Principles of Drug Disposition (Cynthia Valencia, MD) Flashcards
Picture the Therapeutic Triangle in your head
T/F: Pharmacokinetics is concenred with the relationship between “concentration” and “dose”
True
What is the basis of pharmacogenetics?
One size fits all may not always apply to drugs
What is the connection between pharmacokinetics and pharmacodynamics?
Concentration
What are the objectives of pharmacokinetics?
- Prediction of therapeutic doses
- Adjustment of individual drug dosage
- Correlation between therapeutic blood concentration and pharmacologic effects
What are the uses of pharmacokinetics?
- Maximize efficacy and safety
- Measure drug concentration in relation with effects and toxicity
- Determine therapeutic human doses
T/F: Digitalis and cyclosporin have a high therapeutic index
False
They have a low therapeutic index.
Rats have how many times more metabolic capability than humans?
20 times
What are the factors affecting the prescribed dose?
Patient compliance
Medication errors
What are teh factors affecting administered dose?
Rate and extent of absorption
Body size and composition
Distribution in body fluids
Binding in plasma and tissues
Rate of elimination
What are the factors affecting concentration at locus of action?
Physiological variables
Pathological factors
Genetic factors
Interaction with other drugs
Development of tolerance
What are the factors affecting the intensity of effect?
Drug-receptor interaction
Functional state
Placebo effects
What variable is required to determine the quality of generic drugs?
Bioavailability
T/F: Distribution is primarily concerned with protein-binding, drug reservoirs and the apparent volume of distribution
True
What are the two metabolic enzyme systems?
Hepatic microsomal
Non-microsomal
What are the pharmacokinetic principles of elimination?
Clearance and half-life
What are the different membrane transport mechanisms?
What are the two forms of specialized transport?
Carrier-mediated transport and pinocytosis
Active transport is subject to (1), (2), and (3) by co-transported compounds.
(1) saturability
(2) selectivity
(3) competitive inhibition
Enumerate the factors that affect absorption
Physical state
Degree of ionization and lipid solubility
Concentration of drug
Area of absorbing surface
Gastric emptying
Route of administration
Define: First Pass Effect
Drug undergoes disintegration and dissolution even before reaching the target site
How many % of oral medication is destroyed by the liver before it reaches the heart?
90%
Solids must undergo what processes before absorption?
Disintegration
Disaggregation
Dissolution
On average, how long does gastric emptying take?
30 mins - 1 hours
What are the factors that affect absorption of an ingested pill?
- Disintegration time
- Dissolution rate
- Gastric emptying time
- Presence of drug-metabolizing enzymes in intestinal wall
- pH of lumen fluid
- Surface area
- Intestinal transit time
- Transport across columnar cell
T/F: All strong acids and bases are poisons.
True
T/F: Most weak acids and bases exist in their ionized form
False
They exist in their non-ionized forms.
Give examples of weak acids
Aspirin and acetylsalicylic acid
Discuss the relationship between acid/base ionization and absorption
Protonated weak acid and deprotonated weak base are easily absorbed
Give an example of a weakly basic drug
Amphetamine
How do you treat poisoning with an acidic or basic drug?
Alkalinize or acidify the urine to convert the compound into the more excretable form
Which is more hydrophobic - digoxigenin or digitoxigenin?
Digitoxigenin
Which can be orally administered - digoxigenin or digitoxigenin?
Digoxigenin
Which is more easily excreted through the kidney - digoxigenin or digitoxigenin?
Digoxigenin
GIve examples of digoxin glycosides
Digitoxigenin and digoxigenin
T/F: Higher concentration in solution = higher concentration in plasma
True
Compare the surface area of the intestines with that of the stomach.
It is 1000x greater.
Will aspirin be partially absorbed in the stomach in teh presence of HCL?
Yes, because it exists as the non-ionized form.
What is the relationship between gastric emptying time and absorption?
Shorter GET, greater absorption
Why does taking a drug before or after a meal matter?
Drugs can be degraded by the acidic environment of the stomach.
What factors increase GET?
- Hot and heavy meals
- Vigorous exercise
- Lying on left side
- Diseases
- Atropine, opiate drugs and Ach
- Emotion, pain and stress
What factors decrease GET?
- Fasting, hunger and cold meals
- Mild exercise
- Lying on right side
- Bilroth’s procedure or Dumping syndrome
- Prokinetic drugs like cisapride or domperidone
What are local routes of administration in deeper tissues?
- Intraarticular
- Intrathecal
- Retrobulbar
When is the intraarterial route of administration used?
Emergencies and aggressive therapy (e.g. carotid, femoral and brachial arteries)
What are the disadvantages of the oral route of administration?
Patient must be conscious and not vomiting
Not suitable for unpalatable drugs
What pain-relieving drug applied to the chest is given to cancer patients? It’s a potent opioid analgesic 1000x more potent than morphine.
Fentanyl TDS
What are examples of subcutaneous modes of administration?
- Dermojet
- Pellet implantation
- Silaistic implants
T/F: Time to steady state is independent of dosage.
True
What determines the fluctuations in blood plasma drug concentration?
Proportional to dosage interval/half-times
Steady state concentration is proportional to?
Dosage interval and CL/F
Metabolism of estrogen and digoxin by normal gut flora result in?
Increase and decrease of absorption, respectively
Why does less than 10% of isoproterenol and disodium cromoglycate reach bronchi?
Destruction by gut wall metabolism and first pass hepatic metabolism
Define: Bioavailability
Percentage of active drug that enters systemic circulation as a parent compound
What causes the variations in bioavailability?
Metabolism during absorption
T/F: Generic drugs have to
T/F: Bioequivalence is absolute bioavailability
False
It is relative bioavailability.
What are the factors that affect distribution?
- Cardiac output
- Regional blood flow/vascular perfusion
- Relative permeability of tissue membranes to the drug
- Relative partitioning of drug between tissues and blood
T/F: Protein-bound drug is always inactive.
True
Give an example of highly bound drugs
Anticoagulants (99% bound; 2% free (i.e. bishydroxycoumarin))
Protein binding less than (1) is insignificant.
80%
What is the concentration of albumin in the blood plasma?
40 g/L
How much drug would you need to saturate plasma albumin?
116 mg/L
For drugs with a very narrow margin of safety, what is important?
Protein binding
What are drugs with high Vd?
Quinacrine
Digoxin
Meperidine
Amphetamine
Propanolol
Procainamide
Lidocaine
Tetracycline
What are drugs with low Vd?
Penicillin G
Theophylline
Gentamycin
Kanamycin
Salicylic Acid
Phenylbutazone
Tolbutamide
Warfarin
T/F: Phase 1 of metabolism involves simple reactions, while Phase 2 involves coupling reactions
True
What is the rationale behind the use of pro-drugs?
Active form is not palatable at times.
Give examples of produrgs and their active forms
Bacampicillin/pivampicillin - ampicillin
Alpha-methyldopa - alpha-methylnorepinephrine
Enalapril - enalaprat
Fluorouracil - fluorodine monophosphate
Levodopa - dopamine
Prednisone - prednisolone
Mercaptopurine - methylmercaptopurineribonucleotide
What is the most important drug-metabolizing reaction?
Oxidation
What two drugs, when taken together, cause torsades de pointes?
Astemizole and clarithromycin
What is the choice of drug for typhoid here in the Philippines?
Chloramphenicol
Who are the most sensitive to adverse effects of drugs? most tolerant?
Japanese; Germans
Does astemizole have the potential to cause arrythmia in the heart?
Yes, because it affects potassium channels in the heart
What is the number one inducer of microsomal drug metabolizing enzyme?
Phenobarbital
Where are microsomal DMEs found?
Liver, kidney, intestinal mucosa and lungs
Why were infants placed under fluorescent light before?
Light promotes excretion of bilirubin from broken up RBCs.
Where can non-microsomal DMEs be found?
Plasma, cytoplasm and mitochondria of liver cells
Give examples of DME inhibitors
Allopurinol
Isoniazid
Cimetidine
Itraconazole
Clarithromycin
Ketoconazole
Ciprofloxacin
Metronidazole
Chloramphenicol
MAC inhibitors
Diltiazem
Phenylbutazone
Erythromycin
Sulfonamides
T/F: Initial rapid decline of drug reflects distribution of drug throughout the body.
True
What is the most important concept in designing a rational regimen for long-term drug administration?
Clearance
T/F: Clearance is less reliable than half-life.
False
It’s actually more reliable because it’s more stable.
When is clearance optimal?
During teenage years
What are the formulas for clearance?
Cl = Vd x Ke
Cl = D/AUC
Cl = Dosing rate/Css
What are the two types of drug-drug interaction?
Pharmacodynamic
Pharmacokinetic
Describe: Pharmacodynamic Interaction
- Due to drug interaction at common receptor site
- Leads to effects greater than a drug acting alone
Describe: Pharmacokinetic Interaction
- Delivery of drug is modified by another drug
- Increase or decrease of drug concentration at a site
How do in-vitro drug interactions come about?
Pharmaceutical or chemical incompatibility
How do in-vivo drug interactions come about?
Pharmacologic interaction within the body
How do ferrous ions in oral iron supplements diminish absorption?
Formation of insoluble chelates of tetracyline antibodies
What causes increased drug delivery?
- Inhibition of plasma protein binding
- Inhibition of hepatic drug-metabolizing enzymes (inhibition of ketoconazole)
- Inhibition of renal secretion (probenecid to keep penicillin around longer)
- Inhibition of drug transport (ketoconazole inhibits p-glycoprotein)
What are examples of drugs that decrease absorption?
Antacids + metoclopramide
Cholestyramine + mineral oil
H2-receptor antagonists + sulfodecylsulfate
What are examples of drugs that increase absorption?
Antacids
Metoclopramide
What are examples of drugs that affect cellular uptake?
Guanidinium interacting with tricyclic antidepressants blocks hypertensive effect
What are examples of drugs that affect protein binding?
Phenytoin (anticonvulsant) - Aspirin - increased free phenytoin
Warfarin - Aspirin - increased free warfarin
Phenytoin - Valproic acid - increased free phenytoin
What are the inducers of drug oxidation?
Ethanol
Glutethimide
Phenobarbital
Phenytoin
Rifampin
What are the inhibitors of drug oxidation?
Chloramphenicol
Cimetidine
Disulfiram
Ethanol (acute)
Isoniazid
Oral contraceptives
Propoxyphene
Valproate
What are the drugs that affect hepatic metabolism?
Digitoxin + Rifampicin
Carbamazepine + Phenytoin
Acetaminophen + Oral Contraceptives (glucuronidation)
Chlordiazepoxide + Cimetidine
Theophylline + Cimetidine
Chlordiazepoxide + Oral Contraceptives (oxidation)
ALL RESULT IN INCREASED CLEARANCE
What drugs affect renal excretion and how?
Decreased tubular secretion and clearance
Penicillin + Probenecid
Methotrexate + Aspirin
Procainamide + Cimetidine
Decreased tubular reabsorption & increased clearance
Quinidine + Ammonium Chloride
Increased tubular reabsorption & decreased clearance
Quinidine + Sodium Chloride
Aspirin + Ammonium Chloride
