Clinical Pharmacology Revision Lecture 2005

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Clinical Pharmacology Revision Lecture (2005)
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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)

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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!

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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??

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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

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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!

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Drugs and Medical Emergencies
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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 ??

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Management of acute severeasthma in adults in
hospital
Management of acute asthma. Thorax 2003 58
(Suppl I) i1-i92
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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
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Management of acute severe asthma in adults in
AE PEF lt33 predicted
Management of acute asthma. Thorax 2003 58
(Suppl I) i1-i92
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Steroids and other therapyfor acute asthma in
adults
Management of acute asthma. Thorax 2003 58
(Suppl I) i1-i92
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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.

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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.

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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

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Drugs and Chronic Disease Management
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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.
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Stepwise management ofasthma in adults
Pharmacological management. Thorax 2003 58
(Suppl I) i1-i92
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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 ?

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(No Transcript)
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NICE Guidelines for Management of Systolic Heart
Failure - 2003
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Why do Patients vary in their response to Drugs?
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The Origin of patient to patient Variability (1)

• Genetics (PHARMACOGENOMICS)
• Disease
• Age (weight)
• Concomitant drugs
• Gender

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The Origin of patient to patient Variability (2)

• Noncompliance - underestimated
• Route of Administration - bioavailability
• Food - protein malnutrition
• Pollutants - smoking/herbicide residues
• Timing - chronopharmacology

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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)

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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)

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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.

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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

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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

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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.
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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).

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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

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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

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The Goal for your future prescribing

• Make sure it is
• Efficacious
• Safe
• Cost efficient