Basic principles

Principles of pharmacology
half life.
Pharmacodynamics is the drug acting on the body.
Pharmacokinetics is the body acting on the drug.
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 Getting into the body
Administration and formulation
Solutions
Formulations
Suspensions
Liquid
Oral
Tablets Less damage to stomach
10% delivery Preparations
Capsules Tasteless
Dry powder
Inhalation Controlled-release
Aerosols Types
Nebulisers Vascular dermis
Subcutaneous Simple for self-administration insulin
Good absorption
Depot effect
Patient doesnʼt need to swallow tablet Rectal
For lipid-insoluble and non-polar drugs
Oil base which melts in rectum
Administration Intravenous
Potential bleeding problems
Sublingual Less accuracy required for injection
Intramuscular Unpredictable absorption patterns
Long-term release possible
Slow absorption
Patches (transdermal) Direct on site
Avoids first-pass effect
Topical
Avoids systemic absorption
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 Absorption

Passive absorption

Fick’s law Gastric emptying Ionisation

Rate of diffusion depends on:
Concentration difference,
Surface area,
Permeability.
Empty stomach = quicker absorption. Ionised Neutral
Fed stomach = slower absorption.
More lipid soluble Less lipid soluble
Polar groups Better absorption Worse absorption

How does this relate to weak acids?

Polar groups Non-polar groups

More lipid soluble Less lipid soluble

Less water soluble More water soluble

Better absorption Worse absorption

More importantly, how does this
relate to pregnant babies?

Membranes are just lipids.

Active absorption

Requires energy.

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 Distribution
Distribution patterns after IV injection
Blood Brain Muscle Fat
Think perfusion of tissues.
Easy.
Watch out for pH changes.
slightly lower
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 Metabolism
Cytochrome P450 Exposes polar groups
Aromatic hydroxylation
Lignocaine Amide hydrolysis
SUBSTRATES
Nifedipine Caffeine Phase 1
Cyclosporine Phenacetin Nitrogen-dealkylation
Mephenytoin
Erythromycin Theophylline
Taxol Terfenadine Debrisoquine Chlorzoxazone
Coumarin S-Warfarin oxidation
Phenytoin Metoprolol
Tolbutamide Dextromethorphan Cytochrome P450 enzymes
Ifosphamide
Varying specificity
2A6 2C19 2C8 2C9 3A4 2D6 1A2 2E1 2B6 Reactions between terfenidine and
ketoconazole Reactions
INHIBITORS
Quercetin Orphenadrine
Tranylcypromine Ketoconazole Furafylline
8MeOPsoralen Sulphaphenazole Quinidine Disulfiram
INDUCERS Glucuronide Glucuronyl-
Omeprazole Ethanol
Phenobarbitone Rifampicin
Isoniazid
Sulphate Sulpho-
Attachment of endogenous molecule to
drug or Phase I metabolite
Acetyl Acetyl-
Methyl Methyl-
Glucuronide conjugation
Phase 2
Sulphate conjugation
Paracetamol
Cysteine and mercapturic acid
conjugates
10% metabolised in phase 1 - toxic Glutathione conjugation
An example.
Depleted in overdose
Transferases
plus a stack of genetics.
Removes AIs from cells Starvation
Fever Alcohol
Intake
Many substrates/inhibitors/inducers
are also of CYP3A4. Cardiovascular Cigarette
Function Smoking
Liver
Age
Function
P-glycoprotein GENETIC
Massive problem for MDR cancers FACTORS
Renal Sex
Function
Decreased absorption in gut
Decreased CNS penetration Effects Gastrointestinal Disease
Function
Reduced excretion through bile/urine Coded from ABCB1 gene Really really complex.
Dietary Factors Herbals
Drugs
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 Prescribing
Prescribing factors
Factors affecting prescribing
You prescribe for a:
1. Pharmacokinetic Type A adverse effects are predictable.
2. Pharmacodynamic Cure for symptoms,
3. Impact on the patient Type B aren’t.
4. Cost Relief from symptoms, Can you titrate the dose?
5. Patient factors
a. previous treatments?
Prevention of symptoms.
6. Doctor factors
a. Familiarity with drug
Post-marketing surveillance by yellow card system
Sold over the counter
Badly labelled
Thalidomide
Badly trialled
Malformities.
Treated arthritis
Small premarketing trial - 3000 people Benoxaprofen Bad times
Type B side-effects
All of the COX, none of the GI bleed Uncertain from trials.
COX-2 inhibitors
2005 − 92% increased risk of thombotic
events
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