Lecture 34 & 35 - Introduction to Pharmacology and pharmacokinetics concepts

Question 1

what is Pharmacology

Answer 1

effects of chemicals on biological entities
interaction of drugs biologically
effect of drugs
therapeutic an toxic effects

Question 2

pharmacodynamics

Answer 2

specific to drug or drug class

Question 3

pharmacokinetics

Answer 3

non-specific general processes

Question 4

advantages and disadvantages of oral route of administration

Answer 4

convenient, safe, economical

cannot be used for drugs inactivated by 1st pass metabolism or that irritate the gut

Question 5

advantages and disadvantages of intramuscular

Answer 5

suitable for suspensions and oily vehicel
rapid absorption from solutions
slow and sustained absorption from suspensions

dis - may be painful, cause bleeding at site of infection

Question 6

subcutaneous - advantages and disadvantages

Answer 6

suitable for suspensions and pellets
cannot be used to deliver large volumes of fliof
cannot be used for drugs that irritate cutaneous tissue

Question 7

intravenous - advantages and disadvantages

Answer 7

bypass absorption yielding immediate effect

• 100% immediate bioavailibity
• poses more risk for toxicity

Question 8

buccal - advantages and disadvantages

Answer 8

rapidly absorbed
avoids 1st pass metabolism

dis - effect only for low doses
drugs must be water and lipid soluble

Question 9

transdermal

Answer 9

avoids 1st pass metabolism, effective only for low doses of drug that are highly lipid soluble

Question 10

inhalation

Answer 10

produces a localised effect
drug particles must be correct size
dependent on patient technique

Question 11

intrathecal

Answer 11

local and rapid effects
requires expert administration
may introduce infection/toxicity

Question 12

epidural

Answer 12

provides a targeted effect

risk of failure, risk of infection

Question 13

topical

Answer 13

non-invasive and easy to administer

poor lipid soluble not absorbed via skin or mucous membranes
very slow absorption

Question 14

types of oral preparations

Answer 14

tablet - compressed powder - can be coated to protect against stomach acid
capsule - solid dosage enclosed by gelatin shell
solution - dissolved in solvent
suspension - suspended in a vehicle - large amounts of drug

Question 15

what processes are involved in pharmacokinetics

Answer 15

ADME - Absorption

distribution, metabolism and excretion

Question 16

What is absorption

Answer 16

transfer of drug from site of administration into general or systemic circulation

Question 17

What are the factors that affect oral absorption

Answer 17

needs to disintegrate and dissolve in the GIT content to form a solution before becoming absorbed

need to be lipid soluble to be absorbed by the gut

rate of gastric emptying determines the rate at which a drug is delivered to the small intestine.

physiochemical factors - drug-food interactions - insoluble complexes

presence of food may delay absorption
-reduce adverse effects of certain medicine eg. NSAID’s

Question 18

what is the effect of pH on drug absorption

Answer 18

increase in pH leads to an increase in ionisation
acid - increasingly ionised
bases - increasingly unionised

Question 19

What nature of the cell membrane allows drugs to cross the cell membrane?

Answer 19

the cell membrane has a lipophilic nature

only permits passage of uncharged fraction of any drug

Question 20

What is distribution

Answer 20

drug is transferred reversibly from general circulation into tissues as concentrations in blood increase

from tissues into blood as concentrations in blood decrease

occurs by passive diffusion of un-ionised form across cell membrane

Question 21

what happens to distribution after an IV injection

Answer 21

high plasma concentration and drug rapidly equilibrates with well perfused tissue giving relatively high concentrations in these tissues

Question 22

Different types of drug movement

Answer 22

bulk flow transfer - blood transfer
diffusion transfer - molecule by molecule - short distances
lipid solubility - passive diffusion
carrier mediated transfer

Question 23

What are the factors affecting drug distribution

Answer 23

Plasma protein binding - competition
specific drug receptor sites in tissues
regional blood flow - reduced and enhanced blood flow

Question 24

how does lipid solubility and disease affect distribution?

Answer 24

lipid solubility - blood/brain barrier, membrane of GI tract eg, vancomycin, highly water soluble drugs eg. gentamycin

disease - liver disease can low plasma protein levels

renal disease - cause high blood urea levels

Question 25

What happens in drug-protein binding

Answer 25

binding of drugs with albumin and glycoproteins when a patient takes a drug that becomes highly protein bound when they are already taking a drug that is highly protein bound, the drug is displaced and increase in unbound concentrations of drug and activity

Question 26

Albumin bound proteins

Answer 26

furosemide, ibuprofen, phenytoin, thiazides, warfarin

Question 27

Glycoprotein bound

Answer 27

chlorpromazide, propranolol, tricyclic anti-depressants, lidocaine

Question 28

what molecules can cross a cell membrane

Answer 28

those not bound to protein ``` they are crossed by: passive diffusion - high conc to low conc across ion channels transporters - membrane pores vesicle mediated transport ```

Question 29

What is facilitated diffusion

Answer 29

combine with membrane bound carrier protein movement still dependent on conc gradient faster than passive diffusion

Question 30

What is active transport

Answer 30

requires energy | molecule transported against conc gradient

Question 31

How can molecules be transported by pinocytosis

Answer 31

molecules engulfed by cell membrane and vesicle is formed vesicle moved into cell molecule is released within cell

Question 32

distribution to specific organs - brain?

Answer 32

blood brain barrier protects it from toxic chemicals only lipid soluble can enter

Question 33

What is the functional basis of the blood brain barrier

Answer 33

reduced capillary permeability tight junctions between endothelial cells decrease in size and pores in cell membranes presence of surrounding astrocytes efflux transporters - return drugs back to circulation

Question 34

How does distribution work in a foetus?

Answer 34

cross placenta placental blood flow is low compared to other organs - equilibriate slowly with maternal concentrations highly polar and large molecules dont cross foetal liver - lower conc of metabolising enzymes maternal elimination - processes foetal concentrations of drugs effect of drugs given to mother close to delivery produce prolongued effect on a new born

Question 35

what are the 4 aspects of drug metabolism?

Answer 35

Activation of inactive drug Production of active drug with increased activity from active drug Inactivation of active drugs Change in the nature of the activity

Question 36

Factors affecting drug metabolism

Answer 36

``` first pass effect hepatic blood flow liver disease genetic factors -acetylation status other drugs age (impaired hepatic enzyme activity) - elderly and children below 6 months ```

Question 37

First pass metabolism

Answer 37

stomach, SI, LI and lungs - oral and inhalation occurs prior to and during absorption intestinal lumen - digestive enzymes secreted by the mucosal cells and pancreas. some break down proteins so are not absorbed intestinal wall - rich in enzymes - further metabolism liver - major site lung - high affinity for many drugs and are the site for many local hormones

Question 38

Describe the 2 phases of metabolism?

Answer 38

Phase 1 - oxidation, reduction and hydrolysis form more reactive products, sometimes toxic (lipophilic - fat soluble) Phase 2 - conjugation usually form inactive and readily excretable products (becomes hydrophilic water soluble to be excreted)

Question 39

Cytochrome PF50

Answer 39

Large family of enzymes and individual one is called isoenzyme different types of cyt P450

Question 40

Paracetamol poisoning

Answer 40

predominantly metabolised by Phase 2 metabolism when overdosed - phase 2 becomes too saturated body tries to metabolise through oxidation (phase 1 mechanism) - produces toxic metabolite - n-acetyl-p benzoquinone imine damages kidneys and liver

Question 41

Antidote for paracetamol poisoning and how?

Answer 41

n-acetylcysteine enhances phase 2 metabolism

Question 42

DRUGS THAT UNDERGO SUBSTANTIAL FIRST PASS METABOLISM

Answer 42

``` Aspirin Glyceryl trinitrate Levodopa Lidocaine Morphine Propanolol Salbutamol Verapamil ```

Question 43

ENZYME INDUCING DRUGS

Answer 43

Enhance the production of liver enzymes which break down drugs Faster rate of drug breakdown Larger dose of affected drug needed to get the same clinical effect

Question 44

examples of enzyme inducing drugs

Answer 44

``` Phenytoin Phenobarbitone Carbamazepine Rifampicin Griseofulvin Chronic alcohol intake Smoking ```

Question 45

ENZYME INHIBITING DRUGS

Answer 45

Inhibit the enzymes which break down drugs Decreased rate of drug breakdown Smaller dose of affected drug needed to produce the same clinical effect

Question 46

BIOAVAILABILITY

Answer 46

Bioavailability is the proportion of a dose which actually gets into the systemic circulation

Question 47

factors affecting bioavailablity

Answer 47

Pharmaceutical Preparation Particle size, composition of formulation 2. Physicochemical Interactions Other drugs or food may interact with or inactive the drug 3. Patient Factors Malabsorption syndromes, gastrointestinal motility 4. Pharmacokinetic interactions and first-pass metabolism

Question 48

Clerance of a drug

Answer 48

This is the measure of the removal of drug from the body or the volume of plasma completely emptied of drug per unit time This includes metabolic as well as renal and biliary clearance Clearance does not indicate the amount being removed but the volume of plasma (or blood) from which the drug is completely removed or cleared in a given time period.

Question 49

half life of a drug

Answer 49

take taken for concentration to reduce by half

Question 50

What is half life increased by?

Answer 50

Diminished renal plasma flow e.g. heart failure Addition of a second drug that displaces the first from albumin thereby increasing the volume of distribution of the drug Decreased extraction ratio as seen in renal disease Decreased metabolism as seen in liver disease

Question 51

drug elimination

Answer 51

fluids - urine, bile, sweat, tears, milk solids - hair, faeces gases - important for volatile compounds

Question 52

Elimination via the kidney

Answer 52

1. free drug enters GF 2. Active secretion in PCT 3. Passive reabsorption of lipid soluble, unionised drug - DCT 4. Ionised lipid insoluble drug into urine

Question 53

What does elimination via the kidney depend on

Answer 53

blood flow to kidney GFR Active secretion of drugs into tubule at the start passive reabsorption back into the tubule

Question 54

SIGNIFICANCE OF ALTERED RENAL FUNCTION

Answer 54

Care with renally excreted drugs Care with drugs with a narrow therapeutic index Example: digoxin Care with drugs which produce active metabolites Care with drugs that may further reduce renal function

Question 55

what is used to evaluate renal function

Answer 55

creatinine - produced by muscle estimation of creatinine clearnace estimates clearance of drugs filtered at glomerulus

Question 56

COCKCROFT GAULT EQUATION

Answer 56

Estimated Creatinine Clearance in mL/min = (140-Age) x Weight x Constant Serum Creatinine

Question 57

egfr

Answer 57

eGFR uses serum creatinine, age, sex and race (for African-Caribbean patients) This is normalised to a body surface area of 1.73m2 and derived from a specific formula. Absolute GFR = eGFR x individual’s body surface area /1.73

Question 58

drug monitoring

Answer 58

clinical effectMeasuring BP, pain reduction etc biological effect - prothrombin time for warfarin, glucose for insulin etc plasma concentrations when relevant

Question 59

Therapeutic index

Answer 59

ratio of: Dose that causes toxicity Dose that produces desired effect efficacy vs toxicity