ADME of Medicines

Question 1

What are the oral routes of administration of drugs?

What does this mean for their absorption?

Answer 1

• Buccal / sublingual
  
  • ​Direct absorption into the blood stream.
  • Avoids first pass metabolism.
  • Not ideal surface for absorption.
• Gastric mucosa
  
  • ​Enteric coating.
• Small intestine
  
  • ​Main site of drug absorption.
  • Large surface area, more neutral pH.
• Large intestine
  
  • ​Poor absorption, long transit times.
• Rectal mucosa
  
  • ​Direct to systemic circulation.

Question 2

What are the 4 ways in which small molecules cross cell membranes?

Answer 2

• 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.

Question 3

Drugs have physiochemical factors which affect their ionisation.

What does this mean for weak bases and weak acids and their absorption?

Answer 3

• 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.

Question 4

What is the effect of food on drug absorption?

Answer 4

• In general, food tends to slow the rate of gastric emptying.

Question 5

What direct or indirect effects do antacids and proton pump inhibitors have on absorption?

Answer 5

Causes changes in gastric or intestinal pH.

Question 6

What direct or indirect effects do laxatives and anticholinergics have on absorption?

Answer 6

Causes changes in gastrointestinal motility.

Question 7

What direct or indirect effects do vasodilators have on absorption?

Answer 7

Causes changes in gastrointestinal perfusion.

Question 8

What direct or indirect effects does neomycin have on absorption?

Answer 8

Interferes with mucosal function.

Question 9

What direct or indirect effects do tetracycline, calcium and magnesium have on absorption?

Answer 9

Causes chelation

Question 10

What direct or indirect effects does cholestyramine have on absorption?

Answer 10

Causes resin binding

Question 11

What direct or indirect effects does charcoal have on absorption?

Answer 11

Causes adsorption

Question 12

List the factors that affect oral absorption.

Answer 12

• 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.

Question 13

List the parenteral routes by which drugs can be absorbed.

Answer 13

• 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.

Question 14

What factors affect the rate of onset of drugs which are administered parenterally?

Answer 14

• Extent of capillary perfusion.
• Drug vehicle.
• Affected by factors that alter perfusion.

Question 15

Describe inhalation as a mode of administration of drug.

Answer 15

• Drug absorbed by the alveolar epithelium and bronchial mucosa.
• Systemic effects
  
  • ​Lipid-soluble drugs
    
    • Volatile / gaseous anaesthetics
  • Drugs of abuse
  • Accidental poisoning
• Local effects
  
  • ​Modify structure (ipratropium)
  • Particulate size (salbutamol)
  • Selectivity for receptors (salbutamol)
  • Rapid breakdown in circulation (fluticasone)

Question 16

Describe intranasal administration of drugs.

Answer 16

• Easily accessible, rich vascular plexus.
• Advantages
  
  • ​Avoids hepatic first pass metabolism.
  • Ease, convenience, safety.
• Limitations
  
  • ​Limited drugs suitable.
    
    • Requires concentrated drug.

Question 17

Describe the use of the topical route for administration of drugs.

Answer 17

• 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

Question 18

List the different types of intravascular devices (IVDs).

Answer 18

• Peripheral venous catheters
• Central venous catheters (CVCs)
  
  • Peripherally inserted CVCs
  • Skin-tunneled CVCs (e.g. Hickman and Broviac lines)
• Arterial catheters

Question 19

What are the 3 methods of administering intravenous medications?

Answer 19

1. Continuous infusion
2. Bolus injection
3. Intermittent infusion

Question 20

Describe continuous IV infusion.

Answer 20

• Stable drugs
• Short half life
• Time dependent effects
• Needs dedicated IV site

Question 21

Describe bolus injection.

Answer 21

• Rapid response required
• Incompatibilities
• Unstable drugs

Question 22

Describe intermittent infusion.

Answer 22

• Unstable drugs
• Long half life
• Concentration dependent effects
• Less compatibility concerns

Question 23

What are the complications of IV drug administration?

Answer 23

• 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

Question 24

Describe extravasation and infiltration with respect to IV cannulation.

Answer 24

• 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.

Question 25

List the factors which affect distribution of a drug.

Answer 25

* Cardiac output and blood flow * Plasma protein binding * Lipid solubility * Degree of drug ionisation * pH of compartments * Capillary permeability

Question 26

What effect does organ perfusion have on distribution of drugs?

Answer 26

* Initial rate of distribution of drugs depends heavily on blood flow.

Question 27

Describe the effect of albumin binding on the distribution of drugs.

Answer 27

* Albumin is a predominate plasma binding protein (40g/L). * **Lipid-soluble drugs** bind non-specifically. * **Weak acids** bind to a specific, saturable site.

Question 28

List the sites of drug metabolism.

Answer 28

* Gut lumen * Gut wall * Plasma * Lungs * Kidneys * Nerves * Liver

Question 29

List the potential results of drug metabolism.

Answer 29

* Pharmacological deactivation * Pharmacological activation * Type of pharmacological response * No change in pharmacological activity * Change in drug uptake * Change in drug distribution

Question 30

Describe phase 1 and phase 2 of drug metabolism.

Answer 30

* **Phase 1 metabolism** * **​**Generally oxidation, reduction or hydrolysis. * Introcude / reveal a reactive chemical group. * "Functionalisation". * Products are often more reactive * **Phase 2 metabolism** * **​**Synthetic, conjugative reactions. * Hydrophilic, inactive compounds generated (usually).

Question 31

Give examples of oxidations, reductions and hydrolysis reactions in phase 1 metabolism.

Answer 31

* Introduces of unmasks functional group * E.g. -OH, -NH₂, -SH, -COOH etc. * **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

Question 32

Describe mixed-function oxidase system (CP450s).

Answer 32

* **Microsomal (ER) enzymes** * **​**Liver, kidney, lung, intestine etc. * **Consists of:** * **​**Cytochrome P450 * NAPDH-CP450 reductase * Lipid * **Requires:** * **​**Molecular oxygen * NAPDH

Question 33

What are the products of phase 2 metabolism?

Answer 33

* Detoxified, water-soluble, easily secreted products. * Suitable for excretion in bile or urine.

Question 34

Describe the factors which must be considered with respect to drug metabolism.

Answer 34

* **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.

Question 35

In what form are drugs excreted from the body?

Answer 35

* 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.**

Question 36

Describe biliary excretion.

Answer 36

* **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**

Question 37

Describe enterohepatic circulation. Which drugs are metabolised via this pathway?

Answer 37

* Oral antibiotics * Oral synthetic oestrogens

Question 38

Describe renal excretion of drugs.

Answer 38

* **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?