Flashcards in General Principles Deck (65):
What factors affect drug permeation ?
1. Solubility (lipid/water)
2. Concentration gradient (only free, unionized drugs contribute to that)
3. Surface area and vascularity (the greater, the better)
What is the main feature for ionized and non ionized drugs?
Ionized : water soluble - better renally excreted.
Non ionized : lipid soluble - cross membranes.
What is the pKa of a drug ?
The pH at which the drug is half ionized, half non ionized.
Mention 4 weak acid drugs.
4. Loop and thiazide diuretics
Mention 4 weak base drugs.
2. Local anesthetics
What are the pH of stomach, small intestine, blood and urine?
Stomach : 1-2
Small intestine : 6
Blood : 7.4
Urine : 5-8
Mention 4 principal features of renal clearance of drugs.
1. Only free, unbound drug is filtered.
2. Both ionized and non ionized forms of drugs are filtered.
3. Only non ionized forms undergo active secretion and active or passive reabsorption.
4. Ionized forms of drugs are trapped in the filtrate.
How can occur urine acidification or alkalinization?
Acidifying : NH4Cl, vit C, cranberry juice
Alkalinizing : NaHCO3, acetazolamide (historical)
What will happen when acidification of urine occurs?
Increased ionization of weak bases - increased renal elimination.
What will happen when alkalinization of urine occurs?
Increased ionization of weak acids - increased renal elimination.
What mode of drug transport is most often used?
What is the fastest route of drug absorption?
What is the bioavailability of a drug that is administrated intravascularly?
100%. There is no absorption involved and no loss of drug.
What is the minimum effective concentration of a drug?
The drug concentration in plasma at which we fist see the pharmacologic effect.
What is bioavailability of a drug?
The fraction of a drug dose that reaches the systemic circulation.
What is the first pass effect of a drug?
When a drug is administrated orally, it passes through the portal circulation into the liver. There, it is partially metabolized and thus reducing its plasma concentration.
Give 2 examples of drugs that exhibit first pass effect.
What are the two major barriers that forbid drug distribution?
1. Blood-brain barrier : permeable only to lipid soluble drugs or those of very low molecular weight (levodopa vs dopamine).
2. Placenta : not a true barrier though.
What are the major features of a drug safe to pregnacy?
1. Water soluble
What is the apparent volume of distribution?
A kinetic parameter of a drug that correlates dose with plasma level at zero time.
Vd=dose/ plasma concentration at zero time.
What is Vd shows us?
Where the drug is distributed.
If most is in plasma, then Vd is low.
If most is outside plasma, then Vd is high.
What is the redistribution of a drug?
In very lipid soluble drugs there is a redistribution into the fat tissues prior to elimination, thus changing the duration of the action.
Mention an example of drug redistribution.
Thiopental : IV anesthetic - reaches brain in <1min, but has a half life of 9hrs.
What is biotransformation of a drug?
Metabolic conversion of drug molecules to more water soluble metabolites that are more readily secreted.
What are the 3 ways of biotransformation?
1. Drug - Inactive metabolites (most drugs)
2. Drug - active metabolites (benzodiazepines)
3. Prodrug - drug (anti metabolites)
What reactions are involved in phase I of biotransformation?
By definition : modification of the drug molecule via
What are the main features of cytochrome P450 isoenzymes?
1. Localized in the smooth ER.
2. Have an absolute requirement for molecular oxygen and NADPH
3. Oxidations include hydroxylations and dealkylations
4. Multiple CYP families
Mention 5 cytP450 inducers.
5. Chronic alcohol
Mention 6 cytP450 inhibitors.
2. Macrolides (erythromycin)
4. Acute alcohol
5. Grapefruit juice
6. Anti viral drugs
Describe the non microsomal metabolism of phase I.
1/ Hydrolysis : e.g. Local anesthetics.
2/ Monoamine oxidases : metabolize dopamine, NE, serotonin (endogenous) and tyramine (exogenous).
3/ Alcohol metabolism.
What happens in the phase II of biotransformation?
Conjugation with endogenous compounds via the activity of transferase.
What are the main types of conjugation in phase II?
1. Glucuronidation : inducible, may undergo enterohepatic cycling, reduced activity in neonates - morphine + chloramphenicol.
3. Glutathione (GSH) conjugation.
What are the major modes of drug elimination?
1. Biotransformation to inactive metabolites.
2. Excretion via the kidney.
3. Excretion via other modes, e.g. Bile ducts, lungs, sweat.
What is zero order elimination rate?
A constant AMOUNT of drug is eliminated per unit time.
What are the main features of zero order elimination rate?
1. Rate of elimination is independent of plasma concentration (or amount in the body).
2. Drugs with zero order elimination have NO FIXED half-life.
Mention 3 examples of drugs with zero order elimination rates.
1. Ethanol "except low blood levels".
2. Phenytoin "high therapeutic doses".
3. Salicylates (toxic doses) (aspirin).
What is first order elimination rate?
A Constant FRACTION of the drug is eliminated per unit time.
What are the main features of first order elimination rate?
1. Most drugs follow first-order elimination rates.
2. Half life time is a constant.
3. t1/2 is inversely related to the elimination constant k.
What is a steady state of a drug?
Reached when rate in = rate out.
When values associated with dosing interval are the same as those in the succeeding interval.
What is true about the time needed to reach steady state?
1. Is dependent only on the elimination half-life of a drug.
2. It is independent of dose size and frequency of administration.
What is the percentage relationship between half-life and steady state achievement?
50% to SS = 1xHL
90% to SS =3.3xHL
95% to SS =4-5xHL
100% to SS =>7xHL
By convention, clinical SS is accepted to be reached at 4-5 HL.
Does the rate of infusion Ko effect the steady state?
1. Irrespective of the rate of infusion, it take the same amount of time to reach SS.
2. It does determine the plasma level at SS (the more Ko, the higher the plasma level).
What is the importance of the loading dose?
1. It takes 4-5 hours to reach SS, so a loading dose (one time only) puts into the body the amount of drug that should be there at SS.
2. The loading dose is twice the amount of the maintenance dose.
3. LD= Cp x Vd
What single-dose equation gives us Vd?
Vd = D/Co
What single dose equation gives us half-life?
t1/2 = 0.7 x Vd/Clearance
What multiple-dose equation gives us the infusion rate Ko?
Ko = Cl x Css
What multiple-dose equation gives us the loading dose?
LD = (Vd x Cp)/ f
What multiple dose equation gives us the maintenance dose?
MD = (Cl x Css x τ)/f , τ is the interval between doses, f is bioavailability.
What is pharmacodynamics about?
Relates to drugs binding to receptors and their effects.
What is an agonist?
A drug is called an agonist when binding to the receptor results in a response.
What is an antagonist?
A drug is called an antagonist when binding to the receptor is not associated with a response. It prevents an agonist from binding to the receptor.
What is the affinity of a drug?
The ability of a drug to bind to the receptor.
What is the potency of a drug?
Shows relative doses of two or more agonists to produce the same magnitudes of effect.
What is efficacy of a drug?
A measure of how well a drug produces a response.
What happens if you mix an agonist with a partial agonist? (Epi with pindolol)?
The final effect will be somewhere between the full effect of the agonist and the partial effect of the partial agonist. The partial agonist is acting as an antagonist.
Mention 5 non competitive drugs.
What are the main effects of competitive antagonists to an agonist?
1. Shifts parallel the D-R curve for agonists.
2. Can be reversed by increasing the dose of the agonist drug.
3. Appear to reduce the potency of the agonist.
What are the main effects of the noncompetitive antagonists?
1. Cause a no parallel shift to the right.
2. Can be only partially reversed by increasing the agonist dose.
3. Appear to reduce the efficacy of the agonist.
What happens in physiologic antagonism?
Two agonists with opposing action antagonize each other. (Vasodilator vs vasoconstrictor)
What happens in chemical antagonism?
Formation of a complex between effector drug and another compound. (Protamine binds to heparin to reverse its action).
What is the therapeutic index of a drug?
A measure of relative safety of the drug in the population.
TI = toxic dose 50 / effective dose 50
Mention 4 drugs with low therapeutic index (TI).
Mention 6 receptors that utilize th Gs proteins.
1. All the beta receptors for catecholamines.
2. D1 for dopamine.
4. H2 for histamine.
6. Some serotonin subtypes.
Mention 5 receptors that utilize the Gi proteins.
1. α2 receptors
2. M2 for Ach.
3. D2 for dopamine
4. Several opioid receptors
5. Serotonin subtypes.