Pharmacokinetics and pharmacodynamics, basic principles

Question 1

What is the definition of Pharmacokinetics?

Answer 1

Study of rate processes of absorption, distribution and biotransformation of drugs, poisons and other chemicals of both exogenous and endogenous origin

Question 2

What is the concept of Therapeutic Window?

Answer 2

Low therapeutic index: Overlap of therapeutic range and toxic range.

• Drug Examples: lithium, theophylline, phenytoin, carbamazepine, digoxin, etc.

High therapeutic index: little or no overlap of therapeutic range and toxic range.

• Drug Examples: numerous such as antibiotic, analgesics, statins, etc

Question 3

What is the clinical value of knowing drug specific levels?

Answer 3

• Unnecessary when dosage need not be individualised.
• Unnecessary when drug effect can be clinically observed.
• Useless when serum concentration is not related to pharmacological effect.
• Not yet useful when concentration-effect relationship is not defined – new drugs?
• Useful when therapeutic range of serum concentration has been established – this can be debated

Question 4

Why do we request drug levels?

Answer 4

• Therapeutic confirmation
• Suspected toxicity
• Absence of therapeutic response: Drug failure, Non-compliance, Altered clearance, Altered absorption
• Drug Overdose
• Poor dose-response correlation
• Monitoring active metabolites
• Suspected drug interactions

Question 5

What are factors involved in Pharmacokinetics?

Answer 5

• Absorption
• Distribution
• Metabolism
• Excretion

Question 6

What are factors which influence drug disposition?

Answer 6

Demographic factors: Age, Weight, Genetics

Disease related: Liver disease, Renal Disease, Thyroid Disorders (hyper- and hypo-), Cardiovascular disease, GI disease, Cancer, Surgery, Burns, Nutritional State

Extracorporeal factors: Haemodialysis, Peritoneal dialysis, Cardiopulmonary bypass, Hypo- or hyperthermia

Chemical and environmental factors

• Absorption of drug (food or co-administered drug)
• Distribution of drug (competition for plasma proteins or tissue receptors).
• Metabolism of drug, food competes for metabolism or co-administered drug induces (phenobarbitone) or inhibits (ranitidine) metabolising enzyme.
• Excretion of drug, competes for excretory pathway (probenicid), alters urinary flow or may enhance tubular re-absorption (bicarbonate, phenobarbitone)

Question 7

What is drug behavior defined by in compartmental methods?

Answer 7

Behaviour defined in terms of:

• Half-life (t1/2)
• Volume of distribution (VD)
• Clearance (CL)
• Bioavailability (F)

Question 8

What is the definitions of the one compartmental model?

Answer 8

• The model assumes that drug is evenly distributed between all the tissues in the body – assumes absorption is instant, distribution is instant, and elimination is proportional (drug)
• Simply defined, the volume of distribution is the volume of plasma that would be necessary to account for the total amount of drug in the patient’s body, if that drug were present throughout the body at the same concentration as found in the plasma. This value is usually further divided by the patient’s body weight, and the result expressed in terms of litres per kilogram.
• If VD exceeds plasma volume, then would exceed the available volume for equal distribution (as in one compartment model). Therefore, drug must be concentrated in the tissues.

Question 9

What is the Two Compartmental Model?

Answer 9

• Model does NOT treat tissues and plasma as behaving the same – more realistic but more complex
• The absorption phase usually ignored in practice and only the beta phase is used

Question 10

How can sampling be conducted in the two compartmental model?

Answer 10

When to sample – when the distribution phase is over and the drug is mainly in the tissues where it is working – better correlation with effect e.g.

• Digoxin – sample 8hr post dose
• Lithium – sample 12hr post dose

Correlation with toxicity - paracetamol

Question 11

What has to happen before sampling after a dose change?

Answer 11

When changing dose, time must be allowed before retesting otherwise therapeutic misadventure (e.g. phenytoin and digoxin).

Question 12

What is the volume of distribution and halflife of drug poisoning?

Answer 12

• Salicylate: V₀: 0.1-0.2l/kg, T_1/2: 0.28hr
• Ethanol: V₀: 0.5l/kg, T_1/2​: 2.1hr
• Theophylline: V₀: 0.5-1.0l/kg, T_1/2​: 4hr
• Digoxin: V₀: 10.0l/kg, T_1/2​: 40hr
• Amitriptyline: V₀: 10.0l/kg, T_1/2​: 17-40hr
• Morphine: V₀: 3.0-5.0l/kg, T_1/2​: 2-3hr

Question 13

What are the sites of the metabolism of drugs?

Answer 13

Occurs in smooth ER of liver (microsomal fraction) with contribution from kidneys, lung and GI tract. Described as phase I or phase II reactions

Question 14

What are the phases of metabolism?

Answer 14

Phase 1 Reactions: Expose suitable groups in drug for later conjugation via oxidation, reduction and hydrolysis reactions

Phase 2 Reactions: Addition of conjugates to increase water solubility

• Glucuronic acid
• Sulphate
• Amino acids (e.g. glycine)
• Glutathione
• Acetylation

Drug metabolite should now be polar enough for excretion.

Question 15

What makes up the overall net effect renal elimination?

Answer 15

• Glomerular filtration
• Tubular secretion
• Tubular re-absorption (note effect of pH)

These processes are both active and passive.

Question 16

What are the multiple factors that affect the rate of elimination in the kidney?

Answer 16

• Renal integrity
• Molecular Size
• Urine flow
• Urine pH
• Excretion of other compounds

Question 17

Whya re drug not always elimnated in the kidneys?

Answer 17

• Generally, the route of excretion for drugs not excreted via kidney as they are Large (MW>300),Polar and Glucuronide conjugates
• Secretion into bile then intestines. Re-absorption can take place (entero-hepatic circulation) e.g. chloramphenicol.
• Ion trapping effect.

Question 18

What are other excretion routes for Drug elimination?

Answer 18

• Saliva: not significant but has implications for drug screening and free drug measurement.
• Lungs: anaesthetic gases.
• Breast Milk: implications for nursing mothers, examples are: Lithium, Doxepin, Chemotherapeutics, Drugs of abuse

Question 19

What is the definition fo Intestinal failure?

Answer 19

• A reduction in functioning gut mass below the minimal amount required for adequate digestion and absorption of fluid and/or electrolytes.’
• Loss or reduction of section(s) of the GIT causing malabsorption on a massive scale!

Question 20

What are the principal underlying disease causes of intestinal failure?

Answer 20

• Short bowel
• Post-surgical complications – e.g. perforations
• Volvulus (twisting)
• Tumours of small intestine
• Motility disorders e.g. scleroderma
• Injury + trauma
• Congenital causes – born with short bowel. Hirschsprung disease – born without complete bowel nerve network
• Iatrogenic e.g. Bariatric obesity surgery

Question 21

What leads to short bowel?

Answer 21

• Multiple bowel resections e.g. Crohn’s Disease
• Mesenteric artery thrombosis
• Intestinal fistulae

Question 22

What is Crohns Disease?

Answer 22

Crohn’s disease is a cyclical inflammatory condition of unknown cause which can affect any part of the GIT causing severe damage (ulcers and tears)

• Patients who suffer extreme forms can require repeated laparotomies to excise bowel strictures and therefore can develop intestinal failure over a period of time.
• The Crohn’s group represents about half the patients that pass through the Intestinal Failure Unit at SRFT

Question 23

What is Mesenteric Arterial/Venous Thrombosis?

Answer 23

• Blood clot in the GI Tract circulation
• Only way to treat is excision

Question 24

What is a fistulae?

Answer 24

A fistula is any connection formed between two parts of the body that are not normally connected. There are many types:

• Tracheal-oesophageal
• Rectovaginal
• Anorectal
• Enterocutaneous
• Gastrojejunocolic

Apart from those fistulae that occur and are unwanted, there are also some that are deliberately created clinically, e.g. mucous fistula, arterio-venous fistula (e.g. haemodialysis in renal patients)

Question 25

What are the types of Intestinal Failure Classifications?

Answer 25

• Type 1 (Acute)
• Type 2 (Chronic)
• Type 3

Question 26

What is the Type 1 Intestinal Failure?

Answer 26

• Self-limiting
• Short term (< 3 weeks)
• Ileus, Obstruction
• Peri-operative/ ICU setting
• Nutritional Support (temporarily)
• Settles Spontaneously

Question 27

What is the Type 2 Intestinal Failure (Chronic)?

Answer 27

• Short/medium term (weeks/months)
• “Acute” - capable of resolution, with or without specific treatment.
• Underlying “surgical” process, e.g. abdominal sepsis, fistula
• Acute hospital setting
• Nutritional Support: To maintain nutritional status, Pending definitive treatment

Question 28

What is the Type 3 Intestinal Failure?

Answer 28

• Long term (years - life)
• Long term hospital treatment and/or home care
• “Short bowel syndrome”
• Nutritional support required for maintenance
• Other treatment strategies: Pharmacological or Surgery (Transplant/lengthening/tapering procedures)

Question 29

What is involved int einital assessment of intestinal failure?

Answer 29

Determine the Anatomy:

• Contrasts studies (CT/MRI)
• ‘Pill’ cams
• Exploratory surgery
• Measure fluid output

Main questions:

• How much tract is diseased?
• How much could be brought back into circuit/continuity?
• Unrecognised cause for failure to heal
• Unexpected internal fistulas downstream?

Info is used to:

• Prepare surgical treatment plan
• Prepare nutritional support plan

Question 30

What are the 3 main strategies for intestinal failure surgical treatment?

Answer 30

1. Excise it
2. Bypass it, either temporarily (to allow healing), or permanently
   
   • Bypasses can be internal, or external of the body ->The re-joining of sections is called an anastomosis
3. Replace it:
   
   • One section of the GI tract adapting to take over the role of a different section (non-surgical takes a long time)
   • Intestinal transplants
   • GI lengthening

Question 31

What are stomas and ostomies in surgical treatment?

Answer 31

• All options for surgery will often involve the use of Pouches, and Stomas (AKA Ostomies). Main aim is always to preserve as much of the healthy intestine as possible.
• Creating a stoma is creating an external part to aid the bypass of a non-functional section of gut. Different types of stoma exists depending on what region of the intestine is affected

Question 32

What are the examples of Stomas/Ostomies?

Answer 32

• ‘(End) Colostomy’: colon has been cut and the proximal end is brought out through an incision made in the abdominal wall.
• ‘(End) Ileostomy’: for ileum
• ‘=(End) Jejunostomy’: but for jejunum
• ‘Duodenostomy’: for the duodenum
• ‘Urostomy’: ureters draining the kidneys are (usually) re-directed into part of the intestine

Question 33

What are Colostomies?

Answer 33

• When cancer dictates removal of the terminal end of the colon and/or rectum/anus then a colostomy must be formed.
• If the terminal end of the lower bowel is left in place the result can either be a Hartmann’s pouch, or a ‘double barrelled’ colostomy, where the new opening of the distal section of bowel is called a ‘mucous fistula’.

Question 34

What are Ileostomies?

Answer 34

• Loop ileostomy is created to allow the distal gut to rest while the newly created J-pouch ileoanal anastomosis heals.
• Once the pouch has healed the ileum can be resealed and the ileostomy can then be closed.

Question 35

What can Stomas/Ostomies be?

Answer 35

• End’: The distal part of the intestine is left sealed or removed and all output collected from the stoma.
• ‘Loop’: Two holes brought to the surface, output collected from proximal, and mucus collected from distal. Can allow section to ‘rest’ prior to reconnection (anastomosis)
• ‘Double barrelled’: Two different ends brought to surface as two separate openings. Can allow rest. May be temporary or permanent.

Question 36

What is a Pouch?

Answer 36

Sometimes the term ‘pouch’ is applied to an external plastic bag used to collect intestinal waste from an ‘ostomy’. However, there are also a number of surgical meanings:

• Ileostomy pouch: an internal version of the external plastic bag. The pouch may be drained after insertion of a catheter through the stoma.
• Ileoanal pouch
• External Pouch
• Gastric pouch

Question 37

Describe intestinal flow in the GI system in health

Answer 37

• Large volumes of fluid, -6-8 Litres/day, are ingested/secreted into the GI tract.
• Normally 85% of this fluid is reabsorbed in the small intestine and ~15% by the colon. (See the black arrows on the diagram above)
• The ability to reabsorb these large volumes (plus nutrients) can be disrupted or lost in intestinal failure = big problem!
• Impact and severity depends on the region affected

Question 38

What are the fluid flow problems that occur post gastrectomy?

Answer 38

• Not necessarily ‘intestinal failure’, but may have problems with iron absorption, diarrhoea and steatorrhoea.
• Absence of intrinsic factor and acid will mean that vitamin B12 supplements will be required.
• ‘Dumping’ symptoms following meals due to high osmolality in jejunum and hypoglycaemia due to insulin over-secretion.

Question 39

What are the fluid flow problems that occur post Cholecystectomy?

Answer 39

• Cholesystectomy is surgical removal of the gallbladder, due to stones/inflammation
• Very few problems, if bile duct is intact.
• If NOT, then oral pancreatic enzyme replacement therapy is required, but still likely that some steatorrhoea and malabsorption will occur even if remaining bowel is intact.
• Fluid reabsorption should be close to normal.

Question 40

What are the fluid flow problems that occur post Duodenostomy?

Answer 40

• Required if GIT below duodenum is damaged (n.b Duodenum is main intestinal site for digestion)
• Clearly, most of the absorptive capacity of the gut is lost, even if some distal bowel remains in situ. A patient would definitely have ‘intestinal failure’.
• A duodenostomy has a high fluid output maintaining fluid balance will be a big problem. Leads to severe malabsorption and life threatening fluid loss.

Question 41

What are the fluid flow problems that occur post Jejunostomy?

Answer 41

• Absorption of amino acids, carbohydrates, minerals and fats depends on how much proximal jejunum remains, but there would be high fluid losses -> ‘Intestinal failure’.
• Note that proximal jejunum fluid loss may be increased due to raised osmolality following eating.
• Ileal absorption of Vitamin B12 and conjugated bile salts cannot occur. Thus Vit B12 supplements required, and that colonic irritation by bile acids will occur unless bile acid sequestrants are used.

Question 42

What are fluid flow problesm post Jejunectomy?

Answer 42

• Although absorption of amino acids, carbohydrates, minerals & fats normally takes place in the jejunum, the ileum can adapt and take on these functions (takes up to~2 yrs), alongside its usual roles: The ileal mucosa thickens and villous hypertrophy occurs.
• Intestinal function might become normal, or very close to normal after an initial period of ‘intestinal failure’.
• Lack of gut hormone production may cause enhanced gastric fluid secretion.

Question 43

What are fluid flow problesm Post Ileostomy?

Answer 43

• Jejunal absorption of amino acids, carbohydrates, minerals and fats remains, but there would still be high fluid losses = ‘Intestinal failure’.
• Distal ileal absorption of Vitamin B12 and conjugated bile salts may not occur. Thus Vit B12 supplements required, and that colonic irritation by bile acids will occur unless bile acid sequestrants are used.

Question 44

What are fluid flow problesm Post Ileoectomy?

Answer 44

• The jejunum is less adaptable than the ileum following resection of the latter.
• Absorption of Vitamin B12 and conjugated bile salts cannot occur, (requiring Vit B12 supplements and bile acid sequentrants)
• Although ileum is normally important for fluid recovery, if the colon is present it can take over much of this function.

Question 45

What are fluid flow problesm Post-Colostomy?

Answer 45

• Unlikely to count as ‘intestinal failure’ as nutrient absorption and most fluid reabsorption are complete before Colon, but bile salt reabsorption may be reduced.
• The Colon’s large reserve capacity for fluid reabsorption means that fluid problems may not be apparent even after significant resection in its length.

Question 46

What are fluid flow problems after small bowel resection?

Answer 46

• Because of reserve capacity, resections up to 35% of small intestine often produce few problems, particularly if the duodenum and distal ileum are intact.
• Resections up to 50% usually give malabsorption, but may recover normality after ‘adaptation’ - where remaining small intestine may increase absorption 4-fold over a period of time.
• Resections above 75% usually result in ‘intestinal failure’ with a requirement for long term nutritional support

Question 47

What is the effect of the ileocaecal valve in intestinal failure?

Answer 47

• Preservation (or not) of the ileocaecal valve can have a significant impact on bowel function after small bowel resection.
• Normally, the valve prevents reflux of colonic bacteria into the ileum and the bacterial flora either side of the valve are significantly different. If bacteria are able to colonize the small bowel they compute for nutrient absorption
• Valve preservation significantly increases intestinal ‘transit time’ and therefore allows any remaining small bowel to work more efficiently than in its absence.
• Nutrients which reach the colon may become subject to bacterial metabolism rather than being absorbed.

Question 48

What are the therapeutic approaches for intestinal failure?

Answer 48

Pharmacological reduction of fluid losses

• Proton-pump inhibitors to reduce gastric acid/fluid secretion.
• Somatostatin (or analogue, octreotide) to reduce GI fluid secretions, - suppresses production of gastrin, secretin, VIP and GIP hormones which stimulate fluid secretion.
• Gut motility reduction – codeine, loperamide.

Pharmacological prevention of irritation to colon

• Bile acid sequestrants – cholestyramine
• Note that bowel resection reduces drug absorption and so large doses and special preparations of drugs may be required to achieve a therapeutic effect.

Food/mineral/vitamin supplementation and fluid replacement

Question 49

What are alternative treatment approaches for Intestinal failure?

Answer 49

Intestinal transplants

• Still small-scale treatment approach
• Complex surgery
• Poor long-term graft survival
• Patient survival at 1yr = 77% vs. 5yr on HPN =2%
• Survival figures steadily improving.

Gut lengthening

• Novel approach to exploit ability of gut to regrow and adapt
• New gut able to re adapt over time.
• Still in trial at small number of international centres
• 2 approaches – Bianchi and STEP techniques

Question 50

What are associated problems in intestinal failure?

Answer 50

• Long term support from many quarters required for success: Nursing, Surgery, Dietetics, Pharmacy, Radiology, Laboratory, Family, Psychology
• Patients must be physically + mentally ‘fit’ for major surgical procedures. TPN can ‘buy time’ and allow adequate nutrition while infections are treated, bowel is healing after a procedure and/or increasing in function through adaptation, but TPN itself carries a risk and requires scrupulous operation by all involved – including the patient.