ADME of Medicines Flashcards
What are the oral routes of administration of drugs?
What does this mean for their absorption?
-
Buccal / sublingual
- Direct absorption into the blood stream.
- Avoids first pass metabolism.
- Not ideal surface for absorption.
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Gastric mucosa
- Enteric coating.
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Small intestine
- Main site of drug absorption.
- Large surface area, more neutral pH.
-
Large intestine
- Poor absorption, long transit times.
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Rectal mucosa
- Direct to systemic circulation.
What are the 4 ways in which small molecules cross cell membranes?
- Diffusing directly through the lipid.
- Lipid solubility is highly important.
- Diffusing through aqueous pores.
- More likely important for diffusion of gases.
- Transmembrane carrier protein.
- E.g. solute carriers.
- Pinocytosis.
- Mostly macromolecules, not drugs.
Drugs have physiochemical factors which affect their ionisation.
What does this mean for weak bases and weak acids and their absorption?
-
Weak bases
- Ionised in acidic pH
- Absorbed in the small intestine
- Possibly ionised in plasma.
-
Weak acids
- Unionised in acidic pH.
- BUT also absorbed in small intestine.
- Large surface area.
- Weak base will accept a proton, weak acid will donate a proton. In an acidic environment, weak acids are less likely to be ionised; in a basic acid weak bases are less likely to be ionised. But, in an acidic environment a weak base will be ionised.
- This means that in the small intestine, a weak acid will be favourably absorbed (because an unionised drug will move across the membrane more freely), but a weak base in the small intestine will also be absorbed because the SI is specialised for absorption. So, by being ionised a weak base drug is not at a great disadvantage.
What is the effect of food on drug absorption?
- In general, food tends to slow the rate of gastric emptying.
What direct or indirect effects do antacids and proton pump inhibitors have on absorption?
Causes changes in gastric or intestinal pH.
What direct or indirect effects do laxatives and anticholinergics have on absorption?
Causes changes in gastrointestinal motility.
What direct or indirect effects do vasodilators have on absorption?
Causes changes in gastrointestinal perfusion.
What direct or indirect effects does neomycin have on absorption?
Interferes with mucosal function.
What direct or indirect effects do tetracycline, calcium and magnesium have on absorption?
Causes chelation
What direct or indirect effects does cholestyramine have on absorption?
Causes resin binding
What direct or indirect effects does charcoal have on absorption?
Causes adsorption
List the factors that affect oral absorption.
- Particle size and formulation
- GI motility
- First pass metabolism
- First pass metabolism by the gut wall or hepatic enzymes.
- Physicochemical factors
- Direct drug interactions, dietary factors, varying pH.
- Splanchnic blood flow
- Increased flow increases drug absorption.
- Efflux pumps
- P-glycoprotein.
List the parenteral routes by which drugs can be absorbed.
- Subcutaneous
- Slow absorption due to blood flow.
- Intramuscular
- Lipophilic drugs rapidly absorbed
- Polar drugs via bulk flow and endothelial cell junctions.
- High MWT or very liphphobic drugs via lymphatics.
What factors affect the rate of onset of drugs which are administered parenterally?
- Extent of capillary perfusion.
- Drug vehicle.
- Affected by factors that alter perfusion.
Describe inhalation as a mode of administration of drug.
- Drug absorbed by the alveolar epithelium and bronchial mucosa.
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Systemic effects
-
Lipid-soluble drugs
- Volatile / gaseous anaesthetics
- Drugs of abuse
- Accidental poisoning
-
Lipid-soluble drugs
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Local effects
- Modify structure (ipratropium)
- Particulate size (salbutamol)
- Selectivity for receptors (salbutamol)
- Rapid breakdown in circulation (fluticasone)
Describe intranasal administration of drugs.
- Easily accessible, rich vascular plexus.
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Advantages
- Avoids hepatic first pass metabolism.
- Ease, convenience, safety.
-
Limitations
-
Limited drugs suitable.
- Requires concentrated drug.
-
Limited drugs suitable.
Describe the use of the topical route for administration of drugs.
- Healthy skin as a barrier
- Stratified, squamous epithelium
- Keratinised layer
- Sebaceous gland secretions
- Local effects
- Corticosteroids for eczema (hydrocortisone)
- Antihistamines for insect bites (mepyramine)
- Local anaesthetics (EMLA)
- Systemic effects
- Transdermal patches (HRT, GTN, nicotine)
- Accidental poisoning (AChEsterase insecticides)
- Surface area / volume ratio
List the different types of intravascular devices (IVDs).
- Peripheral venous catheters
- Central venous catheters (CVCs)
- Peripherally inserted CVCs
- Skin-tunneled CVCs (e.g. Hickman and Broviac lines)
- Arterial catheters
What are the 3 methods of administering intravenous medications?
- Continuous infusion
- Bolus injection
- Intermittent infusion
Describe continuous IV infusion.
- Stable drugs
- Short half life
- Time dependent effects
- Needs dedicated IV site
Describe bolus injection.
- Rapid response required
- Incompatibilities
- Unstable drugs
Describe intermittent infusion.
- Unstable drugs
- Long half life
- Concentration dependent effects
- Less compatibility concerns
What are the complications of IV drug administration?
- Fear / phobia / pain
- Infection / sepsis
- Thrombophlebitis
- Extravasation / infiltration
- Emboli
- Anaphylaxis / hypersensitivity
- Overdose
- Insufficient mixing
- Stability of medicines in solution must be considered:
- Light [total parenteral nutrition (TPN)]
- Temperature (e.g. insulin, TPN)
- Concentration (e.g. amiodarone)
- pH (e.g. midazolam)
- Interaction of medicines with the syringe or bag
Describe extravasation and infiltration with respect to IV cannulation.
- In both - the needle tip has gone into a tissue space.
- Extravasation is when there is something which is ‘irritant’ but infiltration is just adding volume to the tissue space.
- They can both be dangerous but extravasation is associated with more tissue damage.
List the factors which affect distribution of a drug.
- Cardiac output and blood flow
- Plasma protein binding
- Lipid solubility
- Degree of drug ionisation
- pH of compartments
- Capillary permeability
What effect does organ perfusion have on distribution of drugs?
- Initial rate of distribution of drugs depends heavily on blood flow.
Describe the effect of albumin binding on the distribution of drugs.
- Albumin is a predominate plasma binding protein (40g/L).
- Lipid-soluble drugs bind non-specifically.
- Weak acids bind to a specific, saturable site.
List the sites of drug metabolism.
- Gut lumen
- Gut wall
- Plasma
- Lungs
- Kidneys
- Nerves
- Liver
List the potential results of drug metabolism.
- Pharmacological deactivation
- Pharmacological activation
- Type of pharmacological response
- No change in pharmacological activity
- Change in drug uptake
- Change in drug distribution
Describe phase 1 and phase 2 of drug metabolism.
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Phase 1 metabolism
-
Generally oxidation, reduction or hydrolysis.
- Introcude / reveal a reactive chemical group.
- “Functionalisation”.
- Products are often more reactive
-
Generally oxidation, reduction or hydrolysis.
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Phase 2 metabolism
- Synthetic, conjugative reactions.
- Hydrophilic, inactive compounds generated (usually).
Give examples of oxidations, reductions and hydrolysis reactions in phase 1 metabolism.
- Introduces of unmasks functional group
- E.g. -OH, -NH2, -SH, -COOH etc.
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Oxidations
- Mixed-function oxidase system (cytochrome P450)
- Alcohol dehydrogenase
- Xanthine oxidase
-
Reductions
- Ketone reduction
- Anaerobic cytochrome P450 metabolism
-
Hydrolysis
- Ester hydrolysis (e.g. cholinesterases)
- Amine hydrolysis
Describe mixed-function oxidase system (CP450s).
-
Microsomal (ER) enzymes
- Liver, kidney, lung, intestine etc.
-
Consists of:
- Cytochrome P450
- NAPDH-CP450 reductase
- Lipid
-
Requires:
- Molecular oxygen
- NAPDH
What are the products of phase 2 metabolism?
- Detoxified, water-soluble, easily secreted products.
- Suitable for excretion in bile or urine.
Describe the factors which must be considered with respect to drug metabolism.
-
Many enzymes capable of metabolising drugs.
- Overlapping substrate specificities.
- Metabolism of endogenous compounds.
-
Potential for competition and saturation.
- Drugs and endogenous compounds for the same enzyme.
- Different enzymes for the same substrate.
- Enzyme can be saturated, conjugate depleted.
-
Issues of variation / induction / inhibition.
- Inter-individual responses can vary
- Substantial issue due to broad specificity of enzymes.
In what form are drugs excreted from the body?
- Drugs are eliminated either unchanged or as metabolites.
- In general, hydrophilic drugs eliminated more readily than lipophilic drugs.
- Possible sources of excretion include:
- Breath
- Urine
- Sailva
- Faeces
- Perspiration
- Milk
- Bile
- Hair
- The kidneys are the most important organs involved in the elimination of drugs and their metabolites.
Describe biliary excretion.
-
Transfer of drugs from plasma to bile
- Organic cation transporters (OCTs)
- Organic anion transporters (OATs)
- P-glycoproteins (P-GP)
-
Concentrated in bile, delivered to intestine
- Hydrophilic drug conjugates (e.g. glucuronides)
- Hydrolysis of conjugate can occur
- Reabsorption of liberated drug
- Enterohepatic circulation
Describe enterohepatic circulation.
Which drugs are metabolised via this pathway?
- Oral antibiotics
- Oral synthetic oestrogens
Describe renal excretion of drugs.
-
Glomerular filtration
- Filters drugs below 20kDa in molecular weight
- Not filtered if drug is bound to plasma albumin
-
Tubular secretion
- OATs and OCTs
- OATs transport against electrochecmical gradient
- Cleared even if bound to plasma albumin
-
Diffusion across renal tubule
-
If tubule is freely permeable, 99% of drug is reabsorbed
- Lipophilic drugs excreted poorly
- Polar drugs remain in the lumen
- Urinary pH?
-
If tubule is freely permeable, 99% of drug is reabsorbed
