16. Dosage Form Design for CV drugs II

Question 1

Nasogastric (NG) tubes

Answer 1

• NG tubes run from outside the body into the nose, down oesophagus & to stomach
• 24” to 36” in length
• External diameter of the tube is expressed using the French (Fr) unit: 1 Fr = 0.33 mm
• The diameter varies from 6 to 16 Fr
• Tubes are composed of PVC, polyurethane, silicone or latex
• NG administration is a convenient route for drugs, foods & liquids

Question 2

NG administration of drugs

Answer 2

Following a stroke a patient may be unable to swallow:

Medications often include:

• Statins
• Hypoglycaemia agents
• Anticoagulants

Requires off licence use of medicines as there are no commercially available liquid formulations for tube administration

Consider:

• Dosing accuracy
• Choice of formulations - crushed
• Interactions - given with foods/liquids
• Occupational exposure

Question 3

Warfarin & NG tubes

Answer 3

• Warfarin may binds to food proteins, therefore withhold food
• Warfarin binds plastics with increased binding at lower pHs
• Better to administer with food!

Question 4

NG tubes - SR/CR formulations

Answer 4

• Formulation excipients (SR/CR) may clog NG tubes

- Consider enteric coated formulations

Question 5

Metoprolol

Answer 5

• Beta-blocker which treats angina & hypertension
• Tartrate & succinate salt formulation available in NZ
• Immediate release & controlled release
• Only tartrate IR can be crushed

Question 6

Heparin

Answer 6

Highly sulphated glycosaminoglycan

Highest negative charge density of any known biological molecule

• Cannot cross intestinal epithelium as passive diffusion is restricted to relatively small lipophilic molecules (plus ionic repulsion between drug & biological membranes)
• Both unfractioned (UH) & low molecular weight (LMWH) must be administered parenterally (IV/SC)

Question 7

UFH - Multiparin

Answer 7

• Heparin sodium 5000 IU/mL
• Solution for injection, or solution concentrate for infusion
• MW c.a. 15 kDa
• Loading dose required followed by continuous infusion
• Anticoagulant response is unpredictable so Activated Partial Thromboplastin Time (APTT) monitoring required
• Continuous IV infusion in 5% glucose or 0.9% NaCl, or by intermittent IV injection, or by SC injection
• Short lived effects, therefore infusion or SC injection is preferred to intermittent IV injection
• Metabolised in liver & inactive metabolite renally excreted
• Heparin is incompatible with many injectables, therefore use different lines or thorough flushing

Question 8

LMWH - Enoxaparin

Answer 8

• Equally effective as UH
• More convenient to use – OD/BD dosing SC
• Mean MW 4500 Da:
  + < 2000 Da, 12-20%
  + 2000-8000 Da, 68-82%
  + >8000 Da, < 18%
• Predictable response:
  + Allows for fixed-weight adjustment of SC dose
  + Most patients don’t require lab monitoring
  o Out-patient treatment possible
• Following SC administration
  + Bioavailability c.a. 100%
  + Unlike UH linear absorption (absorption proportional to dose)
• Ow interpatient variation
• t1/2 = 4 hr (single dose) or 7-12 hr (repeated dosing)
• Different LMWH products are not bioequivalent
  + Differences in MW, specific anti-Xa activities
• Available in prefilled syringes, prefilled graduated syringes & ampoules
• Renally excreted
  + Doses should be reduced if CrCl < 30 mL/min, or change to UH

Question 9

Oral heparin

Answer 9

• SNAC (sodium N-(8-(2-hydroxbenzoylamino) caprylate) is a small carrier molecule (200-400 Da) allowing for heparin to be absorbed from the GIT following oral administration
• Weak non-covalent interaction between SNAC & heparin
• Due to hydrophobic moieties of SNAC a drug/carrier complex is created with increased lipophilicity which enhances epithelial membrane permeability
• Drug/carrier interaction is reversible & dissociation occurs in the blood due to dilution effects

Question 10

Percutanous transluminal coronary angiography

Answer 10

• During PTCA a catheter is inserted with the stent & balloon at its tip
• Once guided to the intended site the stent is expanded

Question 11

Bare-metal stents

Answer 11

• To increase blood flow through an artery, e.g. coronary artery
• Stent placed in narrowed diseased artery
• Risk of immune response & cell proliferation over stent
• Risk of stent thrombosis so antiplatelet therapy required

Question 12

Restenosis

Answer 12

• Restenosis is a reduction in lumen diameter of 50% following intervention
• Compared to PTCA alone an implanted bare metal stent reduces occurrence & severity
• Further improvement shown by drug eluting stents over bare-metal stents in maintaining long term patency of blood vessel

Question 13

Drug-eluting stents

Answer 13

• Aim to reduce risk of immune/thrombotic response
• Usually consist of expandable metal framework & a polymer coating which releases drug
• Used non-immunogenic metal alloys
• Polymer coating of metal stent structure provides the extended release of drug
• Immunosuppressant drug to block cell proliferation
• Once drug is exhausted (6-12 months) polymer remains
• Biocompatibility of polymer of vital importance

Examples of drug eluting stents used in NZ:

• Xience Promus (everlimus)
• Endeavour (zotarolimus)
• Cypher (sirolimus)

Question 14

Xience promus - everolimus

Answer 14

• Indicated for improving coronary luminal diameter in patients with coronary artery thinning
• Permanent implant
• Correct stent length & diameter must be determined
• Stent must be fully expanded to ensure position fixture

Question 15

Tenecteplase

Answer 15

• Recombinant DNA, fibrin-specific plasminogen activator
• A thrombolytic agent indicated for use in acute phase of myocardial infarction
• Administration as a single IV bolus (only thrombotic agent as such)
• Device designed for east of administration
• Dose based on bodyweight