Introduction To Pharmacology Lecture Block 14.11.23

Question 1

Define pharmacology

Answer 1

‘The study of how medicines work and how they affect our bodies’ (British Pharmacological Society)

Question 2

Define pharmacodynamics

Answer 2

The biochemical, physiological and molecular effects of a drug on the body

Question 3

Define pharmacokinetics

Answer 3

The fate of a chemical substance administered to a living organism

Question 4

What is the pharmacokinetic processes?

Answer 4

A - Absorption
D - Distribution
M - Metabolism
E - Excretion

Question 5

Describe absorption (pharmacokinetics)

Answer 5

Transfer of a drug molecule from site of administration to systemic circulation

Question 6

In which 2 methods of administration does 100% of the dose reach systemic circulation?

Answer 6

IV (intravenous) and IA (intra-arterial)

Question 7

What are the 10 ways where drugs must cross at least one membrane to reach systemic circulation?

Answer 7

IM (intramuscular)
SC (subcutaneous)
PO (oral)
SL (sublingual)
INH (inhaled)
PR (rectal)
PV (vaginal)
TOP (topical)
TD (transdermal)
IT (intrathecal)

Question 8

What are the 3 mechanisms for drugs to permeate membranes?

Answer 8

Passive diffusion through hydrophobic membrane —> lipid soluble molecules

Passive diffusion aqueous pores —> very small water soluble drugs (eg lithium), most drug molecules are too big

Carrier mediated transport —> Proteins which transport sugars, amino acids, neurotransmitters and trace metals (and some drugs)

Question 9

What are the 2 factors affecting drug absorption?

Answer 9

1. Lipid solubility
2. Drug ionisation

Question 10

What is pKa?

Answer 10

The value at which the ionised and unionised form of the drug are equal (50:50)

Question 11

Where are weak acids best absorbed?

Answer 11

In stomach

Question 12

Where are weak bases best absorbed?

Answer 12

Small intestine

Question 13

What is drug ionisation?

Answer 13

Drugs going from ionised to unionised)

Question 14

What are 5 factors affecting oral drug absorption in stomach

Answer 14

Gastric enzymes - drug molecule may be digested (peptides, proteins) —> Eg. insulin and biologicals

Low pH - molecule may be degraded (benzylpenicillin)

Food (full stomach will generally slow absorption)

Gastric motility (altered by drugs and disease state)

Previous surgery (eg gastrectomy)

Question 15

What are 3 factors affecting oral drug absorption in small intestine?

Answer 15

Drug structure —> Lipid soluble/unionised molecules diffuse down concentration gradient, large or hydrophilic molecules are poorly absorbed

Medicine formulation —> Capsule/tablet coating can control time between administration and drug release, modified release controls (slows) the rate of absorption (less frequent dosing)

P-glycoprotein —> Substrates are removed from intestinal endothelial cells back into lumen

Question 16

What is first pass metabolism?

Answer 16

metabolism of drugs preventing them reaching systemic circulation

Question 17

Define bioavailability

Answer 17

Proportion of administered dose which reaches the systemic circulation

Question 18

What are the ways which first pass metabolism may occur?

Answer 18

Degradation by enzymes in intestinal wall

Absorption from intestine into hepatic portal vein and metabolism via liver enzymes

Question 19

Is the degree of first pass metabolism the same in each person?

Answer 19

No, it differs in each person

Question 20

How can you avoid first pass metabolism

Answer 20

Avoid giving via routes that avoid splanchnic circulation (e.g. rectal)

Question 21

What 2 factors is bioavailability dependant on?

Answer 21

Dependent on extent of drug absorption and extent of first pass metabolism

Question 22

Is bioavailability affected by rate of absorption?

Answer 22

NO

Question 23

How is bioavailability expressed?

Answer 23

% or fraction

Question 24

What 2 ways does bioavailability vary?

Answer 24

Route of administration

Between individuals

Question 25

What are 3 pros of rectal administration?

Answer 25

Local administration Avoids first pass metabolism Nausea and vomiting

Question 26

What are 2 cons of rectal administration

Answer 26

Absorption can be variable Patient preference

Question 27

2 pros of inhaled administration

Answer 27

Well perfused large surface area Local administration

Question 28

1 con of inhaled administration

Answer 28

Inhaler technique can limit effectiveness

Question 29

2 pros of sub-cutaneous administration

Answer 29

Faster onset than PO Formulation can be changed to control rate of absorption

Question 30

1 con of sub-cutaneous administration

Answer 30

Not as rapid as IV

Question 31

2 pros of trans-dermal administration

Answer 31

Provides continuous drug release Avoids first pass metabolism

Question 32

2 cons of trans-dermal administration

Answer 32

Only suitable for lipid soluble drugs Slow onset of action

Question 33

What are the 4 compartments of the body where drugs can be distributed in?

Answer 33

Fat Plasma Interstitial fluid Intracellular fluid

Question 34

What 3 things will influence ability to move between compartments?

Answer 34

Molecule size, lipid solubility, protein binding

Question 35

Small molecule size effect on distribution?

Answer 35

Increased distribution

Question 36

Large molecule size effect on distribution?

Answer 36

Decreased distribution

Question 37

Hydrophilic molecule effect on distribution?

Answer 37

Decreased distribution

Question 38

Lipophilic molecule effect on distribution?

Answer 38

Increased distribution

Question 39

Increased protein bound molecules effect on distribution?

Answer 39

Decreased distribution

Question 40

Decreased protein bound molecules effect on distribution?

Answer 40

Increased distribution

Question 41

Define volume of distribution (Vd)

Answer 41

Theoretical volume a drug will be distributed in the body (apparent volume of distribution) and volume of plasma required to contain the total administered dose

Question 42

Will well distributed or poorly distributed drugs have a high Vd?

Answer 42

well distributed drugs will have high Vd

Question 43

What are the 3 ways for drugs to reach the CNS?

Answer 43

High lipid solubility. e.g. Ѱ drugs usually very lipid soluble (therefore large Vd) Intrathecal administration (e.g. baclofen in MS and spinal cord injury, chemotherapy) Inflammation (causes barrier to become leaky)

Question 44

Define drug elimination

Answer 44

the process by which the drug becomes no longer available to exert its effect on the body

Question 45

What are the 2 phases of drug metabolism

Answer 45

Phase 1: Oxidation/reduction/hydrolysis to introduce reactive group to chemical structure Phase 2: Conjugation of functional group to produce hydrophilic, inert molecule

Question 46

What cytochrome is responsible for majority of phase 1 metabolism?

Answer 46

Cytochrome P450 (CYP450)

Question 47

Where is Cytochrome P450 (CYP450) mostly located?

Answer 47

Liver (extrahepatic: small intestine, lung)

Question 48

What 3 ways can CYP function vary?

Answer 48

Genetic variation Reduced function in severe liver disease Interactions enzyme inhibiting/inducing drugs or food can reduce/increase enzyme activity

Question 49

What drug molecules will readily cross hepatocytes membrane? What does it produce?

Answer 49

Lipophillic unbound drug molecules. Produces a reactive metabolite by creating or unmasking a reactive functional group.

Question 50

What are the 5 most significant CYP enzymes for drug metabolism?

Answer 50

3A4, 2C9, 2C19, 1A2, 2D6

Question 51

How many CYP450 enzymes are there?

Answer 51

57

Question 52

What is phase II metabolism

Answer 52

Conjugation of an endogenous functional group (glycine, sulfate, glucuronic acid) to produce a non-reactive polar (therefore hydrophilic) molecule, Hydrophyllic metabolite can then be renally excreted.

Question 53

What 3 ways can drugs and metabolites be excreted?

Answer 53

Liquids (small, polar molecules): urine, bile, sweat, tears, breast milk Solids (large molecules): faeces (through biliary excretion) Gases (volatiles): expired air

Question 54

What are the 3 processes which account for renal excretion of drugs?

Answer 54

1. Glomerular filtration 2. Active tubular secretion 3. Passive reabsorption

Question 55

How are drugs excreted in glomerular filtration?

Answer 55

20% of plasma filtered Free/unbound drug molecules filtered Very large molecules excluded

Question 56

How are drugs excreted in active tubular filtration?

Answer 56

80% of renal blood flow passes on to peritubular capillaries Drug molecules transported by carrier systems —> Organic anion transporter (OAT) and organic cation transporter (OCT) Can clear protein bound drug Most effective renal clearance mechanism

Question 57

How are drugs excreted in passive reabsorption?

Answer 57

Diffusion down the concentration gradient from tubule into peritubular capillaries Hydrophobic drugs will diffuse easily Highly polar drugs will be excreted

Question 58

What can reduced kidney function lead to (in terms of drug clearance)?

Answer 58

Kidneys excrete drugs and drug metabolites (active and inactive) Reduced kidney function can lead to accumulation and toxicity of renally cleared drugs