boosts mood but it has problems in that it intoxicates
• Positive allosteric modulation of CB1 (don’t directly activate it but tone up effect of endocannabinoids- may have less sedative effects than through direct CB1 activation)
What is Dravet syndrome, what can it cause and what is it caused by? Is it responsive to current conventional medicines? What medicine improved Dravet syndrome?
o Katelyn Lambert suffers from a rare and catastrophic epilepsy disorder called Dravet syndrome
Has led to developmental delays and autistic-like features
Some children also die without warning
Mutation in Scn1a, which encodes a voltage gated sodium channel
o This syndrome is resistant to conventional medicines
Clear unmet clinical needs
o Many families like Katelyn’s have turned to cannabis to treat their children
o The Lambert family saw a dramatic improvement in Katelyn’s condition and have become fierce advocates for medicinal cannabis
What are the materials used in preclinical cannabis epilepsy program?
o Singlephytocannabinoids o Structural analogues o Phytocannabinoid combinations o Full-spectrum extracts o Screening against conventional epilepsy-relevant targets GABAA 5-HT1A Nav1.4 o Dravet mice- Scn1a+/- mice Heat-induced seizures Spontaneous seizures Reduced lifespan Behavioural abnormalities
What is the procedure fpr using Dravet mice-Scn1a mice and what information can be gotten from them?
and clobazam (benzodiazepine) anticonvulsant potentiation o Inject drug-> heat mice up-> look at threshold by which they have the seizure Increased seizure for threshold=increased anticonvulsant effect
Are CBD and clobazam better when administered independently or together? Why?
o CBD and clobazam combined have a greater magnitude effect (potentially additive)
CBD and clobazam work on their own, but greater anticonvulsant action when they work together
Mechanism for this could involve GABAA receptors
What is the effect of CBD on epilepsy?
o CBD is a novel anticonvulsant
CBD 20mg/kg reduces seizure frequency in phase III clinical trials
o Artisanal cannabis extracts in childhood epilepsy
How is carvone and myrcene made?
o DOXP/MEP pathway-> Geranyl diphosphate (GPP)-> carvone and myrcene
How is OA, PA and OLA made?
o Fatty acid biosynthesis-> olivetolic acid (OA), palmitic acid (PA) and oleic acid (OLA)
How is CBGA made?
o Geranyl diphosphate+ Olivetolic acid-> cannabigerolic acid (CBGA)
Through cannabigerolic acid synthase (CBGAS) action
How is THCA made?
o Cannabigerolic acid (CBGA)-> Δ9-tetrahydrocannabinolic acid (Δ9-THCA)
Through tetrahydrocannabinolic acid synthase (THCAS)
How is CBDA made?
o Cannabigerolic acid (CBGA)-> cannabidiolic acid (CBDA)
Through cannabidiolic acid synthase (CBDAS)
What are examples of phytocannabinoid acids?
carvone and myrcene olivetolic acid (OA), palmitic acid (PA) and oleic acid (OLA) cannabigerolic acid (CBGA) Δ9-tetrahydrocannabinolic acid (Δ9-THCA) cannabidiolic acid (CBDA)
Describe CBGA and its actions
o CBGA works at a lower dose than CBD-most interesting
CBGA has multimodal actions
• CGBA did not affect 1698 GPCRs and 74 orphan GPCRs (eurofins screen)
• Inhibited GPR55, Cav3.1 and TRPV1 but was a positive allosteric modulator of GABA
Are THCA and THC synergistic or antisinergistic in their anti-convulsant effects?
• The case for the entourage effect: an interaction between Δ9-THCA and Δ9-THCA
o 6-Hz mouse model of partial seizures
Mixture of THCA and THC are anticonvulsants
• Suggests cannabinoid synergy between THCA and THC for anticonvulsant effect
o THCA and THC have no anticonvulsant effects independently
Describe the endocannabinoid system deficiency in Dravet syndrome
• Endocannabinoid system deficiency in Dravet syndrome
o Reduced hippocampal CB1 and 2-AG in seizure susceptible mice
o Reduced CB1 and 2-AG in mice can lead to brain hyperexcitability (less of a brake on release on glutamate)
o The CB1 positive allosteric modulator GAT229 is anticonvulsant in Dravet syndrome mice
o The MAGL inhibitor ABX1431 is anticonvulsant
What is epilepsy defined as?
• International league against epilepsy (ILAE) defines epilepsy as;
o A disorder of the brain characterised by an enduring predisposition to generate epileptic seizures
o Occurrence of at least one unprovoked seizure
How many people will have a seizure in their lifetime and how many will go on to develop epilepsy?
• 10% of people will have at least one seizure during their lifetime and about 1/3 will go on to develop epilepsy
Besides epilepsy, why might someone have a seizure?
o An individual may have a seizure due to: head trauma, high fever, alcohol withdrawal, dehydration/low blood pressure/osmolyte imbalances
What are the two main types of seizures? Define them
- Focal (partial)- activation of neurons in a relatively small, discrete region
- Generalised- characterised by involvement of both hemispheres and widespread neuronal activation
What are focal seizures and what are their features?
• Focal (partial)- activation of neurons in a relatively small, discrete region
o Clinical manifestation reflects region of brain in which they occur
o Sensory or motor depending on where epileptic foci is
o Complex partial seizures- impairment of consciousness/weird auras
Familiarity (déjà vu), strangeness (jamais vu), automatisms (physical ticks), hallucinations (auditory and visual), temporal lobe epilepsy
What are generalised seizures and what are their features/stages?
• Generalised- characterised by involvement of both hemispheres and widespread neuronal activation
o Tonic stage- extension of the extremities, rigid stretching
o Atonic stage- sudden loss of muscle tone and people will fall to ground
o Clonic (myoclonic) stage- repetitive muscle twitching
o Tonic-clonic (grand mal)- distinct tonic phase followed by a clonic phase (full body spasms with intermittent relaxation)
o Generalised absence seizures (petit mal)-brief lapse of consciousness
What are the mechanisms behind epilepsy? What are examples of what can happen when these mechanisms are off balance?
• The brain has a fine balance between excitation (glutamate) and inhibition (GABA)
• Too much excitation (or too little inhibition)
o Convulsions, anxiety, high blood pressure, insomnia
• Too much inhibition (or too little excitation)
o Sleep, sedition, depression, coma, low blood pressure
How many of newly diagnosed epilepsy patients are drug resistant?
• 25-40% of newly diagnosed epilepsy patients are drug resistant
o Failure of a patient’s seizures to respond to at least two ASDs used
How is compliance to antiepileptic drug treatments monitored?
• Huge variability in disease management
o Compliance, monitor plasma levels to monitor compliance
Epilepsy is mostly disease of life- a lot of people are born with epilepsy (genetic component) although it can be acquired
What are issues/considerations of general pharmacological considerations to epilepsy?
• Doses need to be individualised
o Drug treatment can change depending on epilepsy development/changes-need to be flexible
• Toxicity issues- long term use
What are non-pharmacological treatments to epilepsy?
• Non-pharmacological treatments-
o Surgery
Risky and only used in extreme circumstances
o Vagal nerve stimulation (device)
Device inserted near the brainstem- if someone is feeling they might have a seizure, they can activate a device to give signal/pulse to brain region
o Diet- ketogenic/Atkin’s/low carb diet
o Medicinal cannabis
Describe the history of antiseizure drug development
• History of antiseizure drug development
o 1800s- bromide was used
o 1900s- phenobarbital was discovered and there are first generation/second generation ASDs
o In 1937- started to use animal models for drug screening: meant boom in drug screening/development
o In 1970s- International consortium on epilepsy- lead to another boom for antiseizure drug development- led to third generation drugs
What are the two main mechanisms of anticonvulsants?
• Mechanisms of anticonvulsants-
o Reducing excitation
o Increasing inhibition-elevate GABA in inhibitory synapse
How do anticonvulsants reduce excitation?
• Mechanisms of anticonvulsants-
o Reducing excitation
Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron
Block excitatory amino acid action (glutamate)
How do anticonvulsants enhance sodium channel inactivation? Describe an example of such drugs, how they work, and their ability to be tolerated
Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
• Sodium channel blockers-most commonly used and often first line of defense: drugs are phenytoin, carbamazepine and lamotrigine (lamactil)
o Sodium channels critical for initiation and propagation of action potentials
o Enhance voltage gated sodium channel inactivation
o Use dependent (binding is dependent on the opening of sodium channels which then leads to inactivation)
o Results in a reduction of sustained high-frequency firing of action potentials-specifically act on rapidly firing neurons
o Well tolerated- dizziness, upset stomach, headache, unsteadiness
What are two types of drugs who inhibit excitatory amino acid (glutamate) release for anticonvulsant effects?
Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron
• Levetiracetam (Keppra) and brivaracetam
• Ethosuximide (zarontine)
Describe the effects and mechanisms of keppra and brivaracetam, and their tolerance
Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron
• Levetiracetam (Keppra) and brivaracetam
o Binds to neuronal synaptic vesicle glycoprotein 2A protein (SV2A, coordinate synaptic vesicle exocytosis)
o Inhibits presynaptic CaV channels
o Reductions in neuronal excitability, reduced glutamate release
o Well tolerated-sleepiness, loss of energy, dizziness, anxiety
Describe the effects and mechanisms of ethosuximide, and their tolerance
• Ethosuximide (zarontine)
o Used in the treatment of generalised absence seizures
o T-type calcium channel block: calcium channels are low voltage and found in thalamic neurons
o Well tolerated- upset stomach, diarrhoea
What are examples of drugs that block excitatory amino acid action for anticonvulsant effects?
• Perampanel (Fycompa)-newer drug
Describe the effects of perampanel, its mechanism and tolerance capability
Block excitatory amino acid action (glutamate)
• Perampanel (Fycompa)-newer drug
o Selective non-competitive AMPA receptor antagonist
o Potent (about 200nM)
o Selective for AMPA over NMDA/kainate
o Small side effect profile
What are ways in which anticonvulsants can increase inhibition for their therapeutic effect?
o Increasing inhibition-elevate GABA in inhibitory synapse
Enhance GABA action
Inhibit GABA breakdown
Inhibit GABA uptake
List two examples of drugs that are an anticonvulsant that enhances GABA action, their mechanisms and their tolerance
- Phenobarbitone (Barbiturate)
* Diazepam (benzodiazepine)
Describe phenobarbitone’s mechanism, effect and tolerability
• Phenobarbitone (Barbiturate)-not used very much now (only used if people are in emergency department for status epilepticus-when person will not come out of the seizure) o May act alone or enhance the actions of GABA o Act on all GABAA receptors Increase affinity for GABA Increase Cl- conductance Prolongs the open time of the chloride channel o Unwanted sedative side effects Tiredness, forgetfulness Confusion and dizziness Anaemia Folic acid deficiency Decrease libido, erection problems
Describe diazepam’s mechanism, effect and tolerability
• Diazepam (benzodiazepine)-more widely used
o Enhances the actions of GABA
o Increases the frequency of channel opening
o Act on GABAA receptors containing alpha1, alpha2, alpha3, alpha5 and gamma subunits
Selective
o Binds at the interface between alpha and gamma subunits
o Patients can develop rapid tolerance
o Sleepiness, fatigue, poor coordination
Describe a drug that inhibits GABA breakdown as its anticonvulsant effect, its mechanism, its effect and tolerability
Inhibit GABA breakdown
• Vigabatrin (gamma-vinyl-GABA)
o Synthetic structural analogue of GABA
o Specific inhibitor of GABA transaminase- hence prevents GABA breakdown
o Fatigue, dizziness
o Loss of peripheral vision (up to 30% of patients that take it)
Describe a drug that inhibits GABA uptake as its anticonvulsant effect, its mechanism and its tolerability
Inhibit GABA uptake
• Tiagabine
o Derivative of nipecotic acid (transportable inhibitor)
o GAT1 inhibitor
o Increase extracellular GABA levels
o Well tolerated- sleepiness, tremor, dizziness and anxiety
List pharmacological anticonvulsants with unknown mechanisms
• Pharmacological anticonvulsants-unknown mechanisms o Sodium valproate (epilum) o Topiramate (topomax) o Felbamate (felbatol) o Gabapentin and pregabalin
Describe the mechanism of sodium valproate, its tolerability and its uses/effects
o Sodium valproate (epilum)
Mechanism:
• Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
• Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron
• Inhibit GABA breakdown
Contains no nitrogen atoms-hard to overdose on it
Identified when used as a solvent in anticonvulsant screen (1960’s)
Use-dependent sodium channel blocker
• Weaker than phenytoin and carbamazepine
Calcium channel blocker
Increases levels of GABA (unknown mechanism)
• Focused researchers on GABA, lead to newer generation anticonvulsants
Also clinically used to treat bipolar disorder (lamactil)
Fairly well tolerated-dizziness, upset stomach, headache, tremor, weight gain, hair loss
Describe the mechanism of topiramate, its tolerability and its uses/effects
o Topiramate (topomax)
Mechanism:
• Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
• Block excitatory amino acid action (glutamate)
• Enhance GABA action
Inhibit voltage-dependent sodium channels
Antagonist at AMPA/kainate receptors
Augment GABA at some GABAA receptors
Also used in the treatment of migraines, bipolar disorder, obesity/weight loss
Slightly tolerated-dizziness, confusion, problems with word retrieval, tremor, weight loss and hair loss
Describe the mechanism of felbamate (felbatol), its tolerability and its uses/effects
o Felbamate (felbatol)
Mechanism:
• Enhance sodium channel inactivation- reduce firing frequency of neurons/reduce neuronal excitability
• Block excitatory amino acid action (glutamate)
• Enhance GABA action
Inhibit voltage-dependent sodium channsl
Antagonist at NMDA receptors (NR2B)
Positively modulates GABAA receptors
Fairly well tolerated-headache, weight loss, insomnia, headache
Describe the mechanism of gabapentin and pregabalin, its tolerability and its uses/effects
o Gabapentin and pregabalin
Mechanism unknown
Synthesised as GABA analogues
No proof that they bind to GABA receptors or affect GABA breakdown or reuptake
Do increase total GABA concentrations in cerebrospinal fluid
Bind to the alpha2δ subunit ofvoltage-gated (L-type) calcium channels, thought to be associated with a decrease in neurotransmitter release (mechanism could be Inhibit excitatory amino acid (glutamate) release- blocks calcium channels and hence calcium entry into pre-synaptic neuron)
Fairly well tolerated-sleepiness, weight gain and dizziness
Where are most of the genetic mutations that predispose to epilepsy and where have they been found?
• Brain is predisposed to seizure activity because neurons are so extensively interconnected- a fine balance
• Since the first gene to cause epilepsy was discovered in 1995, more than 30-40 different genes have been found
• Virtually all known mutations that cause epilepsy are found in ion channel subunits
o There are many different mutations in proteins in the brain that have been linked to epilepsy
What are two of the biggest mutations which predispose to epilepsy?
• Mutations-
o GABAA receptor mutation
French family with GEFS+
Lysine 289 to methionine mutation (K289M) in gamma2 subunit of GABAA receptor
Decrease in GABAA receptor amplitude
o Sodium channel mutation
Family with GEFS+
Nav1.1 channel- arginine 1916 to glycine mutation (R1916G)
R1916G renders Nav1.1 non-functional: protein folding
Causes epilepsy because these mutated sodium channels are found in inhibitory GABAergic interneurons
• Affects GABAergic inhibition-less of it
Loss of function mutation
How many females experience depression in life?
• 1 in 4 females
How many males experience depression in life?
1 in 6 males
What percentage of Australians have experienced at least one anxiety disorder, mood disorder or substance mood disorder? Describe
• 45% of Australians aged 16-85 years experienced at least one anxiety disorder, mood disorder or substance use disorder
o Comorbidity between these disorders
How much more common is it to get a mood disorder if a 1st degree relative has it?
• 1.5-3 times more common among 1st degree relatives
o Strong familial components to mood disorders
What is the most common onset for mood disorder?
• Common onset- 16-25
What are the causes of depression?
• Causes- o Spontaneous o Traumatic emotional experience o Chronic stress o Symptom of other disease o Precipitated by drugs
What are the types of depressive disorders?
• Depressive disorders-
o Major depression (episode or disorder)- DSMV
o Persistent depressive disorder (dysthymia)
o Others including atypical depression, premenstrual dysphoria, disruptive mood dysregulation…
What is the DSMV criteria for major depression?
o Major depression (episode or disorder)- DSMV
At least 2 weeks of depressed mood/anhedonia + 3 other symptoms:
• Emotional symptoms
o Depressed mood: sad or empty, hopeless, tearful, irritable
o Inability to experience pleasure (anhedonia)
• Vegetative symptoms
o Significant weight loss or gain/decrease or increase in appetite
o Insomnia or hypersomnia
o Psychomotor agitation or retardation
• Cognitive symptoms
o Feelings of worthlessness/excessive or inappropriate guilt
o Inability to concentrate/indecisive
o Recurrent thoughts of death/suicide
Symptoms must affect social and occupational functioning
• Can be mild or severe
Symptoms must not be due to drugs or another medical condition
What is the DSMV criteria for persistent depression disorder?
o Persistent depressive disorder (dysthymia)
2 years depressed mood for more days than not + additional symptoms that don’t meet criteria for major depression
What is the neural circuitry which regulates mood? Describe
• Neural circuitry which regulates mood
o Frontal cortex (FC) and hippocampus (HP) involved in cognitive symptoms
o Nucleus accumbens (NAc) and amygdala (Amy) involve in emotional symptoms
o Hypothalamus (Hyp) and monoamine brainstem nuclei (Dorsal Raphae, Locus Coeruleus) involved in so-called vegetative symptoms e.g. appetite and energy
Dorsal raphe- serotonin cell body
Locus Coeruleus-noradrenaline cell bodies
What are the major neurotransmitters involved in mood regulation?
• Major neurotransmitters involved : o Noradrenaline o Serotonin (5-HT) o Dopamine o GABA
What is the HPA axis? Describe
• Hypothalamic-Pituitary-Adrenal (HPA) axis-
o Hippocampus, amygdala and monoamine brainstem nuclei input into the hypothalamic paraventricular nucleus, which releases cortico-releasing factor -> acts on the CRF receptors of the anterior pituitary-> anterior pituitary releases adrenocorticotropic hormone -> acts on the ACTH receptors off the adrenal cortex-> releases glucocorticoids which acts on glucocorticoid receptors of the hippocampus and hypothalamic paraventricular nucleus to supress their activity
o Negative feedback loop
What is the monoamine theory of depression? Describe all its versions
• Monoamine theory of depression-
o 1965- depression is caused by a functional deficit of monoamines at certain sites in the brain
But NA and 5-HT are augmented straight away while symptoms take weeks to diminish and delayed therapeutic effect coincides with monoamine receptor downregulation
o 1980s- revised to suggest the hypoNA/hypo5-HT state leads to receptor hyperresponsiveness
So antidepressants increase synaptic levels of NA and 5-HT to normal levels and downregulating the receptors to normal levels accounts for slow action of drugs
• Optimising transmitter and receptor concentrations-> bringing the receptors back to normal responsiveness
What is the neuroplasticity/neurotrophic hypothesis of depression?
• Neuroplasticity/neurotrophic hypothesis
o Neurogenesis- formation of new neurons from stem cell precursors in lateral ventricles and dentate gyrus
o Key players are BDNF (brain derived neurotrophic factor) and TrkB receptors
Major role in birth, survival and maturation of neurons
o 5-HT and noradrenaline promote neurogenesis (likely via 5-HT1A, 5-HT2B and alpha2 and beta receptors), possibly mediated by BDNF
o Stress and depression are associated with:
Neuronal loss in the hippocampus and prefrontal cortex
• Imaging studies of patients show neurodegeneration in these regions
Decreased BDNF and TrKB receptors
Decreased neurogenesis
• Decreased cell proliferation, survival and differentiation
o Depression may be related to a genetic polymorphism in BDNF which predicts chronicity
Describe the neuroendocrine hypothesis of depression
• Neuroendocrine mechanisms-
o Depression arises from a maladaptive response to stress due to HPA axis dysregulation
Chronic stress decreases hippocampal inhibition of the HPA axis (negative feedback response is reduced)
o Plasma cortisol levels are elevated in depressed people
Glucocorticoids interfere with hippocampal neurogenesis and also BDNF
Overactivity of the HPA axis reduces neurogenesis and BDNF levels-> reducing ability to respond to stimuli
o CRF levels are increased in CSF and brain of depressed people
What are the goals/origins/limitations of current therapies for depression?
- Current anti-depressants mainly target noradrenaline and serotonin/5-hydroxytryptamine (5-HT)
- Drugs developed from TCAs, discovered serendipitously 50 years ago
- Effectiveness (about 70%) of medication gave rise to monoamine hypothesis of depression (1965)
- Lack of effectiveness (about 30%) and delay in onset of therapeutic effect indicates that our understanding of the aetiology of depression is incomplete
What are antidepressants used for?
• Primary indication is major depressive disorder o Treatment o Prevention of relapse o Maintenance • Post-partum depression • Anxiety disorders • Bulimia nervosa • Pain • Depression with medical illness • Depression associated with schizophrenia
How do antidepressants work as according to the monoamine hypothesis?
• Antidepressants and the monoamine hypothesis
o Over a period of a few weeks-
Down-regulate postsynaptic NA (beta-adrenoceptors) and/or 5-HT2 receptors
• Reduction in binding sites
• Reduction in agonist response
Increase activity/sensitivity of post-synaptic 5-HT1 receptors in the hippocampus (except MAO-l’s)
Desensitisation of presynaptic alpha2 adrenoceptors and/or 5-HT1 receptors (inhibitory receptors which control NA and 5-HT release)
• Facilitate monoamine release and increased monoamine concentration
o Net effect of chronic treatment is an enhancement of monoaminergic function
Optimise monoamine levels and restore optimal receptor sensitivity
o Slow adaptive changes correspond to the timecourse of therapeutic effect
Beta 2 adrenoceptors downregulated
5-HT2 receptors downregulated
alpha2 adrenoceptors downregulated
o Monoamine hypothesis- monoamines are regulators of gradual adaptive responses, the time course of which is parallel by changes in mood
How do antidepressants work as according to the neuroplasticity/neurotrophic hypothesis?
• Antidepressants and the neuroplasticity/neurotrophic hypothesis
o Antidepressants enhance BDNF signalling, TrKB receptors and neurogenesis
BDNF stimulates gene transcription of SERT and tryptophan hydroxylase in raphe nuclei
5-HT receptor activation stimulates BDNF expression
Thus by increasing 5-HT synthesis, release and cell function, antidepressants may work to restore network function, hence mood
o 5-HT and noradrenaline promote neurogenesis
5-HT1A and 5-HT2B stimulation
beta-adrenoceptor stimulation
alpha2-adrenoceptor blockade
How do antidepressants work as according to neuroendochrine hypothesis?
• Antidepressants and the neuroendocrine mechanisms
o Antidepressants are associated with phosphorylation of Glucocorticoid receptors (GR) via PKA, increasing expression of GR inhibitors to promote neurogenesis in the hippocampus
o Antidepressants promote hippocampal neurogenesis which is necessary for restoration of HPA axis function (that is to inhibit stress response)
What are the antidepressant drug classes?
- Monoamine reuptake inhibitors
- Monoamine oxidase inhibitors (MAOIs)
- Tetracyclic antidepressants
What are examples of TCAs used for depression and what is their structure and danger?
o Tricyclic antidepressants (TCAs)
Examples-
• Amitriptyline
• Clomipramine
• Doxepin
• Imipramine
o What the other tricyclic antidepressants modelled off-> in turn, it is modelled off clopromazine (first anti-psychotic developed)
o Originally developed as a antipsychotic
o Binds to serotonin-noradrenaline receptors
Named after their 3 rings
Overdose with TCAs
• Narrow therapeutic index- toxicity at 2-6x therapeutic dose
• Overdose often deliberate, sometimes accidental
• TCAs strongly potentiate alcohol effects
o Combination can cause death from respiratory depression
What are the types of monoamine reuptake inhibitors used for depression?
• Monoamine reuptake inhibitors-
o Tricyclic antidepressants (TCAs)
o Selective serotonin reuptake inhibitors (SSRIs)
o Serotonin and noradrenaline reuptake inhibitors (SNRIs)
o Noradrenaline reuptake inhibitors (NRIs)
What are examples of SSRIs?
Examples- • Citalopram • Fluoxetine o First one-> revolutionised prescription of antidepressants • Paroxetine • Sertraline
What are examples of SNRIs?
o Serotonin and noradrenaline reuptake inhibitors (SNRIs)
Examples-
• Venlafaxine
• Desvenlafaxine
• Duloxetine
Tend not to bind to other receptors that TCAs bind to
What are examples of NRIs?
o Noradrenaline reuptake inhibitors (NRIs) Examples- • Reboxene • Atomoxetine Questionable efficacy
What are examples of monoamine oxidase inhibitors (MAIOs)?
• Monoamine oxidase inhibitors (MAOIs)
o Examples for irreversible, non-selective inhibitors for MAOA and MAOB-can be deadly
Phenelzine
Tranylcypromine
o Examples for reversible inhibitor of MAO-A (RIMA)
Moclobemide
What are examples of tetracyclic antidepressants?
• Tetracyclic antidepressants o Examples- Mirtazapine Mianserin o 4 rings- less likely to bind to other receptors than target due to lack of long tail
What are general considerations that need to be considered with the use of antidepressants?
• Dosage
o Start with lowest dose and gradually increase
o Abrupt cessation can lead to withdrawal
• Combination of drugs not recommended
• Suicide risk
o Study showed increased suicide risk in persons taking antidepressants
o Suicide by overdose may be attempted
• Treatment resistance
o About 30% of patients do not respond to antidepressants
o May be due to genetic polymorphisms in SERT, NAT, BDNF, tryptophan hydroxylase (rate-limiting enzyme in 5-HT synthesis)
• Prevention of relapse
o Treatment must be taken for at least 6 months to prevent relapse: at least 2 years to see long-term changes in the neural circuitry to prevent further relapse up
o Increased number of episodes increases the chance for more episodes
What are the effects of antidepressants on normal and depressed individuals?
• Do not produce euphoria
• Have no antidepressant effects in non-depressed individuals (except MAO-ls, transiently)
• Have no reinforcing effects (that is, not likely to cause dependence)
• In depressed individuals they:
o Elevate mood
o Increase physical activity
o Improve appetite and sleep patterns
o Reduce morbid preoccupation
o Reduce vegetative, cognitive and emotional symptoms
How do monoamine reuptake inhibitors work?
• Block presynaptic noradrenaline and/or 5-HT transporters-> increase levels of NA and 5-HT in the synapse
• Tricyclics also block mACh, 5-HT and histamine receptors and alpha-adrenoceptors
o Get lots of side effects using tricyclics
How do selective serotonin reuptake inhibitors work?
• Selective serotonin reuptake inhibitors-
o Only block the serotonin transporter at therapeutic doses
Reduction in some of the side effects and reduction in toxicity
Purity of effect increase popularity
o Little action on mACh and histamine receptors
o Have a preferred action of 5-HT on receptors- but this can cause side effects
o NAT: SERT potencies <0.02: that is, > 50 fold selectivity for SERT
o TCAs NAT; SERT potencies 10-0.2 (that is some up to 10x more selective for NAT< some equipotent and others up to 5x more selective for SERT)
How do monoamine oxidase inhibitors work?
Mechanisms of Monoamine oxidase inhibitors-
• Inhibit breakdown of NA, 5-HT and DA-> increase cytoplasmic pool of monoamines-> increase leakage of monoamines into the synapse/extracellular space
How do tetracyclic antidepressants work?
Mechanisms of tetracyclic antidepressants-
• Auto- and hetero- receptors
o When activated by noradrenaline, they prevent further release of the monoamine-> prevent further release of noradrenaline (autoreceptor if it’s on a noradrenaline neuron) and serotonin (heteroreceptor if it’s on a 5-HTergic neuron)
Knockout negative feedback mechanism
• Block alpha2 adrenoceptors-> Increased NA and 5-HT release-> preferred action on 5-HT1 as 5-HT2 and 5-HT3 are blocked
o Selective increase in 5-HT1 receptors and activity has been shown to be important for mitigating mood and anxiety symptoms
What are complementary medicines used in depression treatment?
- St John’s Wort- hypericum perforatum
- 5-HTP (5- hydroxytryptophan)
- Rhodiola
- Omega 3 fatty acid and vitamin D
How does St John’s Wort work?
• St John’s Wort- hypericum perforatum-
o Clinically effective for mild-moderate depression (clinical trials, cf placebo and active controls)
o Short term: inhibits 5-HT, NA, DA, GABA a glutamate re-uptake
Reduces sodium gradient -> reduces transport of neurotransmitters
o Long term- downregulates postsynaptic beta adrenoceptors, increases postsynaptic 5-HT1A and 5-HT2 receptors
Reduction of postsynaptic beta adrenoceptors is correlated with onset of therapeutic effects
Increase in 5-HT1 receptors are important for therapeutic action
o Very low frequency of adverse events
Chosen frequently in children
o A few drug interactions
Induces CYP3A4 so decreases plasma levels of drugs metabolised by this enzyme
How does 5-HTP work?
5-HTP (5- hydroxytryptophan)
o Precursor to 5-HT to boost 5-HT levels
How does rhodiola work?
• Rhodiola
o MAO inhibitor
How does omega 3 fatty acid and vitamin D work on depression?
• Omega 3 fatty acid and vitamin D
o Supplements including fish oil and vitamin D can boost effects of antidepressant medications
What are the major and minor side effects of TCAs in depression treatment?
Major:
-Anticholinergic (blurred vision, dry mouth constipation, sweating, urinary retention)
-Cardiovascular (hypertension, tachycardia, arrhythmias)
Minor:
-CNS (confusion, anxiety, restlessness, insomnia, drowsiness)
-Gastrointestinal (nausea, vomiting, anorexia, diarrhoea)
-Endocrine (disturbances of libido and potency)
What are the minor side effects of MAO-ls in depression treatment?
Minor:
Anticholinergic (blurred vision, dry mouth constipation, sweating, urinary retention)
Cardiovascular (hypertension, tachycardia, arrhythmias)
CNS (confusion, anxiety, restlessness, insomnia, drowsiness)
Gastrointestinal (nausea, vomiting, anorexia, diarrhoea)
Cheese reaction/hypertensive reaction
What are the major and minor side effects of SSRIs in depression treatment?
Major:
CNS (confusion, anxiety, restlessness, insomnia, drowsiness)
Gastrointestinal (nausea, vomiting, anorexia, diarrhoea)
Minor:
Endocrine (disturbances of libido and potency)
Increased violence and aggression/suicide
What are the minor side effects of other depression treatments?
CNS (confusion, anxiety, restlessness, insomnia, drowsiness)
Gastrointestinal (nausea, vomiting, anorexia, diarrhoea)
Endocrine (disturbances of libido and potency)
Increased serum cholesterol
What are depression treatment side effects mostly caused by?
• Side effects mainly through interference with autonomic control
What is the effectiveness of MAOIs depression limited by?
• Usefulness of irreversible MAOIs is limited by their adverse effects and interactions with sympathomimetic agents
o In concert with sympathomimetics such as amphetamines a greater release of monoamines occurs as these agents affect vesicular stores, causing further leakage and release of monoamines
o Leads to a great rise in blood pressure
What can SSRI overdose cause and why?
• Overdosing with SSRIs
o Can cause serotonin syndrome: hyperpyrexia, hyperreflexia, tremor, shivering, myoclonus, agitation, seizures, confusion and delirium, cardiovascular collapse and coma
o Due to serotonin toxicity
Overstimulation of 5-HT1A receptors in central grey (midbrain) and medulla
Possibly overstimulation of 5-HT2 receptors
o Can be caused by:
Excess 5-HT precursors or agonists (e.g. LSD, buspirone, L-tryptophan)
Increased 5-HT release (e.g. amphetamines, MDMA)
Reduced 5-HT reuptake (eg. SSRIs, TCAs)
Reduced 5-HT metabolism (e.g. MAOIs)
What are the contraindications of TCAs?
TCAs/MAOIs (convulsions, hyperpyretic crisis, stroke and death)
SSRIs/SNRIs (CYP2D6 inhibition increases plasma concentration)
Cardiovascular disease (myocardial infarction, heart disease)- Do not take TCAs and MAOIs because of noradrenergic effect
Epilepsy (TCAs and MAOIs lowers seizure threshold)
Glaucoma- do not take with TCAs and MAOIs because of anticholinergic effect
Urinary retention- do not take with TCAs and MAOIs because of anticholinergic effect
What are the contraindications of MAO-ls?
TCAs/MAOIs (convulsions, hyperpyretic crisis, stroke and death)
Cardiovascular disease (myocardial infarction, heart disease)- Do not take TCAs and MAOIs because of noradrenergic effect
Epilepsy (TCAs and MAOIs lowers seizure threshold)
Glaucoma- do not take with TCAs and MAOIs because of anticholinergic effect
Urinary retention- do not take with TCAs and MAOIs because of anticholinergic effect
Liver disease
What are the contraindications of SSRIs?
TCAs/MAOIs (convulsions, hyperpyretic crisis, stroke and death)
SSRIs/SNRIs (CYP2D6 inhibition increases plasma concentration)
5-HT agonists/5-HT releasing drugs (serotonin syndrome)
What are the contraindications of other treatments of depression?
SSRIs/SNRIs (CYP2D6 inhibition increases plasma concentration)
Liver disease
5-HT agonists/5-HT releasing drugs (serotonin syndrome)
Describe the efficacy of currently used antidepressant drugs and what they are compared against?
• TCAs used as gold standard to measure antidepressant effects against
• Newer drugs have reduced side/adverse effects, but not reduced number of treatment resistance persons
o Still 30% of people that do not respond to the treatments
• MAOIs effective in atypical depression with fewer side effects
• SSRIs very effective in reducing anxiety, agitation, retardation associated with depression
o Good therapeutic index-less danger of overdose
• SSRIs as effective as TCAs in treating moderate depression, but possibly less effective than TCAs in treating severe depression
• Reason of efficacy of antidepressants should be considered
o One study showed that some antidepressants weren’t that much more effective to placebo
• Safety in question- Peroxitine increased suicidal tendencies in younger people
What are current events and developments in the treatment of depression?
presenting a challenge for understanding the aetiology, diagnosis and treatment of this condition
• Last 10 years of mood disorder research has moved beyond the monoamine hypothesis of depression. Now investigating:
o Signal transduction mechanisms: kinases, transcription factors, growth factors
o Neurogenesis
• CRF1 antagonists to block HPA- and centrally-mediated stress responses
What is sedation?
• Sedation- reduction in excitement, vigilance and physiological arousal so that person is relaxed, calm or possibly sleepy
What is hypnosis?
• Hypnosis- ability to induce drowsiness and sleep
What parts of the brain and their neurotransmitters are important for sleep? How does this work?
Lesions of the anterior hypothalamus leads to insomnia
• Anterior hypothalamus promotes sleep
o Sleep promoting system: GABA, adenosine and melatonin
Adenosine- levels decrease with sleep and increase with sleep deprivation
• As they increase, adenosine levels increases drive to go to sleep by inhibiting ACH release in the substantia innominata which leads to sleep
What parts of the brain and their neurotransmitters are important for arousal? How does this work?
Lesions of the posterior hypothalamus produces somnolence
• Posterior hypothalamus promotes wakefulness
o Activating/wakefulness- ascending reticular activating system (ARAS): NorA, 5HT, ACH, dopamine and histamine -> causes overall wakefulness
Locus coeruleus- release noradrenaline
• Important for wakefulness
Ventral tegmental area- release of dopamine
Part of the hypothalamus- histamine
Raphe nucleus- 5HT
o Hypothalamus and ARAS system interact through orexin
Orexin is released from lateral hypothalamus and positively regulates ARAS systems to stimulate wakefulness
What does insomnia mean?
• Insomnia- unsatisfactory sleep onset, maintenance or early waking
When is insomnia a problem, in how many people/what gender is insomnia a problem, how can it occur, how is it treated and what diseases is it associated with?
o Insomnia is a problem if it causes distress or impairs activity (6-15% of Australians suffer from this level of insomnia)
o More common in women and in older age
o Can be triggered by a stressful life event
o Would need a sleep diary and may need a sleep study
o Diseases associated with insomnia include anxiety and depression
What are treatments for insomnia?
• Treatments for insomnia
o Cognitive behavioural therapy- reduce conditioned association between bed and lack of sleep (less than 15 minutes in bed awake)
o Pharmacotherapy
What drugs are used to treat insomnia?
Barbiturates: used widely 1903 to 1950s Benzodiazepines: used in 1950s Z-drugs: used in 2000s Melatonin Antihistamines
How do barbiturates work with insomnia and what are its side effects?
Barbiturates: used widely 1903 to 1950s
• Increases length opening and increases channel activity without GABA (at high doses)
o Barbiturate without GABA release leads to greater hyperpolarisation or inhibition of excitability
o Barbiturate with GABA release leads to even greater hyperpolarisation or inhibition of excitability
Makes it a significantly more dangerous drug
• Overdoses of barbiturates will place patient into coma and death, and it is sometimes used for euthanasia
How do Z-drugs work with insomnia and what are its side effects?
Z-drugs: used in 2000s
• Chemically not benzodiazepines but act at benzodiazepines
• Many of the same benefits and problems of benzodiazepines
o Probably less memory/cognition side effects, short half-life so less day-time sedation
o Show some preference for alpah1 (sedative/hypnotic, anticonvulsant) but truly selective drugs still in development
o May produce bizarre sleep behaviours
Urinating, defecating… whilst awake (but they think they’re asleep)
How do melatonin work with insomnia and what are its side effects?
Melatonin
• Endogenous melatonin synthesised in the pineal gland (light, via thalamus reduces melatonin production in pineal gland)
• Role unclear but participates in circadian rhythm and sleep
• 2 GPCR receptors:
o MT1: activation promotes sleep onset
o MT2: activation shifts circadian timing
• Administration can reset seep pattern but use in non-circadian insomnia unsure
• High doses can cause endocrine problems
• Ramelteon, synthetic analogue, used for sleep onset problems and has less rebound insomnia, but not controlled substance
o Not great yet for developed insomnia
How do antihistamines work with insomnia and what are its side effects?
Antihistamines
• Histamine arousing- part of ARAS
o Tuberomamillary neurons that release histamine are active during wake, low in NREM, silent REM
• First generation H1 inverse agonists block this arousing effect
o Able to cross BBB really well-> bind to histamine receptors in the brain
• Most of the over-the-counter sedatives/hypnotics
• Cross the BBB as lipophilic, low molecular weight not P-glycoproteins target
• Less effective than benzodiazepines (not targeting all systems)
• More day-time sedation, fog, memory issues even when drug no longer present
• Lots of side effects: dry mouth, constipation, blurred vision, urinary retention
o Tricyclics and antipsychotic are also H1 antagonists- produce same side effects
What are benzodiazepines and what is their effect on insomnia/any considerations?
• Benzodiazepines
o Major class of clinically prescribed hypnotics in Australia
o Rapidly replaced barbiturates due to lower risk of abuse, overdose and induction of liver enzymes
o Can promote the onset of sleep and ongoing sleep
o Huge number available but mainly vary in pharmacokinetics (and possible receptor sub-type activity)
How do benzodiazepines act to treat insomnia?
o When benzodiapenes are bound with GABA in the GABAA receptor, the GABAA receptor is more greatly activated
Benzodiazepine acts allosterically with GABA- boosts the affinity of GABAA to the receptor and changes how the channel opens
• Benzodiazepine increases affinity and as a result number of openings
Benzodiazepine with GABA release leads to greater hyperpolarisation or inhibition of excitability
Describe the subunits of the GABAA receptor?
o 15 subunits- α1-6, β1-3, γ1-3, δ, ε, θ
o Most receptors made up 2 α, 2 β, 1 γ subunits
o γ subunit replaced with δ, ε or θ in different brain regions (no γ2 no binding site)
What is the effect of different types of alpha subunits in the GABAA receptor?
o The alpha subunit matters-
Genetic knockout and selective drug studies show:
• α1-> sedative/hypnotic anticonvulsant
• α2 and α3-> anxiolytic
• α3 and α5-> myorelaxant
Development of subtype selective agents now a major therapeutic target (but binding sites on α subunits similar so new drugs looking for differential efficacy over affinity)
What are the clinical effects of benzodiazepines?
• Clinical effects of benzodiazepines
o Hypnotic
But reduce total REM stage and alter NREM stages
o Sedative
o Anxiolytic
o Amnesic (especially with alcohol, rohypnol/flunitrazepam)
o Produce strange sleep behaviours
o Antiepileptic
o Range of effects due to expression of GABAA receptors of different make up expressed in different brain regions/neural circuits
Where are GABAA receptors expressed in the brain?
o Benzodiazepine sensitive GABAA receptors in many brain regions including: Amygdala • Emotional learning Prefrontal cortex Hypothalamus Striatum Bed nucleus of the striatum Hippocampus
What are benzodiazepines/Z drugs used for insomnia?
Estazolam Flurazepam Termazepam Triazolam Zolpiderm
What is the half-life and disadvantages of Estazolam?
Half-life: Intermediate
Disadvantages: Some daytime sedation and performance decrements
What is the half-life, advantages and disadvantages of Flurazepam?
Half-life:Long
Advantages: Delayed rebound insomnia Disadvantages: Daytime sedation, high risk of falls and driving errors
What is the half-life and disadvantages of Termazepam?
Half-life: Intermediate
Disadvantages: Some daytime sedation and performance decrements
What is the half-life and disadvantages of Triazolam?
Half-life: Short
Advantages: No daytime sedation
Disadvantages: Rebound insomnia
What is the half-life, advantages and disadvantages of Zolpiderm?
Half-life: Short
Advantages: No daytime sedation
Disadvantages: Rebound insomnia
What half-life is needed for hypnosis effects?
For hypnosis, would use intermediate half-lives
What are activating/arousal neurotransmitters?
o Activating- NorA, 5HT, ACH, dopamine, histamine and orexin
Suvorexant (antagonist to orexin)
• Similar efficacy to Z-drugs
What are sleep promoting neurotransmitters?
o Sleep promoting: GABA, adenosine, melatonin
What is fear?
o Fear-threatening stimulus: state of preparation for danger and results in arousal, vigilance, increased ability to respond and negative feelings
What are the brain parts involved in fear?
o Brain parts- Prefrontal cortex Amygdala Hippocampus Cingulate gyrus
What is the process of fear?
Cortex-> hippocampus-> thalamus-> lateral nuclear complex of the amygdala-> prefrontal cortex, hippocampus and striatum OR
Cortex-> hippocampus-> thalamus-> lateral nuclear complex of the amygdala->central nucleus of the amygdala-> hypothalamus-: periaqueductal gray and monoamine nuclei
What is anxiety?
o Anxiety- state of preparation for danger and results in arousal, vigilance, increased ability to respond and negative feelings but no immediate threatening stimulus
What is the criteria for anxiety disorders?
o Anxiety disorders-
Criteria: patients have to experience symptoms causing significant personal distress with associated impairment in function
What are examples of anxiety disorders?
Include: • Panic disorder • Agoraphobia • Social anxiety disorder • Specific phobias • Generalized anxiety disorder • Post-traumatic stress disorder
Describe how the amygdala and anxiety are linked
• Anxiety and the amygdala
o Amygdala activity up-regulated in fear disorders: appears to play a central role
o Anxiety disorders thought to result from problems with synaptic plasticity in the amygdala circuits
o Trying to understand this so we can develop new treatments
o Regulators of these neural circuits might be possible treatments for anxiety
What are treatments of anxiety?
o Cognitive and behavioural therapy
o Pharmacotherapy-
o Often pharmacotherapy and psychotherapy have similar efficacy- except specific phobias
What drugs are used in the treatment of anxiety?
Benzodiazepines Selective serotonin reuptake inhibitors Serotonin/noradrenaline reuptake inhibitors Tricyclics MAOIs Pregabalin Buspirone Alcohol (self-medication)
What are benzodiazepines in anxiety, what are their advantages and disadvantages, and how do they work?
• Not first line of treatment
• Problematic taking them in the day
• Positive- act rapidly for acute treatment
• Negative- dependence potential, drowsiness
• Drug should be chosen carefully
o Longer half-life for generalised anxiety disorders e.g. Diazepam
o High potency for panic disorder e.g. alprazolam, although not a S8 (high dependence) drug
• At least part action in amygdala
• α2 subunit in the GABAA receptor important for anxiety
• No selective drug but alprazolam and clonazepam have higher α2 affinity
• z drugs not good choice (as some show α1 preference)
How do selective serotonin reuptake inhibitors work in the treatment of anxiety, how often are they used in anxiety treatment and why?
Selective serotonin reuptake inhibitors
• Act by regulating 5HT transporters
o Blocking 5HT uptake transporters-> higher concentration of serotonin at the synapse-> activates effectors and leads to long-term changes-> results in anxiolytic effect over a period of time
• Serotonin
o Serotonin exclusively released from raphe nuclei
o Axons project widely (much more so than dopamine) and influence sleep, arousal, attention, sensory processing in the cortex, emotion and mood
• First choice for treatment of most anxiety disorders-often effective
o Less side effects than some other drugs
o May allow dual treatment for depression
o But very slow to act (as for depression)
o Sometimes side effects difficult
o Have discontinuation syndrome
• E.g. fluoxetine, paroxetine
• If not successful, try another class of drugs
What is the first line of defense in anxiety treatments, and what is the 2nd line of defense?
1st line-Selective serotonin reuptake inhibitors
2nd line-
Tricyclics
• 2nd line therapy due to side effects and other issues
MAOIs
• 2nd line therapy due to side effects and other issues
How does pregablin act?
Pregabalin
• GABA analogue but acts at α2delta subtype of VGCC to increase GABA levels
• Promotes GABA activity in the brain but not direct action
How does buspirone act for treatment of anxiety disorder?
Buspirone
• Partial 5HT1a agonist for treatment of generalised anxiety disorder
• Modest efficacy
• Gi/Go coupled receptor with strong expression in the amygdala, hippocampus, cortex, DR and septum
What is ongoing use and what is a problem with ongoing use of benzodiazepines?
• Ongoing use- maximum length should be 1 month (but unclear whether longer is a problem)
• When stopping, use should be tapered
o They are promoting long-term inhibition: start to develop counter-adaptations to the drug being there
o If suddenly stop taking it, will experience withdrawal symptoms
Headaches, twitching muscles, nausea, difficulty sleeping, bizarre dreams/visions
• Dependence liability should be considered (alprazolam and flunitrazepam now S8-same schedule as morphine…)
• Strange sleep behaviours may occur
• Amnesia
• Falls in elderly
• Combining with other sedatives (including alcohol) can be dangerous
What is schizophrenia caused by?
• Caused by:
o Complex disorder- not completely understood
o Genetics
If one twin has it, then there is a 50% chance that the other twin has it
o Pre-, peri- or post-natal insult leading to altered neural development
o Stress
o Diathesis stress hypothesis-> combination of genetic predisposition coupled with the pre-, peri- or post-natal insult that increases vulnerability in people that is then unmasked by stressful life events at critical periods of development
What are the risk factors of schizophrenia?
• Risk factors for schizophrenia-
o Gene-environment interaction
o Links- not causal factors
o Genes
Multigenic- cumulative effect of numerous small genetic changes or polymorphisms that incur a larger burden on the individual
o Environment
Prenatal/perinatal factors (maternal stress, maternal malnutrition, maternal infection, obstetric complications
Early-life stress (maternal separation, childhood trauma)
Drugs (cannabis, amphetamines)
Stressful life events
What is the DSMV criteria for a schizophrenia diagnosis?
• DSMV criteria for schizophrenia diagnosis:
o Two (or more) of the following symptoms, including at least one positive symptoms, persisting for 1 month or more:
Delusions
Hallucinations
Disorganised speech
Grossly disorganised or catatonic behaviour
Negative symptoms
o Social/occupational dysfunction
o Continual signs of the disorder persist for at least 6 months, including 1 month of symptoms that meet criterion A
o Schizoaffective and mood disorders ruled out
o Drug abuse and another medical condition ruled out
What are the symptoms of schizophrenia?
• Symptoms-
o Positive symptom (distortion of normal function)
Hallucinations (distortions of perception)
• E.g. auditory, somatic, tactile, visual
Delusions (distortions of inferential thinking)
• E.g. persecution, grandiosity, thought broadcasting, mind reading
Disorganised thought and speech
• E.g. tangentiality, incoherence, illogicity, pressure of speech
o Negative symptoms
Flattened affect
Alogia
• Restrictions in the fluidity and productivity of speech and thought
Avolition/apathy
• Restrictions in initiation of goal directed activities
Anhedonia
• Inability to experience pleasure
o Cognitive symptoms
Impaired memory
Impaired executive function
What were old treatments of schizophrenia?
• Treatments for schizophrenia
o Frontal lobotomy (20th century)
Stick probe into orbital socket and swish around prefrontal cortex
• Had enormous effect of behaviour but did not improve quality of life
o Electroconvulsive therapy (shock therapy)
What are the hypotheses for schizophrenia?
- Dopamine hypothesis for schizophrenia- version 1
- Dopamine hypothesis for schizophrenia-version 2
- Dopamine hypothesis of schizophrenia- version 3
- Dopamine hypothesis of schizophrenia-version 4
- Dopamine hypothesis of schizophrenia- version 5
What was the first dopamine hypothesis for schizophrenia, and the for and against for that hypothesis?
• Dopamine hypothesis for schizophrenia- version 1
o Excess levels of dopamine increase neurological activity which leads to the symptoms of schizophrenia
For:
• Amphetamines and other dopamine-releasing drugs induce a state resembling the positive symptoms of schizophrenia
• Antipsychotic drugs antagonise dopamine D2 receptors
Against
• No evidence of increased dopamine (DA) turnover schizophrenic brain
• Inconsistant changes in concentrations post-mortem
What was the second dopamine hypothesis or schizophrenia, and the for and against for that hypothesis?
• Dopamine hypothesis for schizophrenia-version 2
o Schizophrenia is associated with increased dopamine receptor number or sensitivity
o For:
Increased dopamine (DA) receptors are found in the schizophrenic brain
Increased binding and affinity of DA in the schizophrenic brain
o Against:
Antipsychotics upregulate DA receptors
Antipsychotics increase DA activity immediately at the synapse, but antipsychotics take a few weeks to produce a therapeutic effect
• If there’s too much dopamine/receptors are too sensitive, how come blocking the receptors or reducing dopamine amount doesn’t cause a therapeutic effect straight-away
What was the third hypothesis for schizophrenia, and the for and against?
• Dopamine hypothesis of schizophrenia- version 3
o Hypodopaminergia in prefrontal cortex (mesocortical area) causes negative symptoms
If not enough dopamine in mesocortical areas, then this leads to dishinbition-> more excitation-> overactivity in the mesolimbic system
o Hyperdopaminergia in subcortical regions (striatum-nucleus accumbens) which causes positive symptoms
o For:
Reduced cerebro-blood flow in PFC correlated with low CSF DA metabolite levels
PFC DA neuron lesions-> increased DA and D2 receptor density in striatum
Higher DA metabolite levels related to greater positive symptoms
o Against:
Evidence in humans is indirect
Relies mainly on animal studies
Multiple routes lead to striatal hyperdopaminergia
o Prevailing understanding but has been elaborated upon
What was the fourth dopamine hypothesis for schizophrenia, and the for and against?
• Dopamine hypothesis of schizophrenia-version 4
o Elevated presynaptic striatal dopaminergic function is the final common pathway in psychosis
Multiple hits (environmental hits, neonatal stress…) can cause this elevation
o Because of the abnormal dopamine release, this leads to aberrant assignment of salience to innocuous stimuli
Effort to interpret these experiences and construct plausible explanations is what leads to psychosis
With an antipsychotic (inhibiting dopamine D2 receptors will reduce dopamine release, abberant salience and hence psychosis
What was the 5th hypothesis of schizophrenia?
• Dopamine hypothesis of schizophrenia- version 5
o GABAergic deficit in hippocampus underlies DA dysregulation in the nucleus accumbens and the medial prefrontal cortex
Overall, what is the current dopamine hypothesis of schizophrenia?
• Overall, dopamine hypothesis of schizophrenia-
o Good evidence for elevated baseline of DA release intreatment-naïve schizophrenia patients and first degree relatives
o Presynaptic DA abnormalities are the major abnormalities
DA levels, synthesis or release are elevated in key brain areas e.g. NAcc, Hipp
Deficiencies in other neurotransmitters (e.g. GABA, glutamate) lead to DA dysregulation
D2 receptors are supersensitive-> blockade reduces overactivity and alleviates psychosis
What are the dopamine pathways in the CNS and what happens to these pathways when antipsychotics target them?
• Dopamine pathways in the CNS-antipsychotics inhibit these pathways
o Mesolimbic/mesocortical pathway- ventral tegmental area in midbrain to cortex and limbic system (emotion, reward, planning, attention, social behaviour…)
Therapeutic effect
o Nigrostriatal pathway- substantia nigra in midbrain to striatum (movement)
Movement side effects
o Tuberoinfundibular pathway- hypothalamus to pituitary gland (hormone regulation)
Endocrine side effects
When were antipsychotics first developed, what for and how?
Antipsychotics-
• First developed in 1952 with the advent of chlorpromazine
• Indications/uses-
o Treatment of psychosis and symptoms of schizophrenia
o Treatment of schizophrenia in treatment resistant patients who fail to respond to other antipsychotic drugs (thioridazine, clozapine)
• Chlorpromazine was the first antipsychotic drug
o Originally synthesised as an antihistamine agent
o It was shown to cause sedation and shown to abolish anti-psychotic symptoms
o It reduced psychotic symptoms in a very individual way
What is the common neurochemical effect of all antipsychotics and is this effect affinity/occupancy dependent? Describe and include discussion of side effects because of this
• All antipsychotics have antagonist effects at dopamine D2 receptors
o Linear correlation between therapeutic efficacy and affinity for the dopamine D2 receptors
the more strongly they bind to the dopamine D2 receptor, the more efficacious they are
o Clinical efficacy of drugs is consistently achieved when D2 receptor occupancy reaches up to 80% (60-80% for typicals, 40-60% for atypicals)
Some people do not respond to the treatment
o Side effects occur when D2 occupancy:
Exceeds 72% for hyperprolactinaemia
• Releasing too much prolactine because blocking D2 dopamine receptors in the anterior pituitary
Exceeds 78% for extrapyramidal movement disorders
What were the major classes of first generation antipsychotics?
• First generation-typical antipsychotics o Major classes of chemicals: Phenothiazines Butyrophenones Thiozanthenes
What are examples of phenothiazines?
- Chlorpromazine
- Thioridazine
- Fluphenazine
- Trifluoperazine
- Pericyazine
What are examples of butyrophenones?
Butyrophenones
• Haloperidol
• Droperidol
• Pimozide
What are examples of thiozanthenes?
Thiozanthenes
• Flupenthixol
• Zuclopenthixol
What were the effects of first generation antipsychotics and how did they work?
o Ameliorate positive symptoms of schizophrenia but have little effect on negative and cognitive symptoms
o Potent dopamine D2 receptor antagonists
80% receptor occupancy at therapeutic doses
Slow dissociation from receptors
• Responses to dynamic changes in transmitter levels are reduced
o Moderate affinity for alpha-adrenergic and 5-HT2 receptors
o Weak to moderate affinity for D1 and D4 receptors, histamine H1 and mACh receptors
What are the first line treatments for schizophrenia and why?
• Second generation- atypical antipsychotics
o First line treatment for schizophrenia
Clozapine and olanzapine most effective but must be monitored
Quetiapine and olanzepine are the most commonly prescribed antipsychotics
• Risperidone is also used quite a bit
o Atypical antipsychotics ameliorate both positive and negative symptoms of schizophrenia
o Greater therapeutic efficacy compared to typical antipsychotics
Fewer side effects
• Lower receptor occupancy- greater compliance
More effective in treatment resistant patients (approximately 30% of patients)
• Clozapine reserved especially for this
What are the major drug classes of second generation antipsychotics?
o Major classes of chemicals- Diazepines Dibenzothiazepines Benzamides Benzisoxazols Quinolinon derivative
What are examples of diazepines?
Diazepines • Clozapine (dibenzo-) o Doesn’t cause movements side effects o Made new line of antipsychotics • Olanzapine (thienobenzo-)
What are examples of dibenzothiazepines?
Dibenzothiazepines
• Quetiapine
What are examples of benzamides?
Benzamides-
• Amilsulpride
What are examples of benzisoxazols?
Benzisoxazols-
• Risperidone
• Paliperidone
What are examples of quinolinon derivatives?
Quinolinon derivative-
• Aripiprazole
o First example of dopamine D2 receptor partial agonist
How do atypical (second generation) antipsychotics act? Highlight the actions of benzamides and clozapine especially
o Can take up to 6 months to start seeing reduction in symptoms
o Receptor actions of atypical antipsychotics
Benzamides- antagonise dopamine D2 receptors with high affinity and/or selectivity
• 60% receptor occupancy at therapeutic doses
High affinity for 5-HT2 receptors (except benzamides)
• D2 and 5HT2 receptor affinity and occupancy that led to the development of a whole range of drugs of the atypical antipsychotics- a lot of the drugs have higher affinity for 5-HT2 receptors than they do at the D2 receptors and there is 90% occupancy at the 5-HT2 receptor
• But still need dopamine D2 action, but 5-HT2 antagonism might balance out side effects of D2 targeting
Moderate affinity for alpha-adrenergic (except benzamides) and dopamine D3 receptors
Clozapine and olanzapine have high affinity for dopamine D4 receptors
• These are the two most effective drugs in the treatment of psychosis and schizophrenia-> however, drugs that selectively target D4 not very effective: NEED D2 targeting
Clozapine dissociates rapidly from receptors
• Fewer side effects with rapid dissociation
All have afferent binding profiles
What are the major and minor side effects of first generation antipsychotics?
Major: Movement disorders (D2) (Tardive dyskinesia, extrapyramidal symptoms (EPS) including acute dystonias, akathisia, seudoparkinsonism) Anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention) Endocrine (gynoecomastia, menstrual irregularities (D2), weight gain (5-HT2C))
Minor: Jaundice (phenothiozines) Agranulocytosis -Reduction in white blood cells: deadly Sedation Lowered seizure threshold Prolongation of QTc interval (-> cardiac arrhythmias)
What are the major and minor side effects of second generation antipsychotic drugs?
Major:
Agranulocytosis (clozapine only)
-Reduction in white blood cells: deadly
Metabolic syndrome (weight gain, hyperglycaemia)
Minor:
Movement disorders (D2) (Tardive dyskinesia, extrapyramidal symptoms (EPS) including acute dystonias, akathisia, seudoparkinsonism)
Anticholinergic effects (dry mouth, blurred vision, constipation, urinary retention)
Endocrine (gynoecomastia, menstrual irregularities (D2), weight gain (5-HT2C))
Jaundice (phenothiozines)
Sedation
Lowered seizure threshold
Prolongation of QTc interval (-> cardiac arrhythmias)
What are the short term mechanisms of antipsychotics?
• Short term-
o Blocking D2 autoreceptors increases DA release
o Blocking supersensitive D2 post-synaptic receptors decreases DA inhibition (that is, increases excitation)
o More chance of cell firing
But don’t see change/increase in psychotic symptoms
What are the long term mechanisms of antipsychotics?
• Long term-
o Upregulation of presynaptic D2 receptors reduces DA release
o Blockade of D2 receptors and upregulation of these receptors restores homeostasis
o Less dopamine being released and restores D2 inhibition-> Restores normal cell firing
Describe how schizophrenia is currently treated, the treatment course and the long term goal
• Atypical antipsychotics are first line treatment
o Olanzapine is the most widely prescribed antipsychotic in Australia
• Positive symptoms may improve within 4-6 weeks: short term goal
• Negative and cognitive symptoms may improve within 6-12 months
• Long term goal is to prevent relapse
o Clinical outcome greatly improved with antipsychotics
o Maintenance therapy decreases relapse
80% chance of relapsing if don’t take antipsychotics and 40% chance if you do (but the antipsychosis itself may be a lot less serious)
• People taking antipsychotics usually stay on them for life
What is a problem with current drug design for schizophrenia?
• Problem with drug design for schizophrenia
o One of the principle difficulties in the development of antipsychotic medication is the fundamental lack of understanding regarding the underlying cause and nature of the disorder
o Consequently it is difficult, if not impossible to design treatment either palliative or restorative on a rational basis
What are novel approaches to schizophrenia drugs?
• Novel approaches to schizophrenia drugs
o Enhancing glutamatergic activity
Glycine transporter blockers
Glycine site partial agonists (e.g. D-serine)
o Increasing GABAergic tone
Sodium valproate and benzodiazepines as adjunct therapy
o Ratio of D2/5-HT affinities (e.g. blonanserin)
o D2/5-HT2A antagonism with high affinity 5-HT7 antagonism (e.g. lurasidone)
o D2 partial agonist + SRI (e.g. WS-50030)
What is global intervention to schizophrenia?
• Global intervention
o Prevention and early intervention programs
o Newer improved medications
o Carer education and training
o Psychosocial rehabilitation programs
o Suicide prevention strategies
o Treatment of co-existing substance abuse
o Research into causes and more effective treatments
What is the role of glutamate in schizophrenia?
• For:
o PCP, NMDA receptor antagonist, precipitates symptoms of schizophrenia, both positive and negative
o NMDA receptor knockdown mice show symptoms of schizophrenia
o Changes in glutamate receptor and transporter expression in prefrontal cortex and temporal lobes
o Reduced pyramidal cell dendrites and dendritic spines (hypo-glutamate)
o Antipsychoc drugs enhance NMDA receptor activity
What is multiple sclerosis and how does it progress?
• Multiple sclerosis
o Chronic inflammatory demyelinating disease of the CNS
o Disease process damages myelin sheath, prevents normal axonal conduction, incomplete recovery from this damage leads to a stepwise accrual of damage
Progressive disease due to progressive accumulation of damage to the nerves
What are the 3 identified types of multiple sclerosis?
o Three identified disease types:
Relapsing-remitting (RRMS)- episodes of acute worsening of symptoms with total or partial recovery: no apparent disease progression
• Most common
Primary progressive (PPMS)- steadily worsening symptoms without periods of remission
• Rarer but more serious
Secondary progressive (SPMS)- initial RRMS-type, then steadily progressive
What is the pathophysiology of multiple sclerosis?
• Multiple sclerosis- multiple scars (plaques or lesions) which accumulate overtime in the CNS
• Lesions commonly affect the white matter (myelin-coated axons) of the brainstem, basal ganglia, spinal cord and optic nerve
• Repeated damage ton myelin and chronic inflammation results in neuronal damage and death and subsequent brain atrophy
• Disease episodes (relapse/flare/attack) can affect different areas of the CNS and occur at varying time intervals
o Source of symptoms that someone with MS will get will vary- the symptoms expressed will depend on what area of the CNS is being damaged by the disease process
• No definitive diagnostic test
What are the symptoms of multiple sclerosis?
• Symptoms vary but commonly include: o Optic neuritis (inflamed optic nerve) Impairment in vision o Diplopia (double vision) o Sensory loss/numbness Abnormal sensations- tingling/pain/burning sensation o Limb weakness Damage to nerves o Gait ataxia (uncoordinated gait) o Loss of bladder control o Cognitive dysfunction • Highly affects quality of life
What is the burden of multiple sclerosis disease and what are its possible causes?
• Most common between 20-40 years, most common inflammatory neurological disease in young adults
• 2.2 million cases globally, >10% increase in prevalence last 25 years
• Burden of disease to the Australian community- 1.75$ billion in 2017
o Both cost of the disease and the lack of contribution to the economy of those with MS
• Cause unknown but environmental factors and genetic alleles may alter risk
o Idiopathic disease
What are identified risk factors of multiple sclerosis?
• Identified risk factors include:
o Female sex
3/4 of patients with MS are female
Oestrogen is considered to be protective-> birth control gives lower risk of MS
o Smoking (only identified causal risk factor)
o Geographical location (higher risk in higher latitude)
Vitamin D deficiency
As move further away in equator, risk of MS goes up
• Canada and Greenland have very high incidence of MS
o Obesity
o Virus exposure (e.g. Epstein Barr virus)
o Changes in gut microbiome
How is multiple sclerosis diagnosed?
• Diagnosis of MS with MRI- plaques in the brain
o MRI for lesion/plaque
Focal area of white matter demyelination
Pathological hallmark of MS
What are the neuroinflammatory responses in multiple sclerosis?
• Neuroinflammatory responses in MS
o Activation of T helper (Th) cells in lymph nodes by myelin antigens or non-self-antigens presented by antigen-presenting cells (APC)
o Activation and differentiation of myelin-reactive T cells which circulate in blood and migrate from lymph nodes/spleen to other organs, including CNS
o Activated T cells proliferate in the blood following further antigen exposure
o Levels of chemokines and cytokines rise (that is interleukins 1 and 2, interferon [IFN]-gamma, tumour necrosis factor [TNF]-alpha)
o More T and B cells enter CNS- inflammatory cascade
Activate microglial cells-> releases interferons and interleukins which damage the myelin of the oligodendrocytes
• Oligodendrocytes may be damaged directly by disease process
What are the drug treatments available for MS?
• Drug treatments for MS-
o No cure: symptomatic or disease-modifying treatments (DMTs). DMTs aim to reduce relapse frequency and slow progression of disability
o 15 drugs currently approved by the US FDA, some have severe adverse effects-
Immune modulation interferons Beta
Myelin basic protein mimic Glatiramer acetate
Sphingosine-1 phosphate receptor modulator Fingolimod
Proliferation inhibitions Teriflunomide
Immunosuppressants Cladribine
Dimethyl fumarate
Human immunoglobins Natalizumab, Aletuzumab, Ocrelizumab
Describe the effect of immune modulation interferons Beta on MS, how they work, their effects, their administration, their efficacy, and their side effects
Immune modulation interferons Beta
• Naturally occurring cytokines secreted by immune cells
• Activate JAK/STAT signalling pathway via type 1 IFN receptors 1 and 2 binding-> increased gene expression-> antiviral, immunomodulatory and antiproliferation effects
o Reducing proliferation of T cells and B cells, which is useful of MS
• Effects include:
o Decreased antigen presentation of APC in blood and CNS
Stops activation of T cells
o Inhibits activation of T cells, alters cytokine secretion and shifts differentiation from Th-1 to anti-inflammatory Th-2 type
• SC or IM injection every 2 days- ever 2 weeks
• Reduce disease up to 38%, reduced relapse rate and improves quality of life in RRMS; may reduce mortality
o Does not improve PPMS and SPMS
• Immunogenic- neutralizing antibodies can develop against treatment
• Common Adverse Effects: Flu-like symptoms, headache, thyroid disorders including autoimmunity, depression, allergic reactions, hepatic injury
• Pregnancy: category D
o Beta-interferons inadvisable with someone who is pregnant
o These compounds are associated with fetal risks in humans and mice models
o If still want to reproduce and young, need to be careful taking pregnancy category D drug/family planning is important
Describe the effect of myelin basic protein mimic Glatiramer acetate on MS, how they work, their effects, their administration, their efficacy, and their side effects
Myelin basic protein mimic Glatiramer acetate
• Mixture of synthetic 4 amino acid polypeptides, mimics and competes with endogenous myelin basic protein
• Effects-
o Lowered myelin-reactive T cells
o Higher Th2 cells that secrete anti-inflammatory cytokines and brain-derived neurotrophic factors
o Lower inflammatory T cells in the CNS
o Higher anti-inflammatory responses in macrophages, microglia and dendritic cells
o Lowered B cell numbers and promotes anti-inflammatory B cell phenotype
• May promote remyelination by increasing proliferation and migration of oligodendroglia
• SC injection daily or thrice weekly
• 12% reduction in disease in RRMS and reduces relapse rate.
• Does not alter disease progression in PPMS.
• Minimal long-term safety problems
• Safe in pregnancy
• First line therapy for RRMS worldwide
Describe the effect of sphingosine-1 phosphate receptor modulator Fingolimod on MS, how they work, their effects, their administration, their efficacy, and their side effects
Sphingosine-1 phosphate receptor modulator Fingolimod
• Binding of the signalling sphingolipid S1P with its receptors moves lymphocytes into blood
• Orally-delivered prodrug, metabolized to the active metabolite fingolimod phosphate-> binds to S1P receptors-> internalization of S1P/S1PR complex= functional antagonism of the receptor: prevents lymphocytes leaving secondary lymphoid organs to reduce numbers in the CNS
• Comparable to beta-interferons to reduce relapses, some neuro-protection, approved for RRMS and pediatric MS
• Common adverse effects-
o Bradycardia
o Atrio-ventricular block
o Opportunistic infections
o Cutaneous malignancies
• Pregnancy category D
Describe the effect of proliferation inhibitions Teriflunomide on MS, how they work, their effects, their administration, their efficacy, and their side effects
Proliferation inhibitions Teriflunomide
• Interferes with pyrimidine synthesis and DNA replication of proliferating T and B cells
• Lowered proliferation of activated T and B cells but protective immune responses are maintained since resting T cells use nucleotides from degrading DNA and RNA
• Also lowered inflammatory cytokines and may promote oligodendrite differentiation
• Oral, once daily for RRMS: reduces disability progression and relapse rates up to 36%-approximately equivalent efficacy to injectables
• Adverse effects-
o Nausea
o Diarrhea
o Paraesthesia
o Limb pain
o Liver enzyme changes
o Hair thinning
• Contraindicated during pregnancy (category X)
o Strong evidence that it causes fetal abnormalities- people taking this drug need to take birth control at the same time
• Increased chance of opportunistic infections
Describe the effect of immunosuppressants cladribine on MS, how they work, their effects, their administration, their efficacy, and their side effects
Immunosuppressants Cladribine
• Prodrug, phosphorylated to an active purine nucleoside analog that inters with DNA synthesis and repair, leading to cell death of B and T cells in the periphery while not affecting resting and other immune T cells and B cells
• Preferentially depletes peripheral B and T lymphocytes, other immune and blood cells are preserved
• Significant reductions in relapses and disease progression in RRMS
• Resultant lymphopenia increases risk of severe infections, also higher rates of tumors
• Oral treatments in short cycles with sustained therapeutic effects
• Contraindicated in pregnancy (cat D) with on-going concerns about safety
Describe the effect of dimethyl fumarate on MS, how they work, their effects, their administration, their efficacy, and their side effects
Dimethyl fumarate
• Active metabolite is mono-methyl fumarate
• Antioxidant response (neuroprotective) and multiple changes in immune pathways and CNS including:
o Increased apoptosis of T and B cells
o Anti-proliferation effects
o Decreased cytokine production by activated microglia/astrocytes and increased number of oligodendrocyte precursor cells
• Oral, once daily for RRMS, efficacy may be superior (40% efficacy rate) in reducing disease progression compared to glatiramer/equivalent to fingolimod
• Common adverse effects-
o Nausea
o Diarrhea
o Vomiting (low adherence)
o Flushing
o Upper abdominal pain
• Adherence is a problem
• Safe in pregnancy (B1) but limited data
o May be safe for people planning pregnancy
Describe the effect of Human immunoglobins Natalizumab, Aletuzumab, Ocrelizumabon MS, how they work, their effects, their administration, their efficacy, and their side effects
Human immunoglobins Natalizumab, Aletuzumab, Ocrelizumab
• Natalizumab approved 2004 for RRMS.Binds to the alpha 4-subunit of integrins on leukocytes to inhibit alpha 4-mediated adhesion of leukocytes to endothelial cells, prevents lymphocyte migration across the BBB to reduce inflammation in the brain
o Mediated by T cell changes
• Alemtuzumab targets CD52, a cell-surface molecule on predominantly T and B cells- rapid, long-lasting depletion of these cells by cytolysis
• Ocrelizumab (approved 2017) targets CD20 on B cells, but not stem cells, to deplete B cells. Also slows accumulation of disability in PPMS, particularly in younger patients
o Ocrelizumab (mAb to CD20) demonstrated efficacy in slowing disability progression in PPMS
Modest benefit
Most effect in younger patients with evidence of inflammation
Not on PBS
• Administered IV every 4 weeks, 6 months, or annually with relapse rates in RRMS improved 46-68%, reductions in new CNS lesions and reduced brain volume losses reported
• All approved for RRMS. Ocrelizumab is the only treatment approved for PPMS
• High efficacy but also high risk-adverse effects including:
o Infusion reactions
o Opportunistic infections ie. tuberculosis, thyroid autoimmune adverse effects and malignancies requires long-term monitoring
• Long-term effects of immunosuppression and B cell depletion are yet unknown, safety in pregnancy is unknown and therefore incompatible
What are stem cell treatments of MS, how efficacious are they?
o Stem cell treatments
Stem cells are template cells able to differentiate into a wide variety of cell types, as well as self-renewal
No stem-cell based treatments have been proven to remyelinate or nerve repair in MS
Autologous haematopoietic stem cell transplant (AHSCT or bone marrow transplant) is an immune-suppressing chemotherapy treatment. Patient’s own haematopoeitic (blood) stem cells are employed to reset the immune system, following immune suppression by chemotherapy. High risk treatment for aggressive MS.
Studies of mesenchymal or neuronal stem cells, human embryonic stem cells and induced pluripotent stem cells in MS are experimental
What is a autologous haemotapoietic stem cell transplant and what is its process?
Autologous haematopoietic stem cells transplant (AHSCT)
• AHSCT is an immunosuppressive chemotherapy treatment combined with reinfusion of blood stem cells to rebuild the immune system
• Steps:
o Administer pre-treatment to release blood stem cells from bone marrow into the bloodstream
o Collect the blood stem cells from the bloodstream
o Freeze the blood stem cells in the laboratory until they are required
o Administer chemotherapy to remove or partially remove the immune system
o Return thawed blood stem cells by infusion into the vein
o Provide supportive medical treatment for at least 4 weeks as the immune system rebuilds
Describe the treatment considerations of MS
• Treatment consideration-
o Pharmacotherapy progress over the last decade but significant challenges remain, including severe adverse effects
o Risks and benefits for patients must be considered
o No evidence that any currently approved agents benefit patients with non-active MS. No agreement when treatments should be started, stopped or slowed
o Global price rises are of concern
What is Parkinson’s disease and its risk factors?
• Progressive neurodegenerative movement disorder with no cure of disease-modifying treatments
• Mostly idiopathic- age is the greatest risk factor
o Slightly greater risk of getting Parkinson’s disease if male
What is the economic strain of Parkinson’s disease on Australia?
• About 110,000 cases in Australia with a disease duration of about 20 years. 2018 total economic cost: $12.3 billion
o Not just direct medical costs of patient treatment, but other indirect costs and loss of their ability to earn in the economy
What are the clinical symptoms of Parkinson’s disease?
• Clinical triad of tremor at rest, muscle rigidity and bradykinesia
o Bradykinesia- people have trouble initiating and carrying out movements
• Non-motor symptoms include autonomic system dysfunctions (bladder and bowel dysfunction, sexual dysfunction), hyposmia (reduced ability to smell), micrographia (tiny handwriting) , depression, constipation, early subtle cognitive changes and an increased dementia risk in late disease
What are the primary pathological features of Parkinson’s disease?
• Primary pathological features are:
o Progressive dopaminergic neuron death in substantia nigra
o Deposition of abnormal alpha-synuclein protein (Lewy bodies) in substantia nigra
o Normally, direct pathway activity facilitates movement: loss of dopamine results in reduced activity in direct pathway and increased activity in indirect pathway= bradykinesia
o Tremor and rigidity arise via other mechanisms
Describe the direct loop of the basal ganglia
Direct path via globus pallidus pars interna (GPi)
• Cortex excite striatum with glutamatergic connections-> Striatum contains GABAergic neurons which inhibit the globus pallidus pars interna so that it can no longer inhibit the thalamus-> thalamus sends excitatory input to the cortex
• Increases excitatory thalamocortical feedback
• Excitatory feedback loops
• 90% of neurons in the striatum are inhibitory (contain GABA)
Describe the indirect loop of the basal ganglia via the globus pallidus pars externa
Indirect pathway via globus pallidus pars externa (GPe)
• Cortex excites the striatum-> striatum inhibits the globus pallidus pars externa which prevent inhibition of the globus pallidus pars interna-> globus pallidus pars interna inhibits thalamus which prevents thalamus from sending excitatory input to the cortex
• Reduce the excitatory thalamocortical feedback
• Diminishes feedback to the cortex
• Negative feedback loop
Describe the indirect loop of the basal ganglia via the subthalamic nucleus
Indirect pathway via subthalamic nucleus (STN)
• Cortex excites the striatum-> striatum inhibits the globus pallidus pars externa which prevents GPe inhibition of the subthalamic nucleus-> subthalamic nucleus provides excitatory input to the globus pallidus pars interna -> Globus pallidus pars interna send inhibitory input to the thalamus-> thalamus can no longer send excitatory input to the cortex
• Reduce the excitatory thalamocortical feedback
• Negative feedback loop
How is dopamine synthesised?
• Dopamine biosynthesis:
o Tyrosine-> L-dopa through tyrosine hydroxylase action-> dopamine through Dopa decarboxylase action
How can L-DOPA be used to treat parkinson’s disease? Why is it so effective?
• Oral dopamine doesn’t cross the blood brain barrier- problem with directly just giving dopamine
• Standard treatment- oral administration of L-DOPA
o Start at 150 mg per day
o As disease progresses, require more frequent treatment and a larger dose of L-DOPA per treatment
Because number of dopaminergic cells are continuing to die-> less neurons for L-DOPA storage and conversion
• Instead, give precursor- L-DOPA
o Current gold standard treatment
o L-DOPA can cross the blood brain barrier and get into the surviving neurons
o Problem with L-DOPA
It can also stimulate peripheral targets after dopamine conversion (such as D2 receptors)
• Can make patients extremely nauseous and induce vomiting
What are the treatment mechanisms of L-DOPA?
DOPA treatment-mechanisms:
o Increase L-DOPA in the system to enable surviving neurons to produce more dopamine
o L-DOPA is taken up through the blood brain barrier into the dopaminergic neuron and being converted to dopamine, where it is released into synaptic cleft and stimulates D1 and D2 receptors
o Problem:
A lot of L-DOPA is going to be metabolised in the periphery by DOPA decarboxylase in periphery or aromatic amino acid decarboxylase
Orally-> only 1 % will go through blood brain barrier
What are the mechanisms used to improve L-DOPA treatment and how do they work?
• Modifications for improvement
o If given with an inhibitor of DOPA decarboxylase (such as benserazide and carbidopa), then this reduces breakdown of L-DOPA in the periphery and more is available to be taken up in CNS
Increases efficacy of orally administered L-DOPA by 3-15%
o Administer the patient with an inhibitor of monoamine oxidase B (MAOB)-> reduces rate at which synaptic dopamine is broken down-> means that dopamine will hang around for longer
Inhibitors used include rasagiline, selegiline and safinamide
Can be taken alone or with L-DOPA
o Administer COMT inhibitor
COMT breaks down L-DOPA in the periphery
Include entacapone, opicapone and tolcapone
• Entacaponne and opicapone reduce the rate at which L-DOPA is broken down at the periphery-> more gets in the CNS
• Tolcapone active not only in the periphery, but also in the CNS
o Second way in which can reduce the metabolism of dopamine in the brain-> increasing time dopamine can hang around synaptic cleft
Describe the clinical response timeline to L-DOPA
• Oral L-DOPA and clinical response
o Begin L-DOPA therapy: 1-3 years
Very good at attenuating symptoms
They are on- have clinical benefit from L-DOPA treatment
o End-of-dose akinesia: 4-6 years
Start getting off period- have no clinical benefit with treatment
Clinical response starts to fluctuate: sometimes have very good benefit and sometimes benefit is not so marked
o Hyper/dyskinesias start: 6-10 years
Clinical benefit from L-DOPA gets smaller: only lasts a short period of time
More and more variable responses
Not only have off period, but also begin to have too much movement (develop uncontrollable movements) as result of treatment
• Major side effect of L-DOPA treatment-> may be due to pulsatile nature of stimulation of dopaminergic neurons to basal ganglia reflective to pulsatile administration of the drug
o Reduces motor symptoms of Parkinson’s
o Takes around 40 minutes to work
o Half-life of L-DOPA is fast
Each dose only lasts a few hours
What are 3 alternative L-DOPA administration methods and how do they work?
• Alternative L-DOPA administration methods
o Rytary- Extended release L-DOPA + carbidopa table with immediate + slow release formulation allowing 6 hourly dosing in both early and advanced disease
o Stalevo: L-DOPA+ carbidopa+ entacapone allowing central dopamine supplementation and inhibited dopamine metabolism in the periphery in one tablet
o Duo-dopa: L-DOPA+ carbidopa gel for continuous intestinal administration via percutaneous endoscopic gastrostomy for treatment of advanced disease with severe motor fluctuations
Problem: may be infections
What are other drug treatments for parkinson’s disease?
- Dopamine agonists-
- Anticholinergics
- Amantadine
How are dopamine agonists used in the treatment of parkinson’s disease and what is their advantage? What is their effectiveness?
• Dopamine agonists-
o Family of agonist drugs that directly stimulate D1 and D2 receptors on the postsynaptic membrane in that direct and indirect pathway
o Unlike dopamine treatment, dopamine agonists are not dependent on the fact that have a cohort of dopamine surrounding neurons to convert L-DOPA to dopamine-> dopamine agonists can directly stimulate dopamine receptors
o If give L-DOPA, assuming that there are still a population of dopaminergic neurons around that can convert L-DOPA to dopamine
o None of the dopamine agonists are as effective in relieving Parkinson’s disease symptoms-> L-DOPA remains the gold standard
o Only given in early stage diseases
What are the two main dopamine agonists for Parkinson’s disease?
o Dopamine agonists include:
Ergot-derived (first isolated from ergot fungus)
Non-ergot derived
What are examples of ergot-derived dopamine agonists used in parkinson’s disease?
Ergot-derived (first isolated from ergot fungus) • Bromocriptine • Cabergoline • Alpha-dihydroergocriptine • Lisuride • Pergolide
What are examples of non-ergot derived dopamine agonists used in Parkinson’s disease?
Non-ergot derived • Piribedil • Pramipexol (std and slow-release) • Ropinirol (std and slow-release) • Apomorphine (injection) • Ratigotine (transdermal)
What are side effects of dopamine agonists used for Parkinson’s disease?
o Side effects: Cardiac fibrosis • Ergot-derived especially Excessive daytime sleepiness Impulse control disorders • Off-target effect: dopamine is part of the reward system (stimulate limbic system) • Particularly compulsive gambling • Obsessive disorders Hallucinations
What are examples of anticholinergic drugs used to treat Parkinson’s and how do they work?
• Anticholinergics o Examples- Benzhexol Benztropine Orphenadrine Biperiden Procyclidine o Cholinergic interneurons in the striatum are usually inhibited by dopamine-> when dopamine isn’t there, then have overactivity of cholinergic antineutrons o Muscarinic antagonists- dampen down cholinergic activity o Not given that often
How do amantadine drugs work?
• Amantadine
o NMDA receptor antagonism
o Reduction of glutaminergic overactivity in subthalamic nucleus
What are side effects of L-DOPA short term and long-term?
• Side effects for L-DOPA o Short term: Nausea and vomiting Sleepiness Psychiatric effects • Especially with dopamine antagonists- do not give with people with prior addictive behaviours or people who are mentally frail o Long-term Dyskinesia Dose shortening Fluctuations
What are common contraindications of anti-parkinson’s disease drugs?
• Common contraindications of anti-PD drugs: o Metoclopramide o Prochlorperazine o Haloperidol Anti-psychotic drugs
What are normal changes that occur with aging?
• Many normal changes that occur with aging do not compromise quality of life
o Motor co-ordination
o Sleep
o Mental functions
What is dementia and the prevalence of the three most common dementias?
• Dementia- clinical syndrome characterised by impaired memory and other intellectual functions which interfere with normal functioning and impair quality of life (can coexist with or without behavioural and personality changes)
o Alzheimer’s disease- 70%
o Stroke- 15%
o Parkinson’s- 15%
• Dementia is a progressive decline in mental function
What are treatable dementias?
• Treatable dementias (not neurodegenerative diseases)-
o General paresis- rare, syphilis
o Normal pressure hydrocephalus- stable increase ICP
o Chronic subdural haematoma-head injury
o Nutritional deficiencies-
Wernicke-Korsakoff syndrome (thiamine)
Pellagra (B3), B12 deficiency
o Chronic drug intoxication (ETOH, barbiturates)
o Endocrine-metabolic disorders
Myxedema, Cushing’s disease, hepatic encephalopathy
o Brain tumours
o Pseudodementia- psychiatric illness
What are degenerative dementias?
• Degenerative dementias- o Alzheimer’s disease o Dementia with Lewy bodies o Vascular dementia o Frontotemporal dementia (e.g. Pick’s disease) o Prion diseases (Creuzfeldt-Jacob disease-CJD) o Huntington’s disease o Thalamic dementia
When was Alzheimer’s disease first described and how many people does it affect?
Alzheimer’s disease-
• Alzheimer’s disease: first described by Aloysius Alzheimer in 1906
• Affects less than 20% over 65, more than 40% over 80
• No cure or effective therapy
What is the cost for Alzheimer’s?
• Big cost to community-ageing population
o An estimated 413, 106 Australians currently live with dementia
o Without a significant medical breakthrough, that is expected to soar to above 900,000 by 2050
o This year, dementia is estimated to cost Australia 14.67 billion
o This is projected to be 36.85 billion a year by 2056
o Costing Australia a massive 1.034 trillion over the next 40 years
What are the risk factors of Alzheimer’s?
• Risk factors for AD-increased age, sex (women have higher incidence of Alzheimer’s), family history, maternal age at birth, repetitive head injuries
What are the clinical features of Alzheimer’s disease?
• Clinical features of AD
o Initially, subtle changes in memory and cognition
Misplacing items, forgetting appointments, dysnomia
o Changes in spatial and temporal orientation
o Difficulty forming new memories
o Altered judgement and behavioural changes
o Can coexist with moodiness, depression and apathy
o Eventually institutionalisation with:
Dysphasia/aphasia (speech)
Apraxia (movement)
Agnosia, prosopagnosia (loss of knowledge)
Paranoia, psychosis
o May also see overt parkinsonism (approximately 20%)
What are the pathological features of Alzheimer’s disease? Describe each one
• Pathological features of Alzheimer’s disease (examined post-mortem)
o 4 main types of pathology:
Cerebral atrophy and ventricular enlargement
Neuronal loss with gliosis (glial proliferation-scar)
• Happens in different areas of the brain
o Hippocampus-involved in memory
o Cortex
o Amygdala
o Olfactory system
o Nucleus basalis
Amyloid plaques (extracellular aggregates of amyloid proteins)
• Most common pathology associated with Alzheimer’s disease
• Predominant protein is the amyloid-beta peptide (Abeta) 39-43 amino acids
• Derived from amyloid precursor protein (APP)
Neurofibrillary tangles
• Abnormal bunches of filaments within neurons
• Hyperphosphorylated tau protein (microtubule-associated protein)
o Plaques, tangles and neuronal cell loss are usually associated
What is the neurochemistry of Alzheimer’s disease and their effects on the disease?
• Neurochemistry of Alzheimer’s Disease
o Acetylcholine- deficit in central cholinergic transmission (main one)
Loss of cells in nucleus basalis (use acetylcholine)
Decrease in choline acetyltransferase (synthesis)
Decrease in acetylcholine esterase (degradation)
Decreased choline uptake
o Amines
Loss of cells in locus coeruleus- decreased NA synthesis
Loss of cells on raphe nuclei- decreased 5HT synthesis
Linked to psychological symptoms of Alzheimer’s
o Glutamate
Reduction in glutamate transporters
Induce excitoxicity
What are the genetics of Alzheimer’s disease? Describe the impact and effect of each gene
o Multifactorial disease, multiple genes may contribute
Amyloid precursor protein (APP)-chromosome 21
• Precursor of beta-amyloid
• Down’s syndrome- trisomy 21-AD in their 30s
Presenilins (PS1 and PS2)-chromosomes 1,14
• May affect processing of APP (more Aβ42 compared to Aβ40)
• Aβ42 most common in amyloid plaques
Apolipoprotein E (apoE)-determines the age of onset of AD
• ε4 allele- onset in 80s, ε2- onset in 90s
• Important role in cholesterol transport and uptake
• 3 alleles- ε2, ε3, ε4
• APOE2 is protective, APE4 increases risk (diminished with age)
• APOE4 is associated with early onset of AD (less than 80 years old)
• Elevated cholesterol may disrupt processing of APP
• People taking statins to reduce cholesterol biosynthesis have reduced incidence of AD
o More than 95% of AD cases are sporadic- no genetic basis
Describe how APP processing and plaque formation occurs in normal brains and alzheimer’s disease
• APP processing and plaque formation
o Alpha secretases or beta secretases can cleave APP
o Depending which enzyme cleaves the APP component of the transmembrane domain will determine how long the C-terminal tail is
When alpha secretase cleaves, produces a C83 protein
When beta secretase cleaves produces a C99 peptide
o C83 and C99 peptides then cleaved by gamma secretases- cleave in the middle of the transmembrane domain
o Depending on size of the initial product, get different final products
What is gamma-secretase and how is it activated?
o Gamma-secretase:
Complex of presenilin, nicastrin, APH1 and presenilin enhancer 2
Complex is activated by cleavage of presenilin to expose the asp-asp catalytic site
Peptide based inhibitors bind to catalytic site and prevent activity
NSAIDs may also disrupt secretase activity (mechanism is unclear)
• Could be why long term NSAID use is protective for dementia
What are the treatment options for Alzheimer’s disease? What is the first line of treatment and evaluate its usefulness
• No well established effective drugs- many experimental drugs
• Therapy treats symptoms, does not halt progress of disease
• Current drugs relieve symptoms-not very effective
• Treatments-
o Cholinergic drugs (main drugs used)
Acetylcholinesterase inhibitors
• Inhibit enzyme that breaks down acetylcholine-> try to increase cholinergic transmission
Side effects are considerable
Need acetylcholine neurons to release acetylcholine
First choice: cholinesterase inhibitors
Describe the cholinergic drug tacrine, its mechanism of Alzheimers disease treatment, its duration of action and its side effects
Drug: Tacrine (Cognex 1993) Mechanism: Reversible cholinesterase inhibitor
Duration: Around 6 hours Side effects: Abdominal cramps, vomiting, liver toxicity
Describe the cholinergic drug rivastigmmine, its mechanism of Alzheimers disease treatment, its duration of action and its side effects
Drug: Rivastigmmine (Exelon 2000)
Mechanism: Slowly reversible (pseudoirreversible ) cholinesterase inhibitor Duration: Around 8 hours Side effects: Nausea, vomiting, diarrhea, weight loss, loss of appetite, muscle weakness
Describe the cholinergic drug donepezil, its mechanism of Alzheimers disease treatment, its duration of action and its side effects
Drug: Donepezil (Aricept 1996)
Mechanism: Piperidine derivative, non competitive cholinesterase inhibitor Duration: Around 24 hours Side effects: Nausea, vomiting, diarrhea
Describe the cholinergic drug galantamine, its mechanism of Alzheimers disease treatment, its duration of action and its side effects
Drug: Galantamine (Reminyl 2001)
Mechanism: Reversible cholinesterase inhibitor, allosteric ligand at nicotinic receptors
Duration: Around 8 hours Side effects: Nausea, vomiting, diarrhea, weight loss, loss of appetite
What are pharmacological treatments for Alzheimer’s disease?
o Cholinergic drugs (main drugs used)
o NMDA antagonists
o Antidepressants and neuroleptics (co-prescribed)
How are NMDA antagonists used to treat Alzheimer’s disease and what are its side effects?
o NMDA antagonists
Memantine (Namenda 2003)
• Low affinity NMDA antagonist
• Targets glutamate toxicity in Alzheimer’s
• Duration of action is around 6 hours
• Side effects- dizziness, headache, constipation, confusion
What is the use of antidepressants in Alzheimer’s? Describe mechanism
o Antidepressants and neuroleptics (co-prescribed)
Modulate NA and 5-HT neurotransmission
Improve emotional state, but do not affect the core symptoms
Cholinesterase inhibitors, NMDA antagonists and antidepressants relieve symptoms but do not halt progress of disease
What are experimental drugs/targets used in the treatment of Alzheimer’s and what are they based on?
• Experimental drugs/targets
o Based on major advances in understanding the pathology of AD
o Strategies to disrupt or prevent formation of Aβ plaques
o Experimental drugs aimed at halting progression of disease (particular focus on disrupting Abeta formation)
o Types-
β-secretase inhibitors (BASE inhibitors)-difficult to develop
γ-secretase inhibitors
Antibiotic clioquinol, lipoic acid
Immunotherapy
How would Beta-secretase inhibitors be used to treatment Alzheimer’s and why are they not current used?
β-secretase inhibitors (BASE inhibitors)-difficult to develop
• Inhibiting beta secretase could inhibit Aβ42 production-> prevent plaques
How would gamma-secretase inhibitors be used to treatment Alzheimer’s and why are they not current used?
γ-secretase inhibitors
• Easier to develop, side effects- cleaves many other proteins
How would clioquinol be used to treatment Alzheimer’s and why are they not current used?
Antibiotic clioquinol, lipoic acid
• Zinc (and copper) promotes the formation of amyloid plaques
o Chelation of zinc reduces plaque formation
• Antibiotic clioquinol and also lipoic acid chelate zinc and reduce plaque formation
• Promising results in animal studies but this has not translated a lot in humans
How would immunotherapy be used to treatment Alzheimer’s and why are they not current used?
Immunotherapy
• Immunization with β-amyloid
• Reduces plaque formation because body will clear β-amyloids as they form
• Protective in a mouse model of AD
• Toxic in recent human clinical trials- ongoing
Describe the current state of Alzheimer’s disease therapeutics and the impact of this current state on our understanding of Alzheimer’s disease
• Repeated clinical failures continue to question the amyloid hypothesis of AD and the current understanding of AD causality
o To date, therapeutics that reduce brain amyloid in AD patients have demonstrated no effect in reversing the associated decline in cognition or function indicating that the amyloid hypothesis is either incorrect or that there is a point when the disease becomes independent of Aβ production or is refractory to any type of therapeutic intervention
o The clinical failures of inhibitors of tau aggregation, neurotransmitter modulators and drugs repurposed from AD-associated disease indications tend to support this latter viewpoint
o Current understanding of Alzheimer’s disease causality is thus incomplete, a situation that has been compounded by a debate on whether AD is a singularly distinct form of dementia and by the dogmatic promotion of hypotheses over actual clinical data
o The latter has repeatedly led to compounds lacking efficiency in Phase II trials being advanced into Phase III where their lack of efficacy is routinely recapitulated
What are nootropics, their effects and some examples of them?
• Nootropics-
o Drugs which have the ability to enhance integrative brain mechanisms associated with mental performance
o Features
Ability to enhance learning and memory
Facilitate flow of information between hemispheres
Enhance resistance to chemical or physical assault
Lack of peripheral, sedative or neuroleptic effects
o Examples-
Piracetam, pramiracetam (positive allosteric modulator AMPA)
• Enhance release of acetylcholine
• Cognitive enhancement in rats
• No effects on patients with dementia
