Introduction To Pharmacology Lecture Block 14.11.23 Flashcards
Define pharmacology
‘The study of how medicines work and how they affect our bodies’ (British Pharmacological Society)
Define pharmacodynamics
The biochemical, physiological and molecular effects of a drug on the body
Define pharmacokinetics
The fate of a chemical substance administered to a living organism
What is the pharmacokinetic processes?
A - Absorption
D - Distribution
M - Metabolism
E - Excretion
Describe absorption (pharmacokinetics)
Transfer of a drug molecule from site of administration to systemic circulation
In which 2 methods of administration does 100% of the dose reach systemic circulation?
IV (intravenous) and IA (intra-arterial)
What are the 10 ways where drugs must cross at least one membrane to reach systemic circulation?
IM (intramuscular)
SC (subcutaneous)
PO (oral)
SL (sublingual)
INH (inhaled)
PR (rectal)
PV (vaginal)
TOP (topical)
TD (transdermal)
IT (intrathecal)
What are the 3 mechanisms for drugs to permeate membranes?
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)
What are the 2 factors affecting drug absorption?
- Lipid solubility
- Drug ionisation
What is pKa?
The value at which the ionised and unionised form of the drug are equal (50:50)
Where are weak acids best absorbed?
In stomach
Where are weak bases best absorbed?
Small intestine
What is drug ionisation?
Drugs going from ionised to unionised)
What are 5 factors affecting oral drug absorption in stomach
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)
What are 3 factors affecting oral drug absorption in small intestine?
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
What is first pass metabolism?
metabolism of drugs preventing them reaching systemic circulation
Define bioavailability
Proportion of administered dose which reaches the systemic circulation
What are the ways which first pass metabolism may occur?
Degradation by enzymes in intestinal wall
Absorption from intestine into hepatic portal vein and metabolism via liver enzymes
Is the degree of first pass metabolism the same in each person?
No, it differs in each person
How can you avoid first pass metabolism
Avoid giving via routes that avoid splanchnic circulation (e.g. rectal)
What 2 factors is bioavailability dependant on?
Dependent on extent of drug absorption and extent of first pass metabolism
Is bioavailability affected by rate of absorption?
NO
How is bioavailability expressed?
% or fraction
What 2 ways does bioavailability vary?
Route of administration
Between individuals
What are 3 pros of rectal administration?
Local administration
Avoids first pass metabolism
Nausea and vomiting
What are 2 cons of rectal administration
Absorption can be variable
Patient preference
2 pros of inhaled administration
Well perfused large surface area
Local administration
1 con of inhaled administration
Inhaler technique can limit effectiveness
2 pros of sub-cutaneous administration
Faster onset than PO
Formulation can be changed to control rate of absorption
1 con of sub-cutaneous administration
Not as rapid as IV
2 pros of trans-dermal administration
Provides continuous drug release
Avoids first pass metabolism
2 cons of trans-dermal administration
Only suitable for lipid soluble drugs
Slow onset of action
What are the 4 compartments of the body where drugs can be distributed in?
Fat
Plasma
Interstitial fluid
Intracellular fluid
What 3 things will influence ability to move between compartments?
Molecule size, lipid solubility, protein binding
Small molecule size effect on distribution?
Increased distribution
Large molecule size effect on distribution?
Decreased distribution
Hydrophilic molecule effect on distribution?
Decreased distribution
Lipophilic molecule effect on distribution?
Increased distribution
Increased protein bound molecules effect on distribution?
Decreased distribution
Decreased protein bound molecules effect on distribution?
Increased distribution
Define volume of distribution (Vd)
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
Will well distributed or poorly distributed drugs have a high Vd?
well distributed drugs will have high Vd
What are the 3 ways for drugs to reach the CNS?
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)
Define drug elimination
the process by which the drug becomes no longer available to exert its effect on the body
What are the 2 phases of drug metabolism
Phase 1: Oxidation/reduction/hydrolysis to introduce reactive group to chemical structure
Phase 2: Conjugation of functional group to produce hydrophilic, inert molecule
What cytochrome is responsible for majority of phase 1 metabolism?
Cytochrome P450 (CYP450)
Where is Cytochrome P450 (CYP450) mostly located?
Liver (extrahepatic: small intestine, lung)
What 3 ways can CYP function vary?
Genetic variation
Reduced function in severe liver disease
Interactions enzyme inhibiting/inducing drugs or food can reduce/increase enzyme activity
What drug molecules will readily cross hepatocytes membrane? What does it produce?
Lipophillic unbound drug molecules. Produces a reactive metabolite by creating or unmasking a reactive functional group.
What are the 5 most significant CYP enzymes for drug metabolism?
3A4, 2C9, 2C19, 1A2, 2D6
How many CYP450 enzymes are there?
57
What is phase II metabolism
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.
What 3 ways can drugs and metabolites be excreted?
Liquids (small, polar molecules): urine, bile, sweat, tears, breast milk
Solids (large molecules): faeces (through biliary excretion)
Gases (volatiles): expired air
What are the 3 processes which account for renal excretion of drugs?
- Glomerular filtration
- Active tubular secretion
- Passive reabsorption
How are drugs excreted in glomerular filtration?
20% of plasma filtered
Free/unbound drug molecules filtered
Very large molecules excluded
How are drugs excreted in active tubular filtration?
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
How are drugs excreted in passive reabsorption?
Diffusion down the concentration gradient from tubule into peritubular capillaries
Hydrophobic drugs will diffuse easily
Highly polar drugs will be excreted
What can reduced kidney function lead to (in terms of drug clearance)?
Kidneys excrete drugs and drug metabolites (active and inactive)
Reduced kidney function can lead to accumulation and toxicity of renally cleared drugs
