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PPE Revision > Pharmacology 2 > Flashcards

Pharmacology 2 Flashcards

1
Q

Explain the action of statins

A
  1. Inhibit HMG-CoA reductase so decrease cholesterol production in liver
  2. Increase production of LDL receptors on cell membrane
  3. Increased uptake of LDL cholesterol, further reducing circulating cholesterol
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2
Q

What are the contraindications of statins?

A

Pregnancy

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3
Q

What are the important drug-drug interactions of statins?

A
  • CYP inducers/inhibitors
  • OATP2 inhibitors - prevents excretion into bile
  • May increase effect of warfarin - increase INR
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4
Q

What are the secondary benefits of statins?

A
  • Anti-inflammatory
  • Cause plaque reduction
  • Improve endothelial cell function
  • Reduce thrombotic risk
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5
Q

Describe the action of cholesterol absorption inhibitors and give an example

A

Ezetimibe

Inhibits cholesterol absorption in small intestine. This causes decreased [cholesterol] in liver which upregulates LDL receptors, causing further decrease in circulating cholesterol

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6
Q

Describe the action of niacin

A
  • Inhibits lipolysis in adipose tissue
  • Reduces production of free fatty acids - decrease in triglyceride synthesis in liver
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7
Q

What is the difference between enteral and paraenteral delivery of drugs?

A

Enteral = drug routes via GI tract

Paraenteral = drug routes not via GI tract

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8
Q

Describe factors affecting systematic entry of a drug

A

Passive factors:

  • Drug lipophilicity
  • Molecular size
  • pH changes

Active factors:

  • Presence of active transport systems
  • Splanchnic blood flow (reduced in HF and shock)
  • Drug destruction by gut
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9
Q

What is bioavailability?

A

Fraction of dose that finds its way into a body compartment

e.g. bioavailability for IV bolus is 100%

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10
Q

Name some factors that affect bioavailability

A
  • Drug formation
  • Age
  • Food (water soluble drugs less likely to be affected by food)
  • Vomiting
  • Malabsorption
  • First pass metabolism
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11
Q

What is oral bioavailability? How is it calculated?

A

Proportion of orally taken drug (or any other route that is not IV) that enters systemic circulation unchanged

Oral bioavailability = [AUC (oral)/AUC (IV)] x 100

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12
Q

What is first pass metabolism? What can affect first pass metabolism?

A
  • Any metabolism that occurs before the drug enters systemic circulation
  • Can occur in gut lumen, gut wall, liver
  • Drugs affecting gut motility and pass/active absorption will affect uptake of original drug
  • Liver disease will affect amount of metabolism of drug in liver
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13
Q

What does drug distribution mean?

A

Ability of a drug to enter different compartments of the body (plasma, ECF, ICF)

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14
Q

What factors can affect drug distribution?

A
  • Lipophilicity
  • Protein binding - reduced entry into tissues
  • Volume of distribution
  • Tissue protein binding - e.g. bind to muscle
  • Tissue mass/volume and binding site density
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15
Q

What is volume of distribution?

A

A hypothetical measure of how widely a drug is distributed in body tissues

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16
Q

When is displacement of drugs from proteins important?

A

If there is:

  1. High protein binding
  2. Low Vd
  3. Narrow therapeutic ratio
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17
Q

What is phase I metabolism?

A

Reactive group on parent molecule exposed or added by oxidation, reduction or hydrolysis reactions

Requires CYP450 enzymes and NADPH (high energy)

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18
Q

Name the CYP450 inducers?

A
  • P = phenytoin
  • C = carbamazepine
  • B = barbituates
  • R = rifampicin
  • A = alcohol (chronic)
  • S = sulphonylureas & St John’s Wort
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19
Q

Name the CYP450 inhibitors

A
  • G = Grapefruit juice
  • O = Omeprazole
  • D = Disulfiram
  • E = Erythromycin
  • V = Valproate
  • I = Isoniazid
  • C = Cimetidine & Ciprofloxacin
  • E = Ethanol (acute)
  • S = Sulphonamides
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20
Q

How are drugs excreted in the kidneys?

A
  • Passive glomerular diffusion
  • Organic anion and cation transporters - active tubular secretion
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21
Q

What factors will affect renal excretory elimination?

A
  • Protein binding
  • Tubular secretion - NSAIDs reduce tubular secretion
  • Urinary pH
  • Renal blood flow
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22
Q

What does phase II metabolism involve? Give the common molecules used

A

Conjugation of reactive intermediate with polar molecule to form water-soluble complex

Glutathione, sulphate ions, glucoronic acid

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23
Q

Define clearance with regards to pharmacodynamics.

A

Volume of plasma that is completely cleared of drug per unit time.

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24
Q

How does the heart affect drug elimination?

A

Reduced organ perfusion (reduced cardiac output or excessive vasodilation)

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25
Q

Which drugs exhibit zero order/non-linear kinetics at therapeutic doses?

A
  • High dose aspirin
  • Phenytoin
  • Verapamil
  • Fluoxetine
  • Alcohol
  • MDMA
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26
Q

What is the difference between first order and zero order kinetics?

A

First order = elimination determined by concentration of drug

Zero order = drug eliminated in set amount per time

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27
Q

What is the action of salbutamol?

A
  • Activates B2-adrenoceptors on bronchial smooth muscle
  • Increases cAMP, increases PKA, sequesters Ca2+ in SR, decreases intracellular calcium
  • Prevents binding of calcium to myosin light chain
  • Causes vasodilation
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28
Q

What is the mechanism of action of inhaled corticosteroids in asthma?

A
  • Binds to intracellular receptors that travel to nucleus
  • Up or down-regulates gene transcription
    • Inhibits pro-inflammatory cytokines from Th2
    • Inhibits phospholipase A2 - blocks arachidonic acid and therefore prostaglandins production
    • Increases B2-adrenoceptor expression
    • Stabilises mast cell membane - decreases histamine
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29
Q

Describe mechanism of action of muscarinic receptor antagonists used in asthma

A
  • Blocks action of M3-adrenoceptor
  • Prevents phospholipase C activated release of Ca2+ from SR
  • Causes bronchodilation
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30
Q

Which patients should antimuscarinics be used in with caution?

A
  • Prostatic hyperplasia
  • Bladder outflow obstruction
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31
Q

Which patients should omeprazole be avoided in?

A
  • Omeprazole is a CYP450 inhibitor - increases concentrations of other drugs
  • Those on warfarin or phenytoin
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32
Q

What is important therpaeutically regarding PPIs?

A
  • PPI action takes 2-3 days for max efficiency
  • Not all pumps active all the time
  • It also takes a few days for restoration of stomach acid, de novo synthesis
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33
Q

Which patients should cimetidine be avoided in?

A

Cimetidine is a CYP450 inhibitor and therefore should be avoided in patients on warfarin or phenytoin

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34
Q

What is the mechanism of action of bulk laxatives?

A

Increase volume of non-absorbable solid residue in gut causing distension and therefore stimulating peristaltic movement

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35
Q

What is the mechanism of action of faecal softeners?

A

Lubricate and soften stool - given as an enema or suppository

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36
Q

What is the mechanism of action of osmotic laxatives?

A

Increase water content of bowel via osmosis

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37
Q

What is the mechanism of action of irritant laxatives?

A

Irritates mucosa causing increase peristalsis and water/electrolyte secretion by mucosa

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38
Q

What is the mechanism of action of anti-motility antidiarrhoeals?

A
  • Act on opioid receptors in bowel reducing motility
  • This increases time for fluid reabsorption
  • It also increases anal tone and decreases sensory defecation reflex
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39
Q

What is the mechanism of action for D2-receptor antagonists used as anti-sickness medication?

A
  • Blocks D2 receptors found in chemoreceptor trigger zone
  • This prevents stimulation of vomiting centre in lateral reticular formation of medulla
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40
Q

What is the mechanism of action of serotonin antagonists?

A
  • Block serotonin receptors in chemoreceptor trigger area
  • Blocks serotonin receptors of vagal sensory fibres stimulated by serotonin released from enterochromaffin cells
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41
Q

What is the mechanism of action of fibrates?

A
  • PPAR agonist (peroxisome proliferator-activated receptors)
  • Increases production of lipoprotein lipase
  • Increases fatty acid uptake and B-oxidation which reduces triglyceride production
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42
Q

What channel do thiazide diuretics inhibit?

A

Na/Cl co-transporter in early DCT

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43
Q

Which channel do loop diuretics block?

A

NaK2Cl co-transporter in thick ascending loop of Henle

44
Q

What channels do aldosterone antagonists act on?

A
  • Na/K-ATPase
  • ENaC
  • ROMK
45
Q

Why should caution be given to prescribing thiazides/loop diuretics and steroids together?

A

Increased risk of hypokalaemia

46
Q

Why should caution be given to prescribing thiazides/loop diuretics and digoxin together?

A

Increased risk of hypokalaemia

47
Q

Describe mode of action of biguanides?

A
  • Insulin sensitisers
  • Increases insulin receptor sensitivity - improves peripheral glucose uptake
  • Reduces hepatic gluconeogenesis
  • Slows intestinal absorption of carbohydrates
48
Q

Describe the mode of action of sulphonylureas

A
  • Block ATP-sensitive K+ channels in B-cells of pancreas
  • Results in depolarisation causing Ca2+ influx and insulin exocytosis
49
Q

What are the important drug-drug interactions of sulphonylureas?

A
  • NSAIDs = reduced GFR = prolong action
  • Warfarin, MAOIs = compete for enzymes
  • Thiazides, glucocorticoids decrease action
50
Q

Which drugs are contraindicated in pregnancy?

A
  • Sulphonylureas
  • Statins
  • Aminoglycosides
  • Streptomycin
  • Warfarin
  • ACE inhibitors
  • Anti-epileptic medication
  • Methotrexate
51
Q

What is the mode of action of glitidines?

A

Same as sulphonylureas but less potent

  • Block ATP-sensitive K channels causing increased release of insulin
52
Q

What is the action of thiazolidinediones?

A

Agonist of PPAR-gamma = regulates transcription of insulin responsive genes causing increased insulin sensitivity in adipose tissue, liver and skeletal muscle

53
Q

What drug classes are the following drugs?

  1. Adenosine
  2. Amiodarone
  3. Atenolol
  4. Amlodipine
  5. Amiloride
A
  1. Adenosine - opens ACh sensitive K+ channels causing hyperpolarisation therefore slowing conduction through AV node
  2. Amiodarone - Blocks K+ channels in cardiac myocyte, slowing repolarisation and extending action potential
  3. Atenolol - B-blocker
  4. Amlodipine - Calcium channel blocker
  5. Amiloride - Diuretic, ENaC channel blocker
54
Q

What is the role of Levodopa?

A

L-DOPA is immediate precursor to dopamine

It is able to penetrate the blood brain barrier and replenish dopamine lost in neostriatum

55
Q

What is usually given in combination with levodopa?

A

A peripheral DOPA decarboxylase inhibitor which reduces peripheral breakdown and the amount needed for therpaeutic response

56
Q

Give an example of a dopamine receptor agonist used in the treatment of Parkinson’s disease

A

Ropinirole

57
Q

What is the problem of long term use of levodopa?

A

Levodopa induced dyskinesias

Loss of efficacy with long term use - on/off fluctuations

58
Q

What are the drug classes that can be used in Parkinson’s disease?

A
  • Levodopa
  • Dopamine receptor agonists
  • Monoamine oxidase inhibitors (MAOIs)
  • Catechol-O-methyl transferase inhbitors
  • Anticholinergics
  • Amantadine
59
Q

What is the mode of action of monoamine oxidase inhibitors?

A
  • Inhibit monoamine oxidase B which is responsible for the breakdown of dopamine in the brain
60
Q

What is the mode of action of catechol-O-methyl transferase inhibitors?

A
  • Blocks action of COMT which degrades dopamine
61
Q

What is the mode of action of amandatine with regards to Parkinson’s disease treatment?

A
  • Stimulates neuronal dopamine release and inhibition of its reuptake
  • REMEMBER: Amantadine is also used as an anti-viral - blocks M2 ion channels preventing acidification of endosome and therefore viral disassembly
62
Q

What are the 3 core symptoms fo depression?

A
  1. Low mood
  2. Anhedonia (lack of enjoyment)
  3. Decreased energy
63
Q

What are the 3 theories surrouding depression?

A

Depression due to:

  1. Deficiency of monoamine neurotransmitters (NA, serotonin, dopamine)
  2. Abnormality in the receptors
  3. Deficiency in molecular functioning - problem post receptor
64
Q

What is the mode of action of SSRIs? Give an example

A
  • Selective serotonin reuptake inhibitors
  • Prevent the reuptake of serotonin into pre-synaptic neurone - therefore increasing concentrations in synaptic cleft
  • Highly selective
  • Fluoxetine, Citalopram, Paroxetine
65
Q

Why must caution be used when prescribing fluoxetine comparted to other SSRIs?

A

Displays zero-order kinetics

66
Q

What are the important drug-drug interactions for SSRIs?

A
  • MAOIs - fatal serotonergic syndrome
67
Q

What is the mode of action of SNRIs?

A
  • Serotonin/noradrenaline reuptake inhibitors
  • Inhibit reuptake of serotonin and noradrenaline thus potentiating activity in CNS
  • Dose dependent - high dose = noradrenaline, low dose = serotonin
68
Q

Was is the therapuetic use of Naloxone and why?

A
  • Reversal of opioid mediated respiratory depression
  • High affinity, competitive antagonist at opioid receptors
69
Q

What is the therapeutic window? How is it calculated?

A
  • Concentration of drug that is high enough to have a therpeutic effect, but not so high that it has a toxic effect
  • Therapeutic index = toxic dose in 50% of people/effective dose in 50% of people
70
Q

Define specificity and selectivity with regards to pharmacodynamics

A
  • Specificity - how specific the drug is for binding to the receptor
  • Selectivity - how selective the drug is for the tissue being targeted
71
Q

Define affinity, efficacy and potency

A
  • Affinity - the ability of a drug to bind to a specific receptor site
    • Calculated using dissociation constant (Kd)
  • Efficacy - Maximum response achievable from a drug
    • Agonist = 100%
    • Antagonist = 0%
  • Potency - Defines overall response seen by the receptor once the ligand has bound
    • Calculated using EC50
72
Q

Describe the difference between on-target and off-target ADRs

A
  • On-target = Exaggerated therapeutic effect of drug, usually by increased dosing
  • Off-target = interactions with other receptors types secondarily to the one intended for therpeutic effect
73
Q

What is the action of warfarin?

A
  • Block vitamin K’s reduction to its active form
  • Vitamin K required as cofactor in the synthesis of factors II, VII, IX, X
74
Q

What is the mechanism of action of azathioprine?

A
  • Metabolised to meracaptopurine (liver)
  • Inhibition of purine synthesis therefore inhibition of DNA synthesis
  • Selective for cells with higher mitotic rate
75
Q

What is the mechanism of action of mycophenolate mofetil?

A
  • Pro-drug converted into mycophenolic acid
  • Inhibits inosine monophosphate dehydrogenase required for guanince synthesis
  • Highly selective for B and T cells as they synthesise guanine de novo and other cells have guanine salvage pathways
76
Q

What is the mechanism of action of cyclophosphamides?

A
  • Creates crosslinks between DNA therefore inhibiting DNA replication
  • Selective for cells with high mitotic rate
77
Q

What is the mode of action for calcineurin inhibitors?

A
  • Binds to cytosolic proteins which inhibits calcineurin
    • Cyclosporin - cyclophilin protein
    • Tacrolimus - tacrolimus binding protein
  • Inhibits IL-2 gene and therefore production
  • Inhibits clonal proliferation of T lymphocytes
78
Q

What is the mode of action of glucocorticoids as an immunosupressant

A
  • Binds to intracellular receptors, taken to nucleus
  • Acts as gene transcription factor
  • Inhibits pro-inflammatory cytokines from Th2 and proliferation
  • Inhibits phospholipase A2 preventing synthesis of prostaglandins
79
Q

What is the mechanism of action of methotrexate?

A
  • Competively antagonises dihydrogolate reductase
  • Prevents regeneration of intermediates required for purine and thymidine synthesis
  • Therefore inhibits DNA synthesis
80
Q

Describe the mechanism of action of aminosalicylates

A
  • Drug carried to colon where it is cleaved by bacteria
  • Releases 5-aminosalicylate acid
  • Mechanism unclear - ?scavenges ROS produced by neutrophils
81
Q

What is the mechanism of action of anti-TNF agents

A
  • Monoclonal antibodies against TNF-alpha
  • Inhibits pro-inflammatory effects of TNF-alpha
82
Q

What is MIC with regards to antimicrobials?

A
  • The minimum concentration of antibiotic required to prevent visible growth of microorganism on a culture plate left over night
83
Q

What is the mechanism of action of amantadine?

A
  • M2 channel blocker
  • Prevents acidification of endosome carrying virus
  • This prevents breakdown of viral coat anf release of viral RNA into host cell
84
Q

What is the mechanism of action of of neurominadase inhibitors?

A
  • Inhibit neurominidase enzyme which prevents cleaving of newly formed virus from membrane
85
Q

What is the mechanism of action of beta-lactam antibiotics?

A

Inhibit bacterial peptidoglycan cell wall synthesis

86
Q

What is the mechanism of action of glycopeptides? Give an example

A
  • Inhibit bacterial peptidoglycan cell wall synthesis
  • Vancomycin
87
Q

What is the mechanism of action of tetracyclines?

A

Inhibit bacterial protein synthesis

88
Q

What is the mechanism of action of aminoglycosides? Give an example, what is an important ADR?

A
  • Inhibit bacterial protein synthesis
  • Gentamicin
  • Ototoxicity - destruction of sensory cells in cochlea and vestibular organ
  • Nephrotoxitiy - damage to kidney tubules
89
Q

What is the mechanism of action of macrolides? Give an example

A
  • Inhibit protein synthesis by effect on ribosomal translocation
  • Erythromycin
90
Q

What is the mechanism of action of sulphonamides?

A
  • Competitive binding of enzyme required for folic acid synthesis
91
Q

What is the mechanism of action of trimethoprim?

A
  • Inhibits dihydrofolate reductase - enzyme required for folic acid synthesis
  • Inhibits production of purines
92
Q

What is the mechanism of action of quinolones? Give an example

A
  • Inhibits topoisomerase II (DNA gyrase)
  • Prevents transcription of bacterial DNA
  • Ciprofloxacin
93
Q

What are the 4 classes of drugs used in cancer therapy?

A
  • Antimetabolites - methotrexate, 5-flurouracil
  • Alkylating agents - cyclophosphamide, cisplastin
  • Intercalating agents - doxorubicin, danunorubucin
  • Spindle poisons - vincristine, vinblastine
94
Q

What is the mechanism of action of intercalating agents used in cancer therapy?

A
  • Intercalation of drug between base pairs of DNA
  • Therefore inhibit DNA and RNA synthesis
95
Q

What is the mechanism of action of spindle poisons

A
  • Either promote assembly but prevent diassembly
  • Or prevent spindle formation altogether
96
Q

What is the mode of action of voltage-gated sodium channel blockers used in epilepsy?

A
  • Blocks voltage-gated sodium channels, preventing spread of depolarisation and release of neurotransmitters
  • They prolong the inactivation state
  • Only access site when channel becomes depolarised
  • Detach from binding site when membrane potential back to normal
97
Q

What is the mechanism of action of sodium valproate?

A
  • Weak inhibition of GABA inactivation enzymes therefore increases GABA
  • Weak stimulus of GABA synthesising enzymes
  • Weak VGSC blocker and weak Ca2+ blocker
98
Q

What is the mechanism of action of benzodiazepines?

A
  • Act on distinct receptor site on GABA chloride channel - hyperpolarisation
  • GABA or benzodiazepine enchance eather others binding - positive allosteric effectors
99
Q

What is the mechanism of action of heparin? What is the difference between unfractionated and low molecular weight heparin?

A
  • Activates antithrombin III
  • Which forms a complex with thrombin (factor IIa) which prevents further coagulation
  • Heparin increases rate of formation 1000-fold
  • Both inhibit factor Xa, but unfractionated also acts at factor IIa
  • Also LMW has a longer half life
100
Q

How do you monitor warfarin and unfractionated heparin

A
  • Warfarin - INR - extrinsic pathway
  • Heparin - aPTT - intrinsic pathway
101
Q

What is the mechanism of action of aspirin

A
  • Inhibits COX-1 enzyme
  • Prevents formation of thromboxane A2 (+ phospholipase C = increase [Ca2+] causing platelet aggregation)
  • Prevents aggregation of platelets
102
Q

What is the mechanism of action of dipyridamole?

A
  • Inhibits phosphodiesterase enzymes
  • Prevents cAMP = prevents increased [Ca2+]i =prevents platelet aggregation
103
Q

What is the mechanism of action of clopidogrel?

A
  • ADP antagonists
  • Prevents ADP-ADP receptor interaction
  • Prevents platelet aggregation
104
Q

What can be used for the reversal of warfarin and heparin?

A
  • Warfarin - vitamin K, fresh frozen plasma
  • Heparin - protamine sulphate
105
Q

What are the 5 classes of drugs that commonly contribute to drug-drug interactions

A
  1. Anticonvulsants - phenytoin, carbamazapine
  2. Anticoagulants - warfarin
  3. Antidepressants - MAOi
  4. Antibiotics - quinolones, macrolides, rifampicin
  5. Antiarrhythmics - amiodarone
106
Q
A

PPE Revision (16 decks)

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