PHARM; Lecture 22, 23 and 24 - Adverse drug reactions, Opioids and Diuretics

Question 1

What is an adverse drug reaction?

Answer 1

Preventable/unpredicted medication event with harm to patient

Question 2

What are the 3 kinds of classification of adverse drug reactions?

Answer 2

Onset (acute <1h, sub-acute 1-24h and latent >2d), severity (mild = no change in therapy, moderate = change in therapy, additional treatment and hospitalisation, severe = disabling/life threatening) and type (A, B, C, D, E)

Question 3

What occurs in a severe adverse drug reaction?

Answer 3

Results in death, life-threatening, requires/prolong hospitalisation, causes disability, causes congenital abnormalities in foetus, requires intervention to prevent permanent injury

Question 4

What is Type A adverse drug reaction?

Answer 4

Most common. Extension of pharmacologic effect usually predictable and dose dependent responsible for at least two-thirds of ADRs e.g., atenolol and heart block, anticholinergics and dry mouth, NSAIDS and peptic ulcer

Question 5

What is Type B adverse drug reaction?

Answer 5

Idiosyncratic or immunologic reactions includes allergy and “pseudoallergy” rare (even very rare) and unpredictable e.g., chloramphenicol and aplastic anemia, ACE inhibitors and angioedema

Question 6

What is Type C adverse drug reaction?

Answer 6

Associated with long-term use involves dose accumulation e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity (build up is toxic)

Question 7

What is Type D adverse drug reaction?

Answer 7

Delayed effects (sometimes dose independent) carcinogenicity (e.g. immunosuppressants) teratogenicity (e.g. thalidomide)

Question 8

What is Type E adverse drug reaction?

Answer 8

Withdrawal reactions: Opiates, benzodiazepines, corticosteroids (due to body not being able to produce its own). Rebound reactions: Clonidine, beta-blockers, corticosteroids “Adaptive” (not good for you) reactions: Neuroleptics (major tranquillisers), psychotropic drugs mainly -> lots of different involuntary movements which can be disabling

Question 9

What is a rebound reaction - use Clonidine as an example?

Answer 9

Used as alpha 2 agonist, can make patients drowsy and tired; missing one or 2 doses of clonidine can lead to substantial rise in BP -> long term use of clonidine causes long term suppression of peripheral NA production, leading to compensatory upreg in adrenergic receptors on post synaptic neurone -> meaning when NA inhibition is removed and NA is released, it will have more receptors to act on, causing a greater effect, rise in BP

Question 10

What are the different types of adverse drug reactions?

Answer 10

Augmented pharmacological effect Bizarre Chronic Delayed End-of-Treatment/Dosage

Question 11

What are the 4 types of allergies?

Answer 11

Type I - immediate anaphylactic (IgE - anaphylaxis with penicillin), type II Ab-dependent cytotoxicity (IgG+IgM - methyldopa and haemolytic anaemia), type III serum sickness (IgG+IgM), type IV delayed hypersensitivity (T cells)

Question 12

What are the pseudoallergies that can occur?

Answer 12

Aspirin/NSAIDS -> bronchospasm (inhibit protanoids and increase leukotriene production occurs as the precursors are shoved down the leukotriene pathway, which are bronchoconstrictors); ACE inhibitors -> cough/angioedema (stop (brady)kinin breakdown, which triggers coughing when accumulated)

Question 13

What are the common drugs causing adverse drug reactions?

Answer 13

Antibiotics Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAID/Analgesics* CNS drugs* *account for two-thirds of fatal ADRs

Question 14

How are adverse drug reactions detected?

Answer 14

Subjective report = patient complaint; objective report = direct observation of event, abnormal findings (physical examination, lab test, diagnostic procedure) -> problem with detection = Rare events will probably not be detected before drug is marketed

Question 15

What is the yellow card scheme?

Answer 15

x

Question 16

What is the incidence of drug-drug interactions?

Answer 16

x

Question 17

What are the 3 types of drug interaction?

Answer 17

Pharmacodynamic (drug’s effect in body), pharmacokinetic (body’s effect on drug) and pharmaceutical (drugs interacting outside body - IV infusions)

Question 18

What are the 3 effects of pharmacodynamic drug interactions?

Answer 18

Additive effects - two drugs add together E.g. overlapping toxicities of ethanol and benzodiazepines Synergistic effects - two drugs potentiate each others’ actions to get a great effect than expected E.g. synergistic actions of antibiotics Antagonist effects - drugs that antagonise each others’ actions E.g. amitriptyline and acetylcholinesterase inhibitors

Question 19

What are the 4 pharmacokinetic drug interactions?

Answer 19

Alteration in absorption Protein binding effects Changes in drug metabolism Alteration in elimination

Question 20

How do you alter the absorption of a drug?

Answer 20

Chelation -> Irreversible binding of drugs in the GI tract Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)

Question 21

How do you alter protein binding interactions of a drug?

Answer 21

Competition between drugs for protein or tissue binding sites Increase in free (unbound) concentration may lead to enhanced pharmacological effect Many interactions previously thought to be PB interactions were found to be primarily metabolism interactions PB interactions are not usually clinically significant but a few are (mostly with warfarin)

Question 22

How do you alter the elimination of a drug?

Answer 22

Almost always altered in renal tubule -> probenecid and penicillin = good, lithium (mood stabilising drug) and thiazides = bad as you get increase excretion of Na with lithium being retained, causing build up which can be toxic. Usually most drugs are cleared by the kidney unchanged. When undergoes phase I reaction can be excreted in liver/kidney. When undergoes p1 then p2 or just straight to p2, then excreted only in the kidney.

Question 23

What are the deliberate interactions of certain drugs?

Answer 23

Levodopa + carbidopa = lower doses of levodopa used as it isn’t broken down in the periphery ACE inhibitors + Thiazides = increase anti hypertensive effects Penicillins + Gentamicin = staph infections Salbutamol + ipratropium = asthma

Question 24

How is drug metabolism altered?

Answer 24

• Drug metabolism inhibited or enhanced by coadministration of other drugs
• CYP 450 system has been the most extensively studied
• CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others
• Phase 2 metabolic interactions (glucuronidation, etc.) occur.
• CYP450 substrates -> Metabolism by a single isozyme (predominantly)
• Metabolism by multiple isozymes: Most drugs metabolized by more than one isozyme
• Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19, If co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme

Question 25

What are some CYP450 inhibitors (very rapid)?

Answer 25

Cimetidine Erythromycin and related antibiotics Ketoconazole etc Ciprofloxacin and related antibiotics Ritonavir and other HIV drugs Fluoxetine and other SSRIs Grapefruit juice

Question 26

What are some CYP450 inducers (takes hours/days)?

Answer 26

Rifampicin Carbamazepine (Phenobarbitone, Phenytoin - psych drugs) St John’s wort (hypericin) May be many more but haven't been identified yet

Question 27

What is pharmacogenetics?

Answer 27

The study of genetically determined inter individual differences in therapeutic response to drugs and susceptibility to adverse effects -\> few genes of interest

Question 28

How do we determine genotype of a patient?

Answer 28

Pcr

Question 29

How can you determine phenotype?

Answer 29

Determination of metabolic rate (original level of drug/metabolite in urine); after admin of drug given can check parameters= half life, clearance, plasma levels

Question 30

How are the phenotypes distributed in the population?

Answer 30

Multimodal, bimodal, trimodal

Question 31

What is polygenic control of drug metabolism?

Answer 31

Many genes at play which cannot be differentiated

Question 32

What is monogenic control of drug metabolism?

Answer 32

Discontinuous distribution

Question 33

What are you studying in family studies?

Answer 33

Single gene being studied, because you know which one you're looking for. Need to know whether it is a dominant or recessive gene. -\> if alleles in parents are different there is a different level of synthesis and other things

Question 34

What is an opiate?

Answer 34

Alkaloid derived from poppy - Papaver somniferum; opiods are everything in the family of opioids

Question 35

What is the structure-activity of opiates?

Answer 35

Hydroxyl group at position 6: Oxidise the OH group and lipophilicity Increases 10-fold for morphine

Question 36

What is the difference between heroin, codeine and morphine in terms of structure?

Answer 36

For heroin, it is acetylated and increases capability of penetration of tissues -\> heroin reaches receptor faster and more effectively than morphine but acts the same. Codeine -\> adding acetyl group changes metabolism and potency of drug

Question 37

What is the difference between methadone and fentanyl and morphine?

Answer 37

Quat carbon to 3ry carbon makes fentanyl a more potent opiate than all the others. Methadone has the N group to attach to the receptor, quat carbon and cyclic group which is the same as morphine

Question 38

How are opioids absorbed - oral vs IV?

Answer 38

* Oral isn't a great route as it is a weak base and is likely to be ionised in the stomach and poorly absorbed; * in small intestine it will be unionised and more readily absorbed but first pass metabolism decreases bioavailability; * \<20% of drug unionised in blood which is available; * patches aren't great for morphine due to lipid solubility, but for fentanyl it is fine. * IV is better as it will be directly into the blood but takes some time to enter the brain

Question 39

Which opioids are more lipid soluble and what does that mean?

Answer 39

Question 40

What is the relevance of metabolism rates when trying to wean people off opioids?

Answer 40

When weaning off morphine (10% = active metabolite) or fentanyl, then you need to give a slow metabolising opioids such as methadone, so that the effects are longer lasting

Question 41

How are opioids metabolised?

Answer 41

The majority of opioids are metabolised in the liver by either CYP3A4 and CYP2D6. In the case of codeine, CYP2D6 metabolism is slow but converts codeine to morphine i.e. codeine is a prodrug. CYP3A4 metabolises and deactivates codeine. As a result only 10% of the codeine is metabolised to produce morphine – this is what is responsible for codeine analgesic property. Some individuals have a 2D6 polymorphism, so won’t respond well to codeine. Morphine is the major exception – metabolised by uridine 5 diphosphate glucoronosyltransferase.

Question 42

What are the endogenous opioid peptides?

Answer 42

Endorphins, enkephalins and dynorphins/neoendorphins

Question 43

What are the specific opioid receptors in the body and where are they?

Answer 43

x

Question 44

What are the effects of the opiate receptors?

Answer 44

Ca current would have led to exocytosis but is depressed -\> OVERALL decreases activity of cell

Question 45

What are the effects of opioids?

Answer 45

Question 46

How do opiates cause analgesia?

Answer 46

Decrease pain perception Increase pain tolerance. Central pain perception (?)

Question 47

How is pain perceived?

Answer 47

* Pain enters the dorsal horn, goes to the thalamus (gatekeeper) and then goes to the cortex (with pain being exacerbated by emotions) -\> * also need to be able to depress feeling of pain (pink route); * periaqueductal gray region (PAG) is integrating centre for pain tolerance, and receives signals from the thalamus and cortex with cortex either increasing or decreasing stimulus. * Then nucelus raphe magnus (NRM) is activated which inhibits the feeling of pain and modulates how much pain is felt at dorsal horn. * Nucleus reticularis paragigantocellularis (NRPG) which is the negative feedback site, which automatically activates pain tolerance, kick starting the pain tolerance pathway. * Hypothalamus tells PAG the current state of health which the individual is in. * LC (locus coeruleus) is similar to the SNS in the pathway, which causes suppression of pain

Question 48

How does the dorsal horn modulate pain transmission?

Answer 48

Substantia gelatinosa = Mini brain in spinal cord which is further processing the pain information -\> subtler response in diminishing pain sensation

Question 49

Where do opioids act?

Answer 49

Question 50

Where would opiates act in the reward pathway?

Answer 50

Act to depress GABA neurones, to increase VTA and release of DA

Question 51

How do opioids acts as anti-tussives?

Answer 51

* Central effects: Reduced 5HT1A receptor function in the dorsal raphe nucleus leads to an increase in 5HT levels (increase firing of 5HT1A receptors leads to suppression of serotonin which activates cough centre) and depress discharges from inspiratory motorneurones. NTS is a strong candidate for the cough centre. Opioids desensitise the 5HT1A receptor so Serotonin levels rise which inhibits motor neurones that connect cough centre with larynx. * Peripheral effects: μ-opioid receptors located in the airway vagal sensory neurons and opioids inhibit both eNANC nerve activity and cholinergic contraction of smooth muscles. Occurs via action on sensory neurones that relay to vagus, using as NT ACh and neurokinin. Irritant in airways activates sensory nerves, releasing ACh and Neurokinin, activating CNX which activates cough centre. * Stop irritant information from being relayed to cough centre, prevent cough centre from decreasing serotonin.

Question 52

How does respiratory depression occur?

Answer 52

* The most opioid sensitive aspect of respiration is rhythm generation. * The pre-Bötzinger complex is a small area in the ventrolateral medulla that can generate a ‘respiratory’ rhythm. * The pre-Bötzinger complex is active during inspiration and is inhibited by opioids. * Central chemoreceptors provide tonic drive to the respiratory motor output by sensing changes in pH and are inhibited by opioids. * OPIOIDS: General suppressive effect on resp control centre and from detecting CO2 levels in resp control centre

Question 53

How do opioids cause nausea/vomiting?

Answer 53

Low doses of opioids activate mu opioid receptors in the chemoreceptor trigger zone (CTZ), thereby stimulating vomiting.

Question 54

How do opioids cause miosis?

Answer 54

* NB: can be extremely important in diagnosing Heroin OD -\> unconciousness usually leads to mid dilation of pupils but in heroin you have pinpoint pupils. * Large number of opioid receptors in Edinger-Westphal nucleus. * Opioids activate CNIII independent of optic nerve function. * Several opioid receptor types can be demonstrated on myenteric neurons, and both κ- and μ-receptor agonists regulate cholinergic transmission in the myenteric plexus.

Question 55

What happens to GI function with opioids?

Answer 55

Constipation, slowing down of gut function

Question 56

How do opioids cause urticaria?

Answer 56

* Opioids stimulate histamine release, with those on skin being most sensitive; * not receptor mediated event, but influences PKA and OH group at 6 is needed for this to occur. * Not all opioids cause histamine release – in fact it is the combination of the N-methyl group and the 6-hydroxyl group that is common to all opioids that induce non IgE mediated histamine release.

Question 57

How do opioids cause tolerance?

Answer 57

Cause tissue tolerance -\> upregulates the levels of arrestin in tissue, which promotes receptor internalisation (normal process), but then over-internalise receptors in upregulation; less receptors available to recognise the opioids

Question 58

How do opioids cause dependence?

Answer 58

When opioids are withdrawn, overactive AC is left, which leaves you with psychological problems, but after 2 weeks(ish) the cell activity decreases

Question 59

What occurs in an opioid overdose?

Answer 59

Question 60

Where do diuretics target?

Answer 60

Along the whole length of the kidney

Question 61

What occurs in the proximal tubule cell?

Answer 61

* In paracellular transport most tends to diffuse from apical to basal side of cell, dependent on gap junctions between cells. Lot of Na reabsorbed in prox tubule; * on apical side there are Na channes that allow Na to diffuse into the epithelial cell and then water can follow Na into the cell via osmosis. * Once Na is in the cell, Na/K ATPase pumps Na out of cell and into blood in exchange for K.-\> * Oncotic pressure exerted by proteins in the blood in the capillaries exerts important force in drawing water into the capillaries. * A lot of Na, HCO3 (Na/HCO3 cotransporter and Na/H exchanger) and water is reabsorbed. * Drugs can be removed via transport proteins that pick up drugs as they pass through the kidneys and transport them into the lumen -\> about 65-70% of filtered fluid is absorbed in PCT

Question 62

What are diuretics?

Answer 62

Drugs that act on renal tubule to promote excretion of Na/Cl and H20

Question 63

What is the countercurrent effect?

Answer 63

NB: capillaries pass through this in the opposite direction to flow of fluid, with lots of the fluid in the interstitium ending up in the capillaries; as interstitium becomes more conc the collecting duct becomes more permeable to water (VP) -\> system very important in making sure we don't lose too much fluid. A) Descending limb is permeable to water. Ascending limb – impermeable to water. B) Na+ leaves the ascending limb and enters medullary Interstitium. Fluid in ascending limb decreases in osmolarity. Na transport into interstitium occurs in ascending limb, so interstitum becomes hypertonic and fluid in asc limb is hypotonic. C) Hypertonic medullary interstitium draws water from the permeable descending limb Fluid in descending limb becomes hypertonic. D) More fluid enters and forces fluid from descending to ascending limb – this fluid has increased in osmolarity due to increased Na+ concn in the medulla. E) Na+ leaves the ascending limb and enters medullary Interstitium. Fluid in ascending limb decreases in osmolarity, eventually have a very concentrated interstitium

Question 64

How do diuretics work?

Answer 64

Inhibit reabsorption of Na/Cl, increase excretion; increase osmolarity of tubular fluid, decrease osmotic gradient across epithelia

Question 65

What are the 5 main classes of diuretics and where do they act on the nephron?

Answer 65

1. Osmotic diuretics - e.g. mannitol 2. Carbonic anhydrase inhibitors e.g. acetazolamide 3. Loop diuretics e.g. frusemide (furosemide) 4. Thiazides e.g. bendrofluazide (bendroflumethiazide) 5. Potassium sparing diuretics e.g. amiloride, spironolactone. NB: osmotic diuretics and carbonic anhydrase inhibitors are NOT classically used as diuretics, cause diuresis but not what used for clinically

Question 66

Where does Mannitol act - osmotic diuretics?

Answer 66

Question 67

What is the action of Carbonic anhydrase inhibitors - Acetazolamide?

Answer 67

Question 68

Where do loop diuretics act?

Answer 68

* Thick ascending limb - leak of K adds to positive charge in lumen, which leads movement of positive ions into the cell. * Target Na/K/2Cl triple transporter, so Na reabsorption is impaired, retained in lumen; * promote 15-20% fluid loss; also remove K recycling (usually K drives other +ve ions across cells via paracellular pathway, creating positive lumen potential which drives +ve ions across epithelium via paracellular route), some loss of Mg and Ca as well as they are not driven into the interstitium via the paracellular route

Question 69

What is the action of loop diuretics - frusemide?

Answer 69

x

Question 70

Where do thiazide diuretics (bendroflumethiazide) act?

Answer 70

Act in the distal convoluted tubule. Not as powerful as loop diuretics because the distal tubule is only responsible for 5-10% of fluid; bind to Na/Cl cotransporter, so more Na/Cl is lost in urine and if at high dose can cause 5-10% fluid loss

Question 71

What is the action of thiazide diuretics - bendroflumethiazide?

Answer 71

Question 72

What effect would diuretics have on renin secretion and which diuretic would have the most powerful effect on renin secretion?

Answer 72

Protein on apical membrane of macula densa cells is same as those on loop of Henle, which is blocked by loop diuretics so Na can't enter the macula densa cells; reduction in Na is a stimulus for Renin secretion, which stimulates Na reabsorption, (all diuretics do this) which is a problem as you are trying to reduce Na and fluid reabsorption and BP, but activating RAAS causes vasoconstriction and promotes aldosterone production, increasing Na reabsorption, negating effects of diuretics. Thus need to usually administer ACE inhibitors with diuretics.

Question 73

What occurs in the descending limb of the loop of henle?

Answer 73

Freely permeable to water, with water moving straight from tubule lumen through the epithelial cells into the interstitium

Question 74

What occurs in the ascending limb of the loop of henle?

Answer 74

* Not permeable to water; * Na/K/2Cl transporter is responsible for transporting those ions into epithelial cell from the lumen: 2 channels on basolateral membrane to move the electrolytes into the interstitium -\> Na/K ATPase, K/Cl cotransporter; * present throughout nephron because it maintains concentration gradient that allows absorption of electrolytes from lumen into cell

Question 75

What occurs in the distal tubule cell?

Answer 75

Overall: H2O, Na and Cl are transported out of the tubule. Any Na left in filtrate will be transported by the Na/Cl transporter in the apical membrane and eventually it will enter the capillaries; more distally in the nephron = more aldosterone and AQP importance

Question 76

What occurs in the collecting duct cell?

Answer 76

Aldosterone and VP are very important in mediating collecting duct function; aldosterone increases production of Na channels and Na/K ATPase, VP synthesises AQP2 allowing water to follow Na

Question 77

What is the overall loss and gain of ions and water in the renal tubule?

Answer 77

x

Question 78

What is the action of mannitol (osmotic diuretics)?

Answer 78

Not directly used as diuretics but used to raise plasma osmolarity to draw out fluid from cells and tissues -\> mechanism that causes polyuria in people with diabetes mellitus using mannitol instead of glucose

Question 79

Where do carbonic anhydrase inhibitors (acetazolamide) act upon?

Answer 79

Proximal tubule -\> Prevents H and HCO3 from entering epithelial cells from the lumen, so less Na/H exchange; overall less Na reabsorbed so water remains in lumen, increasing urine volume

Question 80

What are the uses of loop diuretics?

Answer 80

Main effect is large increase in urine volume and Na/Cl/K loss (Ca/Mg as well); Oedema is main use (can be due to HF - in acute left ventricular failure it reduces pulmonary oedema, helping reduce breathlessness); unwated effects: Hypovolaemia, hypotension, K loss (and Ca/Mg), metabolic alkalosis

Question 81

What are the uses and side effects of thiazide diuretics?

Answer 81

Moderate increase in urine volume and increase in Na/Cl and K loss (Mg loss), cardiac failure, hypertension (anti effect initially due to decrease in blood volume, and also vasodilators), idiopathic hypercalciuria, nephrogenic diabetes insipidus; unwanted effects: K loss leads to metabolic alkalosis and inhibits insulin secretion (DM not good)

Question 82

What are the 2 types of K sparing diuretics and where do they act?

Answer 82

Late distal tubule and collecting duct. 2 types: Aldosterone receptor antagonists (spironolactone) and inhibitors of aldosterone sensitive Na channels (amiloride)

Question 83

What do K sparing diuretics act on in the cell?

Answer 83

Spironolactone blocks the mineralocorticoid receptor antagonist so blocks the MR and stops aldosterone's effects (decreases Na reabsorption, diuretic effect); amiloride blocks Na channel

Question 84

What are the actions of K sparing diuretics?

Answer 84

x

Question 85

What are the uses and side effects of K sparing diuretics?

Answer 85

Main effect: small increase in urine volume and Na loss; amiloride = admin with K losing diuretics; spironolactone = HTN/HF and hyperaldosteronism; unwanted effects = hyperkalaemia, metabolic acidosis, spironolactone isn't specific in targeting receptors so can cause gynaecomastia, menstrual disorders and testicular atrophy

Question 86

Why aren't other diuretics K sparing?

Answer 86

Other diuretics increase conc of Na reaching the CD, leading to increased Na/K exchange in CD, so lots of K lost in urine

Question 87

What are the common side effects of diuretics?

Answer 87

x

Question 88

Why do you get hyperuricaemia with diuretics?

Answer 88

* Drugs in different parts of the kidney are excreted back into the lumen so they can be excreted in the urine -\> * organic anion transporter is the transporter that moves the diuretics across the membrane from blood into lumen, * but competes with uric acid to try to cross into the lumen, * so you get build up of uric acid in blood, hence hyperuricaemia

Question 89

How do we treat HTN with diuretics?

Answer 89

Most countries use thiazides for first line treatment -\> really good for salt sensitive HTN (struggle to excrete Na); as effective as ACEi and beta blockers

Question 90

Why are thiazides good for HTN but not other diuretics?

Answer 90

Initial effect is due to diuresis, but chronic use leads to decrease in TPR

Question 91

How are diuretics used in HF and oedema?

Answer 91

* Body's response to HF is to activate RAAS which makes it worse, as it builds up fluid due to ^ Na and water retention. * Loop diuretics are really good and reduce 30% Na load to reduce acute congestion but can become resistant in chronic use (RAAS activation) and now we use K sparing diuretics as well as loop diuretics, to get a better response