IM FUCKED GOD PLS HELP Flashcards
Lofexidine
non-substitute detoxification, central ⍺2-agonist, suppresses some components of withdrawal syndrome
Methadone
substitution method of detoxification, long-acting drug, no euphoria to morphine
Naltrexone:
opioid antagonist, prevents euphoria to opioids, given daily to addicts to prevent relapses, reduces alcohol-induced reward
Buprenorphine
partial agonist, substitution method of detoxification
Clonidine:
⍺2-adrenoceptor agonist inhibits excessive transmitter release happening during withdrawal
Propranolol
β-blocker blocks excessive symp
Acamprosate
weak NMDA antagonist interferes with synaptic plasticity, reduces crave
Disulfiram
causes accumulation of acetaldehyde making alcohol consumption unpleasant
Nicotine replacement therapy:
relieves psychological + physiological withdrawal syndrome + reduces cigarette consumption but not nicotine abstinence
Bupropion
Antidepressant blocking monoamine reuptake so NA + DA
Nicotinic antagonist, ↑[DA] in nucleus accumbens
induce seizures, eating disorders, mania (bipolar disorder)
Varenicline (Champix):
partial α4β2 nAChR agonist, full agonist for α7 nACHR, more effective than NRT
Withdrawal syndrome
physical characterised by abstinence syndrome (LC) sweating, gooseflesh (cold turkey), irritability, aggression
psychological characterised by craving to avoid withdrawal effects
Chronic drug administration
homeostatic adaptive changes to oppose drug action, withdrawal –> rebound effect
eg alcohol causes convulsions
amphetamine causes sedation
Mechanism of dependence (DA)
Less frontal cortex activity + less striatal D2 binding
Mechanism of dependence (α4β2)
Upregulation of α4β2 + rapid development of tolerance – desensitisation of nAch receptors
Impulsive control disorders
- cycle of tension/arousal
- impulsive acts
- pleasure/relief/gratification
- regret/guilt/self-reproach
- REPEAT via positive reinforcement (natural reward)
Compulsive disorders:
- cycle of anxiety/stress
- repetitive behaviours
- relief of anxiety/stress
- obsessions
- REPEAT via negative reinforcement (anti reward)
Positive reinforcement:
social drug-taking
drug induces pleasurable effect
triggering further drug administration via natural rewards
Negative reinforcement:
- drug
- tolerance
- escalating compulsive
- dependence
- negative emotional state triggers craving
- drug administration via aversive, dysphoria experience of withdrawal NOT high
Opioids target
Agonist at μ (δ, κ) opioid receptors
Cocaine target
Dopamine transporter blocker – indirect DA agonist
Amphetamine target
Dopamine releaser – indirect DA agonist
Alcohol target
Facilitates GABAA + inhibits NMDA receptor function
Nicotine target
Agonist at nACh receptors
Cannabinoids target
Agonist at CB1 receptors
Phencyclidine target
NMDA receptor antagonist
Hallucinogens target
5-HT2A agonists
Cocaine
Blocks catecholamine reuptake so↑DA, stimulant effect
Amphetamine
Release cytosolic monoamines (DA)
MDMA (ecstasy)
-Inhibits monoamine transporters
-Large ↑5-HT
-depletion
↑5-HT –> psychotomimetic effects
↑DA –> euphoria followed by rebound dysphoria
Alcohol
- Potentiates GABA-mediated inhibition like Bz
- Inhibits presynaptic Ca2+ entry
- Inhibits transmitter release
- Disinhibits mesolimbic DAergic neurons (↑ reward)
- Induces release of endogenous opioid peptides
Nicotine/tobacco
-nACh receptors, α4β2 subtype
Receptors, ligand-gated cation channels (pre- + post-synaptic)
-↑NT release + neuronal excitability including opioid peptides
-Cortex + hippocampus (↑cognitive function)
-Ventral tegmental area VTA (where DAergic neuron project to nucleus accumbens reward pathways via DA release)
Barbiturates
Positive allosteric modulators
- ↑Affinity of receptor for agonist
- ↓GABA required for same response
- GABA receptor channel opened for longer –> ↑Cl- in less time
Benzodiazepines
- Positive allosteric modulators binding at alpha-gamma interface of pentamer but only bind to alpha 1, 2, 3, or 5
- Stabilise GABAa receptors in open state so ↑binding of GABA
Flumenazil
competitive antagonist at BZD binding site used for OD
Z-drugs
Bind at alpha-gamma interface on GABA-A receptors
5HT1A receptors
metabotropic,presynaptic membrane, auto-inhibitory
Buspirone
For GAD
- 5HT1A agonist
- increased activity of receptors
- body downregulates receptors
- buspirone still inhibits serotonin release but to a smaller extent than before
- overall increase in serotonin release in synapse
α1:
on postsynaptic membrane couples Gq to activate phospholipase C
α2
on presynaptic membrane couples Gi to inhibit adenylate cyclase
β1
on postsynaptic membrane couples Gs to activate adenylate cyclase
- ↑HR, impulse conduction, contraction, ejection fraction
- ↑Renin release by juxtaglomerular cells
- ↑Ghrelin release by stomach for hunger
β2
on postsynaptic membrane couples Gs to activate adenylate cyclase
- SM contraction of bronchus, bronchioles, detrusor muscle, uterine muscle
- Contract urethral sphincter
- ↑Renin release by juxtaglomerular cells
- Glucose metabolism: inhibits insulin release, stimulates gluconeogenesis, glycolysis, lipolysis
- Thickened salivary secretion
Venlafaxine
- 5HT + NA reuptake inhibitor (SNRI)
- Serotonin transporter > NA transporter
- ↓appetite due to activation of adrenoceptors
Trazodone
- 5HT2 receptor antagonist blocks reuptake of serotonin
- α2 antagonist
- 5HT reuptake inhibitor
- 5HT2, 5HT3, H1 antagonist
Mirtazapine
- α2 antagonist
- ↑5HT + NA release in synapse
Mianserin
α2, 5HT2A, α1 antagonist – cause bone marrow depression
Estrogen
treat postpartum depression via monoamine system, GABA system, glutamate system
TCA Amitriptyline
- NA + 5-HT reuptake inhibitor
- Block Mus so anticholinergic + antimuscarinic –> constipation, blurred vision, dry mouth, drowsiness (reversible)
- Block H1 –> weight gain + sedation
- Block α adrenoceptors –> ↓BP, postural hypotension, tachycardia, dizziness
Reversible MAOi
Moclobemide
-Accumulation of NA displaces RIMA so degradation of excess NA
MAOA
breakdown of 5-HT > NA > DA + tyramine – in cheese + wine
MAOB
breakdown DA
Aneuploidy
- Nondisjunction
- Misscariages
- Extra chromosome maternal
Sex chromosome aneuploidy
Lives :)
Trisomy 21
Downs
MOST nondisjunction
Robertsonian translocation
Mosaic
Trisomy 18
Edwards
Maternal meiotic nondisjuntction
MOST trisomy
Die
Trisomy 13
Patau MOST trisomy from maternal nondisjunction Translocations Midline defects Eyes close together
45XO
Turners Paternal meiotic errors Can be mosaic Hands/feet oedema Webbed neck Underdeveloped female
47XXY
Klinefelters Non disjunction paternal/maternal meiosis Mosaic Phenotypically MALE Female fat distribution
47XYY
Paternal meiotic non disjunction
Tall
DiGeorge
De novo
Commonest deletion syndrome
Williams syndrome
De novo + autosomal dominant
Microdeletions
100% penetrant
ELN gene elastin –> CVS disease
Chondrocytes
secrete collagen, proteoglycans, hyaluronan
Hyaluronan
Tethers aggrecan which is held together by collagen type II fibres
GAG
High viscosity
Highly hydrated
Low load + high velocity (hydrodynamic lubrication)
Aggrecan (GAG):
Proteoglycan induces osmotic gel swelling pressure inflates cartilage by creating negative charge
Avascular articular cartilage
nutrients from synovial fluid
Type II collagen fibrils:
hold it together, resist gel swelling tendency
eg Glycosamino-glycan chain (GAG):
chondroitin sulfate, keratan sulfate, hyalauronan
Proteoglycan
= GAG + core protein
Has core protein surrounded by GAG chains fixed negative charge + huge osmotic (swelling) pressure from attracted cations – Gibbs-Donan effect
Achieve stability
- Congruity
- Fibrous capsule + its thickenings into extra-articular ligaments
- Intra-articular ligaments
- Packing improves congruity by: menisci: semilunar cartilages, knee, fat pads
- Muscles acting across joint
Pannus
releases metalloproteinases
TIMPS
released to inhibit activity of metallopeptidases but low conc to make diff
Collagenases
metallopeptidase
cleave collagen type II cleaved + unwind triple helix structure
Metallopeptidases
cleave collagen leaving 1/4 + 3/4 fragment
1/4 fragment reveals antibody binding site (neoepitope)
Aggrecanases
cleave aggrecan at several points in chain
ADAMTS
Aggrecanase
cleave aggrecan at certain points revealing antibody binding sites
DNA ligase
attaches Okazaki fragments by forming phosphodiester bonds via complementary nature of “sticky” ends
ATP driven
G-banding
Few days
Chromosome number
Translocations
LARGE deletions/dup
FISH
Few days Suspect gene/region Chromosome number Translocations Deletions/dup
Q-PCR
Quick
Suspect trisomy
Chromosome number
aCGH
Suspect gene
Point mutations
NGS
Point mutations
Gel electrophoresis
separate DNA fragments by size
Regulatory factors
recognise their target sequence
by interacting through major groove because greater bond variation
TATA box
promoter element which allows the binding of RNA polymerase (TBP, TFII, RNAPII)
Telomerase
Brings RNA fragment to
restore length of lagging strand
Topoisomerase II
molecular clamp unlinks tangled chromosomes using ATP to work clamp
Robertsonian chromosome
Fusion of acrocentric chromosomes
45 chromosomes is stable karyotype
46 chromosome is unstable
Deletion:
Breakage + loss of acentric fragment
Detected by array CGH/FISH
Haploinsufficiency
Deletion in monosomic region
Non-disjunction
failure of separation of chromosomes
Mosaicism
Presence of 2 genetically different cell lines, derived from same zygote eg production of trisomy
EEG awake
HIGH FREQUENCY
Low freq
Desynchronised
EEG sleep
Low freq
HIGH AMPLITUDE
Synchronised
Awake
- photoreceptors converge onto retinal GANGLION cell
- thalamic cells RELAY
- primary visual cortex
Falling asleep
- thalamic cells DONT RELAY
- insensitive to retinal input via inhibitory neurone
- automatically DEPOLARISE
- fire AP w low frequency synchronously
- repeat
- disconnects primary visual cortex from sensory inputs
Serotonin pathway origins/projections
Raphe nuclei: projects throughtout CNS –> analgesia
Ach pathway origins/projections
- Pontomesencephalic tegmentum of brainstem projects to thalamus + cerebellum
- Basal forebrain projects to neocortex + hippocampus
DA pathway origins/projections
- Substantia Nigra projects to basal ganglia
- Ventral Tegmental Area projects to frontal cortex, limbic areas: amygdala, nucleus accumbens
H1 pathway origins/projections
Hypothalamus projects throughout cerebral cortex + thalamus
Orexin pathway origins/projections
Hypothalamus projects to CNS
NA pathway origins/projections
Locus Coerulus of brainstem projects throughout CNS
Extradural haemorrhage
- MMA rupture
- unconcious
- lucid as dura takes time to stretch
- symptoms
Subdural haemorrhage
-Trauma
Blood clot between arachnoid + dural meninges
-Rupture of veins crossing subdural space
Subarachnoid haemorrhage
- External brain vessels rupture
- Berry aneurysm
- Blood below pia/arachnoid following brain contours
- Cerebral spasm –> stroke
Multiple petechial haemorrhage
-Obstruct small arterioles + capillaries
Watershed zone infarction
- profuse haemorrhage
- low BF at arterial territories boundaries
- no O2 to adjacent periphery territory tissue
- infarction
Cerebral contusion
trauma
Microaneurysm
- hypertensive cerebral arteries rupture
- intracerebral haemorrhage
Aortic dissection
- elderly w medial wall degenration
- marfans
Berry sacular
- circle of willis bifurcations rupture
- subarachnoid haemorrhage
AAA
- post atheroma
- rupture
- intraperitoneal haemorrhage
- thromboembolis
- ischamia + gangrene
cingulate gyrus
empathy
mamillary bodies
episodic memory
parahippocampal gyrus
environmental scenes
amygdala
danger detector
orbitofrontal cortex
memory + reward
inhibits inappropriate
AMPA receptor
- Ligand gated Glu
- Activated
- Allows Na in, Glu binds
NMDA receptor
- Ligand + vg Glu
- Remains closed
- Blocked by Mg
Corticospinal tract pathway
- subcortical white matter passing via corona radiata
- posterior limb of internal capsule - bottleneck
- crus cerebri - anterior cerebral peduncle
- basilar pons
- pyramid of medulla
- 90% decussate lowest medulla border
- 10% no decussation
Lateral crossed tract
control distal limb for manual dexerity
Anterior uncrossed tract
decuss at spinal segment controls proximal limb
UMN cell body
in motor/premotor cortex of frontal lobe
UMN axon
- extends spinal cord
- spinal level muscle
- synapses LMN
LMN cell body
in anterior horn of grey or CN motor nucleus
LMN axon
run in peripheral nerve to muscle
M1
Voluntary contralateral body
Precentral gyrus, frontal lobe anterior to central sulcus
Premotor cortex
Movement plan + preparation
Anterior to M1
Corticospinal
voluntary contralateral lib/trunk
Medial surface
lower limb supplied by ACA
Lateral superior
upper limb + hand
Lateral inferior
face + tongue
Corticobulbar
CN motor nuclei in brainstem controls jaw, face, tongue, larync, pharynx
Neural tube
spinal cord meninges
Neural tube lumen
ventricle
Neural epithelial cells
cells making up neural tube makes radial glial cell
Morphogen
ON/OFF genes in newly formed neuroblast
Microcephaly
- loss
- uncontrolled mitosis
- less neuroblast
- less nerve cells
- smaller brain learning difficulty
Neurogenesis
- neural plate
- neural groove
- neural tube
Ach pathway function of pontomesencephalic tegmentum
DESYNCHRONISES thalamus
Inhibits automatic AP firing
Increases thalamic response Restores connection to world
Ach pathway function of basal forebrain
RESPONSE STRENGTH + SELECTIVITY PLASTICITY
Awake, attentive
COGNITIVE, LEARNING, MEMORY
Ach pathway dysfunction
Damaged basal forebrain in Alzheimer
Gets damaged affecting cholinergic system
Lose cortex cells + Ach which tunes system and aids memory
Aricept
Treat Alzeimers
AchE INHIBITORS increase ACh in presynaptic cleft
DA pathway function of substantia nigra
voluntary movements
DA pathway function of ventral tegmental area
Awake + alert to damaging/rewarding stimuli
ADAPTS BEHAVIOUR towards rewarding stimuli
Ach pathway dysfunction of ventral tegmental area
OVER-ACTIVITY SCHIZOPHRENIA (due to amphetamine)
Dopamine Antagonists
treating scizophrenia symptoms
NA pathway function of locus coeruleus
AMPLITUDE + SELECTIVITY Plasticity Awake + vigilant to new stimulus Learning + cognitive Memory consolidation Mood Analgesia
NA pathway dysfunction of locus coeruleus
ANXIETY + DEPRESSION
Serotonin pathway function of raphe nuclei
Quiet waking - zoned out
MOOD + HAPPINESS
Raphe Nucleus Magnus suppresses ascending pain pathway
Impulse-control, patience, relaxing, responses to reward
Serotonin pathway dysfunction of raphe nuclei
ANXIETY + DEPRESSION
H1 pathway function of hypothalamus
WAKE-PROMOTING circuits
Awake + alert
Orexin pathway function of hypothalamus
regulation of sleep/wake cycle, appetite + alertness
Describe wake up
- in HYPOTHALAMUS, HISTAMINE + OREXIN cells activated
- projections towards BRAINSTEM
- activate brainstem ARAS (Ascending Rrticular Activating System)
- includes nuclei of 5-HT, ACH, NA
- activate basal forebrain
- projecting to thalamus
- relay again connecting cortex to world
- wakefulness
- DESYNCHORNIZE EEG
Big brainstem lesion
COMA since damaged ARAS nuclei so thalamus not desynchronised
promotes sleep
Circadian rhythm (SUPRACHISMATIC NUCLEUS)
Tiredness from increased brain activity (ADENOSINE)
Illness (increased IMMUNE BY-PRODUCTS)
Damage to hypothalamic ventrolateral preoptic nucleus
damaged GABA cell lesion so insomina
adenosine
turns the hypothalamic GABA centre on = sleepy
caffeine
ADENOSINE RECEPTOR ANTAGONIST
how to dream
-activation of PONTOMESENCEPHALIC TEGMENTUM + BASAL NUCLEUS
-ON cholinergic system:
Higher cortical activity
ON skeletal muscle paralysis
addiction
- enhance DA in
- nucleus accumbens (VT area projects here) = PLEASURE CENTRE
Microglia
engulf, digest, destroy pathogens + dead cells
Astrocytes
produce sheath wrapping around nerve cells maintaining ECF at optimal conc for Na+K+ by AT Remove used NT Transport nutrients Waste products to capillaries Forms BBB
Electrotonic potential
Small
Slow depolarisation
Exponential decay
Graded
De-inactivate
reset to original position when at RMP
Absolute refractory period:
no AP can be fired as RMP being restored
Relative refractory period:
more depolarisation needed to reach threshold so AP firing controlled
Refractory membrane:
part of axon in refractory period after AP fired
SM contraction
- Ach binds to M3 Gq in GI, eye, bronchi SM
- ↑PLC: breaks PIP2 –> DAG + IP3
- IP3 binds to calcium stores (SR) so calcium release inside cell
- DAG acts on Na+ channels to depolarise sarcoplasmic membrane so vgcc open, Ca2+ influx
- Ca2+ binds to calmodulin forming Calcium-calmodulin complex
- activates MLCK: phosphorylates myosin light chains
- contraction
Para on eye
- Ach stimulate M3 Gq
- contracts contrictor pupillae SM
- miosis
- opens canal of Schlemm behind pupil
- drains aq humour
- reduce intra-ocular pressure
Para on heart
- Ach stimulate M2 Gi
- ↓SAN freq of pacemaker potentials
- ↓Conduction
Para on bladder
Symp -relax detrusor for filling -contract sphincter to hold Stretch receptors activate micturtion reflex -contract detrusor -relax external spinchter
Para on lungs
- M3 Gq
- contract bronchi SM cells
- bronchoconstriction
Ipratopium
anti-mus bronchodilator in COPD
Para on GI
- Ach on M3 Gq
- contract circular + longitudinal SM in GI
- motility
DAT blocking
blocking dopamine transporter so accumulation in synapse eg cocaine
Selegiline
selective MAOB inhibitor so no peripheral effect
MAOB inhibitor
-block DA metabolism
-protect against MPTP toxicity:
preventing conversion of MPP+ (not neuroprotective) to ↑DA in synaptic bouton
-DA leaks out into synapse
Entacapone
COMT inhibitor
slows elimination of L-dopa
Bromocriptine
D2 agonists
mimic dopamine effect
1st line young Parkinsons
Ropinirole
Newer D2 agonist
Longer duration of action
Lower tendency for dyskinesia
Pramipexole
Newer D2 agonist
Antioxidant effects + protective effect on mitochondria
Amantadine
antiviral drug, but ↑DA release
Benzatropine
For resting tremors
Antimus
Stimulate DA release since Mus receptors inhibits DA nerve terminals
Prochlorperazine:
for vestibular dysfunction
Mus, H1, DA antagonists
Promethazine:
for vestibular dysfunction
Mus, H1 antagonist
Hyoscine hydrobromide (scopolamine)
for vestibular dysfunction
Mus antagonist
Zine, diphenyhydramine (Benadryl):
for vestibular dysfunction
H1 antagonists
Monoamine theory FOR
- Overall reduced activity of central NA/5HT systems
- Reserpine depletes brain of NA +5-HT induces depression
- Antidepressants increase [amines] in brain
Monoamine theory AGAINST
- Difficult to show deficits in brain [NA] + [5-HT]
- Plasma responds better to diff AD
- AD take weeks for effect but in amines acute (secondary adaptive changes more important)
- Some AD weak on amine uptake (trazodone) so no increase in 5HT + NA
- Cocaine blocks amine uptake but no AD effect
- Decrease in 5HT in bipolar linked to aggression not depression
Neuroendocrine theory
- NAergic + 5HT neurons input to hypothalamus
- hypothalamus releases corticotropin-releasing hormone (CRH)
- CRH acts on pituitary
- releases adrenocorticotrophic hormone (ACTH)
- cortisol release from adrenal cortex in response to ACTH in blood
Neuroendocrine theory FOR
- CRH – mimic depressive behaviour
- ↑[cortisol]plasma in depressed
- ↑[CRH] in CSF
- Genes + environment affect HPA axis hyperactivity
Robertsonian translocation
- Chromosomal rearrangement between chromosomes 14 + 21
- Short arms of 2 chromosomes break + lost
- Long arms fuse into single chromosome
- Produces 3 copies of long arm 21
- Carrier of robertsonian translocation offspring w Downs
Balanced rearrangements
Due to translocations, insertions, inversions
No genetic material lost/gained
No disease
Gametes less likely to have a normal karyotype
Unbalanced rearrangements
Due to deletions, duplications, isochromosomes, ring chromosomes, marker chromosomes
DNA gained/lost
Abnormal phenotype
Angelman syndrome
Microdeletion
Developmental delay
Speech impairment
Prader-Willi syndrome
Microdeletion
Hypotonia in infancy
Small hands + feet
Obesity
Penetrance:
proportion of people who will go on to develop a disease if they carry a mutation in a gene - Marfans
Anticipation:
worsening of disease severity in successive generations which only occurs in triplet repeat disorders - Huntingtons
Expressivity:
variation in severity of a disorder between individuals with same mutation
Imprinting:
only maternal or paternal alleles expressed
Autosomal recessive inheritance
Genders equally affected
Siblings not parents/offspring
Recurrence risk is 1/4 for each sibling of an affected person
Carrier probability of 2/3 for normal siblings of an affected person
All offspring are carriers
Mosaicism mechanisms
- Post-zygotic nondisjunction: mitotic non-disjunction
- Anaphase lag
Metacentric:
p = q
1-3, 16-18
Submetacentric
p < q, 4-12, 19-20, X
Synaptonemal complex:
lattice of proteins between homologous chromosomes forms at specific locations then spreads to cover entire length of chromosomes
Bivalent:
alignment of homologous chromosomes + crossing over
Synapsis
tight pairing of homologous chromosomes
Phenylketonuria
LOF
Metabolic disorder lack of phenylalanine hydroxylase (PAH)
Homo lack PAH to convert phenylalanine –> tyrosine
SO PKU
De Vivo syndrome
Haploinsuffiency
GLUT1 deficiency
Dominant
Marfan’s syndrome
Dominant-negative
FBN1 encodes fibrillin-1: forms elastic fibres in connective tissue
Mutant fibrillin-1 forms complex with normal fibrillin-1 blocking normal fibrillin-1
Achondroplasia
GOF
Overactive FGFR3 encodes fibroblast growth factor receptor 3
Skeletal development
Dominant
Marfan’s syndrome
Dominane-negative
FBN1 encodes fibrillin-1: forms elastic fibres in connective tissue
Mutant fibrillin-1 forms complex with normal fibrillin-1 blocking normal fibrillin-1
Non-synonymous SNP
Missense
Nonsense
Synonymous SNP
Silent mutation
Promotor SNPs:
Changes in the gene promoter may alter level of gene expression eg TATA