5 Flashcards
What is Prolactomina?And what often causes it?
When there is an overproduction of prolactinA decrease in dopamine often causes it –> this can be fixed by using a dopamine agonist
What is Panhypopituitarism?
A deficinecy in all anterior pituitary hormones
What’s the difference between primary and secondary diseases?
Primary –> Defect with the endocrine organSecondary –> Problems with the release of the hormones (eg, in the pituatary)
What are the differences between T4 and T3?
T4 is a pro-hormone of T3 –> converted by deiodinasesT3 has a shorter half life than T4T3 has a lower binding affinity for binding proteins, but a higher affinity for receptors
Where are thyroid hormones synthesised?
Follicle cells
What is the most common form of hypothyroidism?
Atrophic (autoimmune) hypothyroidismThis uses antithyroid antibodiesMore common in women –> with the incidence increasing with age
How can we differentiate between primary and secondary hypothyroidism?
TSH LevelsHigh = PrimaryLow = Secondary
What’s the common form of hyperthyroidism?
Graves DiseaseAn autoimmune disease that causes the stimulation of TSH receptors
What are the 3 treatment options for hyperthyroidism?
Antithyroid Drugs –> Carbimazole/ThiamazoleRadioiodine –> If rendered euthyroid before (normal thyroid gland)Surgery –> Only if rendered euthyroid before
Where abouts are aldosterone and cortisol specifically made in the adrenal glands?
Aldosterone –> Zona Glomerulosa (ZG)Cortisol –> Zonas fasciculate (ZF) and Zonas reticularis (ZR)
What is aldosterone?
A mineralcorticoidIts secretion is stimulated by elevation in angiotensin IIBinds to the MCR nuclear receptor
What are the 3 triggers for the release of renin?
Decrease in BP in the afferent arterioleIncrease in sympathetic nervous activityDecrease in [NaCl] in the DCT
What are the 3 main effects of primary hyperaldosteronism?
Increase plasma Aldosterone:Renin Ratio (ARR)Increased aldosterone plasma levels –> that cannot be controlled with NaCl infusionIncreased urinary K+ (and so decreased plasma levels)
What is cortisol?
A glucocorticoidIn circulation most of it is bound to plasma proteinsBinds to the GCR nuclear receptorSecretion is stimulated by ACTH from the pituitary
What’s Addison’s Disease?
Primary adrenal insufficiencyAn autoimmune disease that destroys the adrenal cortex –> so less adrenal steroid productionCharacterised by an increase in CRH/ACTH productionAlso due to cortisol levels (due to destruction above) there is a negative feedback loop which creates
What is main reason for people getting secondary adrenal insufficency?And what does it cause?
Long term corticosteorid therapySuppress the hypothalamus-pituitary axis
How do you manage hypoadrenalism long term?
Replacement therapy with gluco/mineralocorticoidsHave a steroid card for emergency servicesKeep an ampoule of hydrocortisone at home for injection by carers/family
What are the 2 types of hypercortisolism (cushings syndrome)?And how do you test for them?
Primary –> Non ACTH dependent, normally caused by a cortisol-secreting adrenal tumourSecondary –> ACTH dependent, usually caused by an ACTH-secreting pituitary adenoma (‘cushings disease’)The high-dose dexamathasone test is the main one
How do you pharmacologically inhibit cortisol synthesis in cushings syndrome?
Metyrapone and KetoconazoleThese block the adrenal 11(B)-hydroxylase
What is the primary transmitter in nicotinic receptors?
Acetylcholine
Explain what M1 and M2 receptors cause when Ach bindsAlso what is the effect of neuropeptides?
M1 –> Causes K+ channels to close, causing a slow EPSPM2 –> Causes an increase in K+ conducatance, causing hyperpolarisation (slow IPSP)Neuropeptides act as co-transmitters –> causing late/slow EPSPs
Why are local anasthetics co-administered with a vasoconstrictor?
To prevent the anasthetic going elsewhere in the body (to keep it local to the ganglion that its injected into)
What are the different drugs that can be used to block different parts of the synthesis pathway of noradrenaline/adrenaline?
(a)-methyl-p-tyrosine –> Inhibits the Tyrosine HyroxylaseCarbidopa –> Inhibits DOPA DecarboxylaseOften taken with Levodopa to reduces levodopas peripheral effects
How is the release of NA regulated?
Normally the depolarisation of a nerve terminal causes Ca2+ channels to open, which cause NA to be released from vesiclesThe NA then binds to presynaptic receptors (a2-adrenoceptors) when there is too muchThis causes the inhibition of adenylyl cyclase, which limits the amount of cAMP thats produced….so less calcium channels are opened
Explain how NA transmission can be terminated?
Neuronal Epinephrine Transporters (NET) are located on the presynaptic membrane, and reuptake NA into the presynaptic nerve terminalsVesicular Monoamine Transporter (VMAT) uptakes NA back into vesicles, with ATP. This is because they have oppostie charges, so vesicle leakage doesn’t occur.Extraneuronal Monoamine Transporter (EMT) actively transports NA into the post synaptic cell, where is it metabolised by catechol o-methyl Transferase (COMT)
How do the following drugs work to prevent NA transmission?MethydopaGuanethidineReserpine
Methyldopa –> An a2 agonist, so promotes the inhibition of adenylyl cyclaseAlso inhibits DOPA decarboylase (like carbidopa)Guanethidine –> A substrate for NET and VMAT (so accumulates in vesicles), preventing depolarisationReserpine –> Inhibits VMAT, so NA floats around outside before being matabolised by MAO
There are 3 types of B, and 2 types of A adrenoreceptors…. but which GPCRs do they bind to?
A1 –> Gq Which activates Phospholipase CB1/2/3 –> Gs Which activates Adenylyl cyclaseA2 –> Gi Which inhibits Adenylyl cyclase
What are some of the uses/effects of direct sympathomimetics?
(A)1 Selective –> Vasoconstrictors (eg, phenylephrine)(A)2 Selective –> Prevent NA release, so reduce BP (eg, clonidine) with their main action in the medullaB Agonists –> Increase cardiac contractility (eg, adrenaline in anaphalactic shock)
Give some example of indirect acting sympathomimeticsAnd how do they work?
Amphetamines –> Substrates of NET/VMAT and inhibit MAO…..so there is a greater conc of NA in the synapseCocaine –> Inhibits NET, so there is more NA in the synapse
Name some examples of non-selective (a)-adrenoceptor antagonists
Labetalol/CarvedilolPhenoxybenzamide –> long lasting due to convalent bondingAlso blocks Ach, 5HT and histaminePhentolamine –> Short acting, and more selective
What are selective A1 antagonists?
-azosin drugs –> eg, Prazosin and DoxazosinDirectly block the action of NA/A on smooth muscle –> Causing vasodialation….and so a fall in BPCauses less tachycardia than non-selective antagonists, but still causes postual hypotension
Name an a2 selective antagonist
Yohimbine
What are some of the unwanted effects of B-Blockers?
Bronchoconstriction –> Via B2 receptorsBradycardiaHypoglycaemia –> due to glucagon release normally occuring due to adreanline binding to B2 receptors. B-Blockers also blocks hypoglycaemia symptoms such as tremors –> causing ‘hypoglycaemic unawareness’FatigueCold Extremities –> Due to loss of B2 mediated vasodialationLucid Dreams
Atenolol and Timolol are example of what?
B1 selective B antagonists (blockers)
What are the key characteristics of Metabolic Syndrome?
Abnormal carbohydrate and lipid metabolismInsulin resistanceElevated fasting blood glucoseHypertensionDyslipidaemia
What are the risk factors for Metabolic Syndrome?
Visceral obesityAge and WeightRace –> More prevelant in afro-carribean/asian populationHaving Non-alcoholic liver diseaseA history of gestational diabetes (pregnancy)Smoking –> due to increasing cortisol levels via the sympathetic nervous system
Having metabolic syndrome is a key risk factor for what 2 other diseases?
T2DM –> 5 fold riskCVD –> 2 fold risk
What are adipocytes?
Three types –> White/Brown/BriteBrown –> Used in thermogeneosis… has high levels in neonates, but falls drastically with ageBrite –> Used in the storage and expenditure of fatsThese secrete adipokines….such as Leptin and Adiponectin
Explain what the 2 adipokines are
Leptin –> Suppresses hunger (stimulates satiety)Its levels increase in obesity….but you can become resistant to it…especially in a high fructose diet!!Adiponectin –> Increases insulin sensitivity and fatty acid catabolism (decreasing triglycerides). Also decreases hepatic glucose productionLevels drop in obesityLevels can be increased by glitzone drugs (thiazolidinediones)
Why is an increased conc of Urea an indicator for metabolic syndrome?
As arginase is increased in MS, causing more of L-arginine to be converted to urea…. instead of being converted to NO (a vasodialator)
What is peroxynitrite?
The end product of ROS reacting with NO……preventing NO from acting as a vasodilator
Why could a faecal transplant be useful for those suffering from Metabolic Syndrome?
As during MS, acetate-producing bacterial populations are selected in the gut due to the high fat/sugar dietThis stimulates insulin and grehlin (hunger hormone) productionTherefore this leads to obesityHowever a faecal transplant can add healthy/normal bacteria back to the gut
An increase in Total Peripharal Resistance (TPR) will occur due to what?
Vasoconstriction
In the contraction of blood vessels, how are GPCRs involved?
Ga(q) –> Stimulates PLC, which causes an increase in Ca2+ release from the SRThis causes MLCK to phosphorylate MLC –> causing contractionGa(i) –> Inhibits PLC
How do Calcium Channel Blockers (CCBs) work?
They block L-type Voltage-Activated Ca2+ channels (L-VACCs)There are 2 different forms of these…Cav1.2a –> Cardiac MuscleCav1.2b –> Smooth MuscleThis allows for a degree of selectivity
What is ‘Calcium Sensitisation’?
Where intracellular process causes inhibitory responses on MLCP (which itself causes relaxation), and so less calcium is needed to be present to causes contraction of muscles and blood vessels
What is Endothelin-1 (ET-1)?And how is it made?
A molecule that increases BP when bound to specific receptors (ET A/B) on smooth muscleSo ET A antagonists can be used to treat hypertensionStimulates vasodialation factors (eg, NO) when bound to ET B receptors in endotheliumIts made via various enzymes such as Furin and Endothelin-Converting Enzyme (ECE) in endothelial cells
What causes the relaxation of smooth muscle?
Opening of K+ channels –> causes hyperpolarisation, which is like a negative feedback to L-type VACCsSERCA2 uptakes Ca2+ back into the SRNitric Oxide and ANPs cause more cGMP to be produced, causing Protein Kinase G to stimulate MLCP (relaxation)The binding of agonists to Gs GPCRs will cause Protein Kinase A to inhibit MCLK (inhibiting contraction)
What are the 3 different isoforms of Nitric Oxide Synthase?
Endothelial (eNOS) –> Constitutively expressed and dependent on calciumWill cause vasodialation in blood vessels and reduce aggregation of plateletsNeuronal (nNOS) –> Used in neurotransmission, gastric emptying and erectionsInducible (iNOS) –> Calcium independentUsed in host defence, often activated by LPS
How is eNOS activated?And what are the effects?
An agonists binds to a GPCR in an endothelial cell, causing an increase in Ca2+. This causes calmodulin (linked with Ca2+) to activate eNOS, which stimulates the production of NONO then activates soluble Guanylyl Cyclase (sGC) in the smooth muscle, increasing cGMP levels…. causing Protein Kinase G to stimulate MLCP (relaxation)
What is Asymmetric dimethylarginine (ADMA)?
An endogenous NOS inhibitor –> So decreases the amount of natural NO that we producePresent in higher levels in people suffering from hypercholesterimia, hypertension, kidney faliure etc…It is a marker of endothelial dysfunction and a risk factor for CVD
Why do men like selective PDE5 inhibitors?
Because they prevent cGMP breakdown, and so less PKA…. so less relaxation occurs….Allowing them to get erections!Eg, sildenafil (viagra)
Explain the synthesis of Prostnoids
Calcium stimulates cPLA2, which forms Arachidonic acidCOX-1 converts this to PGG2 –> PGH2Thromboxane Synthase converts PGH2 –> TXA2 (in platelets)PGD Synthase converts PGH2 –> PGD2 (in mast cells)Prostacyclin Synthase converts PGH2 –> PGI2 (in endothelial cells)
What is Endothelial-derived Hyperpolarising Factor (EDHF)?
An independent cellular pathway that causes vasodialation via hyperpolarisation of smooth muscle cellsUsually caused by K+ channel opening
What are the driving and opposing forces in ultrafiltration?
Driving Forces –> Glomerular capillary hydrostaticOncotic pressure in the bowmans space (normally negligible)Opposing Factors –> Oncotic pressure of the blood plasmaPressure in the bowmans space
Rank the parts of the nephron from first to last in terms of their Na+/Cl- reabsorption
PCTThick Ascending Limb (TAL)Distal TubuleCollecting duct/tubule
Which group of diuretics has the greatest effect?And why has the least?
Greatest –> Loop diureticsLeast –> Carbonic Anhydrase
How do Carbonic Anhydrase Inhibitors, like Acetazolamide, work?
By inhibiting Carbonic Anhydrase…..This prevents bicarbonate from being reabsorbed in the PCT, and so less Na+ is reabsorbed….leading to diuresisCan cause slight urine alkalosis, and mild plasma acidosis (due to less H+ being secreted)
How do Osmotic Diuretics, like Mannitol, work?
Freely filtered into the nephron, and acts on parts that are freely permeable to water (eg, PCT, decending limb of the loop of henle, collecting tubule/duct in the presence of ADH)Increases the osmolarity of the tubular filtrate by decreasing the water absorptionIt also reduces the amount of Na+ reabsorption
How do Loop Diuretics, like furosemide, work?
By the inhibition of the luminal Na+/K+/2Cl-co-transporterThis decreases Na+/Cl- reabsorption –> causing diuresisAlso an increase in K+/Ca2+/Mg2+ secretion
State some of the PKs of Furosemide
Absorbed in the gutStrongly bound to albumin in the plasmaSecreted into the tubular filtrate by OAT in the PCTExcreted in the urine
How do Thiazide drugs, like bendroflumathiazide, work?
By inhibiting the luminal Na+/Cl- Co-transporter in the distal tubuleThis reduces Na/Cl- reabsorption –> diuresisAlso increases K+ excretion, and Ca2+ reabsorption
Which has the longest duration of action….. loop diuretics or thiazides?
Thiazides and thiazide-like drugs
What are the main side effects of thiazides/thiazide-like drugs?
HypotenisonMetabolic Alkalosis –> Due to RAAS increasing H+ excretionCause an increase in urea reabsorption, and so gout can occurHypokalemia (under 3.5mmoL of K+)ED
How do K+ sparing diuretics, like spironolactone, work?And what effects does aldosterone usually have?
Aldosterone activates Na+ channels and increases the synthesis of the Na+/K+/ATPase…..all of which increase Na+ reabsorptionNa+ reabsorption is coupled with K+ excretion/secretion….. so the following drugs will decrease K+ excretionAldosterone Antagonists –> Spironolactone/EplerenoneNa+ Channel Blockers –> Amiloride/Triamterene
What does ADH/Vasopressin do?
Increases the expression of Aquaporin 2 on the luminal membrane in the collecting tubule, via the Gs GPCRThis increases water reabsorption
What are the 2 types of Diabetes Insipidus (DI)
Neurohypophyseal (Central) –> Reduced ADH secretionTreated with desmopressin (synthetic ADH)Nephrogenic –> Normal ADH secretion, but an impaired kideny responseTreated with thiazides
What is the role in Atrial Natiuretic Peptide (ANP) in diuresis?
Causes a decrease in…..AldosteroneNa reabsorptionRenin releaseAlso causes vasodialationThese all cause blood volume to decrease
What’s the difference between Pulmonary and Peripheral Oedema?
Pulmonary –> Left ventricular hypertrophyPeripheral –> Congestive heart faliure (CHF)
How/where is renin secreted specifically?
From the Juxtaglomerular cellsSecretion is stimulated by…..Decrease in blood pressureDecrease in tubular Na+ –> Release of PGE2 (via COX2)Increase in sympathetic stimulation via B1 adrenoceptors
What’s the mechanism in ACEi that can cause a persistant dry cough?And how will using ARBs stop this?
ACEi prevents ACE from breaking down bradykininThis causes the levels of bradykinin to increase –> which stimulates coughingARBs selectively inhibit Angiotensin Receptor 1, so they have no effect on bradykinin
What is known as the “Triple Whammy” Effect?
Use of an ACEi, Diuretic and an NSAID causing very low GFRThe diuretics decrease blood volume, activating the RAAS system….however….ACEi prevents the efferent arteriole from constricting….so GFR goes down furtherThe afferent arteriole can’t relax more due to NSAID inhibition of COX-2, which causes GFR to decrease even more…..
When would CCBs be prescribed?And what are the 3 classes?
Those over 55 years oldPatients of african-american/carribean origin at any ageSevere hypertension in pregnancy (nifedipine)1-4-Dihydropyridines –> Nifedipine/Amlodipine (vascular)Benzothiazepines –> Diltiazem (Intermediate)Phenylalkylamines –> Verapamil (Cardiac)
What’s the mechanism of K+ channel activators
Activation of ATP-sensitive K+ channels in vascular smooth muscleThis causes membrane hyperpolarisation, and so the closure of L-type VACCsResulting in relaxation
What is Minoxidil
A K+ channel activator thats used in servere resistant hypertensionShould be used with a B-blocker and diuretic to prevent reflex tachycardia and fluid retension
What is Hydralazine?
Directly dialates arteries/arteriolesUsed in severe hypertension in pregnancy with a diuretic and B-blockerAlso in heart faliure in people with afro-caribbean origin (with nitrates)
How do B-blockers work?And list some different ones?
By antagonising B1 receptors in the heartAtenolol (B1 selective)Propanalol (non-selective)Nebivolol (B1 selective, and stimulates NO secretion)Pindolol (B1 selective, and partial agonist at low symp levels)Labetalol/Carvedilol (non-selective, with some (a)1 antagonism)
Name 2 (a)1-adrenoceptor antagonistsAnd what are the key adverse effects?
Doxazosin and PrazosinFirst-dose hypotensionDizzinessFatigue
What is the main purpose of central-acting drugs?Eg, clonidine/(a)-methyldopa
Decrease parasympathetic outflow….which will decrease BP
How does Trimetaphan work?
A competitive nicotinic acetylcholine receptor antagonist at the autonomic ganglionBlocks ganglions, but clincially obsolete
How do Guanethidine and Reserpine work?
Guanethidine –> Taken up by NET and VMAT, depeleting the vesicles of NAReserpine –> Taken up by NET and irreversible inhibits VMAT, preventing the uptake of NA into the vesicle and synapse
Define atherosclerosis
A progressive disease of large and medium sized muscular arteries, characterised by inflammation and dysfunction of the lining of the involved blood vessles, and the the build up of cholesterol, lipids and cellular debrisResulting in a formation of a plaque (atheroma)
What are the normal levels of cholesterol in people?
Total = Less than 5mmol/LNon HDL = Less than 4 mmol/LLDL = Less than 3 mmol/LHDL = Greater than 1 for men and 1.2 for women (mmol/L)TC:HDL Ratio = Greater than 6
What things will be raised in the plasma, indicating atherosclerosis?
C-Reactive Protein (CRP) –> Pro-inflammatoryHomocysteineCoagulation FactorsLipoprotein(a) –> Prothrombotic
How are lipoproteins and cholesterol transported around the body?
LDL –> Have a low ratio of protein:cholesterolThis is bigger than HDLsHDL –> Have a high ratio of protein:cholesterolIDL –> Carry mainly cholesterolChylomicrons (CM) –> Transport exogenous (dietary) triglyceridesVLDL –> Transports endogenous cholesterol from the liver to the muscle and adipose tissue
Explain what happens to free cholesterol in the body?
It is esterified (by LCAT) and then transfered to VLDL/LDL (via CETP). The VLDL/LDL then bind to LDL-receptors in the liverOr the free cholesterol is taken up by HDL and binds to SR-B1 receptors in the liver (true also for esterified cholesterol)
What controls the degredation of LDL receptors?
PCSK9 (proprotein convertase subtilisin/kexin type 9)
What are the 5 main stages in the formation of an Atheromatous plaque?
Endothelial Cell Dysfunction (initiation)Lipid accumulation and oxidationImmune cell accumulationSmooth Muscle Cell RercruitmentUnstable atheromatous plaque
What is lipoprotein (a)?
A cholesterol rich LDLA CV risk factor and a proatherogenic marker
Name 4 signs of Familial Hypercholestermia (FH)
Cornal ArcusTendons XanthomataXanthomaSkin Xanthomata
What is Apolipoprotein (a)?
Lipoprotein (a) with an additional protein that is bound via a disulphide bondIt is prothrombotic and profibrotic
How do statins work?
Inhibition of HMG-CoA ReductaseThis prevents the conversion of HMG-CoA to mevalonateThis decreases the amount of LDL in the body by reducing the number of LDL-receptors, and increasing its clearance from the body
What are the 2 types of statins?
Type 1 –> Fungal derived (Pravastatin/Simvastatin)Type 2 –> Synthetically derived (Atorvastatin/Rousuvastatin/Fluvastatin)
What are the 3 statins that are metabolised by CYP3A4s?
LovastatinSimvastatinAtorvastatin
How does Ezetimibe (Ezetrol) work?
Inhibits the NPC1L1 membrane transport proteinThis prevents cholesterol from being absorbed in the gutHowever this includes plant stanols, which are part of a cholesterol-lowering diet
How do Fibrates (Fenofibrate) work?
Agonist of PPAR(a) –> A nuclear transcription factorThis dimerises with RXR (retonoid X receptor) –> Which increase the transption of Lipoprotein Lipase (LDL)So causes an increase in uptake in LDL and formation of HDLAlso decreases VLDL levels
What are bile-binding acid residues? (eg, colestyramine)
They bind bile acids in the gut and reduce reabsorption of cholesterol via the enterohepatic circulationOnly effect is that they decrease LDL (no effect on HDL or triglycerides)
How does Nicotinic Acid (Niacin/Vitamin B3) work?
A precursor of NAD+/NADH/NADP+/NADPHActivates the Gi/o coupled HCA2 receptor in adipocytesIncreases APO-A1 –> which increases HDL levelsInhibits lipolysis
How do Fish Oil Derivitives work?
Act as precursors of ‘beneficial’ eicanosoids……eg prostaglandins/thromboxanes and leukotrienesThey reduce triglycerides and LDL cholesterol
What are Evolocumab and Alirocumab?
Anti-PCSK9 monoclonal antibodiesUsed in hypercholesterolaemia
What is the difference between insulin and glucagon?
Insulin –> Decrease plasma….glucose/AA/FFAsSo stimulates glucose utilization via glycolysis and glycogenesisInhibits glucose production by gluconeogenesis and glycogenolysisGlucagon –> Increases plasma….glucose/ketones
What is the difference between T1DM and T2DM?
Type 1 –> Destruction of the B-islet cells of the pancreasNeeds injected insulin (as they produce none!)Type 2 –> The body cannot produce enough insulin, OR the body cannot respond to the insulin correctly (“insulin resistance”)Usually diagnosed in patients over 40yrs old
What is the IRS pathway of insulin receptor signalling?
Insulin binds to a receptor tyrosine kinase, activating insulin receptor substrate (IRS)This causes several metabolic effects via PI3 kinase and AktMain effect is the expression of more GLUT receptors on the membrane of cells, allowing more glucose to be uptaken into cells (and removed from the blood) –> Eg, GLUT4 recptors in muscle and fat cells
What are some of the effects of insulin resistance?
Increased thirst/urinationFatigueHypertensionLow HDLIncreased fat storesHyperglycemia
What are Sulfonyureas? (eg, gliclazide)And how do they work?
Stimulate insulin secretionThey inhibit the ATP-sensitive K+ channel, causing more depolarization…..causing Ca2+ release…..which stimulates insulin secretionCan stimulate weight gain
What are Meglitanides? (eg, rapaglinide)
“nonsulfonylureas” but act in the same way (by blocking the K-ATP channel)They are more rapidly absorbed in the body, and so have a faster onset of action than sulfonylureasCan be used with metformin
What are Biguanides? (eg, metformin)
Insulin sensitising molecules, so cant be used in T1DM as insulin needs to be present!!!Main action is decreasing the hepatic glucose production (by inhibiting gluconeogensis)Inhibits the mitochondrial respiratory complex 1 (decreased synthesis from ADP –> ATP)Stimulates insulin receptor expression and tyrosine kinase activityDrug of choice in overweight patients as it does not stimulate weight gain
What is the major potential side effect of metformin?
Lactic acidosisExcessive production of lactic acid (lactate) to the blockade of the mitochondrial respiratory chain complexSo pyruvate cannot be converted back to glucose (only lactate)
What are (a)-glucosidase inhibitors? (eg, Acarbose)
They reduce the digestion of complex carbohydrates, and so slows their absorption from the gutAdverse effects are common (flatulence/diarrohea), and so not often used in the western worldDon’t cause hypoglycemia or weight gain
What are Thiazolidinediones (TZDs/Glitazones)
An insulin-sensitising drugAgonists at Peroxisome Proliferator-Activated Receptors (PPARs), and so decrease B-oxidation of fatty acids and cholesterol synthesisMechanism takes several weeks to occurWeight gain is a major side effect!!Metabolised by CYP450s
What are the 2 mechanisms of PPAR(y)?
Transactivation –> Activates gene transcriptionTransrepression –> Represses gene transcription (including NFkB)Therefore TZDs have anti-inflammatory effects
What are incretins?
Glucagon-like peptides (GLP-1) and gastric inhibitory polypeptidesGLP-1 affects insulin biosynthesis and secretion, but only under hyperglycaemic conditions GLP-1 inhibits glucagon release, and is a satiety signal leading to a reduction in food intake –> So aimed at overweight patientsGLP-1 levels are reduced in T2DM!Mimetic example = Exenatide
What are gliptins/DPP-4 inhibitors? (eg, sitagliptin)
DD4 is an enzyme responsible for rapid degradation of GLP-1 and GIP….so inhibitors potentiate GLP-1
What are the SGLT2 inhibitors? (eg, -flozin)
Reversibly inhibit the sodium glucose co-transporter 2 (SGLT2) in the renal proximal convulated tubuleThis reduces glucose reabsorption and increases secretion
