M&R Clinical

Question 1

Hereditary spherocytosis

Answer 1

Spectrin depletion. Erythrocytes round up-> spherical -> increased cell lysis (erythrocytes cleared by spleen) -> haemolytic anaemia

Question 2

Hereditary elliptocytosis

Answer 2

Spectrin defect -> rugby ball shape -> unstable erythrocytes -> increased lysis -> haemolytic anaemia

Question 3

Diuretics

Answer 3

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

Question 4

Cystic fibrosis

Answer 4

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.

Question 5

Diarrhoea

Answer 5

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

Question 6

Hyperkalaemia

Answer 6

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

Question 7

Hypokalaemia

Answer 7

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

Question 8

Local anaesthetics

Answer 8

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)

Question 9

Multiple sclerosis

Answer 9

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

Question 10

Competitive blockers of nicotinic receptors

Answer 10

eg. Tubocurarine.

Binds to molecular recognition site for ACh but doesnt activate the receptor (ie. The channel does not open)

Question 11

Depolarising blocker of nicotinic receptors

Answer 11

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

Question 12

Myasthenia gravis

Answer 12

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

Question 13

Hypercholesterolaemia/hyperlipidaemia

Receptor mediated endocytosis

Answer 13

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

Question 14

Type 2 diabetes

Receptor mediated endocytosis

Answer 14

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

Question 15

Cholera toxin/diptheria toxin and receptor mediated endocytosis

Answer 15

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

Question 16

Nephrogenic diabetes insipidus

Answer 16

GPCR mutation- loss of function of V2 vasopressin receptor

Question 17

Retinitis pigmentosa

Answer 17

GPCR mutation- loss of function of rhodopsin

Question 18

Familial male precocious puberty

Answer 18

GPCR mutation- gain of function of luteinising hormone (LH) receptor -> early puberty -> retards growth due to premature closure of epiphyseal growth plates

Question 19

GPCR agonists as drugs

Answer 19

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

Question 20

GPCR antagonists

Answer 20

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.

Question 21

Cholera toxin

Answer 21

ADP-ribosylation specific for Gs-> covalent modification of G-alpha S -> inhibition of GTPase -> constant activation of G-alphaS mediated pathways

Question 22

Pertussis toxin

Answer 22

ADP-ribosylation specific for Gi causes interference with GTP/GDP exchange -> prevents activation of G-alpha i -> irreversibly inhibits Gi signal pathways

Question 23

Opioids, morphine, buprenorphine

Answer 23

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.

Question 24

Reversible competitive antagonism

Answer 24

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

Question 25

Irreversible competitive antagonism

Answer 25

Eg. Phenoxybenzamine acts on alpha 1 adrenoceptors in hypertension episodes in pheochromocytoma (tumour of adrenal gland) (SNS innervation of alpha 1 adrenoceptors causes smooth muscle contraction)
Antagonist dissociates slowly/not at all -> non-surmountable (ie. You cant get the normal biological response back)

Question 26

Non-competitive antagonism

Answer 26

Antagonist binds to other allosteric sites (not the recognition site for the agonist)
Causes a conformational change -> agonist not longer complementary

Question 27

Object drugs vs precipitant drugs

Answer 27

Object drug: Used at a lower dose than the number of albumin binding sites -> drug is highly bound to albumin (more albumin molecules than drug molecules). Small vol of distribution as drug is not in free state, and a low therapeutic ratio.
Precipitant drugs: used at a dose which is greater than the number of available albumin binding sites. Displaces the object drug (class 1), meaning that the object drug is in its free state and can cause a response.
Eg. Warfarin is an object drug and aspirin is its precipitant drug.
Therefore, if a patient is on an object drug, adding a precipitant drug wiill temporarily cause a higher free level of the object drug -> risk of toxicity (therapeutic ratio)

Question 28

Tachyphylaxis

Answer 28

Excessive exposure to antagonist leads to reduced sensitivity (eg. Heroin addict will need to up the dose for same response)

Question 29

Suprasensitivity

Answer 29

Agonist deprivation/excessive exposure to antagonist causes increased sensitivity

Question 30

Phaeochromocytoma

Answer 30

Adrenal medulla tumour
Intermittent increased secretion of catecholamines (adrenaline/noradrenaline) -> intermittent SNS activity symptoms (sweating, anxiety, tremor, high BP)

Question 31

Angina (suprasensitivity)

Answer 31

Beta blockers (beta antagonist) used to reduce BP. CAuses reduced adrenergic stimulation, reduced heart rate, reduced coronary vasoconstriction.
Excessive exposure to antagonist -> suprasensitivity -> beta receptor up regulation (more receptors on cell surface).
If treatment is suddenly stopped it can cause antagonist withdrawal -> increased receptor numbers causes a relative increase in SNS and leads to SNS symptoms

Question 32

Side effects of non selective muscarinic ACh receptor agonists

Answer 32

Exocrine glands (M1) : increased sweating and salivation
Heart (M2) : decrease HR and CO
Smooth muscle (M3) :Increased bronchoconstriction and GI tract peristalsis

Question 33

Sludge syndrome

Answer 33

Mnemonic for pathological effects of massive discharge of parasympathetic nervous system. Due to chronic stimulation of muscarinic ACh receptors.
Salivation
Lacrimation
Urination
Defecation
Gastrointestinal upset
Emesis (Vomiting)

Question 34

Salbutamol in asthma

Answer 34

Beta2 adrenoceptor agonist. Used in asthma to oppose bronchoconstriction.
Selectivity limits the cardiovascular side effects (increased HR and CO)

Question 35

Dysautonomia

Answer 35

Umbrella term for distinct malfunction of the autonomic nervous system.
Catecholamine disorders, central autonomic disorders, peripheral autonomic disorders, etc

Question 36

Loading dose and maintenance dose

Answer 36

Drug steady state achieved after 5 half lives.
In an emergency, a loading dose can be given (a high dosage giving a quicker response) -determined by the volume of distribution
A maintenance dose is then given to keep the drug at the required concentration