Pharmacology Neurodegeneration Flashcards
1
Q
WHta is a neurone and the parts
A
- Neurone = baic unit of the nervous system
- Cell body = generates the action potential. synthesis of synaptic vesicles
- Axon = transmits action potential, transports vesicles
- Nerve terminal = synthesis, storage and release of NT
- Electrical transmission - AP generated in cell body, conducted along axon and voltage agted sodium channels
- Chemical transmission - NT synthesis & storage in vesicles at synaptic terminal, AP triggers release of stored NT.
- NT bind to post-synaptic receptors to regulate neuronal excitability
- NT bind to pre-synaptic receptors to regulate NT release
- SYnaptic transmission temrinated by degredation or uptake of NT
- Excitatory = increase sprobability of generating AP
- Inhibitory = reduces probability of generating AP
2
Q
How do drugs alter synaptic transmission:
A
- Synthesis - false transmitters
- Storage
- Release
- Receptors
- Uptake mechanisms
- Degredation and metabolism
What complicates these:
- Co transmission - nerve terminals can contain more than one NT
- Receptor diversity - splice variants, differential subtype expression, homodimers, heterdodimers
- Agonism - full, partial, inverse, biased
- Sites - orthosteric, allosteric
- DYnamic systems - desensitisation, adaption
3
Q
CNS Neurotransmitters
A
- Fast ransmission - Ligand gates ion channels = Acetylcholine, GABA (inh), glutaate (Exc), Glycine (inh) and serotonin (5-HT)
- Slow transmission - GPCR = acetylcholine, adenosine, adrenaline, ATP, Dopamine, GABA, Glutamate, histamine, noradrnaline, serotonin (5-HT)
4
Q
‘Brain chemicals’
A
- DOpamine - feel good, happy hormone. Enables motiavtion, learning, pleasure. If deficient then procastination, low self esteem, being anxious etc. Increase by meditate, long term goals
- Oxytocin - hug drug, love hromone. Feeling od trust. If deficient then may feel lonely, stressed, insomnia..Increase my massage, physical touch, exercise
- Serotonin - leadership, happy hormone. feeling significant. If deficient then low self esteem, overly sensitive, mood swings etc Increase by exercise, sunlight, masage, cold shower
- Endorphins - feel good, high hormones. If deficient then anxiety, depression, mood swings, insomnia etc. Increaseby ;aughter or crying, eat spicy foods etc
This is all simplistic, misleading, etc.
5
Q
Examples of neurodegenerative diseases
A
- Parkinsons
- Alzheimers
- Huntingtons
- Multiple sclerosis
- Motor neuron disease (amyotrophic lateral sclerosis)
- Spongifor ecephalopathies (prions)
- Stroke
6
Q
Movement disorder symptoms (in parituclar parkinsons)
A
- Tremor - at rest in limbs, disappears with sleep and movement
- Rigidity - resistance to passiv emovement; jerky
- Bradykinesia - difficulty in initiating voluntary movement, slowness
- Akinesia - Laack of voluntary movement (eg, mask like face)
- Cognitive disturbances - dementia
- Other - stooped posture, speech problems, sweating, microphagia
7
Q
Neuropathology of Parkinsons disease
A
- Selective degeneration of substantia nigra
- 1960- reduction in homovanillic acid in caudate, putament and substantia nigra
- Loss of about 80% dopamine leads to PD
- Lewy Bodies - aggregates of a-synuclein
- 1960s when parkinson patients shown to have depleted DA in basal ganglia and L-dopa regarded as treatment then 1970 when combine duse with carbidopa
8
Q
Catecholamine ysynthesis in neurones
A
9
Q
Dopamine metabolism
A
10
Q
*Dopamine - pharmacology
A
- Chemistry - small molecule, endogenous catecholamine. Precursor of NA and adrenaline
- Target: Agonist at adrenoreceptors (GPCRs) - B1 receptor, a1&2 receptors and some dopamine receptors in periphery
-
Effects:
- Heart B1 - positive chronotropic effect and positive inotropic effect
- Blood vessels - vasoconstriction a1
- CNS - dopamine doesnt cross BBB so few/ no central effects. Endogenous DA mostly in CNS
- Increases BP
- Kidney - possibly via dopamine receptors leads to vasodilationa nd increase in urine production.
-
Pharmacokinetics (body does to drug):
- Absroption - IV rapid onset 5mins. Oral is absored from small intestine and rapidly metabolised
- Distribution - Doesnt cross BBB
- Elimination - duraiton of action of up to 10mins- v short
- Metbaolism - liver, kidney, plasma. COMT, MAO, Aldehyde dehydrogenase. Excreted in urine as metabolites eg, as HVA
-
Pharmacodynamics (drug does to body):
- 1st atrget is adrenergic receptors so by B1 receptor in heart increases rate and force of contraction and at hgiher doses a1 receptor in blood vessels to lead to vasoconstriction and increase TPR. All increases ABP. Sleective distirbution minimised CNS effects
- 1secondary effects - effect on kidneys mediated by dopamine receptors.
11
Q
Parkinsons - treatment strategy
A
STrategy 1:
- Increase dopaminergic NT:
- Increase dopamine synthesis - levodopam (+carbidopa, + entacapone). Cocareldopa is levodopa and carbidopa. Co-beneldopa is levodopa and benserazide 9DDc inhibitor)
- Reduce dopamine metabolism - selegiline, tolcapone
- Activate dopamine receptors - cabergoline, rotigotine
STrategy 2:
- Reduce cholingeric transmission:
- CHolinergic interuneurones in striatum
- Ach inhibits dopamine release and dopamine inhibitd Ach release
- PD -> hyperactivity of cholinergic neruones
- Anti-cholinergic drugs aims to restore balance betwee Ach and DA.
- Antimuscarinic drugs used in parkinsonism
- Benzatropine, orphenadrine, procyclidine and trihexyphenidyl
- Weakly effective
- Used ot manage parkinsonian like side effect associarted with anti-psychotic medication.
12
Q
* Levodopa pharmacology
A
- Chem = small molecule, prodrug, converted to dopamine (active compound) by Dopa decarboxylase
- Target = FUll aognist of dopamine receptors in corpus striatum (GPCRs)
-
Physiology:
- CNS pathway - nigostriatal pathway. Converted to dopamine to restore function
- CNS - mesolimbic and tuberohypophyseal pathways and dopamine causes dysfuncion
- Periphery - dopamine and NA have sympathetic effects
- Clinical indications - parkinsons disease and parkinsonism
- Unwanted effects - Minimised by coadministration of carbidopa. Tics, dyskinesia, ‘on-off’, psychotic behaviour, naursea & vomiting and cardiac arrhythmias.
- Pharmacokinetics: oral or inhalation, passes BBB, half time 1hour, metabolism primary by DD in absence of carbidopa/benserazide
-
PD:
- 1st target = central dopamine receptors. Desired effects are cooridnation of movement via nigrostriatal pathways. A/Es are mesocorticolimbic pathways (cognition/cotivation, psychiatric disorders) and tubero-hypophyseal system- pituitary gland (neuroendocrine, reg of prolactin secretion)
- 2nd target = peripheral adrenergic receptors. A/E minimised by use of carbidopa.
13
Q
* Carbidopa pharmacology
A
- Chem - C-DOPA, small molecule analogue of L-DOPA
- Target = slowly dissociating compeitive inhibitor of L-aromatic amino acid decarboxylase (DDC) and enxyme 4.1.1.28
- Physiology = pic?
- Clinical indications = adjunct in Parkinsons D and parkinsonism
- A/E = disruption of peripheral catecholamine/ serotonin stnthesis.
- PK: Oral, doesnt cross BBB, majority absorbed dose excreted in urine as metabolite, t1/2 is 2-3h.
-
PD:
- Decreases conversion o flevodopa to dopamine in periphery and so decrease levodopa induced adverse effects.
- Improved PK for levodopa so decrease clearance, increase clinical effectiveness, dose reduction and decrease adverse effets from levodopa
- Quiered assosicaiton with inhibition of 5-HT/NA/Adr syntehsis as A/E
14
Q
* Selegiline
A
- Reduce dopamine metabolism
- Class = MAO-B inhibitor
- Chem = small molecules, amphetamine analogue
- Pharm: Irreversible inhibitor of: 1st Taget is MAO-B, 2nd is MAO-A
- Phys = Centrally acting, decrease dopamine metabolism, increase dopamine levels/signalling
- Clinically = alone for early PD, adjunct for late PD.
15
Q
* Entacpone pharamcology
A
- Reduce levodopa metabolism
- Class = COMT inhibitors (COMT is an enzyme that breaks down neurotransmitters (chemical messengers) like dopamine. COMT inhibitors block the action of the COMT enzyme)
- Chem = small molecule, doesnt cross BBB
- Pharm = Compeittive reversible inhibitor of COMT
- Phys: peripheral action, decrease levodopa metabolism, increase dopamine synthesis.
- Clinical = adjunct for PD treatment with levodopa + DDC inhibitor
17
Q
Biased agonism
A
19
Q
* Cabergoline pharmacology
A
- Highly pleiotropic effects
- Receptors for dopamine, serotonin, noradrenaline
- Actvities - full, partial agonists and antagonists
*
20
Q
* Rotigotine pharmacology
A
23
Q
Role of Dopamine in the brain
A
- Nigrostriatal pathway (75%) = Coordination of movement, involved in parkinsons disease
- Mesocorticolimbic pathways = cognition/ motivation, psychiatric disorders
- Tubero-Hypophyseal system = Regulation of pituitary gland and prolactin secretion
26
Q
Parkinsons disease - diagram
A
27
Q
Aetiology of Parkinsons disease
A
- Idiopathic - cause unknown
- Familial/genetic = evidence of increased incidence in some families
- Drug - induced = anti-psychotic medication -> parkinsonism
- Enivornmental factors - MPTP , TCE
- MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Severe parkinsonism in 7 young adult. Loss of neurones in substantia nigra Other similar toxins, e.g. paraquat
- TCE: Trichloroethylen, Solvent, Linked to Parkinson’s Disease TCE – Twin studies reported on BBC
- Viral? Encephalitis lethargica is a possibility
29
Q
Alzheimers disease pathology
A
- Selective loss of cholinergic neurones:
- Basal forebrin: nucleus basalis (of meynert, hippocampus, frontal cortex)
- Loss of choline acetyltransferse
- Cogntiive impairment - memory loss
- Aetiology unknown - protein aggregates
- Aggregates of mis-folded protein:
- Amyloid plaques - b-amyloid. APP is amyloid precursor proteins. Extraclelular aggregates
- Neurofibrillary tangles: Tau - intraneuronal
31
Q
Cholinesterase inhibitors
A
- Increase levels of Ach
- Inhibit AChE and BuChE
- Tacrine - prototype, short acting, cholinergic side effects
- Donepezil - AchE selective, slowly reversible
- Galatamine - may also act as nicotonic receptor agonist
