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Clinical Pharmacology Revision Lecture 2005

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Title: Clinical Pharmacology Revision Lecture 2005


1
Clinical Pharmacology Revision Lecture (2005)
2
Drug Safety has always been a concern . and
should remain so
  • First do no harm it is a good remedy sometimes
    to use nothing.
  • (Hippocrates, 5th Century BC)
  • All things are poisons and there is nothing that
    is harmless the dose alone decides that
    something is a poison.
  • (Paracelsus, 1500s)
  • Patients may recover in spite of drugs or
    because of them.
  • (Gaddum, 1959)

3
Adverse Drug Reactions ADRs
  • Can be defined as, an unwanted or harmful
    reaction experienced following administration of
    a drug, or combination of drugs, under normal
    conditions of use and is suspected as being
    related to the drug (or combination)
  • italics not included in some definitions, which
    therefore allows inclusion of accidental drug
    overdose, failures of patient compliance etc
  • Some sources refer to this wider definition as
    ADEs (Adverse Drug Events)
  • Easy to get lost in the semantics!

4
Importance of ADRs - 1
  • Causes considerable morbidity and mortality
    treating this is very expensive
  • Data on incidence is poor considering the scope
    of the problem
  • Typical figures for the USA (where most studies
    have been done) suggests
  • precipitate 1-4 of acute medical admissions
  • 4-9 of inpatients suffer an ADR
  • 7,000 deaths per annum directly reflect an ADR
  • some sources put the figure closer to 100,000
  • Cost for the US health care system gt 100b/year
  • UK estimate 400m??

5
Importance of ADRs - 2
  • Majority are preventable
  • Strategies for prevention include
  • Ward pharmacists
  • Electronic prescribing and dispensing
  • Already in Primary Care/GPs
  • Extension to Hospitals
  • Better education

6
Evidence-Based Therapeutics
  • What is the evidence that a drug works as
    intended?
  • Efficacy does not necessarily mean it will
    improve clinical outcome e.g.
  • a drug may lower cholesterol but does it affect
    CHD deaths?
  • RCTs (based on clinical outcome) are the
    gold-standard
  • Many areas of therapeutics lack this evidence
    base
  • Be cynical especially of Pharma marketing!

7
Drugs and Medical Emergencies
8
The Use of Adrenaline in Anaphylaxis
  • The problems with its use
  • Variable Absorption - give I.m. AVOID s.c.
  • Arrhythmogenic in high dose - NEVER give 11000
    ADRENALINE I.v.
  • If infusing ADRENALINE, it must be diluted . and
    dont delay administration of ADRENALINE to set
    up IVI and gain IV access.
  • Therefore
  • 1. Give ADRENALINE I.m promptly (can repeat at
    5-10 min intervals)
  • 2. Gain IV access
  • 3. If patient remains shocked resort to IVI thus
    .
  • Dilute 0.5ml of 11000 ADRENALINE in 50ml
    of N/saline (1100,000)
  • 4. Infuse at 0.1-2ml/min (1-20ug/min) until
    haemodynamically stable
  • 5. If using prolonged IVI, add renal-dose of
    DOPAMINE IVI ??

9
Management of acute severeasthma in adults in
hospital
Management of acute asthma. Thorax 2003 58
(Suppl I) i1-i92
10
Management of acute severeasthma in adults in
hospital
Caution Patients with life threatening attacks
may not be distressed and may not have all these
abnormalities. The presence of any should alert
the doctor.
Management of acute asthma. Thorax 2003 58
(Suppl I) i1-i92
11
Management of acute severe asthma in adults in
AE PEF lt33 predicted
Management of acute asthma. Thorax 2003 58
(Suppl I) i1-i92
12
Steroids and other therapyfor acute asthma in
adults
Management of acute asthma. Thorax 2003 58
(Suppl I) i1-i92
13
Treatment of hyperkalaemia-1
  • Depending on the severity, the following measures
    are appropriate
  • Stop any K-sparing diuretic or K supplements
  • Increase gut K excretion with oral (not PR)
    cation-exchange resin, e.g. polystyrene
    sulphonate resin (Resonium A, Calcium Resonium)
  • Move K rapidly from plasma into cells by giving
  • (1) Glucose (50ml of 50 solution) plus 10 units
    of soluble insulin by i.v. infusion.
  • (2) Sodium bicarbonate i.v. (50ml of 8.4
    solution through a central line) and repeating
    this in a few minutes if the characteristic ECG
    changes persist.
  • (3) Nebulised ?2-agonist (5-10mg of salbutamol)
    is effective in stimulating the pumping of K into
    skeletal muscle.

14
Treatment of hyperkalaemia-2
  • In the presence of ECG changes, give Calcium
    gluconate (10ml of the 10 solution) i.v. and
    repeated if necessary in a few minutes - it has
    no effect on the serum K but opposes the
    myocardial effect of an elevated serum K.
  • Ca may potentiate digoxin and should be used
    cautiously, if at all, in a patient taking this
    drug. NaHCO3 and Ca salts must not be mixed in a
    syringe or reservoir because calcium
    precipitates!
  • Dialysis may be needed in refractory cases and is
    highly effective.

15
Who should NOT be thrombolysed?
  • Risk of serious bleeding is low particularly in
    the absence of heparin (lt1 risk in major
    trials).
  • It arises from
  • Lysis of physiological clots
  • A systemic lysis state (depleting fibrinogen,
    FV and FVIII)
  • The following are generally contraindications
  • Active bleeding or haemorrhagic disorder
  • Aortic dissection
  • Significant GI bleed in the previous 3 month
  • Recent cardiovascular surgery or bowel resection
  • Pericarditis
  • Poorly controlled hypertension (DBP gt110 mmHg)
  • Proliferative retinopathy
  • CVA in past 3 months or SOL such as
    abscess/tumour
  • Pregnancy

16
Drugs and Chronic Disease Management
17
2003 BTS Guidelines for Chronic Asthma
Step 1 prn (lt once daily) short-acting ?2
Step 2 regular inhaled GCC (200-800?g/d) Step
3 Add long-acting ?2 (LABA) and assess response
- if none stop and optimise inhaled GCC Step 4
trials of high-dose inhaled GCC (2000?g/d with
spacer) or oral theophylline, leukotriene
antagonist or oral ?2 Step 5 Add oral
prednisolone (/- steroid-sparing agent)
reliever or rescue medication vs.
anti-inflammatory agents as preventers
prn short-acting ?2 agonist
Points to note 1. Patient treatment should be
reviewed/adjusted at least every 3-6 months. 2.
Step down rapidly from high dose oral steroids if
PEFR responds promptly i.e. within a few days,
otherwise need to be stable for 1-3 months before
attempting more gradual step down.
18
Stepwise management ofasthma in adults
Pharmacological management. Thorax 2003 58
(Suppl I) i1-i92
19
Drug Delivery Systems in Asthma Metered-dose
Inhalers MDIs
  • Pressurised MDI (pMDI)
  • CFC (being replaced by HFA) propellant
  • Require co-ordinated activation/inhalation
  • Dry Powder MDI
  • No propellant
  • Require only priming then sucking
  • Low PEFR a problem (lt60L/min)
  • Delivery humidity dependent ?

20
(No Transcript)
21
NICE Guidelines for Management of Systolic Heart
Failure - 2003
22
Why do Patients vary in their response to Drugs?
23
The Origin of patient to patient Variability (1)
  • Genetics (PHARMACOGENOMICS)
  • Disease
  • Age (weight)
  • Concomitant drugs
  • Gender

24
The Origin of patient to patient Variability (2)
  • Noncompliance - underestimated
  • Route of Administration - bioavailability
  • Food - protein malnutrition
  • Pollutants - smoking/herbicide residues
  • Timing - chronopharmacology

25
Variability Pharmacokinetic factors
  • GI Absorption
  • Gastric pH may be influential
  • Enhances weak acid absorption hence antacids and
    PPI/H2 antagonists will interfere (some drugs are
    packaged with an antacid e.g. antiretroviral
    didanosine)
  • Generally maximal in upper SB
  • Enteric-coating or modified-release formulation
    may shift this into the colon (local pH may be
    crucial for release here e.g. 5-ASA SR
    formulations)
  • Gastric emptying often rate limiting hence .
  • AUC may be increased by metoclopramide/erythromyci
    n
  • AUC may be reduced by antimuscarinics/
    phenothiazines/antihistamines (sedating)

26
Variability Pharmacokinetic factors
  • GI Absorption (continued)
  • Direct Indirect effects of food
  • Drugs with high first-pass
  • (verapamil, propranolol) ? effect with food
    intake
  • Specific effects of certain foods
  • grapefruit juice - felodipine/terfenadine/simvasta
    tin
  • milk/antacids tetracyclines
  • Hypericum - CyA
  • Effect of co-administered drugs
  • Anion exchange resins
  • generally reduce absorption (warfarin, T4
    digoxin)
  • Activated charcoal (used in overdose)

27
Variability Pharmacokinetic factors
  • GI Absorption (continued)
  • First-pass metabolism (inactivation before
    entering the systemic circulation)
  • Gut lumen insulin/benzylpenicillin
  • Gut wall metabolism tyramine/salbutamol
  • Liver metabolism propranolol, verapamil,
    lignocaine
  • Transporters (P-glycoprotein) CyA, taxols
  • Avoided by alternate route e.g. sublingual or
    topical GTN, intranasal insulin, pr ergotamine.

28
Variability Pharmacokinetic factors
  • Drug Elimination
  • Liver disease (cirrhosis) affects first-pass by
  • direct impairment of hepatocellular function
  • shunting drug directly into the systemic
    circulation
  • increased bioavailability may be huge (10-fold
    for chlormethiazole)
  • pro-drug activation may be severely impaired e.g.
    ACEIs
  • hypoalbuminaemia will also complicate the picture
    if free fraction affects clearance
  • certain liver diseases have little PK impact e.g.
    acute viral hepatitis

29
Variability Pharmacokinetic factors
  • Drug Elimination
  • Renal impairment affects
  • renal clearance (direct)
  • protein binding hepatic metabolism (indirect)
  • only binding of acidic drugs (e.g.
    warfarin/phenytoin) are affected
  • HD does not restore reduced albumin binding but
    transplant does
  • reduced hepatic clearance (e.g.
    propranolol/nicardipine) depends on dialyzable
    factors in uraemic plasma
  • active metabolites may accumulate e.g.
    morphine-6-glucuronide

30
Interactions with WARFARIN that matter
Reduced absorption cholestyramine or similar
resins. Reduced protein binding
hypoproteinaemic states e.g. nephrotic
syndrome Altered clearance P450 induction by
rifampicin, barbiturate or phenytoin P450
inhibition by amiodarone, metronidazole and
cimetidine. Altered vit K intake vitamin K
rich foods/supplements or antibiotic induced
reduction in gut-derived vitamin K. Altered
levels of clotting factors reduced in
hypermetabolic states e.g. hyperthyroidism
increased in pregnancy. Augmented bleeding
tendency in combination with antiplatelet
agents e.g. NSAIDs. Substitute non-NSAID
analgesics with care dextropropoxyphene and high
dose paracetamol (1.5-2g/d) can block W
metabolism.
31
Points to remember when you write a prescription
  • ALWAYS write legibly in ink or other indelible
  • ALWAYS sign date the prescription (it is a
    legal document!)
  • NEVER abbreviate drug names
  • NEVER use proprietary names
  • ALWAYS use generic names
  • PREFERABLY use plain English for dosing
    directions
  • When you write the INDIVIDUAL DOSE
  • for STRENGTHS gt1g use grams e.g. 100 g
  • for STRENGTHS lt1g use milligrams e.g. 100 mg
  • for STRENGTHS lt1mg use micrograms e.g. 100
    microgram (NEVER use 'µg')
  • AVOID unnecessary decimal points e.g. use 300 mg
    NOT 0.3 g
  •  
  • Unless a specific formulation is required.
  • Only use BNF recommended Latin abbreviations
    (see inside back page of the BNF).

32
Questions you should ask before you prescribe any
drug
  • Is it really necessary could it replace a drug
    already being taken?
  • Avoid polypharmacy wherever possible, especially
    in the elderly
  • Is the dose correct and the route/formulation
    appropriate?
  • Check with the BNF in all cases during your PRHO
    posts
  • Will concurrent medications interact?
  • Check in Appendix 1 of the BNF
  • Should it continue indefinitely?
  • What is the evidence for its efficacy?
  • Efficacy does not necessarily mean it will
    improve clinical outcome
  • RCTs (based on clinical outcome) are the
    gold-standard

33
Medicines Management - the future?
  • What is driving the change?
  • Escalating drug budget
  • Pressure of new agents
  • 13 NHS expenditure (gt8 billion p.a.)
  • Drug safety and clinical governance
  • Escalating cost morbidity of Adverse Drug
    Events
  • How can safety monitoring be improved (Coxibs)?
  • Developments likely to affect you in the short
    term
  • Adoption of PCT-wide formularies
  • Greater emphasis on guidelines for drug
    management
  • Increased use of generic Rx
  • Increased Electronic Rx

34
The Goal for your future prescribing
  • Make sure it is
  • Efficacious
  • Safe
  • Cost efficient
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