Pharmacology Definitions

The Wilcoxon signed-rank test is a non-parametric alternative to the paired Student's t-test for the case of two related samples or repeated measurements on a single sample. The test is named for Frank Wilcoxon (1892–1965) who proposed this, and the rank-sum test for two independent samples

A procedure used in nonparametric statistics to determine whether the means of two populations are equal

The chi-square test statistic can be used to evaluate whether there is an association between the rows and columns in a contingency table. More specifically, this statistic can be used to determine whether there is any difference between the study groups in the proportions of the risk factor of interest. Returning to our example, the chi-square statistic could be used to test whether the proportion of individuals who smoke differs by asthmatic status.

Spearman rank correlation is a statistical method "used as a measure of correlation in nonparametric statistics when the data are in ordinal form

In statistics, the Kruskal-Wallis one-way analysis of variance by ranks (named after William Kruskal and W. Allen Wallis) is a non-parametric method for testing equality of population medians among groups. Intuitively, it is identical to a one-way analysis of variance with the data replaced by their ranks. It is an extension of the Mann-Whitney U test to 3 or more groups.

A constant fraction of the drug in the body is eliminated per unit time.

The rate of elimination is proportional to the amount of drug in the body.

Most drugs eliminated this way.

The absolute amount eliminated is proportional to the blood concentration
ie : high rate at high concentrations and low rate at low concentrations

Volume of Distribution (Vd) is the amount of drug in the body divided by the concentration in the blood.

Lipid soluble eg opiods, digoxin have high Vd

Lipid insoluble, eg muscle relaxants have low Vd

The Clearance (Cl) of a drug is the volume of plasma from which the drug is completely removed per unit time.

L/min

The amount eliminated is proportional to the concentration of the drug in the blood.

Elimination half life (t1/2): the time taken for plasma concentration to reduce by 50%. After 4 half lives, elimination is 94% complete.

The fraction of the drug in the body eliminated per unit time.

This is represented by the slope of the line of the log plasma concentration versus time.

Cl = kel x Vd

1. Cl = ke x Vd
= 0.693 x Vd / t1/2

2. ke = 0.693/t1/2

3. Roe = Cl x Cp
Cp is the plasma concentration

4. Fraction removed = Cl / Vd

5. infusion rate IR = Cl x Css

This is the fraction of the administered dose that reaches the systemic circulation.

depends on incomplete absorption, first pass hepatic metabolism

a constant amount of drug is eliminated per unit time

due to metabolic pathways are rapidly saturated and are working to their limit.

Alcohol, phenytoin, salicylates, theophylline, and thiopentone (at very large doses)

Dosing rate = clearance x desired plasma concentration

loading dose = the volume of distribution x the desired concentration

Steady state is acheived after 4 half lives
Maintenance dose = Rate of Elimination

Can be bypassed by giving loading dose (but will run into side effects if drugs has narrow therapeutic range)

Many drugs are extensively metabolised by the liver.

Hepatic clearance = HER x HBF
(if oral : % absorbed - % reaching systemic circulation )
Volume of plasma where the drug is completely removed by the liver.

Hepatic drug clearance depends on
1. Liver blood flow
2. intrinsic clearance (ei Extraction rate)

Drugs with high intrinsic clearance
-hepatic BF and inducers/inhibitors do not make a difference

Drugs with low intrinsic clearance
ER increased by inducers
ER increased with decreased Hepatic blood flow

Inducers : cigarrettes, antiepileptics (carbamazepine & phenytoin), rifampicin, griseofulvin, alcohol and spironolactone (CAR GAS) also barbiturates

Inhibitors
flagyl, allopurinol, cimetidine, erythromycin, dextropropoxyphene, imipramine, (the) pill (FACE DIP).

HER is the hepatic extraction ratio (E)
=fraction of dose entering the liver from blood which is eliminated during one pass through the liver
E = (Cin – Cout)/Cin
Furthermore Cl = Q x E
E = (fu x CLint) / (Q + (fu x CLint)
Where fu is the unbound free fraction in blood, CLint is the intrinsic clearance of liver

%absorbed = 1 - ER
o there are two limiting cases:
 low hepatic extraction ratio drugs - when Q >>> fu x CLint
 i.e. the unbound fraction x the intrinsic clearance is very small (therefore, using logic, bioavailability is very high)
 i.e. F ~ Q / (Q + 0)
 i.e. F ~ 1
 by the same logic, hepatic CL will be very low, regardless of flow rate
 the clearance of such drugs depends directly on the degree of binding and the activity of the drug's metabolising enzymes
 these drugs have a very low first pass, and bioavailability will be close to 100%
 examples:
 caffeine
 ibuprofen
 increasing or decreasing rate of supply by altering Q will make very little difference to hepatic clearance
 also called capacity limited drugs
 summary: these drugs will have a high bioavailability, and clearance will vary depending on hepatic enzyme activity and plasma binding
 high hepatic extraction ratio drugs - when Q <<< fu x CLint
 i.e. the unbound fraction x the intrinsic clearance is very high (therefore, using logic, bioavailability is very low)
 i.e. F ~ Q / (0 + (CLint x fu))
 i.e. F ~ Q / (CLint x fu)
 by the same logic, hepatic CL will be very high, regardless of changes of CLint x fu
 the clearance of such drugs depends directly on the hepatic flow rate
 these drugs have a very high first pass, and bioavailability will be close to 0%
 examples:
 morphine
 lignocaine
 also called flow limited drugs
 summary: these drugs will have a low bioavailability, and clearance will vary depending on flow rate
 most hepatically cleared drugs can be classified as either low extraction or high extraction
 by classifying a drug in this way, one can determine the critical physiological factors which determine hepatic clerance and bioavailability, and therefore the plasma concentrations and response to the drug after oral and intravenous administrations
• SUMMARY: bioavailability and first pass effect
o F = fraction absorbed x (1 - E)
o some drugs have low E (e.g. caffeine) --> high F (a change in E therefore has a minor effect on F)
o some drugs have high E (e.g. morphine) --> low F (a change in E therefore has a major effect on F)
o the major determinant of oral bioavailability of high extraction drugs is hepatic enzyme activity
• EXERCISE: determine for some low and high extraction drugs, the effect of changes in drug binding on
o clearance
o volume of distribution
o half life
o bioavailability
o unbound stead state plasma concentrations on chronic dosing (IV and oral)
• APPENDIX
o variability in response - for high extraction drugs, a small change in E will lead to a large change in F, leading to more variability in plasma concentrations after oral vs IV doses
o dosage (oral vs. IV) - for a drug with high hepatic extraction, an oral dose will need to be much higher than an IV dose to elicit the plasma concentrations
o other routes - to avoid some first pass effect, use sublingual, transdermal, inhalation, rectal
o drug interactions - other drugs may induce or inhibit hepatic enzymes, and so for high extraction drugs, this can lead to significant changes in bioavailability
o liver disease - if shunts exist because of liver disease, bioavailability will increase because blood flow through liver will be less; therefore, for high extraction drugs given to patients with liver disease, there is the potenital for increases adverse effects

Most drugs bind to proteins,
1. albumin
2 .alpha-1 acid glycoprotein (AAG),

In free state, drugs can
1. diffuse out of plasma into tissue
2. exert its effect
But it therefore is easy prey for metabolising enzymes.

Highly bound drugs
1. low Vd
2. low extraction ratio
3. long elimination half life
4. effect can be modulated by protein binders (competition)

Example of high protein binding
warfarin
diazepam
propranolol
phenytoin.

The amount of albumin does not appear to be hugely relavent.

TI a measure of risk vs benefit of a drug

TI=TD50/ED50 or LD50/ED50

ED50 is dose required to produce a therapeutic effect in 50% of subjects
TD50 is the dose required to produce a toxic effect in 50% of sibjects
LD50 is the dose required to kill 50% of subjects
(the median lethal dose)

Large TI are considered safe with large safety margins

Phase 1
measurement of pharmacological activity, kinetics, and side effects in healthy volunteers

Phase 2
pilot studies in small groups of patients to confirm that the drug works in the target condition and to establish the dosage regimen

Phase 3
formal clinical truials in a large number of patients to determine the drug's efficacy compare to existing treatment and to determine indicence of side effects

phase 4
post marketing surveillance to establish efficacy and toxicity
detection of rare adverse effects

Phase 1
measurement of pharmacological activity, kinetics, and side effects in healthy volunteers

Phase 2
pilot studies in small groups of patients to confirm that the drug works in the target condition and to establish the dosage regimen

Phase 3
formal clinical truials in a large number of patients to determine the drug's efficacy compare to existing treatment and to determine indicence of side effects

phase 4
post marketing surveillance to establish efficacy and toxicity
detection of rare adverse effects

AMIDES

Lidocaine with epi 7mg/kg
Lidocaine plain 3mg/kg
Bupivacaine with epi 3mg/kg
Bupivacaine plain 2mg/kg
Etidocaine 4mg/kg
Mepivacaine 7mg/kg
Prilocaine 12mg/kg

ESTERS
Cocaine 3mg/kg
Procaine 14mg/kg
Chloroprocaine 14mg/kg
Tetracaine 3mg/kg

intercostal nerve blocks (highest level),
paracervical nerve blocks
brachial plexus anaesthesia,
epidural anaesthesia.
Spinal anaesthesia