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PHPY 304 General Principles of Pharmacology

Terms in this set (68)

Pharmacology
study of changes produced in living animals by chemical substances (drugs) to treat disease.
Drug
chemical agent that affects living processes.
-affects processes of mind/body
-compound used in treatment or other abnormal condition
-substance used on CNS
Pharmacokinetics
study of processes of absorption, distribution, metabolism & excretion of drugs. (ADME)
Pharmacodynamics
drug receptor interaction, signal transduction and biological effect of drugs.
Drug Absorption
passage of drug from the site of administration into circulation.
3 "better absorbed" factors affecting drug absorption
Non-ionized
Small molecules
Lipid-soluble drugs
2 "poorly absorbed" factors affecting drug absorption
Ionized
Lagre Molecules
2 examples of uninterrupted cell layers
G.I Tract and capillary beds in MOST organs including brain.
2 organs with interrupted cell layer
capillary beds in Kidney glomerulus and liver. Allows large molecules & lipophobic molecules to pass easily and enter organ.
Describe filtration of glomerular
occurs freely with no limitations except for very large protein molecules.
Describe reabsorption of molecules
regulated by charge/size or lipid solubility of molecules since there are no gaps between endothelial cells.
Drugs that are poorly absorbed and why
streptomycin and gentamycin because they're too polar to cross cell membranes.
What's the effect of pH on drug absorption?
pKa of drug is defined as the pH where half of the drug is ionized.
Absorption of acid and base
protonated form of acid is uncharged and better absorbed compared to the protonated form of a base.
Ion Trapping
Acidic drug would accumulate on basic side of membrane and vice versa.
Clinical significance of ion trapping in fetus
basic drugs taken by mother accumulates in the fetal circulation and breast milk can have harmful effects in the fetus.
Clinical significance of ion trapping from poisoning
excretion of acidic drugs such as phenobarbital & salicylates, intravenous sodium bicarbonate is given
excretion of basic drugs such as amphetamine, ammonium chloride/ascorbic acid is given.
Example of ion trapping
Renal clearance of salicylic acid. treated with NaCHO3 and had a reduction of plasma half lifeand 39% fall in plasma salicylate.
Ineffective orally taken drugs
nitroglycerine, nor-adrenaline and insulin
First Pass effect
concentration of drug is greatly reduced before it reaches the circulatory system. goes to the liver first then reaches the rest of the body.
Cheese-wine reaction
Tyramine found in cheese and wine.
Normally metabolized by monoamine oxidases (MOA) found in G.I wall and liver
If patient taking MOA inhibitor, tyramine will be reabsorbed, reach circulation/nerve terminals and release NE stimulating adrenergic receptors causing tachycardia and HB.
Bioavailability
fraction of an orally given drug that reaches circulation.
(AUC oral/AUC iv) x 100
Plasma Protein
free drug produces pharmacological action while drug bound to plasma protein is inactive.
What happens with displacement of drug from plasma protein?
increases free drug concentration and toxicity for drugs that are highly bound to plasma proteins.
Distribution
reversible movements of drug between body compartments
Factors that affect drug distribution
Ionization, capillary permeability, blood flow and plasma protein binding
Capillary Permeability
capillaries are leaky in liver and spleen allowing drugs to leave regardless of what they are.
Blood-brain barrier
Very specific, only lipophilic drugs diffuse across brain capillaries unless actively transported across.
Clinical implications of blood-brain barrier (Dopamine)
To treat parkinson's disease, dopamine is used but in the form of its precursor L-dopa otheriwse its unable to cross blood-brain barrier.
Clinical implications of blood-barrier (Tumors)
Tumors develop blood vessels and capillaries with no tight junctions allowing penetration of radioactive iodine-labelled albumin to help with diagnosis.
Body Fluid Compartments
60% of body weight is 42L
2/3 intracellular fluid space 28L
1/3 extracellular 12L
1/3 intravascular(plasma) 12
Adult blood 5L
Volume Distribution
Vd: theoretical volume where total amount of given drugs should be uniformly distributed for its plasma or blood concentration
Vd formula
Dose/Plasma Concentration
High Vd
means most of drug is in extravascular compartment due to high concentration of lipid soluble drug (amiodarone)
Low Vd
most of drug is in vascular space due to high bound plasma proteins (warfarin)
Biotransformation
chemical modification of drugs by enzymes making them more polar (less lipid soluble)
Where are drug metabolizing enzymes located?
Liver, G.I. Wall and Lungs
Prodrugs
inactive precursor then becomes active after metabolism.
Examples of prodrugs
Omeprazole, lansoprazole and Levo-dopa
Two-phase biotransformation
Phase 1(Functionalization reaction): oxidoreduc & hydrolytic reactions making drug more polar
Phase 2 Conjugation Reaction: glucuronidation, sulfation and acetylation resulting in durg inactivation
Phase 1 Enzymes
CYP2C9 and C19
CYP2E1, CYP2D6
CYP3A4
CYP3A4
primary enzyme for metabolism of half of all drugs, inhibited/induced by many drugs that can cause DDI's.
Factors that affect drug biotransformation
Enzyme induction and inhibition: Drugs or other substances that can stimulate or inhibit expression of metabolizing enzymes such as CP450 enzymes.
Phase 1 Drug Metabolizing Enzymes
Induction/inhibition of phase 1 enzymes can cause DDI's when 2 or more drugs are metabolized by same enzyme
Induction of enzyme and drug interactions
Inducers cause expression of more CYP enzymes eliminates substrate drugs faster. Lower drug levels can cause treatment failure. Ex. St John's Wort (Herbal antidepressant)
Factors affecting drug biotransformation
Inhibitors stop CYP enzyme activity reducing elimination of substrate drugs that can cause toxicity. Ex) Grapefruit juice and cimetidine
CYP Polymorphism
P450 CYP2D6 7-10 white 2-5 black lack the enzyme making codeine ineffective.
Phase 2 Reactions
conjugated drugs highly polar and rapidly excreted, located in cell cytosol.
Clinical significance of Phase 2 reactions
50% Americans and 60-70% europeans have reduced expressions of acetylating enzymes. Making them slowly metabolize drugs such as isoniazid(antituberculosis), and caffeine
Who are the audiences that take most drugs?
Frail elderly, hospitalized patients and nursing home residents.
3 types of drug interaction
DDI's
Drug food
Drug herb
Explain 2 types of DDI's
Pharmacodynamic: 2 drugs affecting same system
Pharmacokinetic: 1 drug changes absorption, distribution, metabolism and excretion of another
Most common reason for DDI's
one drug affecting metabolism of another drug. 2 drugs metabolized by the same enzyme can compete for the same enzyme.
What does the liver and kidney affect in drug effect?
metabolism, excretion and plasma levels of many drugs.
Clinical significance of drug metabolism
Patient taking two or more drugs should consider drug interactions from metabolism. P450 enzymes should consider interaction with food/herbal
P-glycoprotein
efflux pump that has broad substrate specificity for drugs found in many sites including cancer tissue.
Drugs that increase p-glycoprotein expression
St. John's Wort and rifampin
P-glycoprotein and cancer
overexpressed in tumor cells and pumps put anticancer drugs. Drugs like calcium channel blockers inhibit P-glycoprotein and maybe useful to reverse resistance.
What phenomenon prolongs duration of half-life of drug?
Enterohepatic recirculation
Clinical significance of Enterohepatic recirculation
Oral contraceptive failure when an antibiotic is taken
What does clearance mean?
volume of blood where a drug is irreversibly removed per unit of time
Renal Clearance
only the free-drug is filtered at glomerulus. strong acids/bases secreted in proximal tubule.
Net Removal of Renal Clearance
filtered + secreted - reabsorbed
Most drugs are eliminated by what order?
First order process where a constant fraction of drug is eliminated per time. (equal distribution)
Zero-Order Elimination
a constant amount of drug is eliminated per unit of time because that is maximum rate of elimination when pathway for elimination is saturated. (no more enzymes too much drugs)
Half-life
time required for blood concentration of drug to be reduced by 50%.
How many half lives does it take for the body to effectively eliminate the drug?
5 half-lives for about 97% of a drug
Clinical significance of half-life
fixed dose repeated given at fixed intervals takes about 5 half lives to achieve steady-state concentration meaning elimination rate=administration rate
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