Pharmacokinetics 2

What is absorption?

The process by which unchanged drug proceeds from the site of administration to the general circulation (site of measurement)

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Give an example of a site of administration for intravascular

IV/inter-arterially (placement of drug directly into bloodstream)

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Give examples of sites of administration for extra vascular (9)

Oral, sublingual, buccal, rectal, conjunctival, dermal, intramuscular, auricular, subcuntaneous

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Give examples of absorption from other sites (5)

Lungs (cannabis/salbutamol). Mucous membranes (nasal insufflation/snorting cocaine). Sublingual/buccal (buprenorphine/nitroglycerine, vasodilators). Skin patches (oestrogen/fentanyl/nicotine). Rectally (suppositries morphine)

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What does biopharmaceutics mean?

Influence of dosage form on the therapeutic activity of a drug. Study of the relationship between the physical and chemical properties of a drug and its dosage form. Study of biological effects observed following administration

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What does the therapeutic response of a drug depend on?

An adequate concentration of the drug being first achieved and then maintained at the site of action

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What is biopharmaceutics concerned with?

Onset, intensity and duration of drug at site of action (all influenced by rate at which drug enters the body)

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Outline the mechanism of absorption (3)

Solid drug, drug in solution, absorbed drug

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What happens when to a permeability rate limited drug?

Mostly dissolved before absorption is complete

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What happens to a drug release rate limited drug?

Very little drug at absorption site and absorption is delayed until dissolution occurs

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How does transcellular permeation occur (3)?

Via: passive diffusion, active transport, facilitated transport (vascular absorption predominates as blood flow > lymph flow. Paracellular absorption is always passive)

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What does the rate of absorption depend on in passive diffusion?

Concentration gradient across membrane, SA and permeability constant

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What are the rate limiting steps (2)?

Perfusion rate (very small molecules, membranes not barrier/passage depend on blood flow). Permeability factor (polar hydrophobic compounds/some antibiotics. Insensitive to blood flow dependent on membrane)

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What is the permeability constant determined by (3)?

Physicochemical properties of the molecule. Nature of membrane (thickness varies amongst tissue)/distance between surface of absorption and blood capillary. Partition coefficient of the compound

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Does a drug need to be in solution for oral absorption?

Yes

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Which factors influence the rate at which a drug is absorbed (5)?

GE/effect of food, intestinal motility/transit, blood flow, presence of other drugs, degradation/metabolism (and other factors e.g. patient age/weight)

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What is the main site of drug absorption?

Small intestine

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What is the function of the stomach?

To store, mix and reduce gastric contents to a slurry. Empty contents in a controlled manner to small intestine

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Which factors influence GE (6)?

Presence/absence of food/fluid. Physical state of stomach contents (type of food/quantity/size/temperature/viscosity). Drugs (alcohol decreases GE, metoclopramide treats nausea/increases GE). Disease states (GU/DU decrease GE). Emotions. Exercise

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Describe the fasting or fed state

Fasting (stomach empties every 2-3 hours and clears any remaining undigested food). Feeding (stomach breaks contents into small pieces, 2-4 mm to be ejected into small intestine)

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Ingestion of solid medicines with water promotes what?

Solubility - may increase rate or extent of absorption

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What happens when a medicine is already in solution?

It is rapidly presented to the small intestine

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Are larger volumes of fluid emptied more rapidly?

Yes

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How should medicines be taken orally?

With at least 200 mL of water on an empty stomach (exception - NSAIDs and ibuprofen taken after food)

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How does food affect GE and drug absorption (4)?

Presence of food - decrease absorption (extent/rate). Delay absorption (decrease rate but not extent). Increase absorption (increase extent/alter rate). Have little or no effect

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What is intra and inter-subject variation?

Variation from person to person and variation individually

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Give two examples of decrease absorption

Fatty meal reduces ethanol absorption from stomach by 50%. Retention of captopril in stomach reduces absorption

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Give an example of delayed absorption

Cephadrine (antibiotic) absorbed slower due to their delayed entry into the small intestine

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Give an example of increased absorption

Drugs absorbed from particular site in the small intestine e.g isotretinoin

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Give an example of no (obvious) effect

Phenylbutazone - used for treating inflammation

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What is Levodopa used to treat?

Parkinson's disease. Decreased absorption. Actively absorbed via amino acid transported (competition with amino acids in diet/issue in high protein diet)

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What is tetracycline?

An antibiotic - chelated by calcium and magnesium ions present in milk and antacids (may not be absorbed)

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What is griseofulvin?

An antifungal - very poorly water soluble drug - gets increased if dissolution given with a fatty meal

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What is propanolol?

Extensively metabolised drug - increased hepatic blood flow after meal

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Why is the small intestine the best site for absorption?

Large SA (microvilli, 200 m^2), good blood supply, permeability to drugs greater, GE importance

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Describe intestinal motility/transit

Site of absorption, residence time in SI is important, transit down towards colon (very reproducible). Transit time important for: SR and coated products, drugs absorbed at specific sites in intestine, drugs which dissolve slowly

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Describe features of blood flow

GIT highly vascularised (good blood supply). Reduced blood flow decreases absorption of actively absorbed drugs e.g. phenylalanine. Procainamide (anti-arrhythmic drug) slowly and incompletely absorbed in patients with acute myocardial infarction

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Describe features of gastric emptying and intestinal transit

Food (fat) slows down GE. Hastening GE quickens absorption. 30 mins drug to dissolve in stomach. Binding-ion exchange resins (cholestryamine) binds to acidic drugs (warfarin/aspiring). Drugs compete for same transporter

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How do anticholinergics affect GE?

Slows down GE

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How does metroclopromide affect GE?

Hastens GE

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Absorption may be affected by enzymatically mediated drug metabolism that occurs where (2)?

Intestinal wall or lumen of intestine due to presence of microbes in gut (e.g. sulphasalazine/salicylic derivative used to treater ulceritive colitis and Crohns disease)

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What is the pH-partition hypothesis?

Ionisable compounds penetrate biological membranes primarily in their unionised form (pKa) at a rate dependent upon their lipophilic nature (partition coefficient - log P)

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What are the assumptions in the pH-partition hypothesis?

Compounds only cross intestinal membrane via passive diffusion and the transcellular route. Hypothesis treats intestinal epithelial membrane as layer of lipid/oil (partitioning 1 - aqueous to oil, partitioning 2 - oil to aqueous).

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Outline the route for the partitioning

Aqueous - lumen of intestine - lipid - intestinal epithelial membrane - aqueous - blood

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Where are weak acids absorbed more rapidly?

From the stomach at pH 1.0 (than pH 8.0)

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Where are weak bases absorbed more rapidly?

From the stomach at pH 8.0 (than pH 1.0)

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Does the small intestine absorb acids much quicker from less acidic small intestine?

Yes

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What is pKa?

The amount of drug ionised at a particular pH (depends on pKa of drug)

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What is the Henderson-Hasselbalch equation?

Relates to ionisation of compound to pH of surrounding medium

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What is the equation for acids?

pKa = pH + log (unionised/ionised)

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What is the equation for bases?

pKa = pH + log (ionised/unionised)

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What does pKa = pH mean?

50% of drug is ionised

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Can drugs be destroyed by acid in the stomach?

Yes (enzymes also present in GI tract)

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What are biologics?

Proteins acting as drugs. Given orally (e.g. monoclonal antibody). Extensive degredation/poor intestinal permeability. IV or IM. Absorption of large proteins slow via lymph. Half life rate limited by absorption

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What is bioavailability (F)?

Proportion of drug reaching systemic circulation after oral compared to IV administration

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What is the bioavailability for IV administration?

1

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What is absolute bioavailability?

Assess with reference to IV dose. Measured by comparing AUC for oral against IV doses from 0 to time point when elimination is complete

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What is the equation for absolute bioavailability?

Dose/AUC (IV) x AUC/Dose (oral) - determine amount of drug remaining to be absorbed (calculate amount absorbed relative to amount released)

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What happens if the administered compound is a prodrug?

F measured on active metabolite. IV reference to active metabolite (e.g. ester prodrug - drug in gut wall - absorbed drug)

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What is relative bioavailability?

Used when no IV data is available. Used to compare F between formulations of drug given by route (e.g. tablet vs intramuscular solution)

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What are the uses of relative bioavailability (3)?

Bioequivalence studies (for quality), clinical trials (batch testing before marketing drug). Generic substitution when product comes off patent (calculation is usually innovators product and new preparation should be

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Describe the graph for absolute bioavailability

First curve downwards and second curve up and then down

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Describe the graph for relative bioavailability

First curve moves up and down (lower peak). Second curve up and then down

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Drugs absorbed after oral ingestion pass through which type of circulation into the liver?

Mesenteric circulation

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Describe the first pass effect (3)

Drugs readily metabolised by liver enzymes (lower F). Reduce pharmacological action of parent drug. Metabolise drug in active form (pro drug)

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What is the equation which explains bioavailability?

F = FG. FH

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What is ER?

Extraction ratio. Magnitude of first pass hepatic effect. ER = CLH/Q. Systemic drug F may be determined by extent of absorption and ER. F = f x (1-ER)

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What is Ka?

Absorption rate. Dependent on administration and drug formulation. Zero order (rate independent of amount remaining in gut). First order (rate proportional to drug concentration dissolved in GI)

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Describe the influence of Ka on plasma concentrations

Higher values of Ka lead to higher peaks for plasma concentrations at an earlier time

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Which factors affect bioavailability?

Formulation (time for absorption). Poor intestinal permeability (ranitidine). Mwt. Competing reaction (acid hydrolysis or enzymes). Hepatic extraction. Drugs (e.g. ketamine, morphine, nicotine etc.)

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How does cirrhosis affect oral bioavailability?

F increases (higher concentration of drug in bloodstream/possible overdose)

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What are the three strategies for getting drugs in the body to improve absorption?

Alter physicochemical properties of molecule (absorption of weak acids and bases increase if used in salt form). Change formulation. Administer by different route

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How can absorption be improved in pharmaceutical formulation?

Aspirin (used for GI irritation/rapid hydrolysis). Coat tablets (resistant to stomach acid but not intestinal fluids). Retention in stomach of poorly soluble drugs (eat with fatty foods). Rapid release/controlled release forms

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Why is drug absorption theoretically reduced in older patients?

Due to loss of mucosal intestinal surface. Decrease in GI blood flow. Reduced gastric acidity

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Pharmacokinetics 2

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