M&R Clinical Flashcards
Hereditary spherocytosis
Spectrin depletion. Erythrocytes round up-> spherical -> increased cell lysis (erythrocytes cleared by spleen) -> haemolytic anaemia
Hereditary elliptocytosis
Spectrin defect -> rugby ball shape -> unstable erythrocytes -> increased lysis -> haemolytic anaemia
Diuretics
Reduce the reuptake of Na+ -> prevent reabsorption of water -> decrease blood volume -> decrease blood pressure
Loop diuretics: block NKCC2 in thick ascending limb -> prevents transport of Na+ so prevents reabsorption of water
NOTE: aldosterone up-regulates the transporters (eg. NKCC2), so opposes the action of diuretics
Cystic fibrosis
Autosomal recessive CFTR gene mutation -> faulty CFTR protein
In epithelial cells lining the airways: Na+ gradient set by Na+K+ATPase pump allows symport of 2Cl- into the cell with Na+ and K+ (NKCC2). Faulty CFTR leads to accumulation of Cl- inside the cell, and water moves in from the mucus into the cell by osmosis (Cl- is osmotically active) -> thick/viscous mucus.
Diarrhoea
CFTR ion channel over active (due to phosphorylation by PKA) -> accumulation of Cl- into the gut lumen -> movement of water into lumen by osmosis -> watery faeces
Hyperkalaemia
High K+ conc in blood.
Difference in conc between outside and inside of cell gets smaller -> less K+ efflux -> RMP more positive
Insufficient hyper polarisation results in Na+ channels remaining inactivated -> less channels available to reach threshold -> AP speed slows.
Pacemaker cells: pacemaker potential starts at a less negative RMP so insufficient hyperpolarisation to activate the HCN channels -> slower AP -> slower HR -> bradycardia
Heart may stop when the blood conc of K+ reaches 7mM as there are a lack of voltage gated Na+ channels to initiate ventricular action potential
Hypokalaemia
K+ conc in blood is low.
Conc difference between outside and inside of cell is greater -> more K+ efflux -> hyperpolarisation -> more negative RMP
More VG Na+ channels available to make an AP -> quicker conduction velocity -> if this occurs in pacemaker cells it will cause tachycardia, if it occurs in the myocardium it will cause ectopic beats/arrhythmias
Local anaesthetics
eg. Procaine.
passes through membrane in uncharged state then binds to H+ inside the cell to become charged.
Once charged, the anaesthetic enters the Na+ channels from the inside and blocks it.
Use dependence- anaesthetics block open channels (more open channels = more channels blocked).
Blocks small myelinated axons first -> non myelinated -> large myelinated (sensory before motor)
Multiple sclerosis
Autoimmune condition.
Myelin sheath (oligodendrocytes) around axons in the CNS are removed and replaced with scar tissue.
Conduction velocity slows and saltatory conduction is impaired.
Symptoms: paraesthesia, anaesthesia, blurred vision, muscle weakness, etc
Treatment: steroids (relapse MS), beta interferons modify the disease course
Competitive blockers of nicotinic receptors
eg. Tubocurarine.
Binds to molecular recognition site for ACh but doesnt activate the receptor (ie. The channel does not open)
Depolarising blocker of nicotinic receptors
Eg. Succinylcholine. (Used in surgery)
Cause a maintained depolarisation at the post junctional membrane -> adjacent Na+ channels become inactivated -> depolarisation cant reach threshold -> no AP
Myasthenia gravis
Autoimmune disease.
Attacks nAChRs -> loss of functional ACh receptors -> loss of junctional folds and widening of synaptic cleft ->decrease in endplate potential amplitude (amount of depolarisation) -> muscle weakness/sudden falling.
Treat with acetylcholinesterase inhibitors -> ACh remains in cleft for longer -> increased chance of ACh binding to any remaining available receptors.
Each quantum of ACh released (amount of ACh released from one vesicle) produces a smaller response than in normal muscle because of the reduced number of receptors
Hypercholesterolaemia/hyperlipidaemia
Receptor mediated endocytosis
Non-functional LDL receptor (LDL cant bind but coated pits and internalisation is normal) No internalisation (but receptor binding is normal) LDL receptors found distributed over whole cell surface rather than concentrated in clathrin coated pits Deletion of C terminal cytoplasmic domain prevents interaction with clathrin coat
Type 2 diabetes
Receptor mediated endocytosis
Hyperglycaemia -> increased secretion of insulin -> insulin binds to insulin receptors -> receptor mediated endocytosis -> both insulin and insulin receptor are degrades -> down regulatio of insulin receptors -> desensitivity to insulin/insulin resistance -> type 2 diabetes
Cholera toxin/diptheria toxin and receptor mediated endocytosis
Membrane-enveloped virus.
Can exploit RME- viral membrane fuses with acidic endosome membrane and releases its viral RNA. Acidic pH is favourable for translation/replication of the cell machinery -> forms new viral particles
Nephrogenic diabetes insipidus
GPCR mutation- loss of function of V2 vasopressin receptor
Retinitis pigmentosa
GPCR mutation- loss of function of rhodopsin
Familial male precocious puberty
GPCR mutation- gain of function of luteinising hormone (LH) receptor -> early puberty -> retards growth due to premature closure of epiphyseal growth plates
GPCR agonists as drugs
beta 2 adrenoceptor agonists:
Anti asthma, eg. Salbutamol, salmeterol.
Binds to beta 2 receptor, activates it, causes bronchodilation.
Mu opioid receptor agonists:
Analgesia, eg. Morphine, buprenorphine
Binds to G-beta-gamma subunit -> decreased activity of VOCC -> decreased Ca2+ influx -> neurotransmitter vesicles arent released into synaptic cleft
GPCR antagonists
beta 2 adrenoceptor antagonists (beta blockers)
Eg. Propranolol, atenolol
Binds to receptor but does not activate it. Used to treat hypertension. Blocks beta1 in SAN causing a negative chronotropic effect, and blocks beta 1 in myocardium causing a negative inotropic effect. Blocks beta1 in kidneys causing reduced activity of renin-angiotensin-aldosterone system. Blocks beta 2 in periphery inhibiting release of NA/A and decreasing SNS activity.
Cholera toxin
ADP-ribosylation specific for Gs-> covalent modification of G-alpha S -> inhibition of GTPase -> constant activation of G-alphaS mediated pathways
Pertussis toxin
ADP-ribosylation specific for Gi causes interference with GTP/GDP exchange -> prevents activation of G-alpha i -> irreversibly inhibits Gi signal pathways
Opioids, morphine, buprenorphine
Used for pain relief/recreational, but can cause respiratory depression
Action through Mu-opioid receptors (GPCRs)
Morphine- full agonist, buprenorphine- partial agonist with a higher affinity than morphine but a lower efficacy
This means that buprenorphine can provide adequate pain relief with less respiratory depression. Can be used in gradual withdrawal from overuse of opioids.
Reversible competitive antagonism
Naloxane acts on Mu-opioid receptors with a high affinity- reverses respiratory depression that you get with morphine.
Increasing agonist concentration overcomes the effects of the antagonist.
IC50= concentration of antagonist giving 50% inhibition (index of antagonist potency)
Kd- antagonist affinity
Parallel shift to the right of the agonist concentration response curve
