Pharmacology (Term 2) Flashcards
Detail the hypertension treatment flowchart.
ACEi or ARB (younger than 55) or CCB or thiazide-type diuretic (over 55 or afro-Caribbean). Step 2 is either ACEi/ARB and CCB or ACEi and thiazide-type diuretic. Step 3 is ACEi/ARB and CCB and thiazide-type diuretic. Step 4 (resistant hypertension) is all 3 plus either further diuretic therapy or an alpha- or beta-blocker.
Why are ACEis and ARBs not typically given to those over 55 years of age and those of Afro-Caribbean descent?
Since those people are classified as having low plasma renin activity. Their hypertension is caused by other comorbidities, such as atherosclerosis, in most cases. Hence blocking the RAAS pathway is not very effective.
Describe the role of the If (“funny current”) channel in sinoatrial cells.
A current active in phase 4 - when hyperpolarisation reaches its maximum. It is a hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel. Opened by cAMP.
Insufficient to cause an action potential but slightly depolarises the membrane.
How does sympathetic activity affect the ion channels in sinoatrial cells?
Increases cAMP, increases Ica, increases If
How does parasympathetic activity affect the ion channels in sinoatrial cells?
Decreases cAMP, increases Ik
Give factors affecting myocardial oxygen supply and those affecting myocardial oxygen demand.
Supply: coronary blood flow and arterial O2 content.
Demand: contractility, afterload, preload and heart rate.
How do heart rate, afterload, preload and contractility affect myocardial oxygen demand?
Increased heart rate = more contractions
Increased contractility or afterload = increased force of contraction (primary determinant).
Increased preload = small increase in FOC (Frank-Starling Law) (100% increase in ventricular volume only precipitates a 25% increase in FOC).
Give drugs which influence heart rate and MOA.
B-blockers - decrease If and Ica.
Calcium antagonists - decrease Ica
Ivabradine - decreases If.
Give drugs which influence contractility and MOA.
B-blockers - decrease contractility
Calcium antagonists - decrease Ica
Give the 2 classes of calcium-channel blocker.
Rate slowing (cardiac and smooth muscle actions).
Phenylalkylamines (e.g. verapamil)
Benzothiazepines.
Non-rate slowing (smooth muscle actions - more potent)
Dihydropyridines, e.g. amlodipine.
No effect on heart. Profound vasodilation can lead to reflex tachycardia.
How do organic nitrates and potassium channel openers help treat stable angina?
Organic nitrates promote cGMP through activation of GC, causing relaxation of smooth muscle, and also promote potassium ion channel opening, hyperpolarising the membrane (as do potassium channel openers).
The result is vasodilation, which decreases afterload, and VENODILATION, decreasing preload. They also improve blood flow through the coronary arteries.
Which classes of drugs are the first line treatment for stable angina?
Beta-blockers or CCBs.
Why are Beta-blockers not great at treating stable angina in heart failure patients? Which beta-blockers would you prescribe?
They worsen heart failure since they decrease CO and increase vascular resistance (B2 causes dilation).
They also cause bradycardia (decreasing CO) by decreasing conduction through the AVN.
Use pindolol (which has some intrinsic sympathetic activity) or carvedilol (a mixed A-B blocker, since A1 blockade decreases vascular resistance).
Why may patients on B-blockers complain of cold extremities?
Loss of B2-mediated cutaneous vasodilation in extremities.
What side effects are associated with CCBs?
Phenylalkylamines cause bradycardia and AV block, as well as constipation (blocking gut Ca2+ channels).
Dihydropyridines cause ankle oedema (due to vasodilation and subsequent pressure on capillaries) and headache/flushing (vasodilation). Also reflex tachycardia.
K+ channel openers and organic nitrates cause the same side effects of dihydropyridines.
How are arrhythmias classified by both speed of conduction and site of origin?
Bradyarrhythmias and tachyarrhythmias.
Supraventricular arrhythmia and ventricular arrhythmia. (A complex arrhythmia combines the two origins).
What is the drug of choice for treating supraventricular tachyarrhythmias?
Adenosine. Has a short duration of action so is safer than verapamil (rate-slowing CCB - a phenylalkylamine).
Inhibits cAMP production, opening K+ channels, hyperpolarising the cell. Also, it inhibits L-type Ca2+ channels, preventing Ca2+ influx. Further, interference with the If channel decreases the slope of the phase 4 pacemaker action potential.
Overall, slows HR with the hope of restoring normal rhythm.
Also binds to adenylyl cyclase on vascular smooth muscle to increase cAMP, causing vasodilation.
What does verapamil do in the treatment of arrhythmias?
Reduces ventricular responsiveness to atrial arrhythmias by depressing SA node automaticity and subsequent AV node conduction.
What does digoxin (a cardiac glycoside) do?
Inhibits Na-K-ATPase, reducing Na+ efflux. Hence there is less Na+ for the Ca2+/Na+ exchanger and less Ca2+ is pumped out the cell. Hence, has a positive inotropic effect.
Central vagal stimulation also increases refractory period and reduced rate of conduction through AV node.
Slows heart but increases FOC.
Adverse effects: AV block leading to dysrhythmias.
How does hypokalaemia lower the threshold for digoxin toxicity?
Since K+ competes with digoxin for the binding site on the K-Na-ATPase, hypokalaemia means digoxin binds more readily to the pump.
Describe ACE inhibitors, such as enalapril.
Prevent conversion of angiotensin I to angiotensin II.
Also lead to accumulation of kinins, including bradykinin, which promote vasodilator activity.
Used for treating hypertension, heart failure, post-myocardial infarction, diabetic nephropathy and progressive renal insufficiency.
Reduce preload (venous return) and afterload (TPR).
Describe ARBs, such as losartan.
Antagonists of type 1 (AT1) receptors for angiotensin II, preventing renal and vascular actions of angiotensin II.
Used to treat hypertension and heart failure.
Why are ARBs and ACEis first line treatments for hypertension and what are some of their side effects?
They are well tolerated, particularly ARBs. As such, have greater compliance.
ACEis cause coughs since they prevent the breakdown of bradykinin, which is procough.
They both may cause hypotension and dizziness though blunting of reactive vasoconstriction.
Hyperkalaemia (through lack of aldosterone stimulation)
Renal failure in patients with renal artery stenosis since the glomerular pressure falls.
How are A1 blockers useful as anti-hypertensives?
Give some examples.
They prevent peripheral vasoconstriction.
Prazosin, phentolamine (non-selective).
How can dihydropyridines, such as amlodipine, which don’t show negative chronotropy due to their selectivity for blood vessels, sometimes show positive chronotropy?
They cause powerful vasodilation, leading to a fall in B.P. and decrease in baroreceptor firing, leading to sympathetic stimulation of the heart (reflex tachycardia) and increase oxygen demand.
Give an example of an organic nitrate and describe its administration.
Glyceryl trinitrate (GTN).
A sublingual spray which can be applied prophylactically immediately before exertion.
Increases coronary blood flow (Helps with angina)
Why are ACEis often given with thiazide diuretics?
The thiazide diuretic, e.g. bendrofluazide, acts on the distal tubule of the kidney to reduce active reabsorption of sodium and chloride ions. Inhibits Na+/Cl- cotransporter.
Eventually leads to hyponatraemia and low sodium load in DCT, stimulating RAS.
Define stable and unstable angina.
Stable angina is predictable pain on exertion and is due to a fixed narrowing of the coronary vessels by atheroma.
Unstable angina is characterised by pain following less and less exertion culminating in pain on resting. Usually associated with a thrombus partially occluding the vessel.
When and how would you give a B-blocker to a HF patient?
Given to HF patients whose HF has been stabilised by ACEi and diuretics. Introduced gradually in small doses to improve symptoms and survival, probably because they reduce cardiac work. If not given in this way, can cause disastrous, possibly fatal, drop in CO.
In patients with HF, catecholamine levels are known to increase in proportion to the severity of symptoms. Those with the highest NA have poorest prognosis.
Describe a simplified mesolimbic dopamine system.
Central reward pathway - predominantly used to induce euphoria.
Cell bodies are located in ventral tegmental area. Project into nucleus accumbens. Release dopamine, which causes a feeling of reward.
Compare the speed of onset of different routes of drug administration (intranasal, oral, I.V., inhalational).
Intranasal (“snort”) - slow absorption (mucous membranes of nasal sinuses).
Oral (eat/drink) - very slow absorption.
I.V. (inject) - rapid absorption.
Inhalational (smoke) - fastest (straight into pulmonary circulation).
What are the main active components (cannabinoids) found in cannabis?
Cannabidiol (CBD) and delta9-tetrahydrocannabinol (THC).
Why is “skunkweed” seen as a particular problem?
21st century dosing is 150mg and up, compared to only 10mg in the 70s.
The composition has also been changed, so there is less CBD (cannabidiol) - which is thought to moderate the negative effects of THC.
Why is cannabis’ lipid solubility a particular problem?
Since it is very lipid soluble, it slowly accumulates in poorly perfused fatty tissues. This is a problem in chronic cannabis users as the levels of cannabis in these tissues can build up to far exceed plasma levels.
Cannabis has a half-life of 7 days, and is detectable in the blood up to 30 days after taking it. Why is this so?
Phase 1 metabolism of cannabis is to 11-hydroxy-THC - a MORE POTENT metabolite.
75% of excretion is via bile (25% urine), but since it is so lipid soluble there is a lot of enterohepatic recycling.
Describe the CB1 (cannabinoid) and CB2 receptors.
CB1 receptors found in the brain: hippocampus/ cerebellum/ cerebral cortex/ basal ganglia.
CB2 receptors found on immune cells. Cannabis is therefore an immunosuppressant.
They are type 2 (gi-protein linked) receptors, exerting a negative effect on adenylyl cyclase and hence cannabis is a DEPRESSANT.
The endogenous agonist of these receptors is anandamide.
Describe the role of CB1 receptors in the mesolimbic reward pathway.
CB1 receptors suppress GABA release from neurones which regulate the ventral tegmental area’s neurones. Cannabis binds to CB1 receptors, preventing GABA secretion and hence DISINHIBITNG the endogenous reward pathway, ending with dopamine secretion at the nucleus accumbens.
What is the suggested mechanism for psychosis/ schizophrenia associated with cannabis use?
The anterior cingulate cortex, involved with the brain’s ability to monitor and change behaviour to be appropriate for the circumstance, has marked hypoactivity in cannabis users.
How does cannabis increase food intake?
Presynaptic inhibition of GABA increases MCH neuronal activity in lateral hypothalamus, increasing orexin production, increasing appetite.
Why is death from a cannabis overdose very rare, but memory loss is common?
CB1 receptors are heavily expressed in the brain, but NOT the medulla. Hence, a cannabis overdose is not capable of depressing cardiorespiratory control.
The hippocampus, however, is depressed.
In which circumstances may cannabis be useful as a drug?
Elevation of CB1 receptors helpful in MS/ pain/ stroke.
Sativex (delta9-THC + CBD)
Dronabinol, nabilone (detla9-THC).
Why does oral cocaine take a particularly long time to be absorbed?
pKa= 8.7.
Ionised in GIT.
How does cocaine’s metabolism contribute to its addictive potential?
Cocaine is heavily metabolised into an INACTIVE metabolite. Can also be metabolised in the blood by plasma CHOLINESTERASES!
Hence half life is only 20-90 mins.
This means the euphoria is short-lasting and makes cocaine particularly addictive.
How does cocaine acts as a local anaesthetic?
It blocks Na+ channels.
More potent if cocaine accesses the channel from inside the cell.
Since pH of 7.1 inside the cell is lower than 7.4 outside, it is slightly less ionised outside the cell. It crosses the plasma membrane (unionised) and then ionises to access the channel.
Summarise cocaine’s effect on the mesolimbic reward pathway.
Cocaine blocks catecholamine reuptake transporters (A/DA/NA/serotonin). It hence blocks DA’s reuptake at the NAcc, enhancing the effects of dopamine on the D1R.
Summarise how cocaine can lead to arrhythmias/ sudden death.
By blocking reuptake of catecholamines, cocaine enhances sympathetic activity. This drives coronary vasoconstriction and platelet activation (atherosclerosis), reducing myocardial O2 supply.
It also drives HR, myocardial contractility and BP, increasing myocardial oxygen demand.
This leads to myocardial ischaemia/ infarction.
Coupled with the blockage of Na+ channels reducing left ventricular function, arrhythmias and death may occur.
Why is hyperthermia a particularly problematic effect of cocaine overdose?
Increased agitation, locomotor activity and involuntary muscle contraction increases core body temperature. Cocaine inhibits cutaneous vasodilation and also elevates the threshold for sweating/ cutaneous vasodilation 3 fold.
When couple with hot environments (clubs) - this hyperthermia is dangerous.
Compare the bioavailability of nicotine for nicotine spray, gum, cigarettes and nicotine patch.
Cigarettes = 20% Nicotine spray (intranasal) = 20-50% Nicotine gum (buccal) = 50-70% Patch = 70%
Why is smoked nicotine in cigarettes not absorbed via the buccal route?
Since its pKa = 7.9 and cigarette smoke is acidic (hence it is ionised).
Absorption across alveoli is independent of pH.
Why is the peak effect of nicotine from cigarettes short lasting?
It is quickly metabolised into an inactive metabolite (cotinine).
Cleared quickly.
However, can’t be metabolised in blood; half-life is 1-4 hours.
Summarise how nicotine affects the endogenous reward pathway.
Nicotine binds to a receptor on the cell body of cells in the ventral tegmental area, stimulating the neurone, increasing the amount of dopamine released at the nucleus accumbens.
What effects does nicotine have on the CVS?
Same effects associated with enhanced sympathetic output (nicotinic receptors at all autonomic ganglia) as cocaine.
Additionally, increases concentration of free fatty acids, VLDL and LDL in blood, leading to atherosclerosis. This further reduces myocardial O2 supply.
Why do people who stop smoking tend to put on weight?
Since, like cocaine and caffeine, nicotine is a stimulant.
It increases basal metabolic rate, preventing weight gain.
When people quit, their BMR falls.
What are some of the beneficial effects of nicotine usage?
It has a positive impact on neurodegenerative disorders, since it increases the brain’s ability to metabolise toxins.
E.g. in Alzheimer’s, increased metabolism of B-amyloid is beneficial.
Also, since it’s a stimulant, it increases metabolic rate and hence prevents weight gain.
Summarise caffeine’s effect on the dopaminergic reward pathway.
Adenosine binds to pre- and postsynaptic A1 receptors in dopaminergic synaptic clefts to suppress dopamine’s actions.
Caffeine disinhibits this regulation by binding to and blocking the A1 receptors.
How is a unit of alcohol calculated?
(ABV (%) x volume (ml)) / 1000
Low risk = less than or equal to 14 units per week.
>8 units in one sitting = binge drinking.
How does “drinking on an empty stomach” affect alcohol absorption.
20% of absorption = stomach.
80% = lower GIT.
Speed of onset is proportional to gastric emptying. Fluid in an empty stomach promotes gastric emptying.
Also, in a full stomach, it is more difficult for the alcohol to reach the walls of the stomach to be absorbed.
Describe the metabolism of alcohol.
Converted to acetaldehyde.
85% of metabolism is in the liver:
75% = alcohol dehydrogenase; 25% = mixed function oxidase. This mixed function group is upregulated in response to chronic, heavy drinking.
15% of metabolism in the lining of the stomach by alcohol dehydrogenase.
Acetaldehyde is then converted to acetic acid (inert) by aldehyde dehydrogenase.
What differences in metabolism mean women get more intoxicated by less alcohol?
Women have 50% less alcohol dehydrogenase in their stomach lining than men.
Women have more body fat and less body water by proportion than men, and since alcohol is WATER soluble, it is less well distributed in women.
What is the metabolic basis of the alcohol aversion therapy drug disulfiram?
Disulfiram blocks aldehyde dehydrogenase, so aldehyde builds up and makes you feel dreadful.
How does alcohol cause flush?
Blocks Ca2+ channels, decreasing Ca2+ entry into precapillary sphincters and hence causing cutaneous vasodilation.
This effect is driven by acetaldehyde.
Give acute effects of alcohol. Since it is a small, simple molecule it has low pharmacological potency and acts on many receptors.
Flush (blocks Ca2+ channels).
Euphoria (blocks GABA regulation via opiate receptor).
Depresses corpus callosum, hypothalamus, basal ganglia.
Depresses RAS (reticular activating system)(consciousness) at very high levels.
Depresses hippocampus at relatively high levels
Depresses baroreceptors, activating RAS (renin angiotensin aldosterone system) and increasing HR.
Reduces ADH secretion, leading to diuresis and polyuria.
Why are alcoholics often seen to have decreased cerebral energy supply?
Alcoholics tend to get a lot of their calories from alcohol. This can lead to thiamine deficiency, an important cofactor which drives energy metabolism in the brain.
What are some of the beneficial effects of alcohol?
Reduced mortality from CAD (men 2-4 units/day).
Increases HDL levels.
Increases tPA
Decreases platelet aggregation
What are signs of DVT?
Swollen calf, collateral superficial veins, localised tenderness and pitting oedema on palpation.
What does a D-dimer test test for?
Fibrin degradation products - a positive result diagnoses DVT.
Briefly describe the main 5 anticoagulants.
Dabigatran - a factor IIa (thrombin) inhibitor (oral)
Rivaroxaban - a factor Xa inhibitor (oral)
Heparin (IV, SC) - activates AT-III (antithrombin), inactivating fXa and fIIa
Low molecular weight heparins (SC) - also activate AT-III.
Warfarin (oral) - vitamin K antagonist. Vitamin K required for generation of factors II, VII, IX and X (slow - indirect)
How do you treat white and red thrombi? Define red and white thrombi.
White thrombus = derived from vessel wall. High proportion of foam cells and platelets.
Red thrombus = high proportion of red cells and fibrin.
Red thrombi treated by anticoagulants.
White thrombi treated by antiplatelets.
How is a pulmonary embolism treated?
It is a red thrombus. Treat with heparin.
Once confirmed by ultrasound/ computed tomographic pulmonary angiography, given rivaroxaban/ warfarin as maintenance treatment.
How does treatment differ for a STEMI and a NSTEMI?
STEMI (complete occlusion by white thrombus) = antiplatelets (aspirin and clopidogrel) and thrombolytics.
NSTEMI (partial occlusion of coronary artery by white thrombus) = just antiplatelets.
Describe how thrombin activates platelets.
Binds to protease-activated receptors (PAR) on platelet surface. PAR activation leads to a rise in intracellular Ca2+, leading to exocytosis of ADP from dense granules. ADP activates P2Y12 receptors leading to platelets activation/ aggregation.
PAR activation also liberates arachidonic acid - so COX can generate TXA2 from AA.
TXA2 activation leads to expression of GpIIb/IIIa integrin receptor on platelet surface. Involved in platelet aggregation.
Describe 3 antiplatelet drugs
Clopidogrel (oral) - ADP (P2Y12) receptor antagonist
Aspirin (oral) - irreversible COX 1 inhibitor. Inhibits TXA2 production.
Abciximab (iv, sc) - targets GpIIIb/GpIIa receptor to prevent platelet aggregation.
Give an example of an antithrombolytic drug, used to dissolve preformed clots (STEMI, ischaemic stroke)
Alteplase (iv) - a recombinant tissue type plasminogen activator (rt-PA): converts plasminogen to plasmin which degrades fibrin.
Contrast opiates and opioids.
Opiates = a natural alkaloid derived from poppies, e.g. morphine, codeine. Opioid = anything with opiate-like activity (e.g. heroine).
Describe the key features of morphine’s structure.
Tertiary nitrogen permits receptor anchoring - giving its analgesic properties.
Hydroxyl group at position 3 is required for binding.
Hydroxyl group at position 6 can be oxidised to increase lipophilicity 10-fold.
Need aromatic ring for binding to receptors.
Describe how heroine and codeine are prodrugs, in relation to their structure
The OH group at position 3 is absent - codeine has a methyl group attached, for example.
Describe the absorption of opioids.
They are either ingested or injected.
Weak bases, mostly pKa >8.
Hence poorly absorbed in stomach.
pH in blood is 7.4, <20% unionised.
Describe the relationship between lipid solubility and potency of opioids.
As a general rule of thumb, the more lipid soluble, the more potent (codeine is an exception).
Explain, in terms of metabolism, why heroine is associated with more adverse effects than morphine.
Morphine is metabolised to morphine 3-G- and 6-G-glucuronide.
(Codeine) and heroine are metabolised to morphine.
(These are the active metabolites).
Morphine has higher affinity for U(mu)2 opioid receptor, thought to be responsible for adverse effects, than morphine 3-G- and 6-G-glucuronide.
Which opioid, fentanyl or methadone, has faster metabolism and greater potency?
Fentanyl faster metabolism.
Fentanyl more potent (100:1 morphine).
Which liver enzymes metabolise morphine?
Uridine-5-diphosphate
Glucoronosyltransferase.
Explain how codeine has such a low potency (1:10 morphine)
Opioids (except morphine) are metabolised in the liver by CYP3A4 and CYP2D6.
In codeine, CYP2D6 is slow, but converts codeine to morphine.
CYP3A4 metabolises and inactivates codeine (to norcodeine).
As a result, only 10% is converted to morphine.
Describe opioid receptor location and ligands.
Endogenous opioid peptides = endorphins, enkephalins, dynorphins.
Endorphins act on Mu or Delta receptors in the cerebellum, caudate nucleus, nACC, PAG.
(The following not needed for exams): enkephalins act on delta receptors.
Dynorphins act on kappa receptors.
How are opioid receptors depressants?
They hyperpolarize the membrane(promote K+ efflux), they decrease Ca2+ influx and decrease adenylate cyclase activity.
Give effects and side effects of opioid receptor stimulation.
Analgesia, euphoria, depression of cough centre (anti-tussive).
SEs: depression of respiration (medulla), nausea/vomiting, pupillary constriction, GI effects.
Describe how opioids cause analgesia (decreased pain perception, increased pain tolerance).
Target multiple steps in pain perception pathway.
Stimulates NRPG (nucleus reticularis paragigantocellularis) which automatically activates pain tolerance: enhance this effect.
Nucleus raphe magnus is the effector part of pain tolerance pathway: suppressing perception from dorsal horn.
PAG = integrating centre (hypothalamus, thalamus, cortex). Opioids enhance this tolerance activity. (in PAG and NRPG, opioids DISINHIBIT the neurons).
Opioids depress pain perception by acting within the dorsal horn to interfere with transmission from painful stimuli from periphery to spinothalamic neurons.
TLDR: Depress pain perception, disinhibit pain tolerance.
Describe how opioids cause euphoria.
Opiates bind to Mu receptors on GABAergic neurons projecting to VTA. This depressant activity disinhibits Dopaminergic neurons from the VTA to NAcc, increasing dopamine release to cause feelings of reward.
Explain how opiates work as anti-tussives.
Opiates inhibit stimulation of mechano- or chemoreceptors. They inhibits ACh/NK C-fibre relay to vagus.
Medullary response to afferent impulses inhibited via 5HT1A receptor inhibition.
How can an opiate overdose lead to respiratory depression?
They inhibit central chemoreceptors (which detect PaCO2 and produce the medullary control centre’s drive to breathe).
How can normal doses of opiates cause nausea and vomiting? How do they cause constipation?
They disinhibit chemoreceptor trigger zones, stimulating the medullary vomiting centre, leading to a vomiting reflex.
They depress the many opioid receptors in the enteric nervous system - leading to slower gut motility.
How do opiates cause miosis?
They disinhibit Edinger-Westphal nucleus, leading to parasympathetic activation (constricting the pupil).
Describe opioid tolerance.
Opioids increase arrestin, which mediates receptor internalisation. Hence, the cell is less responsive to opioids.
Withdrawal associated with psychological craving (since the dose has to keep increasing long-term). Some people have flu-like physical withdrawal symptoms.
How would you spot an opioids overdose and how would you treat it?
Signs: coma, respiratory depression, pin-point pupils, hypotensive.
Treatment: naloxone (i.v. opioid antagonist).
Briefly outline atherosclerosis.
Endothelial damage leads to a protective response (production of cellular adhesion molecules). Monocytes and T-lymphocytes attach to the “sticky” surface of endothelial cells. They migrate through the arterial wall to the subendothelial space. Here, they take up oxidised LDL-cholesterol via scavenger receptors, forming lipid-rich foam cells. These foam cells are stuck in the subendothelial space. They form a fatty streak, which is thrombogenic but the plaque is prevented from contacting the blood via a fibrous cap.
Why are vulnerable plaques - with thin fibrous caps - particularly dangerous?
If the plaque ruptures, the blood vessel is exposed to tissue factor - causing thrombosis. This can occlude the whole vessel.
Describe the interactions between HDL, LDL and CHD.
LDL associated with CHD.
HDL has a protective effect for risk of atherosclerosis and CHD. The lower the HDL level, the higher the risk for atherosclerosis and CHD.
Tends to be low when triglycerides high.
Lowered by smoking, obesity and physical inactivity.
Describe statins.
HMG-CoA reductase inhibitors: reduce the synthesis of cholesterol in liver cells. Stimulate an increase in number of LDL receptors on hepatocytes. Reduction in circulating LDL via LDL receptors.
N.B. “rule of 6” - double the dose of any statin only yields a 6% reduction in LDL.
30% reduction in risk of events.
What are fibrates?
PPAR (peroxisome proliferator activated receptors) A receptor activators - which decrease plasma fatty acids and triglycerides and increase HDL levels.
What class of diabetes drugs are related to fibrates?
Fibrates are PPAR A agonists (peroxisome proliferator activated receptor).
Thiazolidinediones are PPAR Gamma agonists. They are insulin sensitisers (mainly peripheral) and modify adipocyte differentiation so that weight gain is peripheral, not central,
Describe ezetimibe.
A drug which inhibits cholesterol absorption from the small intestine. Not as effective as statins, but often used in combination to bypass the “rule of 6”.
