PHARM; Lecture 22, 23 and 24 - Adverse drug reactions, Opioids and Diuretics Flashcards
What is an adverse drug reaction?
Preventable/unpredicted medication event with harm to patient
What are the 3 kinds of classification of adverse drug reactions?
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)
What occurs in a severe adverse drug reaction?
Results in death, life-threatening, requires/prolong hospitalisation, causes disability, causes congenital abnormalities in foetus, requires intervention to prevent permanent injury
What is Type A adverse drug reaction?
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
What is Type B adverse drug reaction?
Idiosyncratic or immunologic reactions includes allergy and “pseudoallergy” rare (even very rare) and unpredictable e.g., chloramphenicol and aplastic anemia, ACE inhibitors and angioedema
What is Type C adverse drug reaction?
Associated with long-term use involves dose accumulation e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity (build up is toxic)
What is Type D adverse drug reaction?
Delayed effects (sometimes dose independent) carcinogenicity (e.g. immunosuppressants) teratogenicity (e.g. thalidomide)
What is Type E adverse drug reaction?
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
What is a rebound reaction - use Clonidine as an example?
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
What are the different types of adverse drug reactions?
Augmented pharmacological effect Bizarre Chronic Delayed End-of-Treatment/Dosage
What are the 4 types of allergies?
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)
What are the pseudoallergies that can occur?
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)
What are the common drugs causing adverse drug reactions?
Antibiotics Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAID/Analgesics* CNS drugs* *account for two-thirds of fatal ADRs
How are adverse drug reactions detected?
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
What is the yellow card scheme?
x
What is the incidence of drug-drug interactions?
x
What are the 3 types of drug interaction?
Pharmacodynamic (drug’s effect in body), pharmacokinetic (body’s effect on drug) and pharmaceutical (drugs interacting outside body - IV infusions)
What are the 3 effects of pharmacodynamic drug interactions?
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
What are the 4 pharmacokinetic drug interactions?
Alteration in absorption Protein binding effects Changes in drug metabolism Alteration in elimination
How do you alter the absorption of a drug?
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)
How do you alter protein binding interactions of a drug?
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)
How do you alter the elimination of a drug?
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.
What are the deliberate interactions of certain drugs?
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
How is drug metabolism altered?
- 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
What are some CYP450 inhibitors (very rapid)?
Cimetidine Erythromycin and related antibiotics Ketoconazole etc Ciprofloxacin and related antibiotics Ritonavir and other HIV drugs Fluoxetine and other SSRIs Grapefruit juice
What are some CYP450 inducers (takes hours/days)?
Rifampicin Carbamazepine (Phenobarbitone, Phenytoin - psych drugs) St John’s wort (hypericin) May be many more but haven’t been identified yet
What is pharmacogenetics?
The study of genetically determined inter individual differences in therapeutic response to drugs and susceptibility to adverse effects -> few genes of interest
How do we determine genotype of a patient?
Pcr
How can you determine phenotype?
Determination of metabolic rate (original level of drug/metabolite in urine); after admin of drug given can check parameters= half life, clearance, plasma levels
How are the phenotypes distributed in the population?
Multimodal, bimodal, trimodal
What is polygenic control of drug metabolism?
Many genes at play which cannot be differentiated
What is monogenic control of drug metabolism?
Discontinuous distribution
What are you studying in family studies?
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
What is an opiate?
Alkaloid derived from poppy - Papaver somniferum; opiods are everything in the family of opioids
What is the structure-activity of opiates?
Hydroxyl group at position 6: Oxidise the OH group and lipophilicity Increases 10-fold for morphine
What is the difference between heroin, codeine and morphine in terms of structure?
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
What is the difference between methadone and fentanyl and morphine?
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
How are opioids absorbed - oral vs IV?
- 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
Which opioids are more lipid soluble and what does that mean?
What are the effects of the opiate receptors?
Ca current would have led to exocytosis but is depressed -> OVERALL decreases activity of cell
What are the effects of opioids?
How is pain perceived?
- 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
How does the dorsal horn modulate pain transmission?
Substantia gelatinosa = Mini brain in spinal cord which is further processing the pain information -> subtler response in diminishing pain sensation
Where do opioids act?
Where would opiates act in the reward pathway?
Act to depress GABA neurones, to increase VTA and release of DA
How do opioids acts as anti-tussives?
- 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.
How does respiratory depression occur?
- 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
How do opioids cause nausea/vomiting?
Low doses of opioids activate mu opioid receptors in the chemoreceptor trigger zone (CTZ), thereby stimulating vomiting.
How do opioids cause miosis?
- 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.
What happens to GI function with opioids?
Constipation, slowing down of gut function
How do opioids cause urticaria?
- 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.
How do opioids cause tolerance?
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
How do opioids cause dependence?
When opioids are withdrawn, overactive AC is left, which leaves you with psychological problems, but after 2 weeks(ish) the cell activity decreases
What occurs in an opioid overdose?
Where do diuretics target?
Along the whole length of the kidney
What occurs in the proximal tubule cell?
- 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
What is the countercurrent effect?
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
What are the 5 main classes of diuretics and where do they act on the nephron?
- Osmotic diuretics - e.g. mannitol
- Carbonic anhydrase inhibitors e.g. acetazolamide
- Loop diuretics e.g. frusemide (furosemide)
- Thiazides e.g. bendrofluazide (bendroflumethiazide)
- 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
Where does Mannitol act - osmotic diuretics?
What is the action of Carbonic anhydrase inhibitors - Acetazolamide?
Where do loop diuretics act?
- 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
What is the action of loop diuretics - frusemide?
x
Where do thiazide diuretics (bendroflumethiazide) act?
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
What is the action of thiazide diuretics - bendroflumethiazide?
What occurs in the descending limb of the loop of henle?
Freely permeable to water, with water moving straight from tubule lumen through the epithelial cells into the interstitium
What occurs in the ascending limb of the loop of henle?
- 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
What occurs in the distal tubule cell?
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
What occurs in the collecting duct cell?
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
What is the overall loss and gain of ions and water in the renal tubule?
x
What is the action of mannitol (osmotic diuretics)?
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
Where do carbonic anhydrase inhibitors (acetazolamide) act upon?
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
What do K sparing diuretics act on in the cell?
Spironolactone blocks the mineralocorticoid receptor antagonist so blocks the MR and stops aldosterone’s effects (decreases Na reabsorption, diuretic effect); amiloride blocks Na channel
What are the actions of K sparing diuretics?
x
What are the common side effects of diuretics?
x
Why do you get hyperuricaemia with diuretics?
- 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
How do we treat HTN with diuretics?
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
Why are thiazides good for HTN but not other diuretics?
Initial effect is due to diuresis, but chronic use leads to decrease in TPR
How are diuretics used in HF and oedema?
- 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
