4. Pharmocokinetics (part three)

Varying in drug concentration levels in plasma

• Normally when a drug is administered, the concentration peaks and then it starts to drop, then by administering more of the drug, the drug concentration will increase again. (causes zig zag pattern)

• By drip infusion you can administer drug at a constant rate so that a steady state can occur.

When does steady state occur in drip infusion?

After five half-lives

What if you urgently need to reach steady state and cannot wait five half-lives.

• You can administer a loading dose

• This is a larger-than-normal initial dose of a medication given at the start of treatment to quickly reach a target therapeutic level in the body.

What do doctors do if pharmocokinetic behavior of drug is so unpredictable?

• Therapeutic drug monitoring

• Doctor takes blood samples to measure concentration of drug in blood

• Happens when effect of drug doesnt occur or if toxicities occur.

• Can be used to check if patients are taking drugs as they should (some drugs do not give immediate effects

Drugs in a formulation

• Drug substances are mostly administered as part of a formulation (tablet, cream, etc.)

• Formulations are combinations with one (or more) ‘pharmacological inactive’ agents that serve varied and specialized functions:

  • Stability

  • protection

  • to allow processing into a tablet

  • etc.

targeted and delayed release

• Targeted release → often a tablet with coating that only released at a certain pH value.

• Delayed release → if you have slow release, then there isn’t a spike in plasma concentration

What are reasons for different formulations

• Besides targeted and delayed release:

• Pharmaceutical, technical or economical reasons

  • Improved stability → lower tablet dose

  • Mask taste or smell

  • To protect the drug against the stomach pH.

• Physico-chemical properties of the active compound

  • Salt, ester, prodrug

  • crystalline structure

  • particle size

• the drug vehicle

  • Disintegrants, surfactants, coatings etc.

  • Solvent(s)

• Production process

  • Compression force

  • Suspension technique, stirring etc.

Tablets

• Convenient

• Stable

• Easy administration

• Palatable

• Flexible

What do tablets contain?

• Diluents or fillers to increase the bulk of the formulation

• Binders to cause the adhesion of the powdered drug and inactive ingredients

• Anti-adherents or lubricants to assist the smooth tableting process

• Disintegrating agents to promote tablet break up after administration

Uncoated tablet

• Rapid disintegration

Why modified release formulations?

Therapeutic reasons, for example

• Site specific delivery

• to achieve a desired pharmacokinetic (PK) profile

• To reduce potential side-effects

Technical or pharmaceutical reasons, for example

• Stability issues (Before or after administration)

• Multiple active components in one formulation

• Taste

• Solubility

What is a modified release formulations

A modified-release formulation (or dosage form) is a pharmaceutical preparation designed to alter the rate and/or site of drug release compared with an immediate release preparation administered by the same route.

What are the technologies behind modified release? (microporous membranes)

• Has drug on inside and microporous membrane on outside.

• This would allow water to slowly penetrate into drug and then building up pressure on the inside.

• Alternatively there is one single small hole that allows penetration of water (EOP)

Capsules

• Hard or soft gelatin

• Outer shell

• Inside: liquid, oil, powder, grains

• Food supplements (e.g. fish oil)

Oral mucosal route

• Buccal mucosa (in cheek)

• Sublingual mucosa (under tongue)

• Only for tasteless drugs (otherwise nastyy)

• Rapid effect

• Avoid first-pass metabolism

Rectal route

• Local action

  • Constipation, inflammatory bowel disease

• For babies or children if they cannot swallow

• Avoides first pass effect.

What are the five parenteral routes?

• Intravenous (i.v.)

• Intramusuclar (i.m.)

• intraperioteneal (i.p.)

• Subcutaenous (s.c.)

• Intradermal (i.d.)

Dosage forms for parenteral routes

• Solutions

• Suspension

• emulsion

• Solids (e.g. for implants)

Steps towards systemic exposure after parenteral routes depending on the different dosage forms

• Solution in water = best → diffuses rapidly into capillaries

• Suspension in oil = hardest → has to dissolve first, then diffuse then partition into tissue fluid → may take a lot of time.

I.v. parenteral nutrition (for who, composition of iv, where, complications)

• Who: patients who are severely malnourished or have contradictions to enteral feeding

• Amino acids, dextrose, fat emulsions, vitamins, trace elements, electrolytes, may add medications

• Where: most often central nervous line

• Complications: secondary to central venous access, infection and sepsis, metabolic complications

Pulmonary adminstration

• Local action (e.g. asthma)

• Systemic action (e.g. anaesthetics)

• Advantage

  • Rapid effect

  • No first pass effect

• Sprays, solutions, aerosols

Transdermal route

• Local action (e.g. corticosteroid cream)

• Systemic action (e.g. morphine patch)