clinical pharmacology

4 primary protein drug targets

receptors

ion channels

carrier molecules

enzymes

4 main families of receptor

ligand gated ion channels

g-protein coupled receptors

tyrosine kinase/cytokine receptor

nuclear/steroid hormone receptors

ligand gated ion channels

activated in resposne to specific ligands, conduct ions through membrane, selective about ions

quaternary structures

milliseconds

nicotinic acetylcholine receptor pore

ligand gated ion channel

two ach molecules, letting cations in

g-protein coupled receptors

takes seconds

monomeric proteins with tertiary structure, ligand activated, mediate signal transduction across cell membrane

tyrosine kinase/cytokine receptor

hours

transfers phosphate groups from atp to tyrosine residues on intracellular target proteins

mediate actions of growth factors, cytokines and certain hormones

vascular endothelial growth factor receptor

example of tyroskine kinase receptor

essential for angiogenesis

nuclear/steroid hormone receptors

in vicinity of dna, dimerisation necessary for function

how do drugs bind to receptors (4)

wan der walls forces

hydrogen bonding

ionic interactions

covalent bonding

affinity

attraction of drug to receptor

efficacy

ability to induce effect

agonists

affinity and efficacy → mimics and turns pathway on

antagonists

affinity but no efficacy → prevents pathway

Kd

measure of affinity, concentration of substance giving 50% binding

EC50

measures potency of agonist, concentration of agnoist producing 50% of max response

inverse agonist

negative efficacy but good affinity, binds to recetors to decrease basal receptor activity

competitive antagonism

reversible - binds to receptor reversibly, meaning more concentration needed to compensate

irreversible - covalently binds to receptor, reducing number of receptors available to agonist

receptor selectivity

determined by drug’s differential affinity for different receptor subtypes, mesured by differences in Kd

specific medication

interacts only with its target → only exerts intended effect

selective medication

preferentially interacts with its target with minimal off target effects

typical antipsychotic medications

pretty selective such as haloperidol for dopamine receptor antagonists

atypical antipsychotic medications

not as selective, tartgeting broader in cns meaning don’t need as high of a dose

e.g. quetiapine and clozapine for serotonin and dopamine receptor antagonists

receptor downregulation

due to chronic agonist administration as fewer receptors are avialble for stimulation

e.g. chronic salbutamol causing internalisation of receptors

receptor upregulation

due to chronic antagonist adminstration as more receptors are synthesised as compensation

e.g. chronic propanolol increasing synthesis of b1 receptors in heart

drug input to pharmacological effect process

drug dosage

absorption into free drug concentration in plasma

• binding to plasma proteins, binding to tissues

elimination - hepatic/extrahepatic metabolism, biliary excretion, renal excretion

drug distribution - reversible flow into tissues and drug concentration at site of action

pharmacological effect

major organs for drug disposition

gi tract

liver

kidneys

lungs

physicochemical properties of interest for drug disposition

solubility

lipophilicity

ionisation

chemical structure - affinity for transport and susceptibility to metabolism

drug absorption definition

transfer of drug from site of administration to systemic circulation

passive diffusion

drive by concentration gradient 

lipophilic, small, uncharged molecules

facilitated diffusion

passive diffusion of molecules through transmembrane proteins

rate of transport generally faster than for simple passive diffusion

active transport

using atp to drive transport across membrane against concentration gradient

requires membrane transporters

secondary active transport

moves molecules against their own concentration gradient using concentration gradient of another molecule

endocytosis and exocytosis

drug take up or released from cell using vesicles

mainly for large molecules

filtration

having holes in barrier + paracellular transport through tight junction

advantages of iv administration

rapid

previse

no absorption required

can be used for irritation substances

disadvantages of iv administration

requires facilities

requires careful prep of site and injected material

sterility

non particulate

hazardous

no recall of drug if overdosed

advantages of oral administration

safe

convenient

economic

no facilities required

disadvantages of oral adminstration

slow

unpredictable rate, extent and reproducibility

zero order input

constant rate, linear increase of conc in blood

first order input

concentration dependent

contributing factors of bioavailability of oral administration

physicochemistry

formulation

gastric emptying

drug food interactions

intestinal motility

transport kinetics

drug metabolising enzymes

volume of distribution definition

theoretical volume a drug would have to occupy to give known blood plasma conc following known dose

gives indication of drug distribution out of plasma into tissues

what determins volume of distribution

body mass and composition

tissue blood flow

tissue and plasma protein binding

paritioning and sequestration into or form tissues

loading dose

initial high dose adminstered to rapidly achieve target concentration

dependent on Vd, larger Vd requires larger loading dose required to achieve target conc

example of ligand dated ion channel

nicotonic acetylcholic receptor pores

gabaa

ionotropic glutamate receptor

example of gpcr

mAChRm adrenergic, dopamine

examples of nuclear/steroid hormone receptors

retonoid x receptor

dimeric orphan receptors

monomeric orphan receptors

example of full agonist

methadone

competitive enzyme inhibition

takes place of substrate

non competitive enzyme inhibition

binds to another site on enzyme, either meaning substrate cannot bind or enzyme activity impaired

monoclonal antibodies

infliximab and adalimumab treating autoimmune disease or targetting tnf

cytotoxic chemotherapy

targeting proliferating cells, generally affecting dna synthesis and function

drug classes of cytotoxic chemotherapy

alkylating

antimetabolites

microtubule disrupters

topoisomerase inhibitors

gastric emptying

rate limiting process for absorption

increased rate → increased absorption

reduced rate → decreased absorption

plasma protein binding

reduction leads to increased elimiation of unbound drugs + no change in steady state unbound drug conc → not clinically relevant

drugs w tiny vd

warfarin → 10 L with high plasma protein binding

drugs with small vd

gentamicin - 18L

drugs w medium vd

theophylline and ethanol - 35L

low plasma protein binding, non polar

drugs w large vd

digoxin - 500 L

sodium potassium atpase binding

chloroquine - 1500L

lipophilic, sequestered into total body fat

metabolism

bio transformation of drugs - enzyme catalysed chemical change 

easier to excrete + losing affinity for receptor

or increased activity + increased toxic metabolites

liver as a site of metabolism

first pass metabolism of PO drugs

cyp enzymes

udp glucuronosyl transferases

lungs as site of metabolism

metabolism of aerosol sprays

gi tract as site of metabolism

cyp enzymes

gut bacteria and proteases

plasma as site of metabolism

esterases

metabolism reactions

oxidation

reduction

hydrolysis

conjugation

cyp1a2

substrates - theophylline and caffein

inhibited by cimetidine

inducted by tobacco, bb1 meat, cruciferous veggies

cyp2e1

substrates - ethanol and paracetamol

increased via chronic ethanol consumption

cyp2d6

substrates - tricyclic antidepressants and codeine

inhibited by fluoxetine

cyp2c9

substrates - s-warfarin

inhibited by cimetidine

cyp2c19

substrates - omeprazole, clopidogrel

omeprazole inhibits it, reducing metabolism of coadminstered substances

cyp3a4

substrates - erthromycin, simvastatin, felodipine

inhibted by erthromucin and grapefruit juice

inducted by rifampicin and st johns wort

clearance

constant describing relationsip between conc and rate of elimination

very rapid clearance drugs

sevoflurane - 621l/h

glyceryl trinitrate - 150l/h

rapid clearance drugs

morphine - 60 l/h

medium clearance drugs

digoxin - 9l/h

getamycin - 6l/h

slow clearance drugs

warfarin - 0.2l/h

zero order elimination

elimination independent of conc → clearance = 0

happens when elimination is saturated

first order elimination

elimination rate proportional to conc

clearance is constant

maintenance dose rate

clearance x target conc / F

absorption half life

x 3 = time to reach peak conc after dose

elimination half life

impacts time required to reach steady state concentration

drug accumulates with repeated dosing, css reached after 4-5 half lives

categories of time and drug

immediate effect

delayed effect

cumulative effect

delayed drug effects due to

distribution to effect site - pharmacokinetics

binding to receptor - binding kinetics

reliance of physiological intermediate

equilibration half life

determined by volume of effect compartment + clearance of effect compartment

polymorphism

distinct form of gene occurs in at least 1% of population

poor metaboliser trait

inherited loss of function of drug metabolising enzyme

may lead to higher levels of drug → increased risk of adverse drug reations

autosomal recessive manner

metabolic ratio

drug/metabolite plasma concentration

high → poor metaboliser

low → extensive metaboliser

clopidogrel

used as antiplatelet therapy w aspiring after percutaneous coronary intervention to minimise risk of ischaemia due to thrombosis

prodrug bioactvated by cyp2c19