Download THE DISTURBANCES OF ABSORPTION

PATHOPHARMACOKINETICS
Pharmacokinetic
the action of the body on the drug, including:
Liberation
Absorption
Distribution
Metabolism
Excretion
Metabolism + Excretion = Elimination
ABSORPTION
process of drug movement from the administration site to the systemic circulation.
Bioavailability of a drug
According to the European Medicines Evaluation Agency (EMEA):
bioavailability means the rate and extent (amount) to which the active substance or active
moiety is absorbed from a pharmaceutical form, and becomes available at the site of
action (in the general circulation).
Bioavailability is defined as the fraction of an administered dose that reaches the systemic
circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%.
When a medication is administered via other routes (such as orally), its bioavailability
decreases (due to incomplete absorption and first-pass metabolism ).
.
disturbances of absorption
Diseases can change:
a) pH chyme
-diseases with lack or deficiency of HCL
b) motor activity of gut ( speed of stomach emptying and intestinal passage )
- patients with slow stomach emptying and patients with pylorostenosis
- patients with slow stomach emptying and patients with slow intestinal passage
→ ↑ first pass effect
- ↑ intestinal passage ( enteritis, gastritis and diarrhoea ) → ↓ absorpition
c) surface of absorption ( quantitative and qualitative changes )
- patients after partial gastrectomy, ileostomy and colon resection
- ↓ permeability of cell membrane- diabetes, adrenocotrtical failure
- ↑permeability of cell membrane – jaundice, allergic diseases
d) vascularity of absorption place
cardiogenic shock, myocardial infarction, heart failure →↓ visceral blood flow →
↓ absorption of drugs administered orally and parenterally
e) contents of substances conditioned drug absorption
- enteropathy and hepatopathy – disturbanes of bile secretion and bile transport
↓ absorption of lipid-soluble drugs
DISTRIBUTION
Transfer of drug between regions of the body
Disribution between blood/plasma, tissues, organ and body fluids
pharmacokinetic parameter - volume of distribution - Vd
The ratio of the amount of the drug in body to its concentration in the plasma or blood
Amount of drug in the body
Vd = --------------------------------------Plasma drug concentration
( Units = volume )
Vd ≈ 5 l – drug in blood
Vd > 40 l – drug in all body fluids
disturbances of distribution
- cardiogenic shock - ↓blood supply of muscles and fatty tissue → ↓drugs distribution to
these tissues
- changes of compartment volume - ↑extracellular fluid ( edema ) – changes of Vd
- disturbances of acid-base equilibrium - interferences of tissue drug uptake
- deficiency of transport activator through cell membrane
- quantitative and qualitative changes of plasma protein composition in hepatic and renal
diseases → changes of binding of drugs by plasma proteins
METABOLISM ( BIOTRANSFORMATION )
Biochemical modification or degradation of drug, usually through specialized enzymatic
systems. Drug metabolism often converts lipophilic chemical compounds into more readily
excreted polar products. Drug metabolism can result in toxication or detoxication - the
activation or deactivation of the chemical.
disturbances of biotransformation ( metabolism )
Metabolism of drugs can be disturbed by:
- hepatic cirrhosis
- chronic active hepatitis
- hepatocellular damage ( toxic factors and starvation )
- acute virus hepatitis
- mechanical jaundice
These pathological states can altered the drugs metabolism by:
- change of hepatic blood flow
- quantitative and qualitative changes of plasma proteins
- presence of joints between portal and systemic circulation
- impairment of hepatocyte ability to drugs uptake from blood, drugs biotransformation
by enzymatic system and their excretion to bile
first-pass effect
the elimination of drug that occurs after administration buy before it reaches the systematic
circulation, eg, during passage through the gut wall, portal blood, and liver for orally
administered drug
- cardiovascular drugs:
acebutolol, alprenolol, diltiazem, labetolol, lidocaine, metoprolol, nifedipine, nitroglycerine,
propranolol, prazosine, tymolol, verapamil
- drugs acting on CNS:
amitryptyline, chlorpromazine, doxepine, imipramine, morphine, nortryptyline, pethidine
- NSAID
acetaminophen, acetylosalicylic acid,
Drugs required reduction of dose or elongation of dosage interval in hepatic
diseases
- cardiovascular drugs:
acebutolol, alprenolol, clofibrate, digitoxin, furosemide, heparine, labetolol, lidocaine,
metildigoxin metoprolol, propranolol, tymolol, verapamil
- NSAIDs:
aminophenazone, acetylsalicylic acid, acetaminophen, naproxen, phenazone, phenacetin,
phenylbutazone,
- OPIOID ANALGESIC:
fentanyl, pethidine, pentazocine
DRUGS ACTING ON C.N.S.:
alprazolam, chlordiazepoxide, diazepam, lorazepam, nitrazepam, pentobarbital,
phenobarbital, valproic acid
EXCRETION
Process by which the drug/nutrient or metabolites are removed from the body primarily by
the kidneys. Other routes of excretion from the body can include in bile, saliva, sweat, tears,
faeces, milk and exhaled air.
The disturbances of excretion
The drugs excreted in bile:
ampicillin, rifampicin, tetracycline, daunorubicin, doxorucicin, vinblastine, vincristine,
can be cumulated in the body in:
-hepatic cholestasia
- mechanical jaundice
In renal failure – changes of:
1) glomerular filtration
2) tubular secretion
3) tubule reabsorption
Drugs exacting reduction of dose or elongation of interval dosage in renal
failure
ANTIBACTERIALS DRUGS:
- Aminoglycosides
- Penicilillines: azlocilin, amoxicilin, carbenicilin, methicillin
- Cephalosporines: cefazolin, cefaclor, cephalotin, cefamandole, cefotaxime, cephradine,
ceftriaxone, cefuroxime
- Amphotericin B
- Lincomycin,
- Tetracyclines
- Vancomycin
NSAIDs
CARDIOVASCULAR DRUGS:
ACE-inhibitors: captopril, enalapril
Ca-blockers: nicardipine, nifedipine
diuretics: acetazolamide, etacrynic acid, spironolactone, triamterene, thiazides
- digoxin
- methyldopa
DRUGS ACTING ON C.N.S.: chlordiazepoxide, phenobarbital
DRUGS USED FOR GOUT: allopurinol, probenecid
ANTITHYROID DRUGS: metylthiouracyl, propyltiouracyl
ELIMINATION - pharmacokinetic parameters
CLEARANCE – CL
The ratio of the rate of elimination of a drug to its concentration in plasma or blood
Rate of elimination of drug
CL = -------------------------------------Plasma drug concentration
( Units = volume per unit time )
CLEARENCE – is a measure of the capacity of the body to remove a drug
Types of clearances:
- renal
- hepatic
- pulmonary
- dermal ( cutaneous )
BIOLOGICAL HALF-LIFE TIME – t1/2,
t0,5
The time it takes for the blood concentration of the drug to fall to 50 %
0.693 x Vd
t1/2= -----------------CL
0.603
t1/2= ----------------kel
( Units = time )
After 4 half lives, elimination is 94% complete.