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Year 2 - LCRS > Pharmacology - Spring > Flashcards

Pharmacology - Spring Flashcards

1
Q

Which four factors affect myocardial O2 supply?

A
  • Heart Rate
  • Preload
  • Afterload
  • Contractility
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2
Q

Which 3 drug classes affect heaart rate and (brielfy) explain how.

A

ß-Blockers - Decrease If and Ica -> diminish rate of depolarisation = prolong heart rate

CCB = Block Ca channels

Ivabradine = Decrease If

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3
Q

Which drug influence heart contractility?

A

ß-blockers (decrease cAMP= decrease PKA) and CCB’s (decrease Ca entry to the cell)

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4
Q

Name the 2 Classes of Calcium antagonists

(Which has greater cardiac selectivity?)

A

Rate Slowing (greater cardiac selectivity)

  • Phenylalkylamines (VERAPAMIL)
  • Benzothiazepines (DILTIAZEM)

Non Rate Slowing
- Dihydropiridines (AMLODIPINE)

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5
Q

Which type of CCB can lead to reflex tachycardia and why?

A

Non-rate slowing. Cause profound vasodilation

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6
Q

What side effects might you see from ß-blocker use?

A
  • Bradycardia
  • Worsening cardiac failure (due to C.O. reduction )
  • Bronchoconstircion (b2 blockade effect)
  • Hypoglycaemia (b2 blockade in liver effect)
  • Cold extremities (b2 = vasodilator so if you block = vasoconstriction )
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7
Q

Outline the Vaughan Williams classification for anti-arrhythmic drugs:

A

Class 1 - Na Channel blockade

Class 2- Beta andrenergic blockade

class 3 - Prolongation of repolarisation (mainly due to K+channel block)

Class 4 - Ca Channel blockade

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8
Q

What is Adenosine used for ?

A

Slow heart rate in Acute SVT. Short lived

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9
Q

Verapamil

Target, effect

A

This mainly targets the L-type calcium channels

This slows down the ability of the nodal tissue to depolarise

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10
Q

Amiodarone

Use, Target, effect

A

Class III antiarhythmic. SVT and VT - often due to re-entry

Amiodarone slows conduction rate and prolongs the refractory period of the SA and AV nodes which prolongs repolarisation

It has a complex mechanism of action that involved multiple ion channel blockade but its main action seems to be through potassium channel blockade

By prolonging repolarisation, you’re prolonging the time during which the heart can NOT depolarise, thus restoring normal rhythm

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11
Q

Digoxin and cardiac Glycosides

What are they used to treat?
How do they do this?
and what condition might lower the threshold of toxicity ?

A

Used to treat AF

Cardiac glycosides inhibit Na+/K+ pump (bind to the external K+site) wich causes in crease in Ca inside the cell = Increase contractility.

Central vagal stimulation causes increased refractory period and reduced rate of conduction through AV node

*Hypokalaemia (usually as a result of diuretic use) lowers the threshold for digoxin toxicity.

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12
Q

Name 5 factors that impact vascular smooth muscle tone

A
  • Symapthetic nerve stimulation
  • RAS
  • Noradrenaline on alpha-1 receptors
  • Prostaglandin
  • Endothelins
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13
Q

What is the first line treatment of hypertension

A

ACEi or ARB (Angiotensin Recepton blocker)

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14
Q

Fill in the blanks

A
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15
Q

What are the limitations of the Vaughan -Williams clssification ?

A

. Many of these drugs have mechanisms of action that are shared with drugs found the other classes

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16
Q

How do drugs of abuse cause euphoria?

A

Dopaminergic neurones from VTA, project to nucleus accumbens (ventral striatum), prefrontal cortex which releases Dopamine

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17
Q

metabolism lipid solubility etc

Outline the pharmacokinetics of Cannabis

A

v. lipid solublem, (build-up in poorly-perfused fat long-term) so is widely distributed.

Heavily affected by 1st pass metabolism.

Effects are long lasting ~30days

11-hydroxy-THC is major metabolite from liver, more potent than delta-9THC, enters enterohepatic circulation

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18
Q

What are the 2 endogenous cannabinoid receptors and where are they found?

A

CB1 in brain on GABA neurones, (cannabis binds + switches off inhibition on dopamine = euphoria)

CB2 (peripheral, immune cells)

can’t overdose (low CB1 receptor conc. in medulla).

G-protein coupled -ively with Adenylate Cyclase so slows cellular activity by depressing adenylate cyclase

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19
Q

What is the mechanism of cocaine action

A

At high dose = local anaesthetic by blocking NA channels

Euphoris by blocking monoamine transport so dopamine remains in the synapse longer = prolonged effect

*no effect on affinity/efficacy

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20
Q

By what mechanisms might cocaine cause infrction and arrhythmias?

A

Increased sympathetic effect:
↑HR
↑BP
↑Vasocontriction
etc = ischaemia = infaarction

Decreased Na transport:
↓LV function
↓Arrhythmia

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21
Q

What is the target for nicotine that drives euphoria ?

A

Cell bodies of neurons in the VTA towaards the Nucleus Accumbens = Euphoria

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22
Q

How many ml / is one unit of alcohol ?

A

I unit = 10ml/ 8g

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23
Q

What is the compnent upregulated in regular drinkers

A

Mixed function oxidases

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24
Q

Why might women become intoxicated sooner than men?

A

They are only 50% body water copared to 59%for men (alcohol is water soluble so equal amount = more dilute in men). Also <50% alcohol dehydrogenase in the stomachs of women.

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25
Q

What drug is used in alcohol aversion therapy?

A

Disulfiram (aldehyde dehydrogenase inhibitor. Acetaldehyde will build up)

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26
Q

How does alcohol cause fatty liver?

A

Alcohol metablism in the liver requires NAD+. Chronic drinking leads to depletion of NAD+ and increase of NADH.

↑NADH inhibits beta-oxidation of lipids =fat build up.

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27
Q

What is the difference between a white thrombus and a red thrombus?

A

_White thrombu_s -

  • forms in artery. ↑platelet concn.
  • More likely in tunica media than in lumen
  • White becasue macrophages absorb fat adn become foam cells

Red thrombus

  • ↑fibrin & ↑erythrocytes
  • Thrombus in the vein
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28
Q

What are Virchow’s Triad risk factors?

A
  1. Rate of blood flow: slow/stagnating blood flow=no anticoagulant replenishment = ↑thrombosis/coagulation.
  2. Blood consistency: pro-anticoagulant balance, genetic conditions shift it.
  3. Vessel wall integrity: endothelial/tunica intima damage=exposes prothrombotic subendothelial structures=↑thrombosis.
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29
Q

OUtline the Cell based theory of coagulation and which classes of drugs act at each stage

A

Initiation - Small scale production of thrombin (ie F2a)

Anticoagulants

​Amplification - Large scale thrombin production on the surface of the platelets

Antiplatelets

Propagation - Thrombin mediated generation of fibrin strands from fibrinogen

Thrombolytics

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30
Q

Where is alcohol metabolised to acetaldehyde? What enzymes are involved?

A

Alcohol → acetaldehyde (toxic)
1) 85% in the liver (first pass hepatic metabolism)
Enzymes:
- Alcohol dehydrogenase (75%)
- Mixed function oxidase (25%)
2) 15% in the GIT
Enzyme:
- Alcohol dehydrogenase

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31
Q

What drugs end in -pril?

A

ACE inhibitors

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32
Q

What is the second line of treatment for hypertension?

A

ACE inhibitor and calcium channel blocker
OR
ACE inhibitor and thiazide type diuretic

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33
Q

What is the third line of treatment for hypertension?

A

ACE inhibitor and calcium channel blocker and thiazide type diuretic

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34
Q

How do ACE inhibitors treat hypertension? What side effect does this cause?

A

Prevents the conversion of angiotensin I to angiotensin II
Also prevents the conversion of bradykinin to inactive metabolytes- this causes a cough

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35
Q

How is nicotine metabolised?

A

70-80% is converted to Cotinine by Hepatic CYP2A6

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36
Q

What effects of drinking alcohol are though to be actually through the effects of acetaldehyde

A

Cutaneous vasodilation
Diuresis (prevents vasopressin secretion)

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37
Q

How does hepatitis result from chronic alcohol abuse?

A

Mixed function oxidase enzyme generates free radicals. These free radicals generate an inflammatory stimulus, which if prolonged, releases cytokines
This is reversible

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38
Q

How does cirrhosis result from chronic alcohol abuse?

A

After hepatitis is the alcohol consumption is prolonged the liver will get cirrhosis

  • Decreased hepatocyte regeneration
  • Increased fibroblasts
  • Decreased active liver tissue
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39
Q

What are the different procoagulants in the blood?

A
  • Prothrombin
  • Factors V, VII-XIII
  • Fibrinogen
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40
Q

What are the different anticoagulants in the blood?

A
  • Plasminogen
  • TFPI (Tissue factor pathway inhibitor)
  • Proteins C & S
  • Antithrombin
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41
Q

How does Dabigatran cause anticoagulation? Why is it rarely used?

A

Inhibits factor IIa
Causes more bleeding (esp GI bleeding) than expected.

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42
Q

How does Rivaroxaban cause anticoagulation? How is it administered?

A

Factor Xa inhibitor
Oral

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43
Q

What is the mechanism of Heparin ?

A

Increases the activity of Antithrombin (AT-III). Which decreases activity of both FIIa and FXa.

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44
Q

What is Dalteparin? How does it cause anticoagulation?`

A

A low-molecular weight heparin
Activates AT-III (↓fXa>than IIa = better pharmacokinetics, decrease bleeding. Can be given SC )

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45
Q

What drug activates AT-III (antithrombin)?

A

Heparin

(also Dalteparin)

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46
Q

How does Clopidogrel prevent platelet activation?

A

ADP (P2Y₁₂) receptor antagonist

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47
Q

How does Aspirin prevent platelet activation?

A

Irreversible COX-1 inhibitor- inhibits production of TXA₂ (thromboxane)

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48
Q

What drug inhibits platelte aggregatino by being an GpIIb/IIIa antagonist?

A

abciximab

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49
Q

How do thrombolytics works and give one example?

A

ALTEPLASE.

Plasmin is a protease that degrades fibrin

Thrombolytics convert plasminogen → plasmin

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50
Q

What is the first line drug treatment of stroke?

A

Alteplase

(recombinant tissue type plasminogen activator)

Needs to be given within 8hrs.

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51
Q

What are the indications for antiplatelet drugs?

A

Acute Coronary syndrom - MI
AF - prophylaxis for stroke.

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52
Q

What are the indication for anticoagulant drugs?

A

DVT and PE
Avoid thrombosis during surgery
Prophylactic treatment of AF to avoid stroke.

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53
Q

Which drugs should be used in which situations?

A
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54
Q

What is a NSTEMI?

A

Non-ST elevated myocardial infarction (MI)
- ‘White’ thrombus → partially occluded coronary artery
Caused by:
- Damage to endothelium
- Atheroma formation
- Platelet aggregation

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55
Q

What are the disadvantages of warfarin?

A

Take ~5-6days to show effect.

Very narrow therapeutic window so patient must be monitored closely

High rate of interaction with other drugs

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56
Q

What are the 5 stages of atherosclerosis?

A
  1. LDL Moves into the subendothelium
  2. It is oxidised by macrophages and smooth muscle cells
  3. The release of growth factors and cytokines attracts inflammatory cells
  4. Foam cell form. (lipid-containing macrophages)
  5. Fibroblast + SM proliferation results in growth of the plaque
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57
Q

What is the absolute first phase of atherosclerosis?

A

Endothelial dysfunction

↑endothelial permeability

Stops making factors that inhibit platelet aggregation and clotting

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58
Q

What is is the earliest recognisable lesion of atherosclerosis and what is it caused by?

A

Fatty Streak

caused by the aggregation of lipid-rich foam cells,

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59
Q

What is the Complicated atherosclerotic plaque formed of?

A

Composed of ipids, dead cells, and fibrous cap.
Results from the death of foam cells in the fatty streak creating a necrotic core.
Migration of vascular smooth muscle cells (VSMCs) to the intima and laying down of collagen fibres results in the formation of a protective fibrous cap over the lipid core

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60
Q

What are the drug therapy options for reducing LDL?

A

Bile Acid Sequestrants
Nicotinic Acid
Fibrates
Statins
Ezetemibe

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61
Q

What is the MOA of statins?

A

Act on MEVALONATE PATHWAY and glock HMG-CoA reductase which prevents production of cholesterol from acetyl-CoA.

By blocking cholesterol synthesis in the liver, the hepatocytes respond by increasing LDL receptors on hepatocytes. These bind more LDL which decreases circulating levels.

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62
Q

What are the two properties of statins that are compared?

A

Cell selectivity ratio: The likelyhood the drug will be concentrated in the liver

Potentcy: The lower the number = the more potent the drug as an enzyme inhibitor.

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63
Q

What is the rule of 6?

A

If you double the dose of any statin, you only get a 6% reduction in LDL. True of all statins and all doses

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64
Q

What are the side effects of statins?

A

Platelet activation

Thrombotic effect
Increased plaque stability

Smooth muscle hypertrophy

Smooth muscle proliferation

Vasoconstriction

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65
Q

Apart from statins which other drug decreases fatty acids and triglycerides

A

Fibrates activate transcription factors called PPAR-alpha receptors. But Poor clinical trial data

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66
Q

How do NSAIDs work?

A

Inhibit the synthesis of prostanoids by COX enzymes.

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67
Q

Name the prostanoids and what they are derrived from

A

Arachidonic acid → COX1 and COX2 →Prostaglandin H2

  • Prostaglandins
  • Thromboxanes
  • Prostacylin
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68
Q

Which drug is selective for COX-2?

A

Celecoxib

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69
Q

Which prostaglandin receptor is found on nociceptors?

A

PGE2

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70
Q

What receptors are activated by PGE₂?

A

EP1
EP2
EP3
EP4

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71
Q

What are the unwanted actions of PGE₂?

A
  • Increased pain perception*
  • Thermoregulation*
  • Acute inflammatory response*
  • Immune responses
  • Tumorigenesis
  • Inhibition of apoptosis

* Targeted by NSAIDs

72
Q

What are the desirable physiological actions of PGE2 and other prostanoids?

A
  • Gastroprotection
  • Renal salt and water homeostasis
  • Bronchodilation
  • Vasoregulation (dilation and constriction depending on receptor activated)
73
Q

How is PGE₂ involved in gastric cytoprotection?

A
  • Downregulates HCl secretion
  • Stimulates mucus and bicarbonate secretion

COX-1 mediated

74
Q

How do NSAIDs cause renal toxicity?

A
  • Constriction of afferent renal arteriole
  • Reduction in renal artery flow
  • Reduced glomerular filtration rate
75
Q

Why do 10% of asthmatics experience worsening symptoms with NSAIDs?

A

COX inhibition. Blocks production of PGE₂ from arachidonic acid
- PGE₂ is a bronchodilator, it also inhibits lipoxygenase enzyem so reduces leukotreines which arer bronchoconstrictors

76
Q

What are the unwanted effects of NSAIDs on the CVS?

A
  • Vasoconstriction
  • Salt and water retention
  • Reduced effect of antihypertensives
    Increased risk of:
  • Hypertension
  • Myocardial infarction
  • Stroke
77
Q

With regards to pootential GI bleeds and potential MI/stroke which Cox enzyme inhibitors mediate which?

A

COX2 inhibition = more MI risk
Cox 1 inhibition = GI bleed risk

78
Q

What is the mechanism of NSAID Aspirin?

A

Unique among NSAIDs

  • Selective for COX-1
  • Binds irreversibly to COX enzymes
79
Q

What causes the anti-platelet actions of aspirin?

A
  • Thromboxane enhances platelet activation. (it is made by Cox1)
  • Prostaglandin PGL2 decreases platelet action (it is made by Cox1 and 2)

Aspirin bind irreversibly to COX1- platelets can’t make more enzymes.

But endothelial cell can synthesise more COX enzymes

leads to overall supression of thromboxane.

80
Q

What are the major side-effects of Aspirin?

A
  • Gastric irritation and ulceration
  • Bronchospasm in sensitive asthmatics
  • Prolonged bleeding times
  • Nephrotoxicity
  • Side effects are more likely with aspirin than other NSAIDs because it inhibits COX covalently, rather than its selectivity for COX
81
Q

What happens if you overdose on paracetamol?

A

Paracetamol forms a toxic metabolite (NAPQI). Normally this is ‘mopped up’ by Glutathione.

In overdose too much metabollite leads to depletion of glutathione stores

The metabolite will oxidise thiol groups of key hepatic enzymes and causes cell death

- Will result in irreversible liver failure

82
Q

What is the antidote for paracetamol poisoning?

A
  • Add compound with -SH groups
  • Usually intravenous Acetylcysteine (in cases of attempted suicide)
  • Occassionally oral methionine
  • If not administered early enough, liver failure may be unpreventable
83
Q

How would an antimuscarinic agent help a patient with COPD who smokes?

A
  • Cigarette smoking causes inhalation of irritants into the lungs which stimulates the PNS to induce bronchoconstriction
  • PNS stimulates muscarinic receptors to induce bronchoconstriction. An antimuscarinic would prevent this
  • If you stop smoking the irritants will clear so the PNS stimulation will stop
84
Q

What endogenous mediators may contribute to the bronchoconstriction observed in patients with asthma?

A
  • Histamine
  • Leukotreines
  • Antibody mediated (IgE)
  • Prostaglandins
85
Q

What are the five major classes of antiemetics?

A
  1. Mixed receptor antagonists
  2. Dopamine type two receptor antagonists
  3. Muscarinic receptor antagonists
  4. Serotonin (5 HT3) receptor antagonists
  5. Cannabinoids
86
Q

What are the consequences of severe vomiting?

A
  • Dehydration
  • Loss of gastric H⁺ and Cl⁻ ions may lead to hypochloraemic metabolic alkalosis (↑ blood pH)
  • Contributes to a reduction in renal bicarbonate excretion and an increase in bicarbonate reabsorption;
  • Increased Na⁺ reabsorption in exchange for K⁺, leading to hypokalaemia
87
Q

What pathways feed into the vomiting centre in the brain?

A
  • Vestibular system
  • CNS
  • Chemoreceptor trigger zone (area postrema)
  • Vomiting centre (nucleus of tractus solitarius)
  • GI tract and heart
88
Q

Which receptors are activated in the vestibular systme to activate vomiting?

A
  • H₁ receptor
  • M₁ receptor
89
Q

What receptors of the chemoreceptor trigger zone contribute to vomiting?

A
  • Chemoreceptors
  • D₂ receptors
  • NK₁ receptor
  • (5-HT₃ receptor)
90
Q

Which receptors in the GI tract and heart contributes to vomiting?

A
  • Mechanoreceptors
  • Chemoreceptors
  • 5-HT₃ receptor
91
Q

What receptors are present in the vomiting centre

92
Q

What is PROMETHAZINE?

A

MIxed receptor antagonist H2>M>D2. (Phenergan)

Acts centrally, blocks vomiting centre activation, CTZ and Vestibular nucleus; Onset 1-2hr, lasts 24hrs;

motion sickness (after onset), labyrinth disorders (e.g. Meniere’s), hyperemesis gravidarium, pre/post-operative

93
Q

Name 2 dopamine receptor antagonists

A

Metoclopramide
Domperidone

94
Q

What is the mechanism of metoclopramide and domperidone

A

Antagonist mainly D2>H1>M1
GIT prokinetic effects:
-Increased smooth muscle motility
-Increased gastirc emtying
-Increased transit of content pace
= Less volume to trigger vomiting

Metoclopromide crosses BBB but Domperidone doesn’t cross.

USES: nausea + vomiting due to severe renal failure, radiation sickness, GI disorders, cancer chemotherapy and Parkinson’s treatments that stimulate D; Not good for motion sickness (doesn’t block vestibular system signals),

95
Q

Name a Muscarinic receptor antagonist anti-emetic and outline its MOA

A

Hyoscine; M>D2>H1; act centrally, esp. in vestibular nuclei/CTZ/vomiting centre to block activation of vomiting centre.

Uses = prevents motion sickness, little effect after nausea/emesis,
pre-op

Side effects = antimuscarinics effects (drowsy, dry mouth, cyclopegia, mydriasis, constipation).

96
Q

Name a Serotonin (5HT3) receptor antagonist used as an antiemetic

A

Ondansetron; Blocks visceral afferents and CTZ transmission

Uses = prevents anti-cancer drugs vomiting (esp. cisplatin), radiotherapy sickness, post-op nausea/vom;

97
Q

What is the name of the synthetic cannabinoid isolated to treat nausea?

98
Q

What is the progression of the defective interaction between mucosal immune system and gut flora in IBD?

A

Complex interplay between host and microbes
↓
Disrupted innate immunity and impaired clearance
↓
Prof-inflammatory compensatory responses
↓
Granuloma formation and physical damage

99
Q

What immune cells and cytokines mediate the response in Crohn’s disease?

A

Florid T cell expansion
Defective T cell apoptosis

  • *Th1-mediated**
    e. g. IFNγ, TNFα, IL-17, IL-23
100
Q

What immune cells and cytokines mediate the response in Ulcerative Colitis?

A

Th2-mediated
e.g. IL-5, IL-13

Limited clonal expansion
Normal T cell apoptosis

101
Q

What are the 4 principal intracellular targets of antibiotics?

A
  1. Nucleic Acid Synthesis
    PABA⇒ Dihydropterate (DHOp) ⇒ dihydrofolate (DHF) ⇒ Tetrahydrofolate (THF) ⇒ DNA synthesis
  2. DNA replication
    DNA gyrase (Topoisomerase) releases tension so enzyems have access
  3. RNA synthesis
    RNA polymerase produces RNA from DNA template. Differs from eukaryotic RNA polymerase
  4. Protein synthesis
    Ribosomes differ from eukaryotic ribosomes
102
Q

Where during prokaryotic protein synthesis do Sulphonamides work ?

A

Nucleic Acid Synthesis

•Sulphonamides inhibit DHOp synthase

103
Q

Where during prokaryotic protein synthesis does Trimethoprim work ?

A

Nucleic Acid Synthesis
Trimethoprim inhibits DHF reductase

104
Q

Where during prokaryotic protein synthesis do Floroquinolones work?

A

DNA replication

•Fluoroquinolones (e.g. Ciprofloxacin) inhibit DNA gyrase & topoisomerase IV

105
Q

c

A

RNA polymerase

•The rifamycins (e.g. Rifampicin) inhibits bacterial RNA polymerase

106
Q

Where during prokaryotic protein synthesis do the Macrolides work ?

A

Protein synthesis - Inhibit ribosomes

107
Q

Name the antibiotics that act at 1a, 1b, 2, 3, 4

A

1.aSulphonamides
1b Trimethoprim

2 Fluoroquinolones (e.g. Ciprofloxacin)

3 The rifamycins (e.g. Rifampicin)

4 Aminoglycosides (e.g. Gentamicin)
Chloramphenicol
Macrolides (e.g. Erythromycin)
Tetracyclines

108
Q

What the 3 steps for bacterial cell wall synthesis?

A

Peptidoglycan (PtG) synthesis
PtG transportation
PtG incorporation

109
Q

How do antibiotics inhibit PtG synthesis?

A

Glycopeptides (e.g. Vancomycin) bind to the pentapeptide on NAM (N-acetyl muramic acid) preventing PtG synthesis

110
Q

How do antibiotics prevent PtG incorporation into the cell wall?

A
  • b-lactams bind covalently to transpeptidase (the enzymes that cross link PtG) inhibiting PtG incorporation into cell wall
  • b-lactams include:
  • Carbapenems
  • Cephalosporins
  • Penicillins
111
Q

How do antibiotics prevent affect bacterial cell wall stability?

A
  • Lipopeptide - (e.g. daptomycin) disrupt Gram +ve cell walls
  • Polymyxins - binds to LPS & disrupts Gram -ve cell membranes
112
Q

List 5 resistance mechanisms adopted by bacteria:

A
  1. Additional target - Bacteria produce another target that is unaffected by the drug
  2. Hyperproduction - Bacteria significantly increase levels of DHF reductase
  3. Alterations in enzymes targetted by the drug
  4. Alterations in drug permeation - Reductions in aquaporins & increased efflux systems
  5. Production of destruction enzymes. eg b-lactamases hydrolyse C-N bond of the b-lactam ring
113
Q

Name 2 drugs that target fungal infections and describe their mechanism of action

A

Azoles
Inhibit cytochrome P450-dependent enzymes involved in membrane sterol synthesis
Fluconazole (oral) ⇒ candidiasis & systemic infections

Polyenes
Interact with cell membrane sterols forming membrane channels
Amphotericin (I-V) ® systemic infections

114
Q

With regards to Hep B and Hep C, which is curable ?

A

Hep B is NOT curable

•

Hep C is CURABLE

115
Q

What drug is used to treat hepatitis B? What is the mechanism of this drug?

A

Tenofovir
Nucleotide analogue, given sometimes with Peginterferon α

Competes with the endogenous deoxynuelotides that would be used to make up DNA

116
Q

What drug is used to treat hepatitis C? What is the mechanism of this drug?

A

Ribavirin and Peginterferon α
Ribavirin: nucleoside analogue prevents viral RNA synthesis
Boceprevir: protease inhibitor most effective against Hep C genotype 1

Note: Hep C is an RNA virus

117
Q

HIV Entry inhibitors, how do they work?

A

HIV GP120 attaches to CD4 receptor on T Lymphocytes

  • GP120 also binds to either CCr5 or CXCR4
  • GP41 penetrates host cell membrane and viral capsid is endocytosed

Enfuvirtide
- Binds to HIV GP41 transmembrane glycoprotein

Maraviroc
- Block CCR5 chemokine receptor

118
Q

HIV Replication inhibitors, how do they work?

A

Replication and integration

  • Within cytoplasm - reverse transcriptase enzyme converts viral RNA → DNA
  • DNA transported into nucleus and integrated into host DNA

1) Nucleoside reverse transcriptase inhibitors
- Activated by 3-step phosphorylation process
e. g. Zidovudine

2) Nucleotide reverse transcriptase inhibitors
- Fewer phosphorylation steps required
* *e.g. Tenofovir**

3) Non-nucleoside reverse transcriptase inhibitors
- No phosphorylation required
- Not incorporated into viral DNA
* *e.g. Efavirenz**

119
Q

What drug inhibits HIV integrase?

A

Raltegravir

120
Q

What drug inhibits HIV protease? What is this typically co-administered with? Why?

A

Saquinavir (1st generation Protease Inhibitor)
Co-administered with Ritonavir which reduced the metabolism of Saquinavir hh(by inhibiting cytochrome P450) - co-administered to boost Squinavir concentrations in the body

121
Q

What is the important structural group in all opiods?

A

Tertiary nitrogen, permits anchoring of the drug to the receptor. Side chain determines if agonist or antagonist. 3+ carbons = antagonist.

122
Q

How is heroin different from morphine?

A

INcreased lipid solubility = penetrates tissues better.

123
Q

What are the shared structural features of opiods?

A

Tertiary Nitrogen

Pheny group

Quaternary Carbon (except phentanyl = tertairy carbon)

124
Q

Why is oral absorption of opiods so poor?

A

Most opiods are weak bases so will be ionised in the stomach = poor absorption but unionised in the small intestine so absorbed relatively well

However, extensive first pass metabolism. Only ~20% opioids get into the blood.

125
Q

Why can methadone and fentanyl be given transdermally?

A

Higher lipid solubility than other opiods.

126
Q

What is morphine metabolised into?

A

10% = Morphine-6-glucuronide which is an active metabolite and undergoes enterohepatic recylcing.

127
Q

Why is methadone used to ween people off heroin?

A

methadone has slow metabolism so is long lasting.

128
Q

Describe briefly the metabolism of Codeine

A

Codeine is a pro-drug. 5-10% is metabolised to morphine.

CYP2D6 = activates -> SLOWLY
CYP3A4 =deactivates -> FAST

129
Q

What are the different endogenous opioid peptides?(What opiate receptors do they bind to?)

A
  • Endorphins (μ Mu or δ Delta)
  • Enkephalins (δ Delta)
  • Dynorphins/neoendorphins (κ Kappa)
130
Q

Where are the μ opiate receptors located? What do they influence?

A
  • Thalamus
  • Amygdala
  • Nucleus accumbens
  • PAG

Pain/mood/CVS

131
Q

Where are the δ opiate receptors located? What do they influence?

A
  • Nucleus accumbens
  • Cerebral cortex
  • Amygdala

Pain/mood/CVS

132
Q

Where are the κ opiate receptors located? What do they influence?

A
  • Hypothalamus

Appetite

133
Q

What is the function of the locus coeruleus in pain perception?

A

Major sympathetic outflow that affects pain response. During stress it is highly active, for example during fight of flight can down regulate pain.

134
Q

What areas of the brain are involved in pain tolerance?

A
  • *PAG** (Periaqueductal grey matter) = Central pain coordinating region
  • *NRM** (Nucleus Raphe magnus) = Effector arm of pain tolerance. Neurons from here relay to the spinal cord to decrease pain sensation
  • *NRPG**- Nucleus Reticularis Paragigantocellularis. = -ive feedback

(Locus Coeruleus)

135
Q

What role does the hypothalamus play in modulation of pain transmission?

A

Regulates PAG response based on health

136
Q

Why is the substantia gelatinosa in the dorsal horn known as the ‘Mini brain’?

A

Can process information coming down from the NRM and regulate pain processing here

137
Q

Where do opioids act in the pain pathway?

A
  • Periphery
  • Dorsal horn
  • NRPG
  • PAG
138
Q

How do opioids cause euphoria?

A
  • Opiates act on μ receptor
  • This reduces GABA firing
    (GABA inhibits VTA (ventral tegmental area)
  • Reduced firing stops inhibition which causes release of dopamine
    = EUPHORIA
139
Q

How do opioids have an anti-tussive effect?

A
  1. Prevent relay of sensory fibres into to vagus
  2. Act directly on cough centre
  3. Inhibit 5HT¹ᴬ receptors

(5HT¹ᴬ in the Dorsal Raphe Nucleus is the negative feedback receptor for serotonin. Firing in this receptor leads to suppression of serotonin which leads to the activation of the cough centre. Opioids desensitise this receptor say serotonin levels rise. More serotonin = less cough)

140
Q

How do opiods depressed respiration?

A

1) Inhibit central chemoreceptors by depressing firing so cannot respond to blood changes in CO2
2) act directly in respiratory control centre pre-Botzinger complex (small area in the ventrolateral medulla) generates respiratory rhythm

141
Q

Why do opioids cause vomiting?

A

Normally Gabba inhibits the chemoreceptor trigger zone preventing nausea but opioids activate mu receptors in the CTZ

142
Q

Why do opioids cause pinpoint pupils?

A

The opioids hijack the parasympathetic CNIII. Lots of mu receptors in the Edinger-Westphal nucleus, so again removal of GABA = removal inhibition.

143
Q

How is tolerance to opioids generated?

A

This is tissue tolerance not pharmacokinetic. Opioid upregulate arrestin within tissue which promotes receptor internalisation, so the tissue becomes less sensitive.

144
Q

How is physical dependence to opioids created?

A

Cells upregulate adenylate cyclase to compensate opioid down regulation of calcium influx. When the drug is removed cells have over active cAMP

145
Q

What are the main effects of opioids?

A

Analgesia

Euphoria

Depression of cough centre

Depression of respiratory centre

Nausea/Vomiting

Pupillary constriction

GI effects

146
Q

What are the three main dopaminergic pathways?

A

Nigrostriatal - Controls movement

Mesolimbic - involved in emotion

Tuberinfundibular - hormone secretion

147
Q

What are the cardinal signs of Parkinson’s disease?

A
  • Resting tremor
  • Rigidity (stiffness, limbs feel heavy/weak)
  • Bradykinesia (slow movement)
  • Postural abnormality
  • Unilateral onset -> then spreads
148
Q

What are the non-motor symptoms of Parkinson’s disease?

A

Depression

  • Sleep disturbance
  • Pain
  • Taste and smell disturbances
  • Cognitive decline/Dementia

Autonomic dysfunction

  • Constipation
  • Postural hypotension
  • Urinary frequency/urgency
  • Impotence
  • Increased sweating
149
Q

What is the altered protein found in Lewy bodies?

A

Alpha-synuclein

150
Q

Why is L-DOPA used to treat Parkinson’s rather than dopamine or tyrosine?

A

Dopamine is hydrophilic so it can’t cross the the BBB, also there are very low levels of dopamine transporter in BBB so it cannot penetrate the brain
L-DOPA uses the same transporter as tyrosine so it can get into the brain
Tyrosine hydroxylase is the rate limiting step so it is better to use L-DOPA instead of tyrosine

151
Q

What is Carbidopa?

A

A DOPA decarboxylase inhibitor

  • It cannot cross the BBB
  • It prevents the conversion of L-DOPA to dopamine peripherally so when used with L-DOPA more is converted in the brain and it also prevents the nausea and vomiting associated with dopamine stimulating the chemotactic trigger zone where there are fewer tight junctions than in the brain
152
Q

How can the dyskinesias be decreased?

A

D2 receptor agonist = longer t1/2 than L-dopa but does cause nausea (treat with domperidone) and hallucinations. Bromocriptine and Pergolide

153
Q

What drugs might allow reduction of L-dopa dosage?

A

MAO-inhibitors. Deprenyl is MAO-B selective

154
Q

Name one more therapeutic approach to treating Parkinsons

A

COMT inhibitors. Prevent breakdown of dopamine in the brain. In the periphery COMT convert L-dopa tp 3-OMD which competes with L-Dopa for transport accross the BBB. COMT Inhibitors stop 3 OMD production so less competition for transporters

155
Q

What are the positive symptoms of schizophrenia?

A

Hallucinations

Delusions

Disorganised thoughts

156
Q

What are the negative symptoms of schizophrenia?

A

Reduced speech

Lack of emotional and facial expression

Diminished ability to begin and sustain activity

Decreased ability to find pleasure in everyday life

Social withdrawal

157
Q

What is the dopamine theory of schizophrenia?

A

Positive symptoms–results from excessive dopamine transmission in the mesolimbic and striatal region (D2-mediated)

Negative symptoms -results from dopamine deficit in the prefrontal region (D1 mediated)

158
Q

What is the Glutamate theory of schizophrenia?

A

NMDA is it glutamate receptor. NMDA receptor agonists cause psychotic symptoms.

Glutamate exerts an excitatory influence over the GABAergic striatal neurons and dopamine exerts an inhibitory influence. These neurons act as a sensory gate and filter input

159
Q

What are the extrapyramidal side effects of schizophrenia treatment?

A
  • Acute dystonia e.g. Open mouth, tongue protrusion, reversible with drug withdrawal or anticholinergics
  • Tardive dyskinesias. Involuntary movements after months or years of therapy made worse by drug withdrawal
160
Q

What other side-effects of schizophrenia treatment are there?

A

Sedation, Weight gain (5HT blockade), orthostatic hypotension (alpha adrenoreceptor blockade), endocrine effects, Cholinergic- muscarinic receptor blockade effects

161
Q

How are adverse drug reactions classified?

A

Onset

Severity

Type

162
Q

What are the different types of onset of adverse drug reactions?

A

Acute
- Within 1 hour
Sub-acute
- 1 to 24 hours
Latent
- > 2 days

163
Q

What is a type A adverse drug reactions? Give examples of drugs which cause type A reactions

A
  • *Extension of pharmacological effect**
  • Usually predictable and dose dependent
  • Responsible for at least two-thirds of ADRs
  • e.g. atenolol and heart block,
164
Q

What is a type B adverse drug reactions? Give examples of drugs which cause type B reactions

A
  • Idiosyncratic or immunologic reactions
  • Includes allergy and “pseudoallergy”
  • Rare (even very rare) and unpredictable
  • 1/10,000 people: irreversible and mostly fatal
  • e.g. chloramphenicol and aplastic anaemia, ACE inhibitors and angiodema
165
Q

What is a type C adverse drug reactions? Give examples of drugs which cause type C reactions

A
  • Associated with long-term use
  • Involves dose accumulation
  • e.g. methotrexate and liver fibrosis, antimalarials and ocular toxicity
166
Q

What is a type D adverse drug reactions? Give examples of drugs which cause type D reactions

A
  • Delayed effects (sometimes dose independent)
  • Carcinogenicity (e.g. immunosuppressants)
  • Teratogenicity (e.g. thalidomide)
167
Q

What are the different types of type E adverse drug reactions? Give examples of causes of each type of reaction

A

Withdrawal reactions
- Opitates, bencodiazepines, corticosteroids

Rebound reactions
- Clonidine, β-blockers, corticosteroids

“Adaptive” reactions
- Neuroleptics (major tranquillisers)

168
Q

What is the ABCDE classification of adverse drug reactions?

A

A Augmented pharmacological effect
B Bizarre
C Chronic
D Delayed
E End-of-treatment

169
Q

What are pharacodynamic interactions?

170
Q

What is the key difference in the mechanism of action of barbiturates and benzodiazepines?

A

Benzodiazepines – increase the frequency of chloride channel opening

Barbiturates – increase the duration of chloride channel opening

171
Q

Name 2 IV general anaesthetics

A

Propofol
Etomidate

172
Q

What are the 2 mechanisms of action of general anaesthetics?

A

Reduced neuronal excitability
Altered synaptic function

173
Q

What are the 2 types of local anaesthetics?

A 
Ester = Cocaine
Amide = Lidocaine
174
Q

What are the 2 pathways of local anaesthesia . State which is more important

A

HYDROPHILIC
hydrophobic

175
Q

Identify the clinical symptoms of alzheimers

A

Memory loss

disorientation/confusion

language problems

personality changes

poor judgement

Year 2 - LCRS (9 decks)

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