Pharmacology (Term 2) Flashcards
1
Q
Detail the hypertension treatment flowchart.
A
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.
2
Q
Why are ACEis and ARBs not typically given to those over 55 years of age and those of Afro-Caribbean descent?
A
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.
3
Q
Describe the role of the If (“funny current”) channel in sinoatrial cells.
A
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.
4
Q
How does sympathetic activity affect the ion channels in sinoatrial cells?
A
Increases cAMP, increases Ica, increases If
5
Q
How does parasympathetic activity affect the ion channels in sinoatrial cells?
A
Decreases cAMP, increases Ik
6
Q
Give factors affecting myocardial oxygen supply and those affecting myocardial oxygen demand.
A
Supply: coronary blood flow and arterial O2 content.
Demand: contractility, afterload, preload and heart rate.
7
Q
How do heart rate, afterload, preload and contractility affect myocardial oxygen demand?
A
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).
8
Q
Give drugs which influence heart rate and MOA.
A
B-blockers - decrease If and Ica.
Calcium antagonists - decrease Ica
Ivabradine - decreases If.
9
Q
Give drugs which influence contractility and MOA.
A
B-blockers - decrease contractility
Calcium antagonists - decrease Ica
10
Q
Give the 2 classes of calcium-channel blocker.
A
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.
11
Q
How do organic nitrates and potassium channel openers help treat stable angina?
A
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.
12
Q
Which classes of drugs are the first line treatment for stable angina?
A
Beta-blockers or CCBs.
13
Q
Why are Beta-blockers not great at treating stable angina in heart failure patients? Which beta-blockers would you prescribe?
A
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).
14
Q
Why may patients on B-blockers complain of cold extremities?
A
Loss of B2-mediated cutaneous vasodilation in extremities.
15
Q
What side effects are associated with CCBs?
A
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.
16
Q
How are arrhythmias classified by both speed of conduction and site of origin?
A
Bradyarrhythmias and tachyarrhythmias.
Supraventricular arrhythmia and ventricular arrhythmia. (A complex arrhythmia combines the two origins).
17
Q
What is the drug of choice for treating supraventricular tachyarrhythmias?
A
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.
18
Q
What does verapamil do in the treatment of arrhythmias?
A
Reduces ventricular responsiveness to atrial arrhythmias by depressing SA node automaticity and subsequent AV node conduction.
19
Q
What does digoxin (a cardiac glycoside) do?
A
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.
20
Q
How does hypokalaemia lower the threshold for digoxin toxicity?
A
Since K+ competes with digoxin for the binding site on the K-Na-ATPase, hypokalaemia means digoxin binds more readily to the pump.
21
Q
Describe ACE inhibitors, such as enalapril.
A
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).
22
Q
Describe ARBs, such as losartan.
A
Antagonists of type 1 (AT1) receptors for angiotensin II, preventing renal and vascular actions of angiotensin II.
Used to treat hypertension and heart failure.
23
Q
Why are ARBs and ACEis first line treatments for hypertension and what are some of their side effects?
A
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.
24
Q
How are A1 blockers useful as anti-hypertensives?
Give some examples.
A
They prevent peripheral vasoconstriction.
Prazosin, phentolamine (non-selective).
25
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.
26
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)
27
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.
28
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.
29
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.
30
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.
31
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).
32
What are the main active components (cannabinoids) found in cannabis?
Cannabidiol (CBD) and delta9-tetrahydrocannabinol (THC).
33
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.
34
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.
35
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.
36
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.
37
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.
38
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.
39
How does cannabis increase food intake?
Presynaptic inhibition of GABA increases MCH neuronal activity in lateral hypothalamus, increasing orexin production, increasing appetite.
40
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.
41
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).
42
Why does oral cocaine take a particularly long time to be absorbed?
pKa= 8.7.
| Ionised in GIT.
43
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.
44
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.
45
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.
46
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.
47
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.
48
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%
```
49
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.
50
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.
51
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.
52
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.
53
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.
54
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.
55
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.
56
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.
57
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.
58
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.
59
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.
60
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.
61
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.
62
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.
63
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.
64
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
65
What are signs of DVT?
Swollen calf, collateral superficial veins, localised tenderness and pitting oedema on palpation.
66
What does a D-dimer test test for?
Fibrin degradation products - a positive result diagnoses DVT.
67
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)
68
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.
69
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.
70
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.
71
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.
72
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.
73
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.
74
Contrast opiates and opioids.
```
Opiates = a natural alkaloid derived from poppies, e.g. morphine, codeine.
Opioid = anything with opiate-like activity (e.g. heroine).
```
75
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.
76
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.
77
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.
78
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).
79
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.
80
Which opioid, fentanyl or methadone, has faster metabolism and greater potency?
Fentanyl faster metabolism.
| Fentanyl more potent (100:1 morphine).
81
Which liver enzymes metabolise morphine?
Uridine-5-diphosphate
| Glucoronosyltransferase.
82
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.
83
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.
84
How are opioid receptors depressants?
They hyperpolarize the membrane(promote K+ efflux), they decrease Ca2+ influx and decrease adenylate cyclase activity.
85
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.
86
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.
87
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.
88
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.
89
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).
90
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.
91
How do opiates cause miosis?
They disinhibit Edinger-Westphal nucleus, leading to parasympathetic activation (constricting the pupil).
92
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.
93
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).
94
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.
95
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.
96
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.
97
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.
98
What are fibrates?
PPAR (peroxisome proliferator activated receptors) A receptor activators - which decrease plasma fatty acids and triglycerides and increase HDL levels.
99
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,
100
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".
101
Describe how proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors are useful in combination therapy with statins, particularly with familial hypercholesterolemia.
Proprotein convertase subtilisin/ kexin type 9 (PCSK9) is a secreted inhibitor of the LDLR.
LDLR and PCSK9 genes are induced by statins.
Hence, co-therapy with PCSK9 inhibitors can enhance the lipid-lowering effects of statins.
102
What are the therapeutic uses of NSAIDs?
Relief of mild-to-moderate pain (analgesic)
Reduction of fever (antipyretic)
Reduction of inflammation (in the name "anti-inflammatory" lol)
Mediated by cyclooxygenase inhibition.
103
Describe prostanoid receptors.
10 known prostanoid receptors. Many, complex functions. We'll focus on PGE2.
Unwanted actions of PGE2: increase pain perception, increased body temperature, inhibition of apoptosis, immune responses, acute inflammatory response, lowers pain threshold, stimulate hypothalamic neurons initiating a rise in body temperature.
Desirable, physiological actions: renal salt and water homeostasis, bronchodilation, gastroprotection (downregulate bicarbonate and mucous production), vasoregulation.
104
Why shouldn't asthmatics take NSAIDS?
Because COX many products cause bronchodilation: COX inhibition favours production of leukotrienes - bronchoconstrictors.
105
How do NSAIDS increase the risk of ulceration?
PGE2 downregulates HCl secretion and stimulates mucus and bicarbonate secretion, hence NSAIDs increase the risk of ulceration, with roughly 1/2 of NSAID deaths attributed to GI causes.
106
Why is the coxib family of NSAIDS (e.g. celecoxib) useful?
COX-1 selective drugs, e.g. aspirin, are particularly bad at causing ulcers.
COX-2 selective NSAIDs cause fewer ulcers. However, evidence COX-2 inhibitors pose higher risk of CVD than COX-1 inhibitors.
107
How can NSAIDs cause renal toxicity?
PGE2 increases renal blood flow: NSAIDs cause constriction of the afferent renal arteriole. This reduces GFR. Leads to salt and water retention.
50% of NSAID deaths CV (hypertension, MI, stroke).
108
When are NSAIDs more likely to pose problems?
When they are used for anti inflammation, since use is often sustained and doses are higher.
When used as analgesics, use is occasional leading to relatively low risks of side effects.
109
What strategies, other than using COX-2 selective NSAIDs, can be employed to limit GI side effects?
Topical application, minimal use in patients with history of GI ulceration, co-administration with omeprazole, minimising usage in patients with other risk factors (e.g. alcohol).
110
Describe the anti-platelet properties of aspirin.
Selective COX-1 inhibition depletes TXA2- which is proplatelet.
COX-1 and 2 in the endothelial cells produce prostaglandin, which is anti-platelet. Since the endothelial cells are nucleated, they replenish COX 1 and 2. Doesn't affect prostaglandin production.
111
What is Reye's syndrome?
A condition associated with aspirin use in patients under 20 - when aspirin is given with a viral infection, it can cause damage to mitochondria leading to ammonia production, which damages astrocytes leading to oedema in the brain.
112
Briefly describe when paracetamol is used and how to treat an overdose.
Paracetamol is NOT an NSAID: it is antipyretic and analgesic but not anti-inflammatory.
In overdose, may cause irreversible liver failure. If glutathione is depleted, a toxic metabolite (NAPQI) in paracetamol metabolism oxidises thiol (SH) groups of key hepatic enzymes, causing cell death. Antidote: i.v. acetylcysteine.
Acetylcysteine used in cases of attempted suicide and accidental poisoning. If not used early enough, liver failure unpreventable and transplant is the only option.
Acetylcysteine promotes the synthesis of glutathione (GSH) to conjugate NAPQI.
113
Explain the metabolism of paracetamol at therapeutic doses and overdoses.
Major phase 2 reactions are sulphation (sulphotransferase, PAPS substrate) and glucuronidation (UDP-glucuronosyltransferase, UDP-glucuronic acid substrate).
Phase 1 metabolism is mediated by CYP450s and results in NAPQI formation - which is very ELECTROPHILIC.
In overdose, sulphate is depleted and glucuronidation may become saturated, resulting in NAPQI levels rising. This depletes glutathione (glutathione is a tripeptide which reacts with electrophilic species). Results in increases covalent binding of NAPQI to proteins/ nucleic acids to cause liver damage and NAPQI can be reduced back to paracetamol, increasing half-life.
All of this results in higher plasma levels of unmetabolised paracetamol and hence a longer half-life.
114
What is inflammatory bowel disease?
An umbrella term: comprises ulcerative colitis (UC) and Crohn's disease (CD).
Distinction incomplete in roughly 10% of patients. Affects 300,000 people in the UK.
Genetic predisposition, environmental risk factors including diet, medication, smoking and microbiome.
115
Describe the mechanism of IBD. Give brief overviews of the 2 most common types.
Defective interaction between mucosal immune system and gut flora (disrupted innate immunity and impaired clearance). Leads to proinflammatory compensatory reactions. Leads to physical damage and chronic inflammation.
Crohn's: Th1 mediated - florid T-cell expansions and defective T-cell apoptosis. All gut layers affected, any part of GI tract. Patchy inflammation (surgery not curative).
Ulcerative colitis: Th2 mediated - limited clonal expansion, normal T-cell apoptosis. Mucosa/ submucosa affected. Rectum, spreading proximally. Abscesses uncommon. Surgery curative.
116
What symptoms are associated with IBD?
Abdominal pain (usually left lower quadrant for UC and right lower quadrant for CD), abdominal cramps, diarrhoea, blood in faeces, mouth ulcers, anaemia, fever, arthritic pain, weight loss, fatigue.
117
What supportive therapies are available for IBD patients?
Fluid/electrolyte replacement, blood transfusion/ oral iron, nutritional support.
118
Describe how aminosalicylates are used to treat IBD.
Mesalazine = 5-ASA (5-aminosalicylic acid). Olsalazine = 2 5-ASA joined together, metabolised by colonic flora.
Poorly absorbed in small colon and bowel.
Binds to PPAR gamma receptors on nuclei of cells lining colon wall. Downregulates NF-kB/MAPK, in turn decreasing production of TNF-A, IL-1B, IL-6.
Effective at induction and maintenance of remission in UC.
Combined oral and rectal administration for generalised disease: rectal administration for local disease: better than glucocorticoids!
Aminosalicylates ineffective at inducing remission in CD.
119
Describe how glucocorticoids (derived from cortisol) are useful in treating IBD.
Powerful anti-inflammatory and immunosuppressive drugs. Activate intracellular glucocorticoid receptors - act as transcription factors.
120
Why is budesonide the preferred glucocorticoid when CD is mild?
When given systemically, glucocorticoids cause many unwanted effects.
Budesonide stays in the gut, so causes fewer side effects than other glucocorticoids.
However, standard oral gcs are better than budesonide at inducing remission in active CD. These, however, should be avoided as maintenance therapy.
121
Describe the use of azathioprine in IBD.
A pro-drug activated by gut flora to 6-mercaptopurine. Now give 6-mercaptopurine directly.
Purine antagonist, immunosuppressive (also used in allografts).
Interferes with DNA synthesis and cell replication.
Impairs cell- and antibody-mediated immune responses, enhances T-cell apoptosis.
Recommended for MAINTAINING REMISSION.
Slow onset of 3-4 months.
122
Describe manipulation of the microbiome as a potentially curative therapy for IBD.
Exclusive enteral nutrition (EEN) - liquid diet - "rests" mucosa - allowing recovery of the gut flora. Unpalatable and hard to maintain (only recommended to induce remission if the patient can't take steroids).
Probiotic therapies - difficult to generalise effects of organisms
Faecal microbiota replacement therapies (FMT) - beneficial in UC.
Antibiotic treatment - Rifaximin. Binds to RNA polymerase: interfering with bacterial transcription. Microbiome modulator - sustained remission in moderate CD.
123
Describe biologic therapies for IBD.
Anti-TNFa antibodies - reduce activation of TNF-a receptors in gut. Reduces downstream inflammatory events. Binds to membrane associated TNF-a and induces cytolysis of cells expressing TNF-a receptors.
124
What do diuretics do (in general) and what are the 5 classes of diruetics?
Promote loss of water and electrolytes in the urine, by inhibiting electrolyte reabsorption (Na+. Cl- usually) which increases the osmolarity of the tubular fluid, decreasing the osmotic gradient so water remains in the tubular fluid.
5 classes: osmotic diuretics, carbonic anhydrase inhibitors, loop diuretics, thiazides and potassium sparing diuretics.
125
Where do osmotic diuretics and carbonic anhydrase inhibitors work?
PCT.
| Osmotic diuretics also work in the descending limb of the loop of Henle and the collecting duct.
126
How do carbonic anhydrase inhibitors work?
Result in less H2O and CO2 production in the lumen and less H+ and HCO3- production in the cell.
H+ is needed for the H+/Na+ antiporter on the luminal membrane and HCO3- for the HCO3-/Na+ symporter on the basolateral membrane.
127
Where do loop diuretics work and how?
Loop diuretics work on the ascending limb of the loop of Henle.
They block the triple transporter, impairing the ability to concentrate the interstitium. Less water is therefore absorbed from the collecting duct (due to the high osmolarity of the tubular fluid and low osmolarity of the interstitium.
Ca2+ and Mg2+ are also lost due to loss of K+ recycling.
30% of Na+ lost. High Na+ delivery to DCT means it is absorbed at the expense of K+ (Na+/K+ ATPase). Hence, the loss of K+.
(N.B. the triple transporter is what the macula densa used to detect Na+ in the DCT, so aldosterone-stimulating ability reduced).
128
Name an osmotic diuretic and a loop diuretic.
Mannitol and furosemide respectively.
129
Name a thiazide and give the specific location it works at.
Bendroflumethiazide.
| Blocks Na+/Cl- co-transporter in DCT.
130
What effects do thiazide diuretics have?
They increase tubular fluid osmolarity in the DCT, reducing H2O reabsorption in the collecting duct.
Increased Na+ delivery to late distal tube means K+ loss in common with thiazides (but less so).
Mg2+ loss (loss of K+ recycling).
Ca2+ reabsorption because Na+/Ca2+ antiporter on basolateral membrane more active.
131
Describe potassium-sparing diuretics.
2 classes: aldosterone receptor antagonists e.g. spironolactone.
Inhibitors of aldosterone-sensitive Na+ channels, e.g. amiloride.
Less Na+ reabsorption (5%), less concomitant K+ secretion.
Increased tubular fluid osmolarity, less H2O reabsorption.
132
Give side effects of diuretic use.
Hyponatraemia, hypokalaemia (thiazide and loop diuretics mainly), hyperkalaemia (potassium-sparing), hypovolaemia (thiazide and loop diuretics), metabolic alkalosis (Cl- loss).
Hyperuricaemia (since diuretics use the uric acid transporters to reach the apical membrane of tubule cells).
133
What are the uses of thiazide diuretics?
Hypertension treatment.
Initial response due to drop in plasma volume. After 4-6 weeks, plasma volume is restored.
Thiazides are good vasodilators, decreasing TPR.
134
What are the uses of loop diuretics?
Treatment of oedema from heart failure.
30% loss of Na+ - reduce congestion.
Activates RAS in the long term (low Na+), so give additional K+-sparing diuretic (aldosterone inhibitors).
30% reduction in death.
135
Contrast pharmacogenomics and pharmacogenetics.
Pharmacogenetics: study of genetically determined inter-individual differences in therapeutic response to drugs and susceptibility to adverse effects. Restricted to genes of interest.
Pharmacogenomics: use of genome-based techniques in drug development. Not restricted. Use of high-throughput technology.
136
What are the 2 principle reasons for differences in clinical responses to a drug, and what underlying interplay underwrites these observable differences?
Pharmacodynamic reasons: different responses of cells, tissues and organs to an equal stimulation.
Pharmacokinetic reasons: different concentrations of drug or active metabolite actually reaching the cell.
These observable differences arise from a complex interplay of many factors which are either environmental or genetic. The only factors which may generally give rise to more than a 2- or 3- fold difference between individuals are genetic.
137
What sort of distribution does polygenic control give?
A continuous or unimodal (Gaussian) distribution of the measured variable. It is not possible to discern the influences of single genes.
E.g. salicylate conjugation with glycine or glucuronic acid.
138
What sort of distribution does monogenic control give?
A discontinuous or multimodal distribution of the measured variable. Gives rise to 2 (or more) phenotypes. Phenotype differences arise from 2 or more allelic forms of the genetic information at a gene locus.
If the population of individuals who are different from the majority are over 1%, it is a polymorphism. If <1%, it is an inborn trait.
139
If one allele is dominant, how many phenotypes would you expect to see? Similarly if they were co-dominant, how many?
Two if dominant, 3 if co-dominant.
140
What factors may blur the distinction between phenotypes in a trait under monogenic control?
Other minor genetic influences and non-genetic factors.
141
Give an example of a polymorphism affecting drug metabolism.
Sulphadimidine (and other drugs) N-acetylation by N-acetyltransferase.
Incidence of low enzyme activity is about 50% in Europeans.
142
Give the Hardy-Weinberg law.
Both allele and genotype frequencies in a population remain constant (in equilibrium) from generation to generation unless specific disturbing influences are introduced.
143
Give the different types of depression.
Unipolar depression: mood swings in the same direction.
Reactive depression: in response to stressful life-events, non-familial.
Endogenous depression: unrelated to external stresses, familial pattern.
Bipolar/ manic depression: oscillating depression/mania. Less common. Early adult onset. Strong hereditary tendency. Treatment = lithium (a mood stabiliser with a very narrow therapeutic window).
144
What is the monoamine theory of depression?
Depression is a functional deficit of central monoamine transmission, and mania is a functional excess.
NA & 5-HT (serotonin).
Downregulation of A2, B adrenoceptors and 5-HT receptors.
145
Describe tricyclic antidepressants (TCAs), e.g. amitriptyline.
Action, pharmacokinetics, unwanted effects.
Neuronal monoamine reuptake inhibitors (NA=5-HT)
Receptor actions: downregulation of A2 and 5-HT2 receptors (different 5-HT receptors).
Rapid oral absorption, highly PPB (90-95%), active metabolites. Plasma t1/2 (10-20hrs).
Unwanted effects: atropine like effects, postural hypotension. Due to peripheral blockade of a-adrenoceptors, muscarinic and histaminic receptors and central serotonin receptors.
CNS: excitement, delirium, seizures--> coma, respiratory depression.
CVS: cardiac dysrhythmias, ventricular fibrillation, sudden death.
146
Describe some interactions TCAs are involved with in the body.
PPB: TCAs can be displaced by drugs such as aspirin, hence dose increases.
Potentiates CNS depressants such as alcohol.
Competes with hepatic microsomal enzymes.
147
Describe monoamine oxidase inhibitors, e.g. phenelzine.
Most are non-selective. Irreversible inhibition with rapid effects.
The delayed effects have the clinical response: down-regulation of B and 5-HT2 receptors (due to greater availability of neurotransmitters).
Also has atropine-like effects (less so than TCAs), postural hypotension, weight gain, hepatotoxicity.
148
Which monoamine oxidases metabolise which monoamines (NA, DA and 5-HT)
```
MAO-A = NA and 5-HT
MAO-B = DA
```
149
Describe the cheese reaction.
An interaction between tyramine containing foods and monoamine oxidase inhibitors.
Tyramine is an independently-acting sympathomimetic drug.
The combination results in a hypertensive crisis (throbbing headache, raised BP, intracranial haemorrhage)
N.B. a hypertensive crisis can precipitate when TCAs are given with MAOIs.
150
What is moclobemide?
```
A RIMA (reversible inhibitor of monoamine oxidase A).
Results in fewer interactions and shorter d.o.a.
```
151
Describe SSRIs, e.g. fluoxetine.
Selective 5-HT reuptake inhibition.
Less troublesome, safer in O.D. but less effective against severe depression.
Competes with TCAs for hepatic enzymes (so avoid co-administration).
Also interacts with MAOIs - avoid co-administration.
Can cause nausea, diarrhoea, insomnia, loss of libido (serotonin causes loss of libido)
Delay onset of action (2-4 weeks) supposed to be due to the downregulation of receptors (the downregulation correlates with the time-delays in action onset).
152
What 5 factors may lead to a relative overdose or underdose (despite same absolute dose administered)?
Environmental exposure to chemicals/drugs (enzyme induction and inhibition).
Food intake (food may interact chemical with drugs altering absorption)
Fluid intake (most drugs are better absorbed if taken with water e.g. may dissolve better/ fluids may stimulate gastric emptying.
Age
Disease (unbalanced diets may lead to deficiency states and enzyme abnormalities, starvation leads to decreased plasma protein and metabolism, obesity leads to increased lipid fraction, GI disorders affect absorption).
153
Why do newborns need to be given lower doses of drugs?
They have more body water than adults, poorer renal function with immature tubular secretion, an immature BBB and a lower capacity for drug metabolism.
154
How are pharmacokinetic interactions in the elderly affected?
Decreased absorption due to decreased absorptive surface of small intestine, altered gastric and gut motility, increased rate of gastric emptying.
Distribution is altered: reduced lean body mass and body water, relative increase in fat leading to lipid soluble drugs having a larger volume of distribution and lower blood levels while water soluble drugs has decreased VDs and increased blood levels. Also, decreased albumin so less PPB.
Less metabolism as splanchnic and hepatic blood flow decreases by 0.3-1.5% p.a., liver size and hepatocyte numbers decrease and hepatic enzyme activity decreases.
MOST IMPORTANT: poor excretion, with a steady decline in renal mass, renal perfusion, GFR and tubular excretion. These are physiological changes, which may be compounded by renal disease.
N.B. older people have increased sensitivity to CNS active drugs, even if metabolism is normal.
155
How can you classify adverse drug events by onset and severity?
Onset: acute (within 1 hour), subacute (1-24 hours), latent (>2 days).
Severity: mild (requires no change in therapy), moderate (requires change in therapy, additional treatment, hospitalisation), severe (disabling or life-threatening).
156
How can you classify adverse drug reactions by type?
Type A = extension of pharmacological event, preventable and dose-dependent. 2/3 of ADRs. E.g. atenolol and heart block, NSAIDs and peptic ulcers.
Type B = idiosyncratic or immunological reactions.
Includes allergy and "pseudoallergy". Rare and unpredictable.
Type C = associated with long-term use. Involves drug accumulation e.g. antimalarials and ocular toxicity.
Type D = delayed effects
Type E = withdrawal reactions (opiates, benzodiazepines, corticosteroids) or rebound reactions (e.g. clonidine, B-blockers, corticosteroids) where the situation is worse than before treatment started.
A = augmented pharmacological event, B = bizzarre, C = chronic, D = delayed, E = end-of-treatment.
157
What are pseudoallergies?
Symptoms appear like allergies (bronchospasm, cough, angioedema) but there is no immunological reaction and the symptoms are pharmacological reactions.
E.g. NSAIDs/ aspirin causes bronchospasm, ACEi causes cough/ angioedema).
158
How are adverse drug reactions detected?
Subjective reports, objective reports (Direct observation of event).
Rare events will probably not be detected before a drug is marketed.
Yellow card scheme is voluntary: for established drugs, only report serious events. For black triangle drugs (newly-licensed) report ANY suspected reaction.
159
Give an overview of drug-drug interactions.
Pharmacodynamic interactions: additive, synergistic or antagonistic effects from co-administration.
Pharmacokinetic interactions: alteration in absorption, protein-binding events, changes in metabolism, alteration of excretion.
Pharmaceutical events: drugs interacting outside the body, mostly IV infusions.
160
Describe pharmacokinetic drug interactions.
Absorption: chelation (irreversible binding of drugs in the GI tract)
Protein binding: competition. Increase in free conc may enhance pharmacological effect. Not usually significant (XS quickly metabolised).
Metabolism inhibited or enhanced by coadministration.
Elimination interactions in renal tubule, e.g. lithium and thiazides (retain lithium at the expense of Na+) and penicillin and probenecid (keeps penicillin in the blood).
161
Give "usual suspect" CYP450 inducers and inhibitors.
Inhibitors: cimetidine (H2 antagonist), erythromycin and related antibiotics, ketoconazole, ritonavir and other HIV drugs, SSRIs, grapefruit juice.
Inducers: rifampicin, carbamazepine, hypericin.
Inhibition is very rapid. Induction takes hours/days (translation etc).
162
Explain how H Pylori causes gastric ulcers.
H pylori is a gram negativen motile bacterium which exclusively colonises gastric-type epithelium. It causes increased gastric acid formation via increased gastrin or decreased somatostatin. This leads to gastric metaplasia due to excessive acid exposure and downregulation of defence factors (e.g. bicarbonate). This results in ulcer production.
It possesses UREASE which catalyses urea into ammonium chloride and monochloramine, which damage epithelial cells. Urease is antigenic - evoking an immune response.
163
How are H pylori infections treated?
Triple therapy: amoxicillin and clarithromycin antibiotics and a proton pump inhibitor to reduce gastric acid production.
This combination therapy treats the cause and the symptoms.
164
How does omeprazole (a proton-pump inhibitor) treat peptic ulcers?
In ulceration, H+/K+ ATPase is overexpressed on parietal cells. Increased secretion of H+ results in ulcer formation. Omeprazole prevents H+ secretion.
165
How do NSAIDs lead to peptic ulceration (and increased risk of bleeding)?
Inhibition of COX1 results in less prostaglandin E2 (PGE2) which increases mucous and bicarbonate secretions and mucosal blood flow. Hence, inhibition of PGE2 leads to ulceration risk.
166
How are ulcers caused by NSAIDs treated?
Removal of NSAID.
PPI or histamine receptor antagonist (e.g. ranitidine)
Somatostatin (inhibits G-cells, ECL cells and parietal cells).
167
Describe gastric acid regulation.
ACh from vagal/enteric neurones acts on M3 receptors to increase Ca2+i
Histamine from ECL cells acts on H2 receptors to increase cAMP
Gastrin from G-cells actons on CCK B receptors to increase Ca2+i.
All 3 lead to translocation of secretory vesicles to the parietal cell apical surface.
PGs from local cells act on EP3 receptors to decrease cAMP (decrease proton secretion and therefore gastric acid secretion).
168
Describe the amyloid hypothesis of Alzheimer's disease.
Amyloid precursor protein (APP) cleaved by a-secretase.
sAPPPa released, which is digested by gamma-secretase.
In pathological processing, APP is cleaved by B-secretase and sAPPb is produced. This is digested by gamma-secretase to produce beta amyloid (AB) protein. This product is not remove, instead it congregates to form B-amyloid plaques.
169
Describe the tau hypothesis of Alzheimer's disease.
Tau is a soluble protein present in axons, which is important for assembly and stability of microtubules.
Hyperphosphorylated tau is insoluble . It self-aggregates to form neurofibrillary tangles, which are neurotoxic. Also, loss of tau means you lose axons stability, contributing to neurodegeneration.
170
Describe the inflammation hypothesis of Alzheimer's disease.
Microglia (the specialised CNS immune cells) are overactive, increasing inflammatory mediators and cytotoxic proteins, increases phagocytosis and decreases levels of neuroprotective proteins.
171
What drugs are used to treat Alzheimer's? N.B. the treatment of Alzheimer's doesn't relate to the pathophysiology.
Anticholinesterases:
Donepezil (reversible)
Rivastigmine (pseudo-reversible AChE and BChE inhibitor)
Galantamine (reversible cholinesterase inhibitor, a7 nAChR)
Increased ACh seems to reverse some symptoms of AD. Treats the symptoms for roughly 2 years.
Memantine - a use-dependent non-competitive NMDA receptor blocker with low channel affinity. Only licensed for moderate-severe AD.
Donepezil is first line.
172
What transporters and metabolic enzymes are involved with dopamine?
DA removed from synaptic cleft by dopamine transporter (DAT) and NA transporter (NET).
MAO-A metabolises (DA), NE, 5-HT
MAO-B metabolises DA
COMT - wide distribution - metabolises all catecholamines.
173
Describe dopaminergic pathways in the brain.
Nigrostriatal pathway - substantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders (PD).
Mesolimbic pathway - VTA to NAcc. Reward pathway.
Mesocortical pathway - VTA to cerebrum. Involved in executive functions and complex behavioural patterns.
Tuberoinfundibular pathway - arcuate nucleus to median eminence. Inhibition = hyperprolactinaemia.
174
Describe Parkinson's Disease.
1-2% of >60. 5% of cases due to mutations in certain genes.
Severe loss of dopaminergic cells in SNc. Lewy bodies and neurites found within neuronal cell bodies and axons respectively.
Consist of abnormally phosphorylated neurofilaments.
Motor symptoms: resting tremor, bradykinesia, rigidity, postural instability.
Autonomic NS effects: olfactory deficits, orthostatic hypotension, constipation.
Neuropsychiatric symptoms: sleep disorders, memory deficits, depression, irritability.
175
Describe dopamine replacement therapy for parkinson's disease.
```
Rate-limiting enzyme in dopamine synthesis pathway = tyrosine hydroxylase.
Give levodopa (L-DOPA) - which is rapidly converted to DA by DOPA decarboxylase.
Levodopa can cross BBB.
Peripheral breakdown of levodopa by DOPA decarboxylase leads to nausea and vomiting.
Long-term side-effects include dyskinesias.
```
176
What adjuncts may given in conjunction with levodopa in dopamine replacement therapy in Parkinson's disease?
DOPA-decarboxylase inhibitors - carbidopa.
Doesn't cross BBB. Prevents peripheral breakdown of levodopa and reduced required dosage of levodopa.
Can also give COMT inhibitors (Entacapone and tolcapone) to increase the amount of levodopa in the brain.
177
Describe dopamine receptor agonist therapy for parkinson's disease.
This therapy is useful as it doesn't require dopaminergic neurones (as the presynaptic membrane is degrading).
Ergot derivatives e.g. bromocriptine, cabergoline, pergolide - potent D2R agonists Associated with cardiac fibrosis.
Non-ergot derivatives e.g. Ropinirole - also available as extended-release formulation.
178
Describe MAO-B inhibitor therapy for parkinson's disease. Describe the "cheese" reaction.
Selegiline, rasagiline. Less dopamine breakdown. Reduce the dosage of L-DOPA required.
Involved with the cheese reaction with tyramine, a substance in certain foods that causes catecholamine release from neurons, metabolised by MAO. Inhibition of MAO means its action is unabated leading to hypertensive crisis. Tyramine can't cross the BBB, so has peripheral sympathomimetic effects.
179
Describe schizophrenia.
Affects roughly 1% of population. Genetic influence. Onset between 15-35 yrs old.
Positive symptoms: increased mesolimbic dopaminergic activity. Hallucinations (auditory and visual), delusions (paranoia), thought disorders (denial about oneself).
Negative symptoms: decreased mesocortical dopaminergic activity. Affective flattening (lack of emotion), alogia (lack of speech), apathy (loss of motivation).
180
Describe first-generation anti-psychotics.
Chlorpromazine: D2R antagonism. Mild extrapyramidal side effects (acute dystonia, parkinsonism, akathisia).
Haloperidol: very potent (x50) D2R antagonist.
Impact on positive symptoms (little impact on negative symptoms). Extrapyramidal side effects due to strong blockade of D2 receptors.
181
Describe second-generation antipsychotics.
Clozapine - most effective.
Antagonist of 5-HT2A receptors. Only drug to show efficacy in treatment resistant schizophrenia and negative symptoms.
Side effects: potentially fatal neutropenia, agranulocytosis, myocarditis and weight gain.
Risperidone - potent antagonist of 5-HT2A and D2 receptors. More EPS and hyperprolactinaemia than other antipsychotics.
Quetiapine - antagonist of H1 receptors. Lower incidence of extra-pyramidal side effects.
182
Describe aripiprazole.
The newest anti-psychotic. PARTIAL agonist of D2 and 5-HT2A receptors.
In theory targets both negative and positive symptoms.
Reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics.
183
Describe GABA metabolism and production.
Glutamate --> GABA (glutamic acid decarboxylase (GAD))
GABA --> succinate semialdehyde (GABA transaminase (GATA-T))
Succinate semialdehyde --> succinic acid (succinic semialdehyde dehydrogenase (SSDH))
GABA autoreceptors sit on presynaptic nerve terminals(act like a2 receptors).
184
Describe the GABAA receptor.
GABA binds, causing Cl- channel to open.
Benzodiazepine binds to its receptor protein, enhancing GABA affinity and influx of Cl-
Barbiturates enhance GABA activity (not reciprocated) and benzodiazepine binding and direct Cl- influx.
BZDs and BARBs have NO activity alone. They have allosteric action (they are positive allosteric modulators)
BDZs = increase the frequency of openings
BARBs = increase duration of openings
185
Define anxiolytics, sedatives and hypnotics.
Anxiolytics: remove anxiety without impairing mental or physical activity.
Sedatives: reduce mental and physical activity without producing loss of consciousness.
Hypnotics: induce sleep.
186
Describe barbiturates as drugs.
Range of uses, including sedation and hypnosis.
E.g. amobarbital. Used to treat severe intractable insomnia.
Not drugs of first choice: low safety margins (depress respiration, overdosing lethal)
Alter natural sleep (less REM) - hangovers/irritability.
Enzyme inducers (care with coadministration).
Tolerance and dependence: withdrawal syndrome
Potentiate effects of other CNS depressants.
187
Describe uses of benzodiazepines as drugs and their pharmacokinetics.
Act at GABAA receptors.
Well absorbed orally.
Bind plasma proteins strongly.
Highly lipid soluble.
Extensive metabolism.
Short acting vs long acting (slow metabolism and/or active metabolites).
Short-acting act as sedatives/ hypnotics.
Long-acting act as anxiolytics (N.B. oxazepam used in patients with hepatic impairment).
188
Give some long acting benzodiazepines.
Diazepam, nordiazepam.
189
Give some short acting benzodiazepines.
Temazepam, oxazepam.
190
Describe how the actions of benzodiazepines compare to barbiturates (without describing barbiturate action).
Benzodiazepines have a wide margin of safety.
Overdose leads to prolonged, rousable sleep. Antidotes = flumazenil.
Mild effect on REM sleep. Don't induce liver enzymes.
Unwanted effects: sedation, potentiate other CNS depressants e.g. alcohol. However, tolerance and withdrawal syndrome (dependence) less than BARBs.
Free plasma BDZs increased by aspirin and heparin.
191
Other than barbiturates and benzodiazepines, what other drugs can be used as anxiolytics?
Some antipsychotic drugs (olanzapine, quetiapine).
Propranolol (improves physical symptoms)
Zopiclone - BDZ receptor agonist - minimal hangover effects but dependency still a problem.
Anti-depressants - SSRIs - less sedation and dependence but delayed response.
192
Describe epilepsy.
A neurological condition causing frequent seizures. Seizures are "sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex.
Prevalence between 2-7%. Incidence has increased over the last few decades.
Overactivity can be addressed by reducing glutamate or enhancing GABA.
193
Describe general seizures.
General seizures begin simultaneously in both hemispheres of the brain.
Tonic-clonic seizures: loss of consciousness --> muscle stiffening --> jerking/twitching --> deep sleep --> wakes up
Absence seizures: brief staring episodes with behavioural arrest.
Tonic/ atonic seizures: sudden muscle stiffening/ sudden loss of muscle control.
Myoclonic seizures: sudden, brief muscle contractions.
Status epilepticus: >5 mins of continuous seizure activity.
194
Define partial seizures.
Begins within a particular area of the brain and may spread out.
Simple: retained awareness/ consciousness
Complex: impaired awareness/ consciousness
195
Describe voltage-gated Na+ channel blocker anticonvulsants.
Carbamazepine: stabilises inactive state of Na+ channel (reducing neuronal activity). Enzyme inducer.
Indications: tonic-clonic seizures and all partial seizures.
Lamotrigine - inactivates Na+ channels --> reducing glutamate neuronal activity.
Indications: tonic-clonic seizures, absence seizures.
196
Describe ethosuximide as an anticonvulsant.
A T-type Ca2+ channel blocker. Reduces activity in relay thalamic nerves by blocking exocytosis of glutamate containing vesicles. Indications: absence seizures,
197
Describe levetiracetam as an anticonvulsant.
It binds to synaptic vesicle associated protein (SV2A) - preventing glutamate release. Indications: myoclonic seizures.
198
Describe topiramate as an anticonvulsant.
Inhibits NMDA and kainate glutamate receptors. Also affects VGSCs and GABA receptors. Indications: myoclonic seizures.
199
Describe the GABAergic synapse.
GABA released tonically (basal release, irrespective of neuronal stimulation) and also following neuronal stimulation.
Activates inhibitory post-synaptic GABAa receptors.
Taken up by GAT and metabolised by GABAT
200
Describe diazepam as an anticonvulsant.
GABAAR - increases GABA-mediated inhibtion. Rectal gel - fast onset (15 mins). Indications: status epilepticus.
201
Describe sodium valproate as an anticonvulsant.
Inhibits GABA transaminase enzyme so more GABA available. Less glutamate produced.
Indicates for ALL forms of epileptic seizure.
202
What are clinically desirable effects of general anaesthesia?
Produce loss of consciousness, suppress reflex responses (the 2 shared properties of all general anaesthetics)
Relief of pain (analgesia), muscle relaxation, amnesia.
203
Name some general anaesthetics.
Gaseous: nitrous oxide, diethyl ether, halothane, enflurane.
Intravenous: propofol, etomidate
All structurally dissimilar.
204
How do i.v. general anaesthetics (propofol, etomidate) work?
They alter synaptic function.
They increase GABAaR activity.
B3 subunits = suppression of reflex responses
A5 subunits = amnesia.
205
How do inhalational general anaesthetics work?
They have many targets.
Halothane, enflurane target GABAaR (50% less effective than i.v.) - target A1 GABAaR subunit and glycine receptors to suppress of reflex responses. Neuronal nicotinic ACh receptor suppression by halogenated anaesthetics confers analgesia.
TREK K+ channels activation by halogenated anaesthetics causes K+ efflux, reducing neuronal excitability, linked with consciousness.
Nitrous oxide blocks NMDA-type glutamate receptors.
206
Explain, in terms of neuroanatomy, how general anaesthetics cause loss of consciousness.
Depresses excitability of thalamocortical neurons
Influences reticular activating neurons (loss of sensory input)
These neurones are GABAaR rich and, RAS neurons particularly, heavily express TREK channels, so firing rate is depressed.
207
Explain, in terms of neuroanatomy, how general anaesthetics suppress reflex responses.
Depression of reflex pathways in spinal cord by inhibiting GABAa and glycine receptors.
208
Explain, in terms of neuroanatomy, how general anaesthetics cause amnesia.
Reduced synaptic transmission in hippocampus/ amygdala.
| Many a5 GABAaR in these regions.
209
Explain what effect blood:gas partition coefficients have on how well inhalational anaesthetics dissolve.
Low blood:gas partition coefficient means it doesn't dissolve very well in blood, remains gaseous but easily transfers into the brain.
A high blood:gas partition coefficient means it dissolves very well in the blood - doesn't transfer very well into the brain.
210
What blood:gas partition coefficient is desirable for inhaled anaesthetics?
Low blood:gas partition coefficient, so once the anaesthetic is removed from the airway (is breathed out) the concentration gradient reverses and the anaesthetic is rapidly excreted from the brain.
Also allows rapid manipulation of degree of consciousness.
211
Contrast inhaled and i.v. general anaesthetics.
Inhaled are rapidly eliminated and allow rapid control of the depth of anaesthesia.
I.V. allows fast induction and less coughing/excitatory phenomena (inhaled anaesthetics can cause airway irritation, which can lead to the cough reflex being initiated).
212
What clinical regimen is often used for general anaesthesia?
Propofol to rapidly induce loss of consciousness
Enflurane to suppress reflexes and maintain anaesthesia.
Opioids to confer analgesia
Neuromuscular block e.g. suxamethonium to relax muscle
Benzodiazepines to confer amnesia
213
Define local anaesthetic. What structural properties are shared by all local anaesthetics?
A drug which reversibly blocks neuronal conduction when applied locally. All have an aromatic region and a basic amine side-chain, joined by an ester or amide bond. Local anaesthetics therefore split into esters and amides.
Example of an ester = cocaine. Example of an amide = lidocaine.
214
Describe the hydrophilic and hydrophobic pathways of local anaesthetics.
LAs are weak bases (pka 8-9).
Hydrophilic (use-dependent) pathway = the LA diffuses into the axon as unionised form (B) and then ionises to form BH+ to enter the inside of the voltage dependent Na+ channels.
Hydrophobic pathways: very lipid soluble LAs tend to dissolve in the membrane and access the inside of the Na+ channel.
215
Are motor or sensory neurons more affected by local anesthetics?
Sensory, due to myelination and slower firing rate of motor neurons.
They selectively block small diameter, non-myelinated fibres.
216
Give the routes of administration of local anaesthetics.
Surface anaesthesia (mucosal surface)
Infiltration anaesthesia (directly into tissues --> sensory nerve terminals).
I.V. regional anaesthesia (I.V. distal to pressure cuff).
Nerve block anaesthesia (close to nerve trunks (e.g. dental nerves)).
Spinal anaesthesia
Epidural anaesthesia.
217
Describe infiltration anaesthesia.
Directly into tissues --> sensory nerve terminals.
Used for minor surgery. Adrenaline co-injection (not for extremities). Vasoconstrictors confine LA (minimising required dose) minimising loss to system (less systemic toxicity) and reduced bleeding.
218
Contrast spinal and epidural anaesthesia.
Spinal (intrathecal) = subarachnoid space (spinal roots). Abdominal, pelvic, lower limb surgery. Low doses, reduced b.p. and prolonged headache.
Add glucose to increase specific gravity.
Epidural = fatty tissue of epidural space. Uses = same as spinal anaesthesia + painless childbirth.
Slower onset, higher doses. More likely to see systemic activity.
More restricted action (doesn't diffuse in CSF), less effect on b.p.
219
How does chemotherapy, such as cisplatin, cause nausea?
Cisplatin is toxic to enterochromaffin cells, causing free radical release. Free radicals cause excessive serotonin release, which activates 5-HT3A receptors on nerve fibres to chemoreceptor trigger zone (CTZ). CTZ activates nerve fibres to vomiting centre (VC) causing nausea.
220
How is chemotherapy induced nausea treated?
Ondansetron: 5-HT3A antagonist (IMPORTANT)
| Glucocorticoids - reduce free radicals (anti-inflammatory)
221
Explain the pathophysiology of motion sickness.
Labyrinth --> neural mismatch --> activates histamine receptors on vestibular nuclei.
Vestibular nuclei activate muscarinic receptors on CTZ. CTZ activates VC, causing nausea.
222
How is motion sickness treated?
Promethazine: H1 receptor antagonist.
| Hyoscine - non-selective muscarinic receptor antagonist.
223
How does gastroparesis cause nausea?
Delayed emptying of stomach allows serotonin to increase, activating 5HT3A receptors on nerve fibres to CTZ which activates nerve fibres to VC.
224
How is gastroparesis treated?
Metoclopramide: dopamine (D2) receptor antagonist (prokinetic, stimulating gastric emptying and inhibits D2 receptors in CTZ) and a 5HT3A receptor antagonist, inhibiting activation of CTZ.
225
Summarise the physiological control of nausea and the main mechanistic triggers.
Physiological control: CTZ receives multiple inputs from areas including the stomach and vestibular nuclei. It communicates with the vomiting centre to produce nausea and vomiting.
Mechanistic triggers: cytotoxic drugs, motion sickness, GI problems, pregnancy.
226
What are the side effect of each main type of anti-emetic?
Hyoscine: drowsiness, dry mouth
H1 antagonists: drowsiness
D2 antagonists: galactorrhea, extrapyramidal effects
5HT3A antagonist: constipation, headaches.
227
How are antimuscarinic drugs useful in patients in the process of quitting smoking but haven't yet done so?
Smoking aggravates the vagal nerve to stimulate bronchoconstriction - antagonising the M3 receptor helps reduce SoB.
It would also reduce mucous secretions, keeping the airways clear.
228
What is methacholine?
A vagomimetic drug (stable analogue of ACh) that isn't broken down, used to agonise muscarinic receptors.
229
Describe anti-viral treatment of viral hepatitis.
Hep B: Tenofovir nucleotide analogue
Hep C: Ribavirin and peginterferon alfa. Nucleoside analogue - preventing viral RNA synthesis.
Boceprevir: protease inhibitor.
230
Describe treatment of herpes simplex virus.
Tropism: HSV-1 = cold sores, HSV-2 = genital herpes.
| Treated with nucleoside analogues, e.g. acyclovir.
231
Describe the treatment of influenza.
Envelope protein is broken down by neuraminidase - allows release of the genetic material (ssRNA).
Tropism = nose, throat, bronchi.
Treatment = oseltamivir (neuraminidase inhibitor)
232
Describe the life-cycle of HIV.
1. Attachment and entry. Viral membrane proteins interact with leukocyte membrane receptors. Viral capsid endocytosis.
2. Replication and integration: within cytoplasm - reverse transcriptase converts RNA to DNA which is transported into the nucleus and integrated in the host DNA.
3. Assembly and release. Host's machinery utilised to produce viral RNA and essential proteins. Virus assembled within cell.
233
Describe HIV drugs which target attachment and entry.
HIV glycoprotein 120 attaches to CD4 receptor. Also binds to CCR5 or CXCR4.
Gp 41 penetrates host cell membrane and viral capsid enters.
Enfuvirtide: binds to HIV gp41 transmembrane glycoprotein - prevents entry
Maraviroc - blocks CCR5 chemokine receptor - entry aborted.
234
Describe HIV drugs targeting replicaiton.
Nucleoside reverse transcriptase inhibitors e.g. zidovudine. Requires 3-step phosphorylation process.
Nucleotide reverse transcriptase inhibitors e.g. tenofovir. Fewer phosphorylation steps required.
Non-nucleoside reverse transcriptase inhibitors (not incorporated into viral DNA) e.g. efavirenz.
235
Describe HIV drugs targeting integration.
Raltegravir is an integrase enzyme inhibitor.
236
Describe HIV drugs targeting assembly and release.
Gag precursor encodes all viral structural proteins: HIV protease cleaves Gag precursor proteins.
Protease inhibitors e.g. saquinavir.
Coadministered with ritonavir booster which reduces the protease inhibitor metabolism.
237
How are fungal infections classified?
By tissue/organs.
1. superficial (outermost layers of skin)
2. dermatophyte (Skin, hair or nails)
3. subcutaneous (innermost skin layers)
4. systemic (primarily resp tract)
238
What are the 2 most common categories of antifungals?
Azoles (e.g. fluconazole) - inhibit CYP450 enzymes involved in membrane sterol synthesis.
Polyenes interact with cell membrane sterols forming membrane channels. E.g. amphotericin.
239
Describe prokaryotic nucleic acid and protein synthesis.
Dihydropteroate (DHOp) - produced from PABA by DHOp synthase.
DHOp produced DHF.
Tetrahydrofolate (THF) produced from DHF by DHF reductase. THF produces nucleic acids.
DNA gyrase/topoisomerase releases tension.
RNA polymerase produces RNA from DNA template - different from eukaryotic RNA polymerase.
Ribosomes produce protein from RNA templates (30s, 50s)
240
Give 5 classes of antibiotics targeting prokaryotic protein synthesis.
Sulfonamides inhibit DHOp synthase
Trimetapham inhibits DHF reductase (these 2 classes prevent nucleic acid synthesis).
Fluoroquinolones and quinolones inhibit DNA gyrase (Affecting DNA synthesis)
Rifamycin (e.g. rifampicin) inhibits RNA polymerase
Aminoglycosides, macrolides (E.g. erythromycin), chloramphenicol and tetracycline target ribosomes.
241
Describe bacterial cell wall synthesis.
A pentapeptide reated on N-acetyl muramic acid (NAM) associates with N-acetyl glucosamine (NAG) forming peptidoglycan.
Ptg is transported across the membrane by bactoprenol.
Incorporated into the cell wall when transpeptidase cross links Ptg pentapeptides.
242
Give 2 classes of antibiotics affecting cell wall synthesis.
Glycopeptides (E.g. vancomycin) bind to pentapeptide, preventing Ptg synthesis.
B-lactams (carbapenems, cephalosporins, penicillins) bind covalently to transpeptidase inhibiting peptidoglycan incorporation.
243
Give 2 classes of antibiotics affecting cell wall stability.
Lipopeptides (e.g. daptomycin) disrupt gram positive cell membranes
Polymyxins bind to LPS and disrupt gram negative membranes
244
Give some policy causes of antibiotic resistance.
Unnecessary prescriptions (50% unnecessary)
Livestock farming (30% of UK antibiotic use)
Lack of regulation (OTC abroad)
Lack of development (few new antibiotics)
245
How does antibiotic resistance arise via destruction enzymes?
B lactamases hydrolyse C-N bonds of the B-lactam ring.
Flucloxacillin and temocillin are B-lactamase resistant due to steric hindrance.
Amoxicillin co administered with clavulanic acid.
246
How does antibiotic resistance arise via additional target?
Bacteria produce another target which is unaffected by the drug. E-Coli produce a different DHF reductase enzyme - conferring resistance to trimetapham.
247
How does antibiotic resistance arise via alteration of target?
Alteration to the enzyme targeted by the drug. Enzyme still effective, drug ineffective.
S. Aureus mutations in ParC region of topoisomerase confers resistance to quinolones.
248
How does antibiotic resistance arise via alterations in permeability?
Reductions in aquaporins and increased efflux systems
| Primarily of importance in gram negative bacteria.
249
Give an example of how antibiotic resistance arises via hyperproduction?
Bacteria significantly increase levels of DHF reductase.
250
Give the unwanted effects of lidocaine, an amide local anaesthetic whose unwanted effects are typical of local anaesthetics.
CNS: stimulation, restlessness, confusion, tremor
CVS: myocardial depression, vasodilation, decreased b.p. (due to Na+ channel blockade).
251
Give the unwanted effects of cocaine, an ester local anaesthetic whose unwanted effects are unique amongst local anaesthethics.
CNS: euphoria, excitation
CVS: increased C.O., vasoconstriction, increased b.p.
All mediated by sympathetic actions.
252
Describe the Vaughan Williams classification of anti-arrhythmic drugs.
Class I: Sodium channel blockade
Class II: B blockade
Class III: prolongation of repolarization (membrane stabilisation due to K+ channel block)
Class IV: calcium channel blockade
Not very useful due to drugs often doing multiple things.
