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Lam Ip

on 20 February 2014

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Transcript of Drug

a single chemical substance with effects on the body

a substance or mixture of substances used in restoring or preserving health

A written order:
what medicine
to whom
what formulation
what route
how frequently
for how long

- what a drug does to the body
- what the body does to the drug

The biochemical and physiological effects of drugs on the body
The mechanism of drug reaction
The relationship between drug concentration and drug effect
Channel-linked receptors
activation opens the channel
ligand gated channels
G-protein-coupled receptors
secondary messenger
adenylate cyclase and guanylate cyclase
Kinase-linked receptor
triggers a cascade or phosphorylation reactions
e.g. insulin
DNA-linked receptors
'nuclear receptors'
promotes or inhibits synthesis of new proteins
may take hours
interfere with the active site
affect co-factors
uniporter, symporter, antiporter
Drugs inhibit their activity
'false substrates'
strength of the complex
drugs dissociate at varying rates
low affinity --> rapid fine modulation
high affinity --> prolonged binding and biological response
produces conformational change
initiate biological response
most binds reversibly
does not produce conformational change
no intracellular signal
non-competitive (e.g. affecting secondary messenger system)
Partial agonist
activates a receptor
does not produce maximal signalling effect
reduces overall response (antagonise)
Reverse agonist
produces opposite effect to full agonist
some degree of activation in absence of ligand binding
constitutive activity
growth factors

Dose-response curve
Linear scale
used in clinical responses
heart rate, bp, gastric pH, blood gloucose
enzyme activity, membrane potential
Log10 scale
expands region where response changes rapidly
ligand concentrate rather then dose
Emax : maximum response
ED50 : dose producing half of Emax
Effective dose range : spanning the straight line segment (20 - 80% or Emax)
Maximum tolerated dose : highest dose without developing dose-related adverse effects
Adding competitive antagonist to agonist
shift curve to the right
higher agonist is needed
Non-competitive antagonist to agonist
impossible to achieve maximum response
shift curve to the right
decrease Emax
Irreversible antagonists
ED50 to the right
Partial agonist to agonist
reduced Emax
ED50 may or may not change
can be bound without replacing full agonist
Efficacy (Emax)
The extent to which a drug can produce a response when all available receptors or binding sites are occupied
The amount of a drug required for a given response
(more potent drugs have lower E50)
Relates to affinity for the receptor
Different between individuals
High Efficacy drugs
same mechanism may cause dose limiting adverse-effects
minimised by titrating the dose
e.g. beta-1 adrenoceptors in the heart
higest efficacy --> more likely
Low potency drugs
overcome by giving higher doses
adverse effects maybe dose-related
mechanism other than receptor-ligand interaction that causes adverse effects
Agonist selectivity
The ratio of EC50 of the dose-response curve of 2 subtypes
response - % maximum
e.g. Beta-adrenoceptor --> beta1 and beta2 both to noradrenaline

Named on the basis of major endogenous agonist
e.g. adrenergic, serotoninergic, opioid
'sub-typed' base on selectivity for agonists or antagonists
Antagonist selectivity
relative shift of agonist dose-response curves achieved by single dose of antagonist
e.g. non-selective beta-adrenoceptor agonist isoprenaline & beta-adrenoceptor antagonist atenolol
post-atenolol ED50 indicates 10 times more isoprenaline is required to overcome effect of atenolol at the heart than the lung
Atenolol - 'cardioselective' beta-blocker

is beta-blocker a antagonist / reverse agonist?
'sub-typed' base on selectivity for agonists or antagonists
The ratio of impact at two receptor sites is >100
Achieved at lowest effective dose
Asthma is protected by beta2-mediated bronchodilating effect of endogenous agonist adrenaline
Atenolol (beta1-selective adrenoceptor antagonist) can interfere and is absolutely contraindicated
Dose and effect
Recommended dose range
dose range that is expected to be close to the top of the top of the dose-response curve
but possible to achieve desired therapeutic response at the lower end of the recommended
Adverse effects often dose-related
Same mecahnism
(atenolol cause heart block as side effect of anti-anginal action - beta1)
Different mechanism
(atenolol cause bronchospasm by antagonising beta2)
Therapeutic index
Ratio of ED50 of dose-response curves of beneficial and adverse effects

Drugs have multiple potential adverse effects
Most drugs >100 but some <10
difficult to prescribe
e.g. anti-cancer drugs
titrated carefully
'therapeutic drug monitoring'
• digoxin (anti-arrhythmic)
• warfarin (anticoagulant)
• theophylline (bronchodilator)
• phenytoin(anthi-epileptic)
• insulin
Inter-individual variation
Pharmacodynamic variation (receptor number, structure, physiological changes)
Pharmacokinetics varation (drug absorption, distribution, metabolism) - different drug exposure
Biological response diminishes when given continuously / repeatedly
Restored by increasing dose
Sometimes, tissue become completely refractory
rapid, sometimes with initial dose (hours)
more gradual (days/weeks)
Pharmacodynamic effectiveness
alterations in the way the drug is handled
Receptor medicated
Non-receptor mediated
Increased drug metabolism
increase capacity of liver to metabolise/inactivate drugs
e.g. cytochrome P450 enzyme system in the liver
drugs induce their own metabolism
anti-epileptic drugs, ethanol, anti-viral drugs for HIV
Receptor downregulation
e.g. beta-adrenoceptor, falls by 10% after 8 hrs of continuous exposure to isoprenaline (agonist)
endocytosis ('ligand-gated' endocytosis) after prolonged agonist binding
New receptors need several days to be synthesised
Protective mechanism against overstimulation
Change in receptor structure
receptor phosphorylation - AA sequence contains certain residue (serine & threonine) mainly in C-terminal, phosphorylation sites of specific kinase, reduce interaction of receptor with G-protein
reactivated by phosphatases / internalised by endocytosis
ion channels linked - desensitise rapidly, e.g. neuromuscular junction, slow conformational change results in tight binding of agonist without opening
used by depolarising neuromuscular blocking drugs e.g. suxamethonium during anaesthesia
Exhaustion of mediators
endogenous store of neurotransmitters released on contact with the drug
e.g. pseudoephedrine - sympathomimetic amine used for nasal congestion, stimulate release of endogenous noradrenaline, activate alpha adrenoceptors, vasoconstriction, more fluid to the nose and reduce inflammation
signaling molecules e.g. secondary messenger
Physiological adaptation
reflex physiological changes
counteract the effect of the drug - homeostasis
e.g. hormonal response in hypertension treatment
diuretics and vasodilator - sympathetic nervous system and renin-angiotensin system
Active extrusion of drugs from cells
Withdrawal effects
chemical, hormonal and physiological changes
e.g. nitrate withdrawal - increased attacks
benzodiazepine withdrawal - enhances inhibitory neurotransmitter GABA - decreased GABA inhibition
The rate and extent to which drugs are absorbed and distributed
The rate and pathways drugs are eliminated from the body by metabolism and excretion
Relationship between time and plasma drug concentration
Drug residence in the body
Enteral routes
survive gastric acid
avoid food binding
cross GI mucosa
survive hepatic 'first-pass metabolism' and 'enterohepatic circulation'
e.g. hypertension
Parenteral routes
no concerns about absorption
no 'first pass' effect
unpredictable in absorption
absorbed well
injected by patient themselves
e.g. insulin, heparin
inhaled into target airways in lung
e.g. salbutamol, beclometasone
Passive Diffusion
molecular size
lipid solubility
protein binding
Reach equilibrium
Volume of distribution
the volume that the dose appears to have distributed into immediately following IV based on plasma concentration
C0 = D/Vd
Larger Vd --> more is distributed in tissue
Phase I
oxidation in microsomal mixed function
oxidase system
NB. enzyme induction/inhibition
e.g. warfarin, morphine, oestrogens
Phase II
conjugation (acetylation/glucuronidation)
Reduces biological activity
Increases water-solubility
shorter half-life
reduced activity
increased exposure for toxic metabolites
Longer half-life
increased activity
Drug accumulation and toxic effect
Hepatic drug interactions
first drug stimulates the liver to produce more metabolising enzymes
e.g. phenytoin, carbamazepine, rifampicin, chronic alcohol
lower dose
first drug competing for the metabolising enzyme
e.g. cimetidine, erythromycin, ciprofloxacin, valproate
higher dose
First-pass metabolism
Drug from stomach pass through the portal venous system and liver sinusoids before systemic circulation
Inactive(pro-drug) --> active metabolic : increased
Active drug --> inactive metabolite : decreased
Active drug --> active metabolite : unchanged
durgs and metabolites removed from the body
fluids, solids, gases
Renal excretion
low-molecular-weight drugs
water-soluble to avoid reabsorption
Drugs bound to plasma proteins are not filtered
urine is more acidic than plasma, may alter pH partitioning of drugs
Some drugs are actively secreted
Biliary excretion
faecal excretion
larger molecular-weight drugs (conjugated with glucuronide)
If still lipid-soluble, unchanged drugs / metabolite may be reabsorbed and re-enter portal vein
Entero-hepatic circulation
bile - small intestine - reabsorbed to liver
active drugs & glucuronide conjugates
prolong residence time
bacterial flora - enzymes to hydrolyse conjugates
broad-spectrum antibiotics etc. can reduce reabsorption and drug availability
volume of plasma completely cleared of drug per unit time
related to half life etc
AUC(oral) / AUC(IV)
for the plasma concentration-time graph
expressed as percentage
Gastric acid destruction
insulin, benzylpenicillin
enteric coated, slow release
first-pass metabolism
lidocaine, morphine, glyceryl trinitrate
solubility, ionisation, food, diarrhoea etc
Age, sex, body weight, impaired organ function, genetic variation, environmental factors, food, drug interactions
Breast milk
First-order (exponential) kinetics
constant fraction of drug cleared
'law of mass action'
Zero-order (saturation) kinetics
constant amount of drug cleared
constant t1/2
Predictable effect of increasing dose
Metabolism has limited capacity
Elimination rate reaches maximum
drug progressively accumulate
Graphs of:
Elimination against dose
Plasma concentration against dose
Moving from first to zero order
enzyme saturated
increase half-life
increase AUC
compare to first order
Titration unpredictable
small dose increase --> significant rise in concentration
(Concentration against dose)
Concentration-time relationship
Repeated dose
Drug concentration needs to be kept over time
Previous dose have not completely eliminated
Drug will progressively accumulate
Steady state
fluctuations (peaks and troughs)
oscillations in effective range
Long Half-life:
slow to reach steady-state
Loading dose needed
Less regular dosing
Short Half-life:
Rapid steady-state
Find control
Not suitable orally
regular dosing
Loading doses:
Long half-life drugs e.g. cardiac glycoside
sub-therapeutic before state-state
initial dose much greater then maintaining dose
Compromise between convenience and constant level
More frequent = less oscillation
Drugs with small therapeutic index
Modified-release formulation
smooth onset and decline
e.g. nifedipine
More responsible for inter-individual varations
Therapeutic drug monitoring
plasma concentration related to clinical effect
Therapeutic efficacy
Compare drugs with same effect but different pharmacological mechanism
e.g. Diuretics: loop diuretics has higher natriuretic effecacy than thiazide diuretics
e.g. Acid suppressing drugs: proton pump inhibitors and H2 antagonists
Adverse Drug Reaction
minor effects that are predictable
Adverse reaction
Harmful or seriously unpleasant effects necessitating withdrawal or dose reduction
Toxic effects
Direct cellular level effects e.g. mutagenicity, carcinogenicity, teratogenicity

Older population
OTC medicines
herbal/traditional medicine
internet medicine
Type A (Augmented)
predictable from known pharmacology of drug
common, usually mild
detected in drug development
e.g. captopril - hypertnesion
Type B (Bizarre)
Unrelated to known pharmacology of drug
idiosynchratic, host factor
rare, often severe
no simple dose dependency
usually undiscovered until post-licensing
e.g. captopril - proteinuria/loss of taste
Type C (Chronic)
continuous exposure effects
e.g. Osteoporosis with steroids
Type D (Delayed)
e.g. drug induced cancer - skin, lymphomas
Type E (End of treatment)
withdrawal syndromes
e.g. headache, anxiety, GI disturbance after paroxetine
Type F (Failure of therapy)
Type G (Genetics)
Animal testing (post-thalidomide)
weeks 2-8 of intra-uterine life
affect cell division or protein/DNA synthesis
e.g. thalidomide, alcohol, cytotoxics, warfarin
Altered Growth
Organs are formed by alteration of growth
e.g. smoking, tetracycline teeth
Interfere with normal labour
e.g. beta-blockers
Post-partum effects
Respiratory or CVS depressants cross placenta
e.g. opioids
Allergic drug reactions
potentially serious
not dose-related
careful history (allergy/atopy)
skin, lungs, haematopoiesis

I - immediate/anaphylatic (IgE, mast cells)
e.g. penicillin, anaesthetics
II - antibody-dependent
e.g. methyldopa- , penicillin-induced haemolysis
III - immune complex-mediated
e.g. 'serum sickness', vasculitis
IV - cell-medicated
e.g. contact dermatitis
the scientific study concerned with the detection and evaluation of adverse effects of drugs
Voluntary reporting system (Yellow card)
Prescription event monitoring
Population statistics
Medical literature
Somatic nervous system
voluntary control
Autonomic nervous system
regulates organ function and homeostasis
nervous system
Efferent autonomic nerves
CNS --> peripheral
heart, blood vessels, gut, bladder, eyes, exocrine and endocrine
Afferent autonomic nerves
peripheral --> CNS
baroreceptors, chemoreceptors
autonomic nervew e.g. vagus, splanchinc, pelvic
Reflex arcs
afferent limb + efferent limb
some involve somatic nervous system
'thoraco-lumbar outflow' T1-L2
paravertebral ganglionic chains - from cervical to sacral region
Some terminate at cervical/adominal ganglia, or to greater splanchnic nerve - synapse with chromaffin cells in adrenal medulla
much longer
to effector organ
Adrenal medulla
synthesise and stores catecholamines
additional enzymes - noradrenaline to adrenaline
sympathetic cholinergic preganglionic fibres - hormonal secretion
release large quantities of catecholamines in stress
Fear, flight or fight
increased bllod
release energy
diverts blood flow
constricts sphincters
heart rate by pacemaker cells in SAN and AVN
conduction rate
stroke volume
cadiac output
Blood vessels
vasoconstriction - smooth muscle contraction - increase peripheral vascular resistance and pressure
vasodilatation - smooth muscle relaxation - increase muscle blood flow
venoconstriction - smooth muscle contraction - mobilise blood - increase venous return
constricts renal arterioles
release renin from juxtaglomerular apparatus
angiotensinogen - angiotensin I - angiotensin II
vasoconstriction, aldosterone release
relaxation of smooth muscle
reduce resistance
Gastrointestinal tract
more viscous secretion in salivary gland
bowel wall - relax smooth muscle - decrease paristalsis
sphincters - constricts smooth muscle - reduce onward transit of food
liver - glycogenolysis, gluconeogenesis
Adipose tissue
adipocytes - lipolysis
relax smooth muscle - avoid voiding
sphincters - constrict
male protate - constrict smooth muscle - difficult to urinate
Genital tract
Female -
contraction of myometrium of pregnant uterus (alpha)
relaxation of non-pregnant uterus (beta2)
pupillary dilatation
Adrenal medulla releases adrenaline
adrenaline & noradrenaline
synaptic contact
MAO in mitochondria
COMT in synaptic cleft
Adrenergic receptors
Alpha 1
blood vessels - vasoconstriction
Alpha 2
presynaptic membrane
feedback by its own release
Beta 1
heart - increase force and rate
Kidney - release renin
Beta 2
lung - bronchial smooth muscle relax
blood vessels - vasodilation
GI tract, liver, uterus, skeletal muscle
Beta 3
fat cells - lipolysis of adipose
Alpha agonists
rarely used
Alpha 1
cadiovascular collapse
nasal congestion
side effects: hypertension, tachycardia, angina
Alpha 2
Alpha antagonists
alpha blocker
hypertension, benign prostatic hypertrophy
Adverse effects: alpha 1 - hypertension, dizziness, nasal congestion
Beta agonist
Non-seletive: adrenaline, isophrenaline (rarely used)
Beta 1:
severe heart failure
adverse: tachycardia, palpitation
Beta 2:
premature labour
adverse: tremor
cadiac arrest
Beta antagonist
Beta blocker
non-selective: propranolol
Beta 1:
angina pectoris
heart failre
adverse: bradycardia, heart failure
Beta 2:
adverse: bronchospasm, cold peripheries
Nicotinic ACh receptor
post-ganglionic neurone
ligand-gated ion channels
Cranial outflow
Sacral outflow
Muscarinic ACh receptor
G protein-coupled
Acetylcholine receptors
Skeletal NMJ
Neuronal CNS
neural (slow EPSP in ganglia)
GI tract: gastric acid secretion
SAN: decrease rate
AVN: decrease conduction velocity
Atrial muscle: decrease force
Ventricular muscle: No effect
K+ channel
Ca2+ channel
Bronchi: constriction
Bladder: contraction, sphincter relaxation
GI tract: increase motility, sphincter dilatation, glands secretion
Salivary glands: secretion
Lacrimal glands: secretion
Eye: pupil constriction, ciliary muscle contration
erectile muscle and salivary gland - dilatation
phospholipase C, increase IP3 and DAG

adenylate cyclase, decrease cAMP

Parasympathomimetic / Cholinomimetic
Drugs that mimic the effect of parasympathetic nerve, by activation of responses mediated by muscarinic cholinergic receptors
Direct acting agonists
Choline esters
too unstable in plasma
not hydrolyzed by cholinesterase, weak as nicotinic, primarily a muscnic agonist
Natural plant compounds
alkaloid with muscarinic actions
Tertiary amine, lipophilic
From Amanita muscaria mushrooms
potential poisoning
Indirect acting agonists

Reversible ACh-esterase inhibitors
Tertiary plant alkaloid
Synthetic quaternary compound
Insecticide (Cabril) synthetic tertiary compound
Irreversible ACh-esterase inhibitors
Insecticides (accidental poisoning)
Ecothiopate (open angle glaucoma)
Military nerve gases (poisoning)
Extremely lipophilic
rapid diffuse
Not given systemically because of CNS effect
Intestinal atony, Urinary bladder atony:
rapid diffuse
Not given systemically because of CNS effect
Muscariniic antagonist
selective (little effect on ganglion and skeletal)
Tertiary amine
Prototypical muscarinic antagonist
Hyoscine (scopolamine)
Tertiary amine
More lipophilic - absorbed through gut or patch, crosses into CNS
Empirical chemistry
Iterative modifications
prototype molecules
improve specificty etc.
Traditional: synthesis, purification, testing
Combinatorial chemistry
rate-limiting --> testing
Physiology and Pathophysiology
hormones, neurotransmitter, receptors, enzymes
e.g. Parkinson's disease, Hypertension, Peptic ulceration, Diabetes
Rational drug design
drug target - 'in silico'
Crystallographic techniques - structure of binding site
chemical libraries
Decline over the last 10 - 15 years
lack of development science to guide translation of molecules to medicine
12 - 15 years
200 - 800 million
1 billion if failure taking into account
Choice of species: similarity to humans
Toxicology studies: dose associated, targets, reversibility
fertility, reproduction, teratogenicity, mutagenicity, carcinogenicity
New biopharmaceutical molecules e.g. monoclonal antibodies - very different
20 - 80 healthy
Initial single dose 'first into man'- repeated dose
6 - 12 months
100 - 200 patients
effectiveness 'proof of concept'
dose-response relationship - determine optimal dose
1 - 2 years
100 - 1000 patients
Verifies efficacy and safety
1 - 2 years
Very costly
100 - 1000 patients
After licensing - regulatory approval
New dosage strengths, indication or formulation
Long term safety and cost-effectiveness
extend the license
Safety profile incomplete
Additional safety studies
Safety risk
Toxicity studies
Acceptable risk
dependent on benefits e.g. cancer
Financial risk
Choose reliable biomarker
Patent: 20 years
'Branded' / 'Generic' medicine
protect market share
herbal remedies
healthcare products
Review ADR
Yellow Card scheme
Regulate clinical trials
British National Formulary
~3000 products
Direct-to-consumer advertising is banned in the EU
Promotion to doctors (Education, meetings, journals)
ABPI Code of Practice
Medicine Management
National bodies
Local bodies
Drug / therapeutics / formulary committees
Guidance and recommendations
drugs / treatments
cost-effectiveness consideration
NHS Evidence
easy access to best possible evidence
Quality standards
standards of healthcare
cost-effectiveness, safety, acceptability
Quality and Outcomes Framework
GPs rewarded for good quality clinical care
Clinical and cost-effectiveness
Clinical trial
Effectiveness and Safety
Observational studies
Natural experiments
observe progression of patients with different drugs - compare
Confounding factor
e.g. Renal impairment as contraindication of Drug A
Treatment trials
Access effects of treatments for particular disease process / symptoms
e.g. hypertension
Prevention trials
Access the ability to prevent occurrence
e.g. stroke
Diagnostic/screening trials
Access method of detecting disease
e.g. blood test
Quality of life studies
impact of treatment on quality of life
Inclusion criteria
diagnosis, type/stage of disease, age, unresponsive to previous treatment
Exclusion criteria
medical condition (renal/hepatic failure), drugs currently taken, pregnancy
Ensure relevant to research question
avoid unnecessary risk

Difficult to find subjects
not 'real world' practice
bias the trial
Parallel group
Factorial group
Cross-over design
Good clinical trials
clearly stated questoin
study design - answer question
minimise bias e.g. allocation, maintenance, blinding, accessing
equal potential confounding factors in baseline characteristics
Stratified - separate randomisation if strata
Blocked - randomise small batches
Clustered - randomise groups
Open label
Doctor and patients know
potential bias
Difficult to conceal
Single blind
patients don't know
Double blind
Neither doctor nor patient know
Control group - Comparator treatment
Placebo / active control
Historical control - unreliable
Outcome measure
Objectively measured: should avoid bias especially if assessor is not blinded e.g. inflammatory changes
Clinically relevant: directly relevant to patients e.g. viral infection
surrogate end-point: assume it can be extrapolated, but may be false e.g. diabetes 2
'equipoise' of treatment arms
informed consent
Avoid coersion, unreasonable incentives
Access to independant medical advice
Declaration of Helsinki
Scientific review by funder
Research ethics committees
Local (LREC)
Multicentre (MREC)
clinial trials approval
Data safety and monitoring boards
Scientific quality of study
Statistical manipulation
Publication (clinical trials registries)
Critical appraisal
systematically examine research evidence to access its validity, results and relevance before informing decision
Randomised controlled trials
not automatically good quality
representativeness of subjects
randomised and comparable
groups treated equally, outcome analysed for most patients
blinded, objective and standardised
Alternative medicines
Complementary medicine
therapeutic approach used together with conventional medicine
e.g. aromatherapy after surgery
Alternative medicine
therapeutic approach used instead of conventional medicine
e.g. garlic to lower blood pressure
Pracetices that are unproven by science and not presently considered an integral part of conventional medicine
Asia, China
fine needles at 'meridians'
in conjunction with Chinese herbal medicine
65 reviews on Cochrane database PONV
infections, puntured organs
Extract of aromatic plants 'essential oil'
massage treatment
may reduced disturbed behaviour, improve motivation in dementia - no reliable studies
infinitesimally low concentration of substances that induces symptoms
e.g. Arnica form Arnica montana, 1 in 1 million or greater
Some argue it is individually tailored - not amenable to assessment by conventioal randomised controlled trials
use of plants or plant extracts
minor or self-limiting conditionlongstanding herbal medicine traditions e.g. Chinese, Ayurvedic, Kampo
Biologically active compounds
Credible evidence
Economic harm
Direct harm:
Medical e.g. cyanide toxicity
Psychological e.g. unjustified guilt
Indirect harm e.g. delay if care
Harm to society, pseudoscience
Herbal adverse effect
Pyrrolizidine alkaloid - hepatic veno-occlussive disease
Germander - weight loss agent but hepatoxicity
Adulateration e.g. Aristolochia - nephrotoxic and carcinogenic
Herbal drug interaction
St John's Wort - serotonin syndrome when co-administered with serotonin reuptake inhibitors
Hyperforin induces metabolism of medicines of cytochrome P450 system
traditional herbal registration scheme
MHRA advised by UK HMAC
Efficacy no required
30 years of use
SPC 'based on traditional use only'
Only licensed herbal medicine for OTC
MHRA advised by ABRHP
Vitamins and minerals
Food Standard Agency
No parasympathetic nerve in blood vessels
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