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ESA 5 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Describe Reason’s Model of Error Causation

A
  1. Latent Conditions
    • Overworked and busy doctors
    • Interruptions during routine tasks
  2. Error-producing Conditions
    • Work environment
  3. Active Failures
    • Slips = attention-based
    • Lapses = memory-based
    • Mistakes = absence of knowledge of protocol
    • Violation = intentionally going against protocol
  4. Defences (Swiss Cheese Model)
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2
Q

Describe some patient-related, doctor-related and pharmaceutical-related problems associated with prescriptions errors

A
  • More rapid throughput of patients
  • Increasing complexity of medical care
    • Multiple morbisities/drugs
  • Level of teaching/examination from medical school
  • Sleep deprived on-call doctors
  • Vast numbers of new drugs
  • Blind adherence to guidelines can lead to dangerous drug interactions
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3
Q

List some factors that influence drug inclusions in local formularies

A
  • Efficacy - how effective it is compared with other drugs or placebo
  • Safety - major and minor side effects
  • Cost
    • Only if safety and efficacy of other options are equivalent
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4
Q

List some examples of modern day formularies

A
  • Is the patient allergic to anything?
  • WIll patient’s illness affect drug distribution/elimination?
  • Are there any alternatives?
  • Is the route of administration appropriate?
  • Correct dose, frequency and timing?
  • Consider any serious side effects
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5
Q

Describe some good practice requirements when prescribing medication

A
  • Write approved drug name
  • Route of administration
  • Dose and/or strength
  • Units in full
  • Frequency
  • Any additional instructions
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6
Q

List the main routes of drug administration into the body

A

Enteral (via GI tract):

  • Oral
  • Sub-lingual
  • Rectal

Parenteral:

  • Intravenous
  • Subcutaneous
  • Transdermal
  • Intramuscular
  • Intrathecal
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7
Q

Describe an overview of the pharmacokinetics process

A
  • Administration
  • Distribution = ability of a drug to ‘dissolve’ in the body
  • Metabolism
  • Elimination
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8
Q

Describe the factors affecting drug absorption

A
  • Rate of uptake
  • First pass metabolism = metabolism of a drug before it enters the systemic circulation
    • By gut lumen (gastric acid) gut wall (proteolytic enzymes) and liver
  • Lipophilicity = ability to dissolve in fats
  • Presence of active transport systems
  • Splanchnic blood flow
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9
Q

What is bioavailability? What factors affect it?

A

The fraction of a dose which finds its way into a body compartment (usually the circulation) compared to the total amount of drug administered

  • Calculated by looking at the total area under the curve of plasma concentration over time
  • Affected by drug formulation, age, malabsorption, first pass metabolism
  • Oral bioavailability = AUC(oral) / AUC(IV)
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10
Q

Describe the factors affecting drug distribution

A
  • Lipophilicity
  • Binding ability to plasma proteins (albumin)
    • High binding reduces entry into tissues and reduces free concentration of drug
  • Binding ability to tissue proteins (muscle)
    • Decreases plasms concentration
  • Mass/volume of tissue
  • Diseased state - hypoalbuminaemia, renal failure, pregnancy
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11
Q

What is the volume of distribution? Why is Vd relevant?

A

How widely a drug is distributed in body tissues

Vd = dose / plasma concentration at t=0

  • A high Vd = high 1/2 life = longer clearance
  • Low lipophilicity = high Vd
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12
Q

Why are protein binding drug interactions important clinically?

A
  • If drug has high protein binding normally = increased free concentration
  • Low Vd
  • Narrow therapeutic window
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13
Q

Describe the overall process of drug metabolism and how this process may be inhibited or enhanced

A
  • Phase I - oxidation/hydrolysis/reduction in the liver by cytochrome P450 enzymes
    • Inhibited by anti-fungals, cimetidine, macrolides, grapefruit juice
    • Induced by carbamazepine, rifampicin, St John’s Wort
  • Phase II - conjugation to become water soluble and enable rapid elimination from the body
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14
Q

Describe some factors that affect drug metabolism

A
  • Sex
  • Age
  • Liver disease
  • Hepatic blood flow
  • Cigarette/alcohol consumption
  • Enzyme inducing/inhbiting drugs
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15
Q

How does the body elminate drugs?

A

Mainly via the kidney

  • Glomerular filtration (unbound drugs)
  • Passive tubular reabsorption (aspirin)
  • Active tubular secretion (penicillin)
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16
Q

What is clearance? How is it related to 1/2 life?

A

The ability of the body to excrete drugs

  • Comprised mostly from GFR
  • Low clearance = high 1/2 life
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17
Q

List some factors that affect excretion of drugs

A
  • Renal blood flow
  • Plasma protein binding
  • Tubular urinary pH
  • Renal disease
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18
Q

How are steady state therapeutic levels reached in plasms?

A
  • 5 half lives are required to reach a steady state
  • Loading doses achieves rapid therapeutic effect
    • Eg. DIgoxin half life is 40 hours so a loading dose is administered in an emergency
  • Maintenance doses keep drug plasma concentration in the therapeutic window
    • Need reducing if renal failure leads to reduced clearance
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19
Q

Describe an overview of paracetemol metabolism and how this becomes saturated during an overdose

A
  • Paracetemol can be metabolised into glucuronide, sulfates and inactive metabolites (via glutathione)
  • During an overdose, these pathways become easily saturated
  • Therefore, NAPQI (intermediate molecules) levels accumulate due to a lack of glutathione
  • NAPQI is toxic to the liver
  • Treat with N-acetylcysteine to increase glutathione levels
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20
Q

Define affinity. How is it measured?

A

The tendency of a drug to bind to a specific receptor type

  • Measured by Kd - concentration at which half the available receptors are bound
    • Low value = high affinity
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21
Q

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

A
  • First order - a constant proportion of drug is eliminated over time
    • Proportional to the amount of drug in the body
  • Zero order - a constant concentration of drug is eliminated over time
    • Ethanol, phenytoin, aspirin
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22
Q

Define efficacy, How is it measured?

A

The ability to produce a response/activate a receptor once bound to it.

  • Expressed in % terms of maximum response
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23
Q

Define potency. How is it measured?

A

The dose required to produce the desired response

  • Measured using EC50 = concentration of drug that produces 50% maximal response
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24
Q

Describe the difference between competitive and non-competitive antagonists

A
  • Competitive = binding of the antagonist at the same site as the agonist
    • Agonist efficacy restored by increasing agonist concentration
    • Different EC50 (increasing concentration)
  • Non competitive = binding at a different site to the agonist
    • Reversible or irreversible
    • Same EC50 (same concentration)
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25
Q

What is the therapeutic window?

A

The concentration range over which drugs exert a clinically useful effect, without exerting significant toxic effects

= TD50 (toxic conc) / EC50 (min conc)

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26
Q

Describe some drug-disease interactions

A
  • Renal disease - reduced clearance of renally excreted drugs (digoxin, aminoglycosides)
    • Disturbances to electrolytes - predisposes to toxicity
  • Hepatic disease - reduced clearance of hepatic metabolised drugs
    • Reduced CYP450 activity
    • Longer half lives = toxicity
  • Cardiac disease = reduced organ perfusion = reduced renal/hepatic blood flow
    • Excessive response to hypotensive agents
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27
Q

Describe some drug-food interactions

A
  • Grapefruit juice - inhibits CYP450 isoenzymes
    • Decrease clearance of simvastatin, amiodarone
    • Increase exposure to drug
  • Cranberry juice - inhibits CYP2C9 isoenzyme
    • Decrease clearance of warfarin = increased anticoagulant effect = increased risk of haemorrhage
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28
Q

What is an adverse drug reaction?

A

Unwanted/harmful reaction which occurs after administration of a drug and is suspected to be due to the drug

  • On target ADR = exaggerated therapeutic effect mainly due to an increased dosing
    • Same receptor in different tissues
  • Off target = interaction of drugs with other receptor types not intended for therapeutic effect
    • Also metabolites that act as a toxin
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29
Q

What are the main causes of adverse drug reactions?

A
  • Polypharmacy
  • Multi-morbidity
  • Ignorant, inappropriate or reckless prescribing
  • Extremes of age
    • Altered renal and hepatic functions
  • Drugs with narrow therapeutic windows
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30
Q

Which drugs are most likely to cause adverse drug reactions?

A
  • Anticonvulsants
  • Antibiotics
  • Anticoagulants
  • Antidepressants
  • Antiarrhythmias
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31
Q

List some reasons for variability in drug response

A
  • Body weight/size
  • Age Sex
  • Genetics
  • General condition of health
  • Dose/formulation/route of drug
  • Resistance to drugs
  • Drug interactions
    • Protein binding
    • GI absorption
    • Metabolism
    • Changes in pH/electrolytes
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32
Q

Describe some drug-drug interactions during the metabolism phase of pharmacokinetics

A

Induction of CYP450: Increased transcription, translation or slower degradation

  • Decreased half life and increased clearance
  • Dosing will have to be increased

Inhibition of CYP450:

  • Increased half life and decreased clearance
  • If dose is not decreased, this leads to toxic concentrations
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33
Q

Describe some drug-drug interactions during the absorption phase of pharmacokinetics

A

Co-administration with drugs that affect gut motility and absorption by the gut will interfere with absorption.

Eg: increased rate of gastric emptying will increase the rate of uptake via the small bowel

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34
Q

Describe some drug-drug interactions during the dsitribution phase of pharmacokinetics

A

Affected by competition of drugs at protein/lipid binding sites

  • If drug has non-linear kinetics or a small therapetuic window, this can lead to toxicity
  • WIth linear kinetics, this is avoided by increasing clearance
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35
Q

Describe some drug-drug interactions during the excretion phase of pharmacokinetics

A
  • Decreased protein binding - increases free unbound drug and accelerates its removal
  • Inhibition of tubular secretion - increased plasma levels of the drug
    • NSAIDs
    • Can be used for therapeutic benefit (penicillin)
  • Changes in urine flow/pH
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36
Q

Describe the hormonal regulation of the female reproductive cycle

A
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37
Q

How are sex steroids made in the body?

A
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38
Q

List some common side effects of increased oestrogen and progesterone

A

Oestrogen:

  • Breast tenderness
  • Nausea/vomiting
  • Thromboembolism
  • Endometrial cancer

Progesterone:

  • Depression
  • Acne
  • Weight gain
  • Irritability
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39
Q

Describe the mechanism of action of COCP

A
  • Progesterone suppresses ovulation by inhibiting LH/FSH via negative feedback on hypothalamus and reduced GnRH
  • Progesterone stops fertilisation by thickening cervical mucous and thinning the endometrium
  • Negative feedback from oestrogen also inhibits LH/FSH on the anterior pituitary
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40
Q

Describe the adverse drug effects of the COCP

A
  • Venous thromboembolism
  • Myocardial infarction
  • Hypertension
  • Stroke in focal migraines
  • Headaches
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41
Q

Describe some drug interactions of COCPs

A

Metabolised by cytochrome P450 in the liver

  • Efficacy reduced by enzyme-inducing drugs
    • Phenytoin
    • St John’s Wort
    • Rifampicin
  • Efficacy increased by enzyme-inhibiting drugs
    • Grapefruit juice
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42
Q

Describe the mechanism of Progesterone-Only Pill

A
  • Thicken cervical mucous
  • Thin endometrium
    • Cannot support implantation
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43
Q

Why are POPs used instead of COCPs?

A
  • Focal migraines
  • Risk of DVT
  • Risk of heart disease
  • Sickle cell disease
  • Breastfeeding women
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44
Q

Name some side effects of POPs

A
  • Irregular menstruation
  • Heavy menstruation
  • Mood swings
  • Weight gain
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45
Q

What are the benefits are risks of hormonal replacement therapy?

A

Benefits:

  • Relieves symptoms
  • Reduces osteoporosis

Risks:

  • Endometrial/ovarian/breast cancer due to unopposed oestrogens
  • Ischaemic heart disease
  • Stroke
  • Venous thromboembolism
  • Further bleeding every month
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46
Q

Name some inhibitors/antagonists of sex steroids and their functions

A
  • Anti-oestrogen (block receptors)
    • Clomiphene = ovulation induction by increasing GnRH/LH/FSH by inhibiting oestrogen
    • Tamoxifen = ovulation induction/breast cancer treatment
  • Anti-progesterone (partial agonist to progesterone receptors which inhibit progesterone action)
    • Mifepristone = termination of pregnancy/induction of labour
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47
Q

Describe the pathophysiology of atherosclerosis

A
  • Damage occurs to endothelial wall (smoking etc)
  • LDLs invade endothelium and become oxidised
  • Inflammatory response to damage recruits macrophages
  • Macrophages ingest oxidised LDL
    • Become foam cells
  • Aggregation of platelets
  • Migration and proliferation of smooth muscle cells
    • Also become foam cells
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48
Q

Name the normal values of total cholesterol, fasting LDL and HDL in mmol/L

A
  • TC = 5
  • LDL < 3
  • HDL > 1.2
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49
Q

Describe some ways to lower blood lipid levels

A
  • Lifestyle - exercise, diet, reduce alcohol intake, smoking
  • Lipid lowering drugs
    • Statins
    • Fibrates
    • Nicotinic acids (niacin)
    • Cholesterol lipase inhibitor
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50
Q

Describe the mode of action of statins

A

Inhibits cholesterol synthesis in the liver by inhibiting HMG-CoA reductase in the pathway from acetyl CoA → cholesterol

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51
Q

Describe the variability in pharmacokinetics of some statins

A
  • Extensive first pass uptake in the liver
  • Intestinal absorption varies between 30-85%
  • Some statins require activation
  • Some statins eliminated via CYP3A4 enzymes
  • Difference in half lives (simvastatin is 1-4 hours and atorvastatin is 20 hours) affects dosing times
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52
Q

Name some adverse effects of the use of statins

A
  • Chronic liver disease
    • Increased transaminase levels
  • Myopathy
  • Arthralgias
  • GI complaints
  • Headaches
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53
Q

Describe some drug interactions of statins

A
  • Affected by CYP enzymes
    • Inhibitors increase risk of myopathy due to increased statin levels
      • Graprefruit juice
      • Verapamil
    • Inducers decrease efficacy
      • Rifampicin
      • St John’s Wort
  • OATP2 (organic anion transport polypeptide) inhibitors decrease efficacy
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54
Q

Describe the mechanism of, indication for, contraindications and side effects of fibrates

A
  • PPARalpha agonist - increases production of lipoprotein lipase
    • Reduces triglyceride production
    • Increases fatty acid uptake and oxidation
  • Used in hypertriglyceridaemia / hyperlipidaemia
  • Not used in hepatic / renal / gallbladder disease
  • Side effects include GI complaints, gall stones and myositis
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55
Q

Describe the mechanism of, contraindications and side effects of nicotinic acids (niacin)

A
  • Reduces VLDL and increases HDL
  • Inhibits synthesis of Lipoprotein A
  • Not used liver disease or peptic ulcers
  • Side effects include hepatotoxicity, flushing, hyperglycaemia, activation of peptic ulcers
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56
Q

Describe the mechanism of, indication for and side effects of cholesterol lipase inhibitors (ezetimibe)

A
  • Selectively inhibits intestinal cholesterol absorption
    • Decreases delivery of cholesterol to liver
    • Increases expression of hepatic LDL receptors
    • Decreases cholesterol content of atherogenic particles
  • Used in statin intolerant patients or to reduce risk of statin ADRs
  • Side effects include headache, abdominal pain, diarrhoea
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57
Q

Why does blood glucose rise in diabetics?

A
  • Inability to produce insulin due to betal cell failure
  • Adequate insulin production with insulin resistance
    • High correlation with obesity/liver fat content
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58
Q

Describe the mechanism of, indications for, contraindicated and side effects of biguanides (metformin)

A
  • Decreases insulin resistance and hepatic glucose production
  • Enhances skeletal and adipose glucose uptake
  • Inhibits hepatic gluconeogenesis
  • First agent of choice - does not induce hypoglycaemia
  • Contraindicated in renal, cardiac and hepatic disease
    • Increase T1/2 and decrease clearance
  • Side effects include GI disturbances, lactic acidosis, vitamin B12 deficiency
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59
Q

Describe the mechanism of, side effects of and contraindications of thiazolineinediones (glitazones)

A
  • Binds to PPAR-ŷ to upregulate insulin signalling genes
    • Increases insulin sensitivity in muscle and adipose
    • Reduction of gluconeogenesis
  • Side effects:
    • CVS concerns
    • Weight gain
    • Fluid retention
    • Bladder cancer
  • Contraindicated in heart failure
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60
Q

Describe the mechanism of, indications for, contraindicated and side effects of sulphonylureas (tolbutamide/glibenclamide)

A
  • Antagonises B-cell K+/ATP channel activity → depolarisation due to decreased K+ current → increases Ca2+ → increased release of insulin from vesicles
  • Indicated in renal, cardiac and hepatic disease, children or in combination with metformin when HbA1c levels > 7%
  • Side effects include hypoglycaemia, GI disturbances, weight gain
  • Contraindicated in elderly (hypoglycaemia) and obese patients
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61
Q

Describe the mechanism of and side effects of a-glucosidase inhitors (acarbose)

A
  • Inhibits breakdown of carbohydrates to glucose by blocking a-glucosidase
  • ADRs:
    • Flatulence
    • Loose stools
    • Diarrhoea
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62
Q

Describe some incretin-based therapies and their mechanism of action

A
  • DPP-4 inhibitors/GLP1 agonists (injection)
  • Increases GLP1 from intestinal L cells
  • Increases insulin secretion and biosynthesis
  • Increases glucose uptake
  • Used with another hypoglycaemic drug if risk of hypoglycaemia or intolerance to sulphonylurea
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63
Q

What is the function of insulin?

A
  • Stimulates uptake of glucose into liver, muscle and adipose tissue
  • Decreases hepatic glucose output by decreasing gluconeogenesis
  • Inhibits glycogenolysis
  • Promotes uptake of fats
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64
Q

Describe the steps used in Type II Diabetes combination therapy

A
  1. Lifestyle changes - diet, exercise, alcohol, smoking
  2. Hypoglycaemic drugs - metformin
    • Add sulphonylurea if HbA1c > 7%
    • Add TZD (PPAR-y agonist) if HbA1c > 7.5% or continue onto insulin
  3. Exogenous insulin if HbA1c > 7.5%
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65
Q

Describe the different types of exogenous insulin

A
  • Short acting
    • Works within 30-60 minutes with 8-10 hour duration
    • Several times a day to cover meals
  • Rapid acting
    • Works within 5-15 minutes with 4-6 hour duration
    • Just before eating - better for children
  • Intermediate acting
    • Works within 1.5-3 hours with 16-24 hour duration
    • Used as basal insulin/overnight control
  • Long acting
    • Works within 2-6 hours with 18-36 hour duration
    • Basal insulin/overnight control (high half life)
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66
Q

List the adverse effects of insulin injections

A
  • Hypoglycaemia
  • Hyperglycaemia
  • Lipodystrophy
    • Reproduction of adipocytes leads to scar tissue
  • Painful injections
  • Allergy
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67
Q

Describe the clinical and self-monitoring of diabetics

A
  • Normal blood glucose of 3.5-6.5 mmol/L
    • Regular monitoring to determine inssulin dosing levels
    • Dietary control is needed
  • Glucose non-enzymatically glycosylates haemoglobin - HbA1c
    • > 7% indicated vascular risk
  • Monitor renal, hepatic, cardiovascular and neurological funtion to detect microvascular disease
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68
Q

Describe some anti-obesity drugs

A
  • Orlistat - gastric and pancreatic lipase inhibitor
    • Reduces fat conversaion to fatty acids and glycerol
    • Causes soft fatty stool and flatus
  • Sibutramine - noradrenaline and serotonin re-uptake inhibitor
    • Appetite suppression
    • Increased thermogenesis due to increased metabolism
    • Causes increased heart rate and BP - not ideal in obese diabetics
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69
Q

What is pharmacovigilance?

A

The process of identifying and responding to safety issues about marketed drugs. It helps to survery safety of drugs and develop strategies to minimise risk and optimise benefits

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70
Q

What are the aims of pharmacovigilance?

A
  • Identify unrecognised drug safety hazards and quantify their frequencies
  • Elucidate those factors predisposing to toxicity
  • Obtain evidence of safety so that a new drug’s uses may be widened
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71
Q

What are the different types of ADR?

A
  • Type A = exaggerated pharmacological response
    • Predictable
    • Common
    • Low mortality
  • Type B = no expected from known pharmacology
    • Unpredictable
    • Rare
    • Higher mortality
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72
Q

List some ways of identifying ADRs

A
  • Spontaneous reporting = presentation due to recognition of a possible ADR
    • Establishing possible causal relationship
  • Cohort studies = identify exposed (drug) patients and observe to determine rate of occurrence of ADRs
    • Compare to controls
  • Case-control strudies = select cases with ADR and compare exposure to risk factor/drug
    • Compare to controls without ADR/disease
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73
Q

What are the advantages and limitations of spontaneous reporting?

A

Advantages:

  • Involves all doctors
  • Occurs as soon as drug is marketed
  • Detects common and rare reactions
  • Cheap

Limitations:

  • Under-reporting
  • Delays in reporting
  • No control group
  • Misleading reports
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74
Q

What are the advantages and limitations of case-control studies?

A

Advantages:

  • Good for rare ADRs
  • Relatively low cost
  • Indicate degree of risk (odds ratio)

Limitations:

  • Needs prior hypothesis
  • Many biases
  • Suitable database may not be available
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75
Q

List some reasons for underreporting ADRs

A
  • Failure of patient to report
  • ADR is too trivial
  • Ignorance of reporting protocols
  • Lack of time
  • Uncertainty of relationship of the drug to the presentation
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76
Q

Describe the steps of viral replication

A
  1. Haemagglutinin fuses with viral envelope and vacuole’s membrane
  2. M2 ion channel allows protons to move through viral envelope and acidify the core which dissembles the virus and release vRNA into cytoplasm
  3. vRNA forms a complex with viral proteins to transport into the cell’s nucleus
  4. RNA polymerase transcribes vRNA into mRNA
  5. mRNA enters cytoplasm and is translated into viral proteins
  6. Viral proteins and RNA assemble and bud off the plasma membrane by exocytosis
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77
Q

Classify the influenza virus. What are the main classes of influenza virus?

A

SIngle-stranded RNA virus

  • Influenza A
    • Multiple hosts
    • Higher mortality
    • Antigenic shift and drift causes constantly mutating virus
  • Influenza B
    • Only humans
    • Lower mortality
  • Influenza C
    • Mainly humans
    • Common cold-like symptoms
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78
Q

How do amantadines work? Which type of influenza are they used on?

A

M2 ion channel inhibitors

  • No movement of protons into virus
  • No acidifcation or dissembling of viral coat so RNA cannot leave

Influenza A only - high levels of signle-point mutation in M2 gene causes rapid resistance emergence

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79
Q

What are the main ADRs associated with M2 channel inhibitors? Which type displays less ADRs?

A
  • CNS
    • Dizziness
    • Anziety
    • Insomnia
    • Hallucination
  • GI disturbance
  • Hypotension

Rimantidine displays less ADRs than amantadine

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80
Q

How do neuraminidase inhibitors work? Which type of influenza are these used on?

A

Oseltamivir/zanamivir

Prevents new viral particles from esacaping the host cell

  • Blocks neuraminidase action
  • So no cleavage of bond with sialic acid membrane glycoprotein residues

Used on influenza A and B

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81
Q

What are the main ADRs of neuraminidase inhibitors?

A
  • GI disturbance
  • Cough
  • Headache
  • Nose bleed
  • Respiratory depression
  • Allergy
  • Liver inflammation
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82
Q

Explain how clinical trial results of neuraminidase inhibitors have informed dosing strategy

A
  • 75 mg : 100 mg showed no difference in outcome
  • Earlier treatment started the shorter the duration of symptoms
  • Oseltamivir could reduce mortality by up to 70% even when dosing as long as after 64 hours
  • Treatment for 6 weeks with 75 mg significantly reduced incidence of flu
    • Prophylaxis
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83
Q

Name some antibiotics that target DNA synthesis and briefly outline their mechanism of action

A
  • Quinolones = prevent bacterial DNA from unwinding and duplicating via topoisomerase ligase
    • Ciproflaxacin
  • Folic acid antagonists = inhibit dihydrofolate reductase to stop cofactor (folic acid) in nucleotide synthesis
    • Trimethoprim
    • Sulphonamides
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84
Q

Name some antibiotics that target protein synthesis and briefly outline their mechanism of action

A
  • Aminoglycosides = binds to 30s subunit of ribosomes
    • Gentamicin
  • Macrolides = prevents peptidyltransferases from attaching tRNA to the next amino acid (binds to P side on 50s subunit)
    • Erythromicin
  • Tetracyclines = blocks attachment of amino-acyl-tRNA to A site on the 30s subunit
    • Doxycyclin
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85
Q

Name some antibiotics that target cell wall synthesis and briefly outline their mechanism of action

A
  • Beta-lactams
    • Penicillin
    • Cephalosporin
    • Carbapenems
  • Glycopeptides = inhibit peptidoglycan synthesis
    • Vancomycin
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86
Q

List some common adverse effects of antibiotics

A
  • Hypersensitivity
  • GI disturbance
  • Renal/hepatic toxicity
  • C. difficile infections
  • CNS toxicity
    *
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87
Q

Why is drug monitoring of antibiotics important? How is this carried out?

A

Ensures adequate but non-toxic dose of antibiotic is administered

  • Markers - FBC, creatine kinase, renal function, stool samples
  • Especially important in aminoglycosides (kidney and vestibulocochlear damage) and vancomycin and any IV antibiotics
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88
Q

Describe the pharmacodynamics of antibiotics

A
  • Time dependent killing = prolonged antibiotic presence at site of infection
    • Not high concentration
    • Fusion over long periods
    • Penicillins, cephalosporins, glycopeptides
  • Concentration dependent killing = high antibiotic conentrations at site of infection
    • Not for long periods of time due to risk of toxicity
    • Aminoglycosides, quinolones
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89
Q

How do you measure antibacterial activity?

A
  • Disc sensitivity testing
  • E tests - find out minimum inhibitory concentration
    • Breakpoint predicts likely response
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90
Q

Briefly describe the biochemical mechanisms of antibiotic resistance

A
  • Drug inactivating enzymes
    • B-lactamases
    • Aminoglycoside enzymes
  • Altered target = target enzyme has lower affinity for antibacterials
  • Altered uptake
    • Decrease permeability (b-lactams)
    • Increase efflux (tetracyclines)
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91
Q

Describe main genetic mechanisms underlying antimicrobial resistance

A
  • Chromosomal mutation
    • Random gene mutation for resistance
    • Non-resistant cells die off
    • Resistant cell replicates and creates a new resistant colony
  • Horizontal gene transfer
    • Conjugation - plasmid transferred through pilus
    • Transduction - gene transferred via a vector (bacteriophage)
    • Transformation - free DNA passes through cell wall
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92
Q

List the main steps to avoid the spread of antibiotic resistance

A
  • Esnure adherence to full course of antibiotics
  • Appropriate antibiotic and dose
    • Follow clinical guidelines
  • Stewardship interventions
    • Persuasive - education/reminders/feedback
    • Restrictive - authorisation/stop orders
    • Structural - expert systems/quality monitoring
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93
Q

Describe the factors governing antibiotic choice

A
  • Patient factors
    • Severity of illness
    • Age
    • Co-morbidity
  • Pathogen factors
    • Resistance patterns
    • Virulence (degree of pathogenicity)
    • Antibiotic sensitivity
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94
Q

Name the 3 stages of antimicrobial resistance

A
  • Multi-drug resistant = non-susceptibility to at least 1 agent in 3 antimicrobial categories
  • Extensively-drug resistant = non susceptibility to at least 1 agent in all but 2 or fewer antimicrobial categories
  • Pan-drug resistant = non-susceptibility to all agents in all antimicrobial categories
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95
Q

What is rheumatoid arthritis? How is it treated?

A

Inflammatory change and proliferation of synovium leading to dissolution of cartilage and bone

  • Over expression of pro-inflammatory factors (IL-1, IL-6, TNF-a)
  • Treated with regular exercise, DMARDS (methotrexate, sulfasalazine, rituximab) NSAIDs
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96
Q

What are the signs/symptoms of RA?

A
  • Morning stiffness > 1 hour
  • Arthritis of > 3 joints in 1 hand
  • Serum rheumatoid factor
  • X-ray changes/nodules
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97
Q

What is systemic lupus erythematosus? How is it treated?

A

Autoimmune attack of various tissues in the body including:

  • Pericardium and pleura - inflammation
  • Mouth and nose - ulcers
  • Muscles - aches
  • Face - butterfly rash
  • Joints - arthritis

Associated with defects in apoptosis

Treated with corticosteroids (prednisolone) DMARDs, NSAIDs

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98
Q

What is vasculitis? What are the signs/symptoms? Treatment included

A

Autoimmune attack on blood vessels primarily caused by leukocyte migration. Signs/symptoms:

  • Fever
  • Headache
  • Weight loss
  • Visual loss
  • Purpura on skin
  • Hypertension
  • Myalgia/arthralgia

Treat with corticosteroids (predisone) cyclophosphamide

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99
Q

What are the main therapeutic goals of immunosuppressants and DMARDS?

A
  • Symptomatic relief
  • Prevention of organ damage
  • Reduction in mortality
  • Reduction in morbidity by drugs
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100
Q

What are the main treatment options for rheumatological disorders?

A
  • DMARDS
    • Methotrexate
    • Sulfasalazine (sulfapyridine)
    • Azathioprine
    • Cyclosporine
    • Calcineurin inhibitors (ciclosporin/tacrolimus)
  • Anti-TNF
    • Infliximab / rituximab
  • Immunosuppressants
    • Corticosteroids
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101
Q

What is the mechanism of action of corticosteroids?

A
  • Prevents production of interleukin-1 and 6 by macrophages
  • Inhibits all stages of T-cell activation by inhibiting gene expression in the nucleus
  • Anti-inflammatory
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102
Q

List some adverse effects of corticosteroids

A
  • Weight gain
  • Striae
  • Osteoporosis
  • Hypoglycaemia
  • Risk of infection
  • Cataracts
  • Delayed wound healing
  • Drug-induced Cushing’s Syndrome
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103
Q

Describe azathioprine including indication, mechanism of action and adverse effects

A
  • Used as maintenance therapy in SLE and vasculitis, IBD, dermatitis, RA, leukaemia, transplants
  • Cleaved to 6-MP and functions as an anti-metabolite to decrease RNA/DNA synthesis
  • Adverse effects:
    • Myelosuppression
    • Risk of infection
    • Malignancy
    • Hepatitis
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104
Q

Name some calcineurin inhibitors. What is their mechanism of action?

A
  • Ciclosporin - binds to cyclophilin
  • Tacrolimus - binds to tacrolimus-binding protein
  • Complex binds to calcineurin to stop phosphatase activity in activated T cells and prevents IL-2 forming
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105
Q

Describe the indications for, adverse effects of and pharmacokinetics of calcineurin inhibitors

A
  • Used in transplants, atopic dermatitis, psoriasis
  • Used in rheumatology for cytopenic patients
  • Adverse effects:
    • Nephrotoxicity
    • Hypertension
    • Hyperlipidaemia
    • Gingival hyperplasia
    • Hyperuricaemia in gout
  • Drug interactions with P450 agents
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106
Q

Describe mycophenolate mofetil including indication, contraindications, mechanism of action, pharamacokinetics and adverse effects

A
  • Inhibits inosine monophosphate dehydrogenase required for guanine synthesis
    • Impairs B and T cell proliferation (highly selective)
  • Adverse effects:
    • Myelosuppression
    • GI disturbance
    • Metallic taste
  • Used in transplants and lupus nephritis
  • Contraindicated by renal and hepatic disease
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107
Q

Describe cyclophosphamide including indication, mechanism of action, pharamacokinetics and adverse effects

A
  • Cross links DNA by alkylation to stop replication
    • Suppresses B and T cell activity
  • Used in lymphoma, leukaemia, lupus nephritis
  • Interacts with P450 enzymes
  • Excreted by the kidney
  • Adverse effects:
    • Bladder cancer
    • Lymphoma
    • Leukaemia
    • Infertility
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108
Q

Describe methotrexate including indication, mechanism of action, pharmacokinetics and adverse effects

A
  • Inhibits dihydrofolate reductase to inhibit DNA and RNA synthesis during S phase of cell cycle
  • Used in RA, malignancy, psoriasis, Crohn’s
    • Requires monthly toxicity monitoring
  • Taken orally, IM or SC - WEEKLY DOSING ONLY
  • Adverse effects:
    • Myelosuppression
    • Hepatitis / cirrhosis
    • Risk of infection
    • Dry cough / lung problems
    • Teratogenic
  • Interacts with other immunosuppressants, ant-cancer drugs, NSAIDs, penicillin, renal drugs
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109
Q

Describe sulfasalazine including indication, mechanism of action, pharamacokinetics and adverse effects

A
  • Inhibits T-cell proliferation and IL-2 production
  • Used for RA and IBD
  • Poorly absorbed in the gut
  • Adverse effects:
    • Myelosuppression
    • Hepatitis
    • Rash
    • Nausea
  • Safe in pregnancy due to little drug interactions and not carcinogenic
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110
Q

Describe anti-TNFs including indication, mechanism of action, pharamacokinetics and adverse effects

A
  • Decreases inflammation, angiogenesis and joint destruction
  • Only prescribed after methotrexate and other DMARDS due to expense
  • Adverse effects:
    • Skin/soft
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111
Q

Describe the pathophysiology of asthma

A
  • TH2 driven inflammation → Mucosal oedema, bronchoconstriction, mucus plugging
  • Airway remodelling leads to wall thickening, mucous gland hyperplasia and increased smooth muscle
  • Immediate phase = inital response to allergen
    • IgE causes release of histamine - bronchospasm
  • Late phase = release of mediators/chemotaxis to bring leucocytes to area
    • Epithelial damage
    • Thickened basement membrane
    • Oedema
    • Mucous production
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112
Q

Describe the autonomic modulation of airway resistance

A
  • Sympathetic - B2 adrenoceptors
    • Bronchodilation
    • Decreased histamine
    • Increased mucociliary clearance
  • Parasympathetic - M3
    • Maintains smooth muscle tone
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113
Q

Describe the steps in asthma pharamacology

A
  1. Mild intermittent asthma = short acting B2 agonist
    • Salbutamol / terbutaline for symptom relief
  2. Regular preventor = inhaled corticosteroids
    • Budesonide
  3. Add on therapy - long acting B2 agonists in combination with corticosteroids
    • Formoterol / salmeterol
  4. If persistent poor control
    • Leukotriene receptor antagonists
    • Methylxanthines (theophylline)
    • Long acting anticholinergics (triotropium)
  5. Oral steroids or anti-IgE
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114
Q

What is the mechanism of action, adverse effects and interactions of short-acting B2 agonists?

A
  • Acts on airway smooth muscle via Gs
    • Increase adenyl cyclase, cAMP, PKA
    • Bronchodilation by decreasing calcium
  • Adverse effects:
    • Skeletal muscle termor
    • Tachycardia / dysrhythmia
  • Interacts with beta blockers
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115
Q

What is the mechanism of action, metabolism and adverse effects of corticosteroids?

A
  • Suppresses gene transcription in pro-inflammatory cells (mainly eosinophils)
  • Increases B2 receptor expression
  • Decreases number of mast cells in respiratory mucosa
  • Usually inhaled but can be oral - first pass metabolism
  • Adverse effects
    • Sore throat
    • Thrush
    • Immunosuppression
    • Weight gain
    • Delayed wound healing
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116
Q

Why are corticosteroids and long acting B2 agonists often used together?

A
  • Ease of use
  • Increase in compliance
  • Decrease in number of prescriptions

Also reduces exacerbations, improves symptoms and lung function

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117
Q

How do leukotriene receptor antagonists work? What are the adverse effects?

A
  • Blocks LTC4 release
    • Decrease bronchoconstriction
    • Decrease mucus secretion
    • Decrease mucosal oedema
  • Adverse effects:
    • Angio-oedema
    • Anaphylaxis
    • Fever
    • Arthralgia
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118
Q

How do methylxanthines work? What are the adverse effects?

A
  • Inhibits phosphodiesterase to increase cAMP
  • Antagonises adenosine receptors
  • Adverse effects:
    • Fits
    • Arrhythmias
    • Nausea
    • Headaches
    • Cytochrome P450 inhibitors
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119
Q

How do long-acting anticholinergics work? When are they used? What are the adverse effects?

A
  • Binds to M3 in smooth muscle to block constriction from acetylcholine
  • Used when unresponsive to B2 agonists and in COPD
  • Adverse effects:
    • Dry mouth
    • Urinary retention
    • Glaucoma
120
Q

List the treatments for acute severe asthma

A
  1. High flow oxygen
  2. Nebulised salbutamol
  3. Oral prednisolone
  4. Add nebulised ipatropium bromide
  5. Conider IV aminophylline if no improvement
121
Q

How do pharmacogenetics affect aziothioprine metabolism?

A
  • Eliminated by the enzyme TPMT
  • Genetic polymorphism can create variations in number of TPMT enzymes in different individuals
  • Increased TPMT = undertreatment
  • Decreased TPMT = toxicity
122
Q

What are the main therapeutic effects of NSAIDs

A
  • Analgesia
  • Anti-inflammatory
  • Anti-pyresis
123
Q

Describe the prostaglandin synthesis pathway

A

Cell membrane phospholipids

(Phospholipase A2)

Arachidonic acid

(COX-1/COX-2)

PG G

(COX-1/COX-20

PG E / F / G / I

124
Q

What is the inflammatory response? Name some of its mediators

A

The response to injurious stimuli to reduce risk of further damage to the organism. It alerts the body to the injury via signalling through the pain pathway

  • Molecular mediators (autacoids) = bradykinin, histamine, neuropeptides, NO, leukotrienes, cytokines
  • Prostaglandins (eicosanoids)
    • Localised release
    • Short half lives
125
Q

Describe COX-1 and COX-2 including expression and function

A
  • COX-1 = constitutively (all the time) expressed
    • Cytoprotection in gastric mucosa, myocardium, renal parenchyma
    • Short T1/2 - requires constant synthesis
    • Most ADRs by NSAIDs due to COX-1 inhibition
  • COX-2 = induced by inflammatory mediators (bradykinin)
    • Main therapeutic effects of NSAIDs
    • Larger ‘tunnel’ allows inhibition by larger drugs
126
Q

How does prostaglandin mediate the pain I (afferent nociception) pathway?

A

PGE2 (released from tissue/neurons following trauma) binds to EP1 (Gq) on C fibre

  1. Increases neuronal sensitivity to bradykinin
  2. Inhibition of K+ channels
  3. Increase in Na+ channel sensitivity
  4. Increase intracellular calcium to increase neurotransmitter release

= INCREASE C FIBRE ACTIVITY

127
Q

How does prostaglandin mediate the pain II (central nociception) pathway?

A
  1. Sustained nociception peripherally increases release of cytokines in dorsal horn cell body
    • Increases COX-2 to increase production of PGE2
  2. PGE2 binds to EP2 (Gs) to increase sensitivity of secondary interneurones
    • Removal of glycinergic inhibition
    • Increase cAMP to increase PKA
  3. Increased pain perception
128
Q

Name some adverse effects of NSAIDs

A
  • GI - pain, nausea, heartburn, bleeding, ulceration
    • Decrease in cytoprotective mucus
    • Increase in acid secretion
  • Renal - reduced renal bloodflow = decreased GFR
    • Ion and water retention = hypertension
  • HRH compromisation
  • Vascular = increase in bleeding time and bruising due to effect on thromboxane
  • Hypersensitivity
    • Bronchial asthma
129
Q

Describe some drug interactions of NSAIDs

A
  • Other NSAIDs - competition for protein binding sites
  • Sulphonylurea - hypoglycaemia
  • Warfarin - bleeding
  • Methotrexate - toxicity
130
Q

Describe what happens in paracetemol overdose

A
  • Phase 2 conjugation with glucoronide/sulphate becomes saturated
  • Phase 1 oxidation using glutathione also becomes saturated due to depletion of glutathione
    • Zero order kinetics
  • Accumulation of toxic NAPQI
    • Necrotic hepatic cell death
131
Q

How is paracetemol overdose treated?

A
  • Activated charcoal orally if
  • N-acetylcysteine if 0-36 hours
132
Q

What is the therapeutic use of paracetemol?

A
  • Analgesic and anti-pyresis
    • No anti-inflammatory action
  • 1st agent for mild to moderate pain and fever
  • 1st pass metabolism
    • T1/2 2-4 hours
    • Caution in alcoholics or liver disease
133
Q

What is the mechanism of action of aspirin?

A
  • Irreversibly inhibits COX-1 by acetylation
    • Inhibits platelet generation of thromboxane A2
    • Antithrombotic effect
  • Also inhbits COX pathways to block production of prostaglandins
    • Analgesic and anti-pyretic effect
  • T1/2
134
Q

Describe the general pathway involved in pain and how opioids inhibit this

A
  • Nociceptor → Dorsal root of spinal cord (via A deta/C fibres)
  • Dorsal root → Thalamus/primary sensory cortex
    • Inhibited by interneurones in substantia gelatinosa
    • Also inhibited by descending inhibition from cortex
      • Mimicked by opioiods to reduce pain

Opioids inhibit the release of Substance P from nerve terminals to mimic inhibitory descending pathways

135
Q

Distinguish between endogenous and exogenous opioids

A
  • Endogenous = peptides distributed in CNS and PNS that play roles in processing pain signals
    • Endorphins
    • Enkephalins
    • Dynorphins
  • Exogenous = natural and synthetic agents with actions on endogenous opioid receptors
    • Eg: morphine
136
Q

What are the different classes of opiod receptors? Where are they mainly found?

A
  • Mu (MOP)
    • Supraspinal
  • Delta (DOP)
    • Spinal cord
  • Kappa (KOP
    • Everywhere (enkephalins)
137
Q

What is the mechanism of action of opiates on their respective receptors?

A
  • Increases efflux of potassium to decrease excitability
  • Decreases influx of calcium via channels
  • Decreases cAMP synthesis
  • Via Gi

Overall decreases intracellular calcium to decrease neurotransmitter release and block transmission of pain signals

138
Q

Name some adverse effects of opioids

A
  • Nausea/vomiting
  • Constipation
  • Drowsiness
  • Miosis
  • Respiratory depression
    • Increased risk with pulmonary deficit, sleep or other depressant drugs
  • Hypotension (relaxes smooth muscle)
  • Dependence / tolerance
  • Dysphoria
139
Q

Describe the different pharmacological nature of opioids

A
  • Full agonists - morphine, codeine, methadone
    • Higher affinity for mu
  • Partial agonists/antagonists - nalbuphine
    • Analgesia without euphoria
  • Full antagonists - naloxone
    • Mainly mu
    • Reversal of fatal agonist effect
140
Q

Name some clinical uses of opioids

A
  • ALL - analgesic for moderate to severe pain
  • Morphine - terminal illness, diarrhoea
  • Diamorphine (heroin) = terminal illness
  • Methadone = maintenance in dependence
  • Codeine = mild to moderate pain
  • Fentanyl / alfentanil = anaesthetic
  • Naloxone = reverse opioid toxicity and dependence
141
Q

Name some drug interactions of opioids

A
  • Other CNS drugs - increase analgesic effect
    • Naloxone (IV) is highly competitive with opiates to reverse overdose/toxicity
  • Important to monitor closely
142
Q

Describe the pharmacokinetics of opioids

A
  • Given enterally and parenterally
    • IV for rapid response
    • Intrathecal for severe pain
  • Hepatic and renal failure increases T1/2 to up to 50 hours
    • Consider with palliative care treatment
  • Varying oral bioavailability due to hepatic first pass metabolism and protein binding
    • Dose adjustment is necessary
  • CODEINE - CYP2D6 interactions
143
Q

What are the medico-legal aspects of prescribing opioids?

A
  • Misuse of Drugs Act 1971 / Misuse of Drugs Regulation 2001
  • Some opiiod analgesics are controlled drugs
    • Diamorphine (heroin)
    • Morphine
    • Remifentanil
    • Pathidine
144
Q

What are the main factors involved in abnormal haemostasis?

A

Virchow’s triad:

  • Hypercoagulability
    • Genetic
    • Acquired - smoking, OCP, cancer
  • Endothelial damage
    • Athermoma - MI, CVA
    • Hypertension
    • Toxins - smoking, homocysteine
  • Stasis
    • Immobility - post-op, health, social class
    • Cardiac abnormalities - AF, congestive heart failure, MI, mitral valve
145
Q

How do thrombi form?

A

Plaque build up and rupture

  • Aggregation of platelets
  • Tissue factor activated
    • Cleaves prothrombin into thrombin
      • Cleaves fibrinogen into fibrin
    • Thrombin increases aggregation of platelets
146
Q

How does warfarin work?

A
  • Inhibits production of vitamin K dependent clotting factors
  • Competitive inhibition of Vitamin K reductase
    • Stops conversion of Vitamin K to active form
147
Q

Describe the pharmacokinetics of warfarin - administration, onset, metabolism

A
  • Given PO due to good GI absorption
  • Slow onset of action due to slow turnover of clotting factors
    • Use heparin at beginning of treatment
    • Stop 3 days before surgery to allow synthesis of new clotting factors
  • Heavily protein bound
  • Metabolised by P450 system in liver
148
Q

How do you monitor warfarin and its effectiveness?

A
  • Extrinsic pathway clotting factors
  • Prothrombin time
  • International Normalised Ratio - measure of clotting
    • Should be between 2 and 3 if on blood thinners
    • If > 6 stop warfarin until
149
Q

Describe some drug interactions of warfarin

A
  • Potentiating warfarin (increases concentration and INR)
    • Inhibit hepatic metabolism - amiodarone, quinolone, cimetidine, alcohol
    • Inhibit platelet function - aspirin
    • Decrease vitamin K from gut bacteria - cephalosporin
  • Inhibit warfarin (induce hepatic enzymes to decrease concentration and INR)
    • Antiepileptics
    • Rifampicin
    • St John’s Wort
150
Q

Name some therapeutic uses of warfarin

A
  • DVT (3-6 months)
  • PE (6 months)
  • AF (until risk > benefit)
  • Mechanical prosthetic valves
  • Recurrent thromboses
  • CVA
  • Thrombophilia
  • Cardiomyopathy
151
Q

What are the adverse effects of warfarin?

A
  • Bleeding/bruising
    • Intracranial
    • GI loss
    • Epistaxis
  • Teratogenic - crosses placenta
    • Can cause brain haemorrhage in foetus in later stages
152
Q

How do you reverse warfarin therapy?

A

If INR > 6

  • IV Vitamin K
  • Prothrombin Complex Concentrate - active clotting factors
  • Fresh frozen plasma - active clotting factors
153
Q

What are the 2 groups of heparin and how do they work?

A
  • Unfractionated - binds to anti-thrombin III to increase activity
    • Inactivates thrombin (IIa) and vrious other clotting factors
    • Large enough to bind simultaneously to IIa and ATIII to catalyse inhibition of IIa
  • Low Molecular Weight Heparins - binds to anti-thrombin III but does not inactivate thrombin
    • Only inactivates factor Xa (due to smaller molecules)
154
Q

Describe the pharmacokinetics of heparins - administration, clearance, onset

A
  • Unfractionated = IV
  • LMWH = subcutaneous
  • Poor GI absorption so given parenterally
  • Rapid onset and offset
  • LMWH more predictable dose-response and bioavailability
    • No monitoring required
  • Cleared by kidneys
155
Q

What are the therapeutic uses of heparin?

A
  • Prevention of thrombo-embolism
    • Peri-operative (low dose)
    • Immobility (frail/unwell patient)
  • DVT/PE/AF prior to warfarin
    • Rapid onset compared to warfarin
  • Acute Coronary Syndromes
    • Reduces recurrence of coronary artery thrombosis
  • Pregancy
    • Not teratogenic
156
Q

What are the adverse effects of heparin?

A
  • Bruising/bleeding
  • Thrombocytopenia (autoimmune)
  • Osteoporosis
157
Q

How do you reverse the effects of heparin?

A

Protamine sulphate - dissociates heparin from anti-thrombin III

158
Q

Name some anti-platelet drugs and their mechanism of action

A

Inhibit platelet adhesion, activation and aggregation

  • Aspirin - COX-1 inhibition by covalent acetylation of serine
  • Dipyridamole - phosphodiesterase inhibitor
    • Positive ionotrope and vasodilator
    • Secondary prevention of stroke
  • Clopidogrel - ADP antagonist
    • Blocks P2Y12 receptor (Gi)
    • ACS, PCI
  • Glycoprotein IIb/IIIa inhibitors - decreases platelet aggregation/cross linking by fibrinogen
    • Used in ACS/post PCI
159
Q

What is the mechanism of action of thrombolytic therapy?

A
  • Alteplase - generates plasmin (via recombinant tPA)
    • Cleaves fibrin and other coagulation factors
  • Streptokinase - binds to and activates endogenous plasminogen
    • Plasminogen is converted to plasmin by plasminogen activators (tPA/uPA)
    • Works preferentially in presence of fibrin (clot specific)
160
Q

Why can streptokinase not be use twice?

A
  • Bacterial protein - antigenic
    • Can cause allergic reaction
  • Generation of blocking antibodies
161
Q

What is the clinical use of thrombolytic therapy?

A
  • Acute MI (
  • Pulmonary embolism
  • Major venous thrombosis
162
Q

What are the adverse effects of thrombolytic therapy? How would you treat these?

A
  • Haemorrhage - brain / GI
    • Transfusion of blood / volume expanders
    • Tranexamic acid / clotting factors to prevent further fibrinolysis
  • Anaphylaxis
    • Adrenaline, oxygen. IV fluids, antihistamine
  • Hypotension when being infused (streptokinase)
    • Slowly/stopping infusion
163
Q

What are the contraindications of use of thrombolytic therapy?

A
  • Peptic ulcer / other potential bleeding source
  • Recent trauma or surgery
  • Previous cerebral haemorrhage or stroke
  • Uncontrolled hypertension
  • Coagulation defect
164
Q

What are the different types of anaesthesia used? Name some examples

A
  • General
    • Inhalational - fluranes, NO
    • IV - propofol, thiopental
  • Local
    • Regional - lidocaine
165
Q

Describe the inhibitory ligand gated ion channels and how they produce anaesthesia

A
  • GABA activated chloride channels (IV/inhalational)
    • Increases sensitivity to GABA = increases chloride currents = hyperpolarisation = decreases excitability
  • Glycine activated chloride channels (IV/inhalational)
    • Increase sensitivity to glycine = increases chloride currents = hyperpolarisation = decreases excitability
    • Important in spinal cord and brainstem
166
Q

Describe the excitatory ligand gated ion channels and how they produce anaesthesia

A
  • Neuronal nicotinic Ach receptors (N2O, NO, ketamine)
    • Decreases excitatory Na+ currents to cause analgesia and amnesia
  • NMDA receptors (glutamate)
    • Decreases calcium current to decrease modulation of synaptic response
167
Q

What is MAC?

A
  • Minimum Alveolar Concentration = concentration of inhaled anaesthetic that abolishes response to surgical stimuli in 50% of patients
    • Lower MAC = higher potency
    • Increased by pregnancy, alcoholism, hyperthermia
    • Decreased by other anaesthetics, opioids
    • Controlled by spinal cord
168
Q

Describe the important pharmacokinetic features of inhalational anaesthetics

A
  • Minimum Alveolar Concentration affected by lipid solubility
  • Blood:Gas coefficient = volume of gas (L) that can dissolve in 1L of blood
    • 1.4 = 1.4L of gas in 1L blood
    • If coefficient is increased, more gas readily enters blood
  • Tissue:Blood coefficient = how readily anaethetic moves from blood to tissue
    • If brain is 1.6 and muscle is 3.2, muscle takes up 2x more anaesthetic
  • Anaethetic REDISTRIBUTES into tissue compartments depending on solubility
169
Q

How is inhalational anaesthetic eliminated?

A
  • NOT metabolised
  • Source is removed so blood concentration drops causing anaethetic to move out of the cell membranes and into the venous system
  • Back to alveoli to be eliminated unchanged
  • Followed by brain/kidney/liver, then muscle, then fat stores
    • Can cause long recovery due to large capacitance in different tissues
170
Q

Describe the pharmacokinetics of IV anaesthetics

A
  • Two stage distribution profile:
    • Rapid distribution to CNS (5 mins)
    • Redistribution via circulation into muscle/fat
    • Further dosing required
  • Propofol - hepatic and extrahepatic conjugation
    • T1/2 = 2 hours
171
Q

Describe the synergistic interactions of CNS drugs during surgery

A
  • Benzodiazepine - anxiolysis and amnesia
  • Propofol (IV) - sedation
  • Nitrous oxide - analgesia
    • Also reduces MAC of fluranes
  • Opioids - analgesia
  • Neuromuscular blocking agents - muscle relaxant
    • Competitive NAChR antagonists (tubocurarine)
    • NAChR depolarising agents (succinylcholine)
    • Abolish normal muscular reflexes
172
Q

Describe some adverse drug reactions of anaesthetic

A
  • Fluranes - cardiovascular/respiratory depression via decreased neuronal activity in medullary control centres
    • Arrythmias / hypotension / increased ICP
    • Bronchodilation / coughing / laryngospasm
  • NO = diffusion hypoxia = decreases alveolar oxygen concentrations when diffusing out of blood
    • Expansion of airway cavities
  • Propofol = CV/respiratory depression
  • Benzodiazepines/opioids = respiratory depression
173
Q

Describe the peri-surgical procedures before administering anaethesia

A
  • Patient assessment - age, BMI, medical/surgical history, medication, airways
  • Monitoring (anaesthetic and adjuvant delivery)
    • Monitor % partial pressures of O2, fluranes, N2O, N2
    • Rate of mechanical ventilation
  • Physiological monitoring
    • CV and thermoregulatory function
    • ECG, BP, pulse oximetry, expired CO2, EEG
174
Q

Describe the stages of an anaesthetic procedure

A
  • Induction - administer propofol and start inhalational agent delivery / adjuvants
  • Maintenance - keep adjuvants in balance by regular adjustment to maintain anaesthetic depth
  • Recovery - agents withdrawn and physiological function monitored closely
    • With/without antidotes
175
Q

Describe the stages of anaesthetic depth

A
  1. Analgesia
  2. Excitement (delirium/aggression)
    • Usually bypassed due to fast onset
  3. CNS depression and muscles relaxed
    • MAC 1.2-2.2
  4. Medullary depression - respiratory/cardiac arrest
176
Q

What are adjuvant drugs?

A

Drugs that have few pharmaceutical effects on their own but increase the efficacy or potency of other drugs when given in combination

  • Eg: decreases MAC of fluranes
177
Q

Describe the functions of the kidney

A
  • Regulatory - fluid/acid-base/electrolyte balance
  • Excretory - waste products/drug elimination
    • By glomerular filtration or tubular secretion
  • Endocrine
    • RAAS
    • Erythropoeitin
    • Prostaglandins
  • Metabolism
    • Vitamin D
    • Polypeptides (insulin, PTH)
178
Q

Describe RAAS

A
  • Renin is produced by the kidney is response to low BP/volume/Na+ at macula densa
  • Renin cleaves angiotensinogen (from liver) into angiotensin I
  • Further cleaved to angiotensin II by ACE
    • Increases aldosterone
    • Increases H20 and Na+ retention
    • Vasoconstriction
  • Increases BP
179
Q

Describe carbonic anhydrase inhibitors including name, mechanism of action, site of action, indications and adverse effects

A
  • Acetazolamide
  • Inhibits carbonic anhydrase on PCT epithelium to stop conversion of H2O+CO2⇔HCO3- + H+
    • Inhibits reabsorption of HCO3- which inhibits NHE and therefore Na+ reabsorption
  • Indicated in glaucoma and cystinuria
  • ADR - electrolyte imbalance (Cl-) renal stones, allergic reaction
180
Q

Describe osmotic diuretics including name, mechanism of action, site of action, indications and adverse effects

A
  • Mannitol
  • Increases osmolarity of tubular fluid to prevent water reabsorption
  • Indicated in acute renal failure (increase urine volume) and reduce increased intracranial and intraocular pressure
  • ADR - dehydration, hypernatraemia, pulmonary oedema in heart failure patients
181
Q

Describe loop diuretics including name, mechanism of action, site of action, indications and adverse effects

A
  • Furosemide, bumetamide
  • Inhibits NKCL2 channel in thick ascending limb of Loop of Henle, which inhibits reabsorption of NaCL
    • Also decreases reabsorption of Ca2+ and Mg2+ due to positive lumen potential inhibition
  • Indicated in pulmonary oedema, congestive heart failure, hypertension, hyperkalamia/calcaemia, acute renal failure
  • ADR - hypokalaemia, ototoxicity, hypomagnesaemia, allergy
182
Q

Describe thiazide diuretics including name, mechanism of action, site of action, indications and adverse effects

A
  • Chlorothiazide
  • Inhibit Na+-Cl- channel in DCT which inhibitd NaCl reabsorption
    • Also increases Ca2+ reabsorption by enhancing activity of NCX
  • Indicated in hypertension, oedema, nephrogenic diabetes insipidus
  • ADRs - hypokalaemia/natraemia/chloraemia /magnesaemia, hypercalcaemia/glycaemia/ lipidaemia, hypotension, gout, erectile dysfunction
183
Q

Describe K+-sparing diuretics including name, mechanism of action, site of action, indications and adverse effects

A
  1. Na+ channel inhibitors (amiloride) - inhibits ENaC in collecting duct
    • Indicated in pseudo-hyperaldosteronism, CF
    • ADRs - hyperkalaemia, CNS symptoms
  2. Aldosterone antagonists (spironolactone) - inhibits aldosterone to decrease expression and function fo ENaC
    • Indicated in hyperaldosteronism, hepatic cirrhosis and prevention of hypokalaemia
    • ADRs - hyperkalaemia, metabolic acidosis in cirrhosis, impotence, hirsutism, CNS
184
Q

Describe some important indications for diuretics

A
  • Heart failure - loop + thiazide
  • Hypertension - thiazide + spironolactone
  • Decompensated liver disease - loop + spionolactone
185
Q

Describe some important drug interactions with diuretics

A
  • ACE-i + K+-sparing = hyperkalaemia = cardiac issues
  • Aminoglycosides + loop diuretics = oto/nephrotoxicity
  • Digoxin + thiazide/loop = hypokalaemia
  • Beta blockers + thiazide = hyperglycaemia/ lipidaemia / uricaemia
186
Q

Name some nephrotoxic drugs

A
  • ACE-inhibitors - decreases GFR in renovascular disease by dilating efferent arteriole
  • Aminoglycosides
  • Penicillins
  • Metformin
  • NSAIDs
  • Cyclosporin
187
Q

Describe how you would prescribe to patients with chronic renal failure

A
  • Avoid nephrotoxins
  • Reduce dosage in line with GFR if handled by kidneys
  • Increased risk of hyperkalaemia - monitor bloods and ECG
  • Monitor function and drug levels
188
Q

Describe what you would find on an ECG with hyperkalaemia and how you would treat it

A
  • Tall T waves
  • Elongated QRS
  • Lack of P waves

Treatment:

  • Calcium gluconate
  • Insulin / dextrose
  • Sodium bicarbonate
189
Q

How does high blood pressure cause organ damage?

A
  • Stimulates arterial thickening
  • Smooth muscle hypertrophy
  • Accumulation of vascular matrix
  • Loss of arterial compliance
  • Target organ damage
    • Heart
    • Brain
    • Kidneys
    • Eyes
190
Q

What are the causes of hypertension?

A
  • Primary (essential) = no single evident cause
  • Secondary
    • Chronic kidney disease
    • Adrenal tumour
    • Coarction of the Aorta
    • Pregnancy
    • Drugs (OCP)
    • Alcoholism
191
Q

Describe the treatment options for hypertension

A
  • Treat underlying cause
  • Address underlying cadiovascular risk factors
  • Lifestyle advice
    • BMI 20-25
    • Salt intake
    • Alcohol
  • Pharmacological therapy
    • ACE inhibitors
    • Angiotensin Receptor Blockers
    • Calcium channel blockers
    • Thiazide diuretics
192
Q

Describe ACE-inhibitors, including name, mechanism and site of action and side effects

A
  • Ramipril / lisonipril
  • Reduce formation of angiotensin II by inhibiting Angiotensin-converting enzyme
  • Arterial vasodilation
  • Reduces stimulation of aldosterone
  • Potentiates action of bradykinin
  • ADRs:
    • Dry cough
    • Angio-oedema
    • Renal faiilure
    • Hyperkalaemia
193
Q

Describe angiotensin receptor blockers, including name, mechanism and site of action and side effects

A
  • Losartan
  • Binds to angiotensin I receptor to stop conversion into angiotensin II
  • Stops vasoconstriction and aldosterone stimulation
  • ADRs: more tolerable than ACE-i but still:
    • Renal failure
    • Hyperkalaemia
194
Q

Describe calcium channel blockers, including name, mechanism and site of action and side effects

A
  • Amplodipine / verapamil
  • Binds to L-type calcium channels to reduce calcium entry
  • Causes vasodilation to peripheral, coronary and pulmonary arteries
  • ADRs:
    • Amlodipine = tachycardia, flushing, oedema (sympathetic NS)
    • Verapamil = constipation, bradycardia, -ve inotrope
    • Benzothiazepine = bradycardia
195
Q

Describe thiazide diuretics, including name, mechanism and site of action and side effects

A
  • Bendroflumethiazide
  • Decreases Na+ reabsorption in DCT to decrease blood volume and TPR
  • ADRs:
    • Hypokalamia
    • Increase in urea/uric acid
    • Increase in cholesterol/TGs
    • RAAS activation
196
Q

Describe the guidelines for pharmacological therapy for hypertension

A
    • >55 or black = Calcium channel blocker / thiazide
  • If not responsive to those treatments = ACE-i + CCB OR thiazide
  • If not responsive to those treatments = ACE-i + CCB + thiazide
  • If not reponseive = consider other hypertensive therapies
197
Q

Name some other hypertensive therapies, including mechanism of action and ADRs

A
  • Alpha blockers (doxazosin) = antagonise contraction from NA on a-1 adrenoceptors = decrease TPR
    • Postural hypotension, dizziness, oedema
  • Beta blockers (bioprolol) = Decrease heart rate, cardiac output and renin stimulation
    • Lethargy, bradycardia, decreased exercise tol.
    • Contraindicated in asthma
  • Direct renin inhibitor (aliskiren) = blocks cleavage of angiotensinogen to AT1 = vasodilation
    • Contraindicated in pregnancy
198
Q

Decribe the indications and contracindications of using thiazides, beta blockers, calcium channels blockers and ACE inhibitors for hypertension therapy

A
  • Thiazides - Heart failure, elderly
    • Contraindicated in gout
  • Beta blockers - MI / angina
    • Contraindicated in astham, COPD, heart block
  • CCB - elderly
  • ACE-i - heart failure, MI, diabetes
    • Contraindicated in pregnancy, renovascular disease
199
Q

Describe some causes of heart failure

A
  • Ischaemic heart disease
  • Hypertension
  • Cardiomyopathy
    • Alcohol / chemotherapy / iron
  • Valve disease
200
Q

Describe the current guidelines for treating heart failure

A
  • Lifestyle advice - smoking, exercise
  • Pharmacology 1st line
    • ACE-inhibitors
    • Beta blockers
  • Pharmacology 2nd line
    • Aldosterone antagonists
    • Angiotensin receptor blocker
    • Digoxin
201
Q

How do beta blockers work?

A
  • Reduce heart rate via B1 adrenoceptor
  • Reduce blood pressure via reduced cardiac output
  • Reduces myocardial oxygen demand
  • Reduces mobilisation of glycogen
  • Negate unwanted effects of catecholamines (Adrenaline, DA)
202
Q

What is important to remember when first prescribing drugs for heart failure?

A

Initiate at low dose and titrate slowly as failing myocardium is still dependent on heart rate

203
Q

What is cardiac arrhythmia?

A

Either disturbance in pacemaker impulse formation orcontraction impulse conduction.

Causes rate/timing of muscle contraction that is insufficient to maintain normal cardiac output

204
Q

What is the mechanism behind abnormal impulse generation?

A
  1. Automatic rhythms
    • Enhanced normal automaticity = Increae AP from SAN
    • Ectopic focus = AP not from SAN
  2. Triggered rhythms due to abnormal Na+ and K+ channels
    • Delayed afterdepolarisation
    • Early Afterdepolarisations
205
Q

What is the mechanism behind abnormal conduction?

A
  1. Conduction block = impulse not conducted from atria to ventricles
    • 1st degree - slowed conduction
    • 2nd degree - some impulses do not reach ventricles
    • 3rd degree - complete block
  2. Re-entry
    • Circus movement
    • Reflection
  3. Abnormal anatomic conduction = accessory Bundle of Kent pathway causes re-entry and re-excitation (Wolf-Parkinson-White Syndrome)
206
Q

Name the main classes of anti-arrhythmic drugs

A
  • Class I = Na+ channel blockers
    • 1A = quinidine
    • 1B = lidocaine / phenytoin
    • 1C = felcainide
  • Class II = beta blockers (propanolol / bisoprolol)
  • Class III = K+ channel blockers (amiodarone)
  • Class IV = Calcium channel blockers (verapamil)
207
Q

Describe the actions, uses and ADRs of Class I anti-arrhythmic drugs

A
  • 1A - decreases conduction velocity (phase 0) and increases threshold and refractory period
    • Uses = AF and supra/ventricular tachycardia
    • ADR = hypotension, decreased cardiac output, arrhythmia, CNS symptoms
  • 1B - decreases conduction velocity in ischaemic tissue and increases threshold
    • Uses = only ventricular tachycardia
    • ADR = CNS but less proarrhythmic
  • 1C = decreases conduction velocity and automaticity, increases AP duration
    • Uses = supraventricular, WPW syndrome
    • ADR = sudden death (proarrhythmia), CNS
208
Q

Describe the actions, uses and ADRs of Class II anti-arrhythmic drugs

A
  • Beta blockers - increase refractory period in AVN and decrease phase 4 depolarisation
  • Uses:
    • Re-entrant tachycardia
    • Sinus tachy arrhythmias
  • ADR:
    • Bronchospasm
    • Hypotension
    • Decreases BP in heart failure
209
Q

Describe the actions, uses and ADRs and DDIs of Class III anti-arrhythmic drugs

A
  • K+ channel blockers = increases refractory period and threshold, decreases phase 0 conduction and phase 4 depolarisation
  • Uses = wide spectrum
  • ADR:
    • Pulmonary fibrosis
    • Hepatic injury
    • Increases LDLs
    • Thyroid disease
  • DDIs - digoxin and warfarin
210
Q

Describe the actions, uses and ADRs of Class IV anti-arrhythmic drugs

A
  • Calcium channel blockers = slows AV conduction, increases refractory period and phase 4 slope to slow HR
  • Uses = Supraventricular tachycardia
  • ADRs:
    • Damage with AV block (asystole)
    • Hypotension
    • GI disturbance
211
Q

Describe some other anti-arrhythmic drugs

A
  • Adenosine = binds to A1 to activate K+ currents in SAN/AVN to decrease AP duration, AV conduction and calcium currents
    • Uses - re-entrant supraventricular arrhythmia
  • Digoxin (cardiac glycoside) = enhances vagal activity to increase refractory period and decrease AV conduction
    • Uses = atrial fibrillation / flutter
212
Q

What mutation predispose to cancer?

A
  • Proto-oncogenes mutate to active oncogenes
    • Usually control cell division and apoptosis
  • Tumour supressor gene - inactivation
213
Q

Describe the compartmentation of tumour cells and how this can be treated

A
  • A - dividing cells reveiving adequate nutrient and vascular supply
    • Most susceptible to chemotherapy (targets the cell cycle)
  • B - resting cells in G0 phase but able to rejoin cycle
    • Less susceptible as no actively dividing cells
    • Medication to push cells back into cycle?
  • C - cells can no longer divide
    • Only treatment in surgical removal
214
Q

What is the log kill ratio? How is this relevant to treatment?

A

The proportionate killing of cells in a tumour

  • EG: 10^9 - 10^4 cells killed = 10^5 remaining
    • 4 log kill ratio
  • Not all cells available for attack
  • Kill rate for cancer cells must be compared to healthy cells
    • Ensure rate of regrowth of healthy tissues > cancer
215
Q

Name the main classes of chemotherapy drugs

A
  • DNA intercalators / topoisomerase II inhibitors
  • Alkylating agents (cyclophosphamide)
  • Antimetabolites
    • Methotrexate
    • 5-FU
  • Microtubule inhibitors
    • Vinca alkaloids (vincristine)
    • Taxanes
216
Q

Describe the mechanism of action of some DNA structure modifying chemotherapy drugs

A
  • DNA intercalators / topoisomerase inhibitors = intercalate between base pairs to interfere with transcription
    • Stops breaking, rotation and re-ligation of DNA
  • DNA scisson (bleomycin) = binds with NH2 group on DNA, chelates with Fe2+ and produces ROS which attacks phosphodiester bonds
  • Alkylating agents = covalently bonds to 2 DNA strands to prevent uncoiling and replication
    • Bonds via Cl- or platinum
    • Mainly targets S and G1 (enzymes) phase
217
Q

Describe the mechanism of action of some antimetabolite chemotherapy drugs

A

Interfere with nucleotide production by acting as a direct competitive analogue

  • Methotrexate = inhibits DHFR enzyme to interfere with folate metabolism
    • Folate vital for nucleotide production
  • 5-FU = irreversibly inhibits thymidylate synthase to stop production of thymidine
  • Both specific to S phase only
218
Q

Describe the mechanism of action of some microtubule inhibitor chemotherapy drugs

A
  • Vinca alkaloids (vincristine) = binds to beta-tubulin subunit to prevent microtubule formation
    • No mitotic spindle formation
  • Taxanes = bind to beta-tubulin to promote/stabilise microtubules and inhibit dissassembly
    • Cell stuck in metaphase → apoptosis
  • Only target mitosis phase of cell cycle
219
Q

Describe the mechanism of resistance in alkylating agents and how this can be overcome

A
  • Decreased entry or increased exit of agent
  • Inactivation of agent in cell
  • Enhanced repair of DNA lesion

Overcome by using high dose, short term intermittent therapy

220
Q

How is chemotherapy administered?

A
  • Mainly IV bolus
  • PO - based on oral bioavailability
  • Sub cutaneous
  • Into cavity
    • Bladder/pleural effusion
  • Intrathecal
  • Intralesional - directly into tumour
221
Q

Name some general ADRs of chemotherapy

A
  • Acute renal failure (hyperuricaemia due to tumour lysis)
  • GI perforation at site of tumour
  • DIC for acute myeloid leukaemia
  • Alopecia
  • Skin toxicity - extravasation at site of entry
  • Mucositis - sore throat, diarrhoea, GI bleed
  • Vomiting
222
Q

Describe some treatment specific ADRs of chemotherapy

A
  • Doxorubicin (intercalator) - cardiomyopathy
  • Cyclophosphamide (alkylating agent) - arrhythmia
  • Bleomycin (DNA scisson) - lung fibrosis
223
Q

Describe some important pharmacokinetic considerations when prescribing chemotherapy

A
  • Absorption - decreased in GI cancer
  • Distribution
    • Weight loss
    • Ascites (ovarian cancer) - increased toxicity
  • Elimination - renal/liver/bladder cancer
    • Other drugs
  • Protein binding - low albumin in liver cancer
224
Q

Why is chemotherapy so toxic? How is dose altered for each patient?

A
  • Narrow therapeutic indices
  • Significant side effects
  • Dose altered based on:
    • Surface area/ BMI
    • Renal/liver function
    • General wellbeing
225
Q

Name some important drug interactions with chemotherapy drugs

A
  • Vincristine + itraconazole (anti fungal) = increased neuropathy
  • 5-FU + warfarin/St John’s Wort/grapefruit = increased drug levels
  • Methotrexate + penicillin/NSAIDs = increased drug levels
226
Q

How can the response to chemotherapy be monitored?

A
  • Response of cancer:
    • Imaging
    • Tumour marker blood tests
    • Bone marrow
  • Drug levels
  • Organ damage
    • Creatinine (GFR)
    • ECG
227
Q

What is epilepsy? What is the criteria for diagnosis?

A

Episodic discharge of abnormal high frequency electrical activity in the brain leading to seizures.

  • Diagnosis requires evidence of recurrent suizures unprovoked by other identifiable causes
228
Q

What is the classification of epilepsy?

A
  • Partial (focal) seizures = affects only one area of the brain
    • Simple = fully conscious during seizure
    • Complex = unresponsive/unconscious
    • Secondary generalised = seizure begins as partial but spreads to all areas of the brain
  • Generalised = centrally generated and spreads through both hemispheres with loss of consciousness
    • Tonic-clonic = stiffness followed by limb jerk
    • Absence = ‘switching off’
    • Atonic = loss of all muscle tone
229
Q

Describe some causes of epilepsy

A
  • Primary = idiopathic
  • Secondary
    • Vascular
    • Tumour
    • Infection
    • Head injury
230
Q

Name some of the major precipitants of epilepsy

A
  • Sensory stimuli
  • Brain disease/trauma
  • Metabolic (hypoglycaemia/calcaemia/natraemia)
  • Infection
    • Febrile convulsants in infants
  • Drugs
231
Q

What are the complications associated with epilepsy?

A
  • Physical injury during seizures
  • Status epilepticus = prolonged seizure length
    • Medical emergency - if untreated can cause brain damage or death
  • SUDEP (sudden death in epilepsy)
  • Hypoxia
  • Brain dysfunction
  • Cognitive impairment
  • Adverse effects of medication
232
Q

Describe the major drug classes used to treat epilepsy and their general sites of action

A
  • Voltage-gated sodium channel blockers = reduce probability of high abnormal spiking activity by binding to Na+ channels in the inactive state and prolonging this period. It detaches when membrane potential is back to normal so doesn’t interfere with physiological function
    • Carbamazepine, phenytoin, lamotrigine
  • GABA-mediated inhibitors = Agonists to GABA(A) receptor - increases chloride current into to neuron to increase action potential threshold. Makes membrane potential more negative.
    • Sodium valproate, benzodiazepines
233
Q

Describe carmazepine including uses, ADRs, interactions and monitoring

A
  • V-G sodium channel blocker
  • Treats generalised tonic-clonic and all partial
  • ADRs = CNS (dizziness, ataxia, motor disturbance) GI disturbance, BP variation, rashes, hyponatraemia
  • Strong inducer of CYP450
    • Decreases concentration of phenytoin, warfarin, corticosteroids, OCP
  • Interacts with other antidepressants
  • Needs monitoring and dose adjusting as half life decreases over time
234
Q

Describe phenytoin including uses, ADRs, pharmacokinetics, interactions and monitoring

A
  • V-G Na+ channel blocker
  • Treats generalised tonic-clonic and all partial
  • ADRs = CNS, gingival hyperplasia, rashes
  • Strong inducer of CYP450
  • Non liner pharmacokinetics = variable half life
    • Dose is specific to patient
    • Monitoring of free plasma concentration
  • Competitive binding with valproate and NSAIDs
  • Interactions with OCP (decreases) and cimetidine (increases)
235
Q

Describe lamotrigine including uses, ADRs, interactions and monitoring

A
  • V-G Na+ channel blocker and Ca2+ channel blocker
  • Treats generalised tonic-clonic, all partial and absence
  • ADRs - CNS (less) nausea, rashes
  • Decreases with OCP and increases with valproate
  • Safer in pregnancy
  • Linear pharmacokinetics with no CYP450 induction
    • Less monitoring required
236
Q

Describe sodium valproate including uses, ADRs, interactions and monitoring

A
  • Pleiotropic - GABA agonist, VGSC blocker, CCB
  • Treats generalised tonic-clonic, all partial and absence
  • ADRs (less severe) - CNS, liver damage (increases transaminases)
  • Interactions - antidepressants (D VP) antipsychotics (D threshold) and aspirin (I VP)
  • Close monitoring of free plasma concentration essential
    • Blood, metabolic and hepatic disorders
237
Q

Describe benzodiazepines including uses, ADRs and treatment for overdose

A
  • Positive allosteric effector on GABA
  • Used in status epilepticus (lorazepam) and short-term for absence
  • ADRs = sedation, tolerance, confusion, aggression, respiratory/CNS depression
  • Overdose treated with flumazenil
238
Q

Describe some safe prescribing principles in epilepsy

A
  • Choice based on individual patients/condition
  • Aim for monotherapy
    • Start on low dose and increase gradually
  • Monitor plasma levels - polypharmacy is common
  • Monitor liver function - enzyme inducer or inhibitors
  • Cessation should be gradual to avoid withdrawal
    • Could trigger seizures
239
Q

Why are there safety concerns involving anti-epileptic drugs and pregnancy?

A
  • AEDs increase failure of conception rate
  • Dangers to foetus
    • Congenital malformations
    • Facial/digital hypoplasia
    • Learning difficulties
    • Neural tube defects (valproate)
  • Balance between teratogenic risk and trauma risk of seizures
  • Lamotrigine safest, valproate worst
  • Consider giving folate (neural tube) and Vitamin K (coagulopathy) supplements
240
Q

Describe the treatment for Status Epilepticus

A
  1. ABC
  2. High flow oxygen
  3. Bloods - exclude hypoglycaemia
  4. IV lorazepam (benzodiazepine)
    • Phenytoin if unresponsive
241
Q

Name the general rule of thumbs for presribing for the different epilepsy seizures

A
  • Generalised - valproate sodium
  • Partial - carbamazepine
  • Women of child bearing age - lamotrigine
  • Status Epilepticus - lorazepam
242
Q

What is Parkinsonism? What could cause it?

A

Clinical syndrome characterised by TRAP symptoms:

  • Tremor
  • Rigidity
  • A/bradykinesia
  • Postural instability

Causes:

  • Drugs (antipsychotics)
  • Vascular
  • Multiple systems atrophy
  • Infections - AIDs, CJD, encephalitis lethargica
243
Q

How can idiopathic Parkinson’s be differentiated from other causes of Parkinsonism?

A
  • Structural neuroimaging - MRI shows no abnormalities in Parkinson’s
  • Response to treatment
  • Functional neuroimaging
    • DaTSCAN - shows loss of dpoaminergic neurons
244
Q

Briefly describe the pathophysiology of Parkinson’s

A
  • Loss of dopaminergic neurons in Substantia Nigra
    • Reduced inhibition in neostriatum
    • Decreased motor planning, reward-seeking and learning
  • Increased production of aceylcholine (excitatory)
  • Abnormal signalling = impaired mobility
245
Q

Name the classes of drugs used to treat Parkinson’s

A
  • Levodopa (L-DOPA) = precursor to dopamine that can cross the BBB
  • Dopamine receptor agonists
  • MAO inhibitors = Prevents breakdown of dopamine by monoamine oxidase
    • Smooths out motor response
  • COMT inhibitors = reduces peripheral breakdown of L-DOPA to 3-O-methyldopa
    • Used with L-DOPA to reduce ‘wearing off’
  • Anticholinergics (tremor treatment) = inhibits the antagonistic effect of acetylcholine on dopamine
246
Q

Describe L-DOPA including ADRs, interaction and uses

A
  • Precursor to dopamine that can cross the BBB
    • Given with DOPA decarboxylase to prevent conversion to dopamine in peripheral tissues
  • ADRs - nausea, anorexia, hypotension, psychosis, tachycardia
    • Motor = dyskinesia, dystonia, freezing
  • Interacts wtih pyridone (D LD) antipsychotics (block receptors) and MAOIs (hypertension)
  • Loss of efficacy long term - not given in young patients
247
Q

Describe dopamine receptor agonists including ADRs and uses

A
  • De novo/add on therapy
  • Non-ergot (ropinirole) doesn’t cause fibrosis of heart valves and other tissues
    • Ergot does
  • ADRs = less motor, more psychiatric (hallucinations) sedation
    • Impulse control disorders - gambling, hypersexuality, shopping
  • Direct acting but less efficacious than L-DOPA
248
Q

What other treatment options are there for Parkinsons patients?

A

Surgery - if significant side effects with L-DOPA and no psychiatric illness

  • Lesion in thalamus for tremor
  • Lesion in Globus Pallidus Interna for dyskinesias
  • Deep brain stimulation
    • Subthalamic nucleus
249
Q

Name some complications associated with Parkinson’s

A
  • Mood and cognitive changes
  • Loss of bladder control
  • Swallowing problems
  • Sleep disorders
  • Constipation
  • Orthostatic hypotension
  • Smell dysfunction (olfactory bulb affected first)
250
Q

What is myasthenia gravis? Name some symptoms

A

A neuromuscular disease caused by autoimmune attack on acetylcholine receptors on the post-synaptic membrane. Symptoms:

  • Muscle weakness
    • Ptosis
    • Dysphagia
    • Facial expression
    • Respiratory
  • Fatiguability
251
Q

Describe the management of myasthenia gravis

A

Acetylcholinesterase inhibitors = decreases breakdown of acetylcholine in neuromuscular junction

  • Enhances neuromuscular transmission in skeletal and smooth muscle
  • ADRs:
    • Bradycardia
    • Hypotension
    • Bronchoconstriction
    • SLUDGE (sweating, lacrimation, urinary incontinence, diarrhoea, GI upset, emesis)
252
Q

Describe the complications of myasthenia gravis

A
  • Acute exacerbation = myasthenic crisis
    • Beta blockers
    • Aminoglycosides
    • ACE-inhibitors
  • Overtreatment = cholinergic crisis (depolarising block)
253
Q

Describe the 3 hypotheses of the pathophysiology of depression.

A
  1. Deficiency of monoamine neurotransmitters (noradrenaline/serotonin)
    • Treat with MAO inhibitors to block MAO from destroying neurotransmitters
  2. Abnormality in monoamine receptors
  3. Deficiency in molecular functioning
254
Q

Describe the symptoms of depression

A
  • Core (need at least 2):
    • Low mood
    • Anhedonia (decreases pleasure in activities)
    • Decreased energy
  • Secondary
    • Decreased appetite
    • Self harm/suicide
    • Hopelessness
    • Sleep disturbance
    • Psychosis
255
Q

Name the classes and examples of anti-depressants and their mechanism of action

A
  • Selective serotonin uptake inhibitor (fluoxetine) = prevents reuptake of serotonin into neuron so increases synaptic concentration
    • First line for moderate to severe depression
  • Tricyclic antidepressants (antitryptillin)
    • Inhibits NA uptake
    • Muscarinic cholinoceptor block
    • Alpha1 adrenoceptor blockade
  • Non-selective monoamine uptake inhibitors (duloxetine) = prevents reuptake of monoamines
    • Second/third line
256
Q

Describe SSRIs including pharmacokinetics, ADRs and overdose

A
  • Long half life = once daily dosage
    • Takes weeks to be 100% effective
  • Metabolised by liver
  • ADRs:
    • Common = anorexia, nausea, diarrhoea
    • Rare = mania, suicidal ideation, tremor, extrapyramidal (dystonia, tardive dyskinesia etc)
  • Safe in overdose
257
Q

Describe tricyclic antidepressants including pharmacokinetics, ADRs and overdose

A
  • Long half lives
  • Metabolised by liver
  • ADRs:
    • CNS = sedation, lower seizure threshold
    • CVS = tachycardia, postural hypotension, decreased contracility
    • Constipation
    • Decreased glandular secretions
  • Overdose causes arrhythmia
    • Cardiac monitor
258
Q

Describe SNRIs including ADRs and pharmacokinetics

A
  • Short half life
    • Withdrawal syndrome if suddenly stopped
  • Side effects same as SSRIs
    • Increased BP
    • Hyponatraemia
    • Dry mouth
259
Q

What is paranoid schizophrenia? Describe its causes and symptoms

A

Psychosis - lack of contact with reality

  • Caused by drugs, depression, dementia
  • Symptoms:
    • Hallucination = perception in absence of external stimulus
    • Delusion = fixed false belief that is out of keeping with someone’s culture/beliefs
    • Behavioural changes, disturbances in thinking, apathy, self neglect
260
Q

Describe the typical drugs used to treat paranoid schizophrenia including uses, side effects and toxicity

A
  • Drugs are antipsychotic, sedatives and tranquilisers
  • Eg: Haloperidol (emergencies) = blocks DA, ACh, alpha-adrenergic and antihistamine
  • Side effects:
    • Extra-pyramidal = Parkinsonism, tardive dyskinesia (horse mouth)
    • Neuroleptic malignant syndrome = rigidity, hyperthermia
    • Postural hypotension, weight gain, prolactinaemia
  • Toxicity = CNS depression, cardiac toxicity
261
Q

Describe the atypical drugs used to treat paranoid schizophrenia including uses and side effects

A
  • 1st line treatment (olanzapine, risperidone)
  • Side effects
    • Less extrapyramidal so more tolerable
    • Sedation
    • Weight gain
    • Prolactinaemia
262
Q

What is anxiety? Describe symptoms, treatment and principle neurotransmitters

A

Fear out of proportion to a situation

  • Symptoms = light headedness, dyspnoea, hot/cold flushes, nausea, palpitations, numbness
  • Treatment:
    • Non pharmacological = CBT (exposure-response prevention)
    • Treat coexisting disorder
    • Drugs - antidepressants, anxiolytics, antipsychotics
      • Benzodiazepines short term
  • Neurotransmitters = GABA, 5-HT, NA
263
Q

Describe benzodiazepine including use, mechanism of action, pharmacokinetics, side effects and toxicity

A
  • Short term management of anxiety (+ status)
    • Diazepam/lorazepam
  • Full GABA agonists = increase enhancement of GABA (inhibitory effects)
    • Highliy lipid soluble so rapid CNS diffusion
  • Renal excretion
  • Side effects:
    • Common = drowsiness, dizziness, psychomotor impairment
    • Occasional = blurred vision, ataxia, hypotension
    • NB: tolerance and dependence!!
  • Toxic to foetus - cleft lip/palate
  • Overdose = respiratory depression
    • Treat with flumazenil (many doses as shorter half life)
264
Q

What is bipolar disorder? Describe it’s symptoms and treatment

A

Episodes of depression and mania

  • Mania symptoms:
    • Unusually excited/happy
    • Overactive
    • Poor sleep
    • Poor concentration
    • Psychosis
  • Treatment = lithium, antipsychotics (atypical), antiepileptics (valproate sodium, carbamazepine)
    • Avoid anti depressants due to increased manic episodes
265
Q

Describe lithium including theories of mechanismof action, pharmacokinetics, side effects and toxicity

A
  • Theories:
    • Compete with Mg2+ and Ca2+ ions
    • Increases 5-HT / decreases 5-HT receptor sites
    • Attenuates effects of certain neurotransmitters
  • Renal excretion BUT nephrotoxic so check eGFR
  • Narrow therapeutic window - tailor dose to patient
  • Side effects = memory problems, thirst/polyuria, tremor, weight gain, rashes, hypothyroid
  • Treat toxicity (renal/thyroid) with IV fluids and anticonvulsants
    • Haemodialysis may be necessary
266
Q

Describe dementia, including symptoms and treatments

A

A chronic brain degeneration marked by memory disorders, mood changes and impaired reasoning

  • Acetcholinesterase inhibitors - increases ACh in synapse
    • Side effects = GI upset, fatigue insomnia, bradycardia, worsens COPD, gastric ulcers
  • NMDA receptor antagonist (memantine)
    • Side effects = hypertension, dyspnoea, headache, drowsiness
267
Q

List the defensive and aggressive factors affecting the intergrity of the gastric mucosa

A

Defensive:

  • Epithelial integrity
  • Cell replication/restitution
  • Mucous barrier

Aggressive:

  • Acid
  • Helicobacter pylori
  • Drugs (NSAIDs)
268
Q

Describe the physiology of acid secretion by the parietal cells

A
  • Gastrin → CCK-B
  • Histamine → H2 receptor
  • Acetylcholine → M3 receptor

All increase activity of H+/K+ exchanger to increase secretion of H+

269
Q

Describe antacids including indications and mechanism of action

A

Rennies / Gaviscon (bicarbonates)

  • Neutralise gastric acid to stop irritation of stomach mucosa and heal ulceration
  • Used in combination with an alginate to protect inflamed mucosa
  • Indicated in GORD, oesophagitis, ulcers
270
Q

Describe H2 receptor antagonists including indications, mechanism of action, side effects and pharmacokinetics

A

Cimetidine / ranitidine

  • Blocks histamine receptor to decrease acid production
  • Short half life - taken as required / twice a day
  • Cimetidine side effects = CYP interaction, gynecomastia, diarrhoea, hypotension, headache, fatigue
  • Less potent than PPIs = less severe side effects
  • Used in ulcers, GORD, dyspepsia
271
Q

Describe proton pump inhibitors including indications, mechanism of action, side effects and pharmacokinetics

A

Omeprazole / lansoprazole

  • Inhibits K+/H+ ATPase to completely block acid secretion
    • Only binds to active pump so patients need to eat for it to be effective
  • Side effects - diarrhoea, increased infections (C. diff) headache, flatulence, pain, fatigue
  • Indicated in GORD, dyspepsia, ulcers, H. pylori eradication
272
Q

Describe the treatment of GORD

A
  • Lifestyle changes - alcohol, smoking, losing weight
  • Antacids + alginates
  • H2 receptor antagonists
  • PPI
  • Surgery (fundoplication) = reinforcement of the lower oesophageal sphincter
273
Q

What is the role of Helicobacter Pylori in development of a peptic ulcer? How is it treated?

A
  • Releases ammonia and other chemicals that are toxic to epithelial cells
  • Causes inflammation which allows stomach acid to overwhelm the mucous barrier

Treated with PPI + clarithromycin + amoxycillin

274
Q

Describe the control of gastric motility

A
  • Myogenic - slow waves of depolarisation through smooth muscle causing rhythmic contraction
    • Pacemaker = Interstital cells of Cajal
  • Neural:
    • Post-ganglionic cholinergic enteric nerves increases contraction
    • Non-adrenergic inhibitory nerves decreases contraction
  • Hormonal = gastrin, secretin, CCK etc
275
Q

Describe the stages of emesis

A
  1. Stimulus (pregnancy, toxins, pain, sensory) activates the vomiting centre = chemoreceptor trigger zone
  2. Preliminary signs = nausea, salivation, sweating, pallor
  3. Vomiting
    • Pyloric sphincter closes which cardia and oesophagus relax
    • Contraction of abdominal wall and diaphragm propels gastric contents up oesophagus
    • Glottis closes and soft palate elevates to prevent any entry of vomit into trachea and nasopharynx
276
Q

What is the chemoreceptor trigger zone? Name some active neurotransmitters there

A

Area of the medulla oblongata that initiates vomiting in response to triggers

  • Located within postrema (floor of 4th ventricle)
  • Neurotransmitters = ACh, histamine, 5-HT, dopamine
277
Q

Name some tests used to measure gastrointestinal motility

A
  • Gastric emptying scintigraphy = ingesting a radiolabelled food with gamma camera images taken to measure emptying
  • Nondigestible wireless capsules - measure pH changes, pressure and temperature throughout GI tract
278
Q

Name some anti-emesis drugs including indication and ADRs

A
  • Dopamine D2 receptor antagonists (domperidone) = acts on postrema and stomach to increase rate of gastric emptying
    • Indicated in nausea/vomiting by L-DOPA
    • ADRs - prolactin release, dystonia (rarely)
  • 5-HT receptor antagonist (ondansteron) = stops vagal stimulation when 5-HT released into gut
    • Indicated in radiation sickness and chemotherapy
    • ADRs = headaches, constipation, flushing
  • Metoclopramide = D2 antagonist, anti-cholinergic and blocker of vagal 5-HT stimulation
    • Indicated in GI causes, migraine, post-op
    • ADRs = extra-pyramidal, galactorrhoea
279
Q

Describe the treatment of constipation

A
  • Treat underlying medical cause - diabetes, Parkinson’s, cancer etc
  • Lifestyle - increase fluid and fibre intake, exercise
  • Laxatives
    • Bulk
    • Faecal softeners
    • Osmotically active
    • Irritant/stimulant (soft faeces)
280
Q

Describe the different types of laxatives

A
  • Bulk = insoluble substances which distend the gut to activate stretch receptors and contraction
    • Used in IBS, pregnancy
    • Contraindicated in other adhesion/ulcerations due to obstruction
  • Faecal softeners = lubricate and soften stool
    • Indicated in adhesions/haemorrhoids
  • Osmotically active (Mg/Na salts) cause water retention to increase peristalsis
    • Used in ‘resistant’ constipation
    • Lactulose in liver failure (DC ammonia)
  • Irritant/stimulant (senna) = excites sensory nerves endings to cause water and electrolyte retention
    • Used in faecal impaction or before surgery
281
Q

Name some ADRs of laxatives

A
  • Dehydration - lightheadedness, headaches, dark urine
  • Hypokalaemia
  • Flatulence
  • Bloating
  • Nausea
  • Diarrhoea
282
Q

Name some medications for diarrhoea

A
  • Anti-motility (increases time for fluid absorption, increases anal tone, decreases sensory defaecation reflex)
    • Opiate analgesics (codeine)
    • Opiate analogue (imodium)
    • Contraindicated in IBD
  • Bulk forming (ispaghula) via water absorption
    • Indicated in IBS and ileostomy
  • Fluid absorbents (kaolin) = produces more formed stool
283
Q

What is Irritable Bowel Syndrome? How is it treated?

A

Symptoms based diagnosis based on chronic abdominal pain, discomfort, bloating, alteration of bowel habits (diarrhoea/constipation) weight loss, bloody stools

  • Treat with mebeverine = relieves spasm of intestinal muscle
    • Increase fibre intake
284
Q

What is pharmacogenetics?

A

Understanding how individual genotypes influence the metabolic pathways of a drug which can determine therapeutic and adverse effects of the drug

285
Q

How does genetic polymorphism affect pharmacogenetics and pharmacodynamics?

A
  • Pharmacokinetics - differences in ADME
  • Pharmacodynamics
    • Receptors
    • Enzymes (CYP etc)
286
Q

Name some risk factors for drug inefficacy/toxicity

A
  • Drug-drug interactions
  • Age
    • Renal/liver function
  • Co-morbidity
  • Lifestyle - smoking/alcohol/diet/exercise
  • Genetic variation - metabolism
    • Younger and caucasions have higher RAS activity = more effective response to ACE-inhibitor
287
Q

Give examples of Type A and Type B ADRs

A
  • A = metabolism
    • Increased expression of CYP2D6 = rapid metabolism and decreased effiacy
    • Absent CYP2D6 = ADRs by reduction in first pass metabolism, drug accumulation or metabolic re-routing
  • B:
    • Hepatic porphyrias = enzyme deficiency in liver (sedatives, antipsychotics)
    • Haemolytic anaemia = G6PD deficiency causes loss of oxidative damage protection
288
Q

Describe the adrenal cortex layers and what they secrete

A
  • Glomerulosa - mineralocorticoid (aldosterone)
  • Fasciculata - glucocorticoid (cortisol)
  • Reticularis - sex steroids
289
Q

What is the role of corticosteroids?

A
  • Increase glucose concentrations
    • Glycogenolysis
    • Gluconeogenesis
    • Proteinolysis
290
Q

Describe what happens in deficiency and excess of cortisol

A

Deficiency = Addison’s

  • Hypoglycaemia
  • Weight loss
  • Nausea
  • Hypotension

Excess = Cushing’s

  • Hyperglycaemia
  • Weight gain
  • Increased appetite
  • Hypertension
291
Q

Describe what happens in deficiency and excess of aldosterone

A

Deficiency:

  • Hyponatraemia
  • Hyperkalaemia
  • Dehydration
  • Hypotension

Excess:

  • Hypernatraemia
  • Hypokalaemia
  • Hypertension
292
Q

Describe the pharmacokinetics of steroids

A
  • Very lipid soluble = increase bioavailability
  • Renal and hepatic clearance
    • Decreases with age
  • Many different routes of administration
    • Topical to avoid systemic (Cushing’s) side effects
293
Q

Name some clinical uses of steroids

A
  • Anti-inflammatory - asthma, IBD, eczema, RA
    • Decreases B/T cell response, phagocytic function and cytokine transcription
  • Immunosuppression
  • Malignancy
  • Adrenal insufficiency
294
Q

List some side effects of mineralocorticoid and glucocorticoids

A

Mineralocorticoid:

  • Fluid retention → hypertension
  • Hypokalaemia

Glucocorticoids:

  • Osteoporosis (inhibits osteoblasts)
  • Hypertension
  • Diabetes
  • Impaired growth
  • Skin atrophy
  • Increased infections
  • Cushingoid (central obesity and dorso-cervical fat pad)
295
Q

Why are steroids not stopped suddenly?

A

Risk of hypoadrenal crisis:

  • Hypotension
  • Hyperkalaemia
  • Hypoglycaemia
  • Dehydration
  • Hyponatraemia

ESA 5 (2 decks)

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