Pharmacology Mbchb4

ADVERSE DRUG REACTIONS (ADR)

1. Definition - adverse effect
a. Harmful, unpleasant and significant effect
b. At a therapeutic dose
c. Cf - Side effect which is usu undesirable but can be desirable
2. Statistics
a. 5-7% of hosp admissions thought to be a consequence an ADR (eg – PU bleeding from NSAIDs)
b. 6% suffer an ADR during their hospital admission – 0.3% thought to die from it
c. Approx ½ of ADRs occurring in hospital are preventable
3. Reducing adverse effects
a. Don’t prescribe medication that is not reqd
b. Avoid medications with serious adverse effects if a better tolerated alternative is available
i. Eg – b-blockers and amiodarone equally effective for rate control in AF
ii. Amiodarone assoc with incr side effects – eg ILD, Thyroid dis, Photosensitiviity, Peripheral neuropathy, Hepatic steatonecrosis
iii. Only use amiodarone if all other drugs (eg b-blockers, diltiazem) are ineffective
c. Don’t use high doses if not reqd
i. Eg – Digoxin for rate control
ii. Renal impairment causes decr excretion and thus incr drug concentrations
iii. Higher concentrations will cause toxicity – eg vomiting
iv. Reduced digoxin dose reqd in renal impairment
d. Failure to recognise adverse effects early in occurrence
i. Eg – Carbimazole for thyrotoxicosis
ii. Uncommon but serious side effect of carbimazole is neutropenia
iii. Warn pt that they should see their doctor if they have a fever and sore throat as these can present as the first sign of neutropenia
iv. If concerned about pt – check their wcc
v. Early recognition of neutropenia can prevent a life threatening problem
4. Types of ADR
a. Type A - Augmented
i. Predictable from known pharmacology
ii. Exaggeration of known effect
iii. Usu dose related (higher dose = higher chance of ADR)
iv. Ex. – hypotension related fall after starting high dose anti-HTN agent
b. Type B – Bizarre
i. Idiosyncratic
ii. Usu not dose related
iii. Can occur even with small doses
iv. Many are immunologically mediated
1. incr likelihood with proteins – eg antibody forming against insulin
2. drug binds to carrier protein becoming immunogenic eg penicillin metabolite ‘penicilloyl’ causes ADR
a. 20 years ago, more impurities in penicillin; impurities were immunogenic
b. If uncertain of penicillin allergy, skin testing may be appropriate
c. Always ask pt when they had their penicillin allergy, have they been prescribed amoxicillin or augmentin by their GP and if so what happened – bottom line, many pts reporting a penicillin allergy don’t actually have one!
5. Antibody mediated reactions
a. Immunological mediated – typically type 1 IgE antibodies
b. Pseudoallergic reactions – eg codeine, contrast medium
i. Drugs which directly activate mast cells w/o Ig involvement
c. ?IgG - Methyldopa – centrally acting anti-HTN agent
i. IgG antibodies causing haemolytic anemia
d. Serum sickness type reactions
i. Antibodies form immune complexes causing rash (urticarial), fever, arthritis
ii. Originally identified from horse serum
iii. Eg - cefaclor
6. Cell mediated reactions
a. T cell mediated reactions
b. Eg – Carbimazole and neutropenia
c. Eg – Fluclox, Omeprazole and Interstitial nephritis
i. Assoc w renal impairment
ii. WCC in sterile urine
iii. Renal changes in interstitium – when drug stopped, pt returns to normal
7. Susceptibility to drug reactions
a. Renal or hepatic impairment leading to incr concentrations – eg digoxin and vomiting
b. Slow metabolism – genetic polymorphisms
i. Ex – CYP 2D6 occurring in 6-10% of Caucasian populations
ii. Perhexiline (last line anti-anginal agent for refractory angina in candidates unsuitable for revascularisation)
iii. Hepatoxocity related to slow metabolism of Perhexiline in pts w 2D6 genetically slow metabolisers
c. Elderly – related in part due to reduced hepatic metabolism and reduced renal clearance but also due to polypharmacy
8. Recognition of drug reactions
a. Clinical trials
i. Typically 1-3000 particpants
ii. Children and elderly often excluded
iii. High chance of picking up ADRs if more than >1%
iv. Rare ADRs unlikely to be picked up – eg aplastic anemia with chloramphenicol 1/25,000
b. Spontaneous reporting
i. Dunedin – centre for adverse reactions to medicines (CARM)
ii. Encourage all doctors/health professionals to report any serious or unexpected ADRs – via website
iii. Eg – ACEI causing cough was picked up through this (cough is an unexpected side effect)
c. Intensive Medicines Monitoring Program (IMMP)
i. Certain medications are flagged
ii. All ADRs assoc w these medications
iii. Currently – olanzapine, respirodone, quetipine (anti-psychotics)
1. Typically weight gain, incr DM risk in addition to weight gain, incr stroke risk
d. RCTs
i. Eg – COX2 inhibitors assoc w incr MI risk
ii. Most vigorous method but often not possible, esp if adverse effects are rare
e. Cohort Study
i. Whole group of individuals with those who get medication compared to those who dont
f. Case control study
i. Group of pts who present with a problem
ii. Compare those who were treated with drug and those who were not
iii. Eg – Fenoterol and asthma death
9. Is it an ADR?
a. Timing – does the ADR occur soon after giving the drug
b. If you stop the drug, does the ADR stop
c. If in doubt, re-challenge (not always ethical)
10. Class Effect
a. Eg – all statins assoc w myositis

DRUG INTERACTIONS

1. Definition
a. Drug interaction – when the effect of one drug is changed by the presence of another
b. Synergistic (more than additive) or Antagonisitic
c. Beneficial or Undesirable
d. Thousands of interactions have been reported but only a small proportion are clinically relevant
2. Beneficial Interaction
a. Eg – Naloxone antagonises opiate overdose
b. Eg – Anti-cholinergic agents (benztropine) to counter extra-pyrimdal effects of neuroleptic drugs such as haloperidol
3. Case example
a. 80 M c/o dizziness when standing up
b. Current txs – frusemide, alendronae, digoxin, doxazosin, fluoxetine, omeprazole, warfarin
c. Doxazosin and Furosemide – combine to cause dizziness, postural hypotension
d. Warfarin metabolism inhibited by fluoxetine – cause incr warfarin conc
4. Interactions in elderly more likely bec -
a. Tx w >1 med
b. Impaired homeostatic mechanisms
c. Reduced renal clearance, hepatic clearance
5. Take a complete medication hx
a. OTC meds – eg aspirin
b. Herbal meds – eg St johns wart
c. Inhaled meds
d. Other topical meds
e. OCP
6. Drug Interactions
a. Pharmacodynamic
i. Where one medicine influences the action of another medicine w/o changing the conc
ii. Receptor mediated
1. Salbutamol and B-blockers
2. Adrenaline and B-blockers
3. L-dopa and metoclopramide
4. SSRI and MOA
a. Serotonin Syndrome – characterised by myoclonus, hypereflexia, confusion, shivering, sweathing, tachycardia, nausea, diarrhea, abdo cramps
iii. Non-receptor Interactions
1. NSAIDs and fursemide – NSAIDs may antagonise the effects of furosemide
2. B-blockers and diltiazem – decr HR leading to incr risk of heart block
3. Aspirin and warfarin – may be beneficial or harmful
4. Amiloride and spironoloactone – both k sparing
5. Alpha-blockers and frusemide
6. Benzodiazepines and alcohol
b. Pharmacokinetic
i. Where one medicine alters the conc of another med eg where one med induces or inhibits the metab of another med by the liver
ii. Act by influencing -
1. absorption
a. Antacids – form insoluble complex when co-administered with tetracyclines or fluoroquinolones leading to reduced absorption
b. Ketaconazole – requires acidic evt for absorption, PPI reduces absorption
c. Bisphosphonates – food and calcium salts interfere w absorption (take on empty stomach)
d. Antibiotics –
i. In 10% of individuals digoxin is metabolised by intestinal flora, A/B thus can incr absorption of digoxin
ii. ?OCP – intestinal bacteria hydrolyse conjugates of ethinyloestradiol prior to enterohepatic recirc; effects of A/Bs on efficacy of oral contraceptives is controversial
iii. Warfarin – Vit K is synthesed by intestinal bacteria; Broad spec A/Bs can potentially incr INR by decr Vit k absorption
2. hepatic metabolism
a. induction or inhibition of metabolism by CYP450 can occur
b. most impt is 3A4 (and 3A5, 3A7) and others incl 2D6, 2C9, 2C19
c. CYP3A4
i. Macrolide antibiotics
ii. Benzodiazepines
iii. HIV protease inhibitors
iv. CCBs
v. HMG CoA reductase inhibitors
vi. Cyclosporine
d. CYP2D6
i. B-blockers
ii. TCAs
iii. SSRIs
iv. Antipsychotics
v. Codeine, dextromethorphan, tramadol
e. 2C9
i. NSAIDs
ii. Oral hypogly agnets
iii. AT2 R Antagonists
f. 2C19
i. PPIs
ii. Anti-convulsants
g. Enyzme Induction
i. Results in synth of new enzyme
ii. Leads to incr drug metabolism and thus decr concentrations of the drug
iii. Occurs w CYP3A4, CYP2C9 but not with 2D6 or 2C19
iv. Inducers of 3A4
1. Hypericin (active component of St johns wart) bind to pregnane X receptor (PXR)
2. PXR promotes transcription of gene for CYP3A4
3. Induces or 3A4 incl phenytoin, phenobarbitone, rifampicin, carbamaepine, St johns wart
h. Enzyme Inhibition
i. Reversible binding of med to P450 enzyme
ii. Irreversible binding
iii. Inhibitors of 3A4
1. Protease inhibitors
2. Macrolides – erythromycin, clarithroymcin
3. Azole antifungals – ketaconazole
4. Grapefruit juice
iv. Fluoxetine
1. Inhibitory effects on phenytoin, warfarin, TCAs
a. Phenytoin - ↑ conc (narrow t.index)
b. Warfarin - ↑ INR
2. Long ½ life so reactions can persist for ~2 wks
i. Warfarin
i. Large number of interactions
ii. Impt bec narrow t.index
iii. Inducers → ↓ conc - eg rifampicin, carbamazepine
iv. Inhibitors → ↑ conc - eg *amiodarone, co-trimoxazole, metronidazole, fluoxetine
j. Not all interactions that involve inhibition involve P450
i. Azathioprine converted to 6-mercaptopurine which in turn is metabolised by xanthine oxidase
ii. Allopurional inhibits xanthine oxidase
iii. If start allopuriol, then have to reduce the dose of azathioprine by 2/3s
k. P-glycoprotein is an efflux pump
i. Pumps drugs across bbb and into lumen of gut and renal tubules
ii. Many drugs that are substrates for CYP3A4 are also substrates for P-glycoprotein
iii. Digoxin is also a substrte for p-glycoprotein
iv. Digoxin-erythromycin interaction is due to competition for p-glycoprotein
3. renal clearance
a. interactions can occur when drugs share the same mechanism for tubular secretion
b. A number of acidic drugs share the same transporter –
i. Probenecid-penicillin
ii. Methotrexate

CLINICAL PHARMACOLOGY – PRINCIPLES OF THERAPY

Visit 1

35 F
Receiving tx for asthma and HTN
Current meds
1. Fluticasone (250mcg) 2 puffs bd
2. Salbutamol (100 mcg) 2 puffs prn
3. Bendrofluazide 2.5 mg od
4. Ethinyl oestradiol 30 mcg + Levonorgestrel 150 mcg od
Her asthma is well controlled, few sxs and hardly ever uses salbutamol inhaler, lung function tests invariably normal
She had a single generalised seizure one year before; she was not started on anti-convulsants at this time
Last BP 165/100

PC – fever, muscle aches, running nose, sore throat, asthma has not become worse, BP similar to before
1. Dx – viral illness
a. Strep infection – usu no running nose or myalgia
2. Management
a. A/Bs not reqd – explain likely viral illness, that A/Bs wont work and there is a risk of side effects, developing resistance etc
b. Paracetamol
c. Nasal decongestant
d. Rest
3. BP – ask her return in approx 4 wks for a repeat BP

Visit 2

Her BP remains high on further measurements – 160/100
Note - OCP can cause HTN
She is already taking bendrofluazide, what other classes can you choose from –
1. ACEI / AT2R Blockers
2. B-blockers
3. CCBs
4. A-blockers

What considerations are made when choosing a medicine – ECA IEC
1. Efficacy
a. A-blockers – theoretical, no real EBM of efficacy
b. B-blockers – less effective at preventing stroke
c. All 3x other drugs equally effective
2. Contraindications
a. B-blockers – C/I in asthma
3. Adverse effects
a. ACEI – cough
b. B-blockers – fatigue
c. CCBs – swollen ankles, headache, flushing
d. All classes relatively equal in adverse effects except possibly less with AT2R Blockers
4. Interactions
5. Ease of administration
a. OD meds have greater compliance eg Cilazapril
b. BD meds less compliance eg Quinapril
6. Cost
a. Prices similar except thiazides dirt cheap and AT2 R blockers expensive

Felodipine 10 mg od is added to tx regime (contradicts the ABCD rule, but this is apparently ok; thiazides and CCBs work well together)

She returns 3 weeks later
BP is 130/75, but she is c/o of ankle swelling, flushing and headache (common side effects of felodipine)

Felodipine 10 mg od is a large dose
Choice of dose should be influenced by –
1. dose-response r/ship – eg graph of conc vs dose?? (as dose incr, therapeutic effect may not incr much, but side effects can incr sig)
2. therapeutic index – narrow therapeutic index means small changes in dose can have dramatic effects on side effects
3. disease states that influence the response of the medicine –
a. eg renal impairment can impact on drug conc levels
b. eg benzos and respiratory depr in COPD (dis state causes incr sens to medication)
4. potential drug interactions – drug concentrations affected by presence of other drugs

Principle – Use the lowest dose that has desired effect
Felodipine reduced to 2.5 mg od
BP 140/85 (target BP for her) and adverse effects have resolved

Visit 3

She expresses concerns about the high dose of inhaled steroid she is taking
Low dose inhaled steroids are generally safe
High dose inhaled steroids can have side effects due to systemic absorption – eg skin thinning, osteoporosis

It is appropriate to reduce her inhaled steroid from 250 to 125 mcg 2 puffs bd

Principles
Meds should be reviewed at regular intervals and meds not of value should be discontinued

Polypharmacy
1. incr likelihood of adverse effects
2. incr likelihood of interactions
3. reduced compliance

Visit 4

6/12 later has seizure
Tx – sodium valproate started

Is there any point in measuring serum drug concentration?
No – poor r/ship betw serum conc of drug and therapeutic effect
Therapeutic drug monitoring (TDM) may be helpful –
1. when there is a r/ship betw serum conc of drug and its effect
2. narrow therapeutic index
3. difficulty measuring clinical outcome

www.bnf.org (British MIMS)

THERAPEUTIC DRUG MONITORING (TDM)

1. Misconceptions
a. You should measure a drug conc bec you can
i. Eg – digoxin 0.125 mg /day for rate control in AF
ii. If well controlled AF and no adverse reactions, there is no need to measure the conc
iii. Only measure a drug conc if there is an ineffective response or you are suspicious of side effects
b. You should adjust the dose so that it is in the normal range
i. The normal range is only a guide
ii. Variability of response
1. Single greatest effect on variability of response = compliance
2. Clearance has the 2nd most sig effect on response (ADME = absorption, distbn, metab, excretion)
3. Measuring a serum conc overcomes these two most sig effects
iii. Clinical endpoints are easily measured
1. Eg – BP for anti-HTN meds
2. Eg – Lung function tests for bronchodilators
3. Eg – INR for warfarin
4. EG – BG for oral hypoglycaemics
2. Application of TDM
a. Not necessary if no need for a drug to be individualised - Eg – penicillin for strep pharyngitis – the dose far exceeds any individual response
b. Unhelpful if serum conc not related to pharm effect – eg phenothiazines for psychosis
i. Exception is clozipine – low conc and ineffective requires incr dose
c. May be useful for narrow t.index where even a small incr may lead to toxicity
d. May be useful if event is potentially serious but occurs infrequently – eg epileptic seizures, cardiac arrhythmias
i. Phenytoin, Carbazemepine – low conc = high risk of seizures
e. Role in detecting non-compliance – ie if serum conc undetectable, it is unlikely the pt is taking their meds
f. Can help determine whether a sx is due to an adv effect or not
3. Timing of serum concentrations
a. Wait until steady state – 4-5 ½ lives
b. Commonly measure trough concentrations (consistent and reproducible)
i. Esp impt if short ½ life, less impt if long ½ life
4. TDM is essential with some meds due to risk of toxicity
a. Lithium
b. Aminoglycosides
c. Perhexiline (hepatotoxicity – if they reach this stage, likely fatal)
5. TDM is helpful (but not essential) in other meds (ie TDM not reqd if pt is doing well)
a. Phenytoin
b. Carbamazepine
c. Theophylline
d. Digoxin
e. Cyclosporin – subtherapeutic levels means incr risk organ rejection
f. Clozapine
6. Lithium
a. Indication - BPAD (bipolar affective d/o)
b. 100% renal clearance
c. Narrow T.index – high risk of adv effects
d. Adv effects –
i. Mild – n/v, diarrhea, abdo pian, sedation
ii. Severe – dsyarthria, ataxia, seizures, coma
e. Conc can be incr by
i. Dehydration – incr renal tubule absorption of lithium
ii. Thiazides
iii. NSAIDs – incr lithium resportion
f. Monitor every 3-6 months (more often with intercurrent illness)
g. Measure trough levels (12 hours post dose)
h. Therapeutic range 0.6-1 mmol/L
7. Aminoglycosides (Gentamicin)
a. Ototoxicity – hearing/vestibular
b. Nephrotoxicity – acute tubular necrosis, small rise in creat common but severe RF can occur
c. If Gent >1 day – TDM essential
d. In young person, 2 doses/days of tx negligible effect (more risk with renal impairment)
e. OD dosing – conc should be negligible at 24 hrs (trough levels measured)
f. If measure 2x levels >4 hrs apart – can calc area under curve
8. Digoxin
a. Measure conc 6 hrs post dose
b. Absorption – Plasma – Cardiac Muscle
i. 2 hrs for absorption to plasma, 4 further hrs for absorption into cardiac mus
c. Conc = 1-2.6 nmol/L
d. DIG study – Digoxin in CHF/Sinus rhythm – Aim for lower end of therapeutic range assoc w improved survival
e. Give digoxin at night to facilitate testing the following morning
f. Wait 4-5 ½ lives for steady state – approx 1 wk
9. Theophylline
a. 3rd line med in a/w dis
b. 90% liver metab (1A2)
c. 4x variation in clearance in a normal popn
d. Clearance further decr in HF and concomitant…
e. Initiate tx w low dose + check conc at steady state (approx after 3 days)
f. Therap range 55-110 umol/L – but benefit may occur at lower concentrations
10. Phenytoin
a. Displays saturation kinetics
b. Most drugs have linear kinetics – ie double the dose = double the conc
c. Exceed capacity of the liver to metabolise and a small incr in dose may have large effect on conc
d. Small incremental changes in dose reqd
e. Long ½ life – wait 1-2 wks before checking conc after dose adjustment

Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License