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Pharmacology and Toxicology
1 Routes of drug administration
- Enteral, directly placed in GI tract (oral, buccal, sublingual and rectal) and
parenteral (topical/injections)

- Dermal/transdermal, Pulmonary, nasal, ocular/ophthalmic, otic (ear), vaginal,
urethral

- Injections: subcutaneous, intravenous, intramuscular, intra-arterial, intradermal,
intraperitoneal, intrathecal, intraosseous, intraarticular, intracardiac

- Invasive and non-invasive
- Local effect (applied directly to local site of action) or systemic therapy (treatment
is targeted to conditions that affect the body as a whole/organ systems)

- Bioavailability: fraction of drug dose that is absorbed from site of administration
and reaches systemic circulation unchanged, intravenous is 100%, non
invasive is less than 100%

- Majority of drugs absorbed due to partition and diffusion, other processes such as
active transport and transcytosis also play a role

- Factors determining drug uptake: Dissociation constant (pKa), pH at absorption
site, Lipid solubility of the drug

- Fick’s law, mechanism of passive diffusion, first order rate uptake proportional to
concentration over a wide drug range
- Carrier mediated transport, specific carrier proteins recognise the drug and
transport it across the membrane, can be active or passive (facilitated diffusion
or energy dependant, uses ATP)
2 Sites and mechanisms of action of drugs

- Drugs bind to targets, usually proteins (receptor (agonists/antagonists), ion
channels (stimulator/blocker), enzymes (enhancer/inhibitor), carrier
molecules/transporters (accelerator/inhibitor)

- Signal transduction - converting extracellular signal to an intracellular response
- Primary messenger in ECF binds to membrane receptor and activates it,
membrane protein activated, may activate protein kinases/enzymes which
create secondary messenger
...
alter ion channel
gating, b
...
alter enzyme activity of protein
kinases, Protein modification affects metabolic enzymes, motor proteins, gene
expression, membrane transport and receptor proteins

- Ligands - endogenous (within, i
...
neurotransmitters and hormones including
autocoids (local hormones), chemical messengers) and exogenous (outside,
i
...
drugs, poisons, toxins), has a central pore

- Ionotropic receptors (Ligand-gated ion channels), takes milliseconds
...
Targets for G-Proteins are Adenylate
cyclase/cAMP, Phospholipase and ion channels

-

Intracellular receptors, within cytoplasm, when activated they enter the nucleus
Kinase-linked receptors, such as cytokine receptors, takes hours to work
Nuclear receptors such as oestrogen receptors, takes hours
Drug receptor theory, receptor occupancy theory, affinity and KA, EC50
The EC50 is the concentration of a drug that gives half-maximal response
(effective concentration 50)

- Clarks theory describes receptor theory of agonists, linear
- Occupancy vs response, full agonists can have spare receptors and still have max
-

response
Selectivity: agonist binds preferentially to receptor but increasing conc results in
binding/activation of other receptors

- Specificity: agonist only binds to its “specific” receptor, increased conc does not
affect other receptors
...


- No drug is totally specific, they are selective
- Agonists: Interact with and stimulate or active receptors, trigger a response, mimic
action of endogenous ligand, affinity for receptor (binds) , efficacy (once bound
triggers a response)

- Partial agonists: despite 100% receptor occupancy, do not produce 100%
response, sub maximal response

- Inverse agonists: inhibits activity of receptor, opposite effect of agonist
...

- Mechanisms of desensitisation: change in receptors, loss of receptors, exhaustion
of mediators, increased metabolic degradation, physiological adaptation, active
extrusions

- Pharmacology graphs
3 Methods and measurement in pharmacology

- Bioassays: Isolated tissue baths, conc response curves, human subjects
- Animal models of disease, similar pathophysiological phenotype (face validity),
-

causation (construct validity) and response to treatment (predictive validity)
Transgenic animals, genetically manipulated, inactivate individual genes or mutate
them to pathological forms, introduce human genes, insert additional copies of
genes (overexpression)
Selective breeding such as hypertensive rat, obese mice and epileptic dogs

- Measuring drug efficacy and safety:
- randomised controlled trials
- Steady state drug levels are continuously within a therapeutic range,
4 Absorption and distribution of drugs

- Absorption, Distribution, Metabolism, Excretion
- Absorption can be vascular (directly into bloodstream) or extravascular (cross
biological membrane)

- Passive diffusion from exterior (relatively high drug concentration) to interior
(relatively low drug concentration)

- Lipophilic/Lipophobic
- Octanol has similar properties to the hydrophobic portion of the cell membrane,
water coefficient

- LogP (Log10 (Conc in octanol/conc in water) higher the value the more lipophilic,
and LogD (Log10 (Conc in octanol/conc unionised and ionised in water)

-

LogP/LogD ratio ideally between 0 and 3, exceptions
pH of log D must be noted
Passive diffusion, from high concentration to low concentration over a membrane
Right combination of Hydrophilic/hydrophobic properties
Most drugs are weak acids or weak bases, acid and base dissociate, dissociated
compounds form ions (ionised), ionised compounds will not partition into
octanol

- Can be passed through by transporter proteins (proteins within cell membrane)
- All xenobiotics absorbed via oral route go to the liver
- Absorption is: generally maximal in small intestine, effect of food is unpredictable,
first-pass metabolism

- Affected by: patient disease state, age, site of absorption, co-administration,
frequency of administration

- Distribution affected by LogP/LogD, blood flow to tissue or organ, molecular
shape/size, binding of compound to blood and plasma proteins and membrane
transporters

- Blood Brain Barrier, efflux transporter protects brain against harmful xenobiotics
- Partition coefficient
- Blood transports xenobiotics so areas with highest blood flow will be exposed to
more of the drug in a given time

- Albumin is slightly basic so will bind acidic drugs i
...
warfarin
- Glycoproteins are slightly acidic so will bind basic drugs i
...
e
...


- Pharmacogenomics: study of multiple PK/PD genes, often using high-throughput
-

data (sequencing, expression, proteomics)
Phase 1 reactions: oxidation, hydroxylation and hydrolysis, produces biologically
active drug & may produce intermediates of inactivation/drug degradation

- Phase 2 reactions: N-acetylation, glucouronidation, sulfation or methylation,
produces water soluble compound for easier excretion

- Phase 1 metabolism catalysed mostly by P450 cytochromes
- CYP2D6, CYP2D6*1 is wild type, CYP2D6*4 and CYP2D6*5 are poor
metabolisers point mutations (PM)
CYP2D6 intermediate metabolisers (IM)

- ultra-rapid metabolisers (UM) such as CYP2D6*2x3
- EMs
- Phase 2 reactions affect drug inactivation and excretion: N-acetyltreansferase and
uDP glucuronosyltransferase, Glutathione S-transferase (GSTs), Thiopurine Smethytreansferases (TPMT)
7 Therapeutic drug monitoring

-

Therapeutic index, TD50 divided by minimum ED50, high TI is preferred
TD50 = toxic dose 50, ED50 = effective dose 50, LD50 = lethal dose 50
Steady state principles
IC50 Inhibitory concentration can be determined from concentration-response
curves

- NOAEL no observed adverse effects level, highest concentration that does not
produce toxic response

- LOAEL lowest observed adverse effects level, lowest concentration that produces
-

a toxic response
TDM affected by pharmokinetics, pharmacodynamics, dose, sampling time and
type, testing methodology, genetic polymorphisms (inter-patient variability)

- TDM is carried out to ensure drug remains within therapeutic range
8 Chemical mediators of the autonomic nervous system and other peripheral
mediators

- Pre-ganglionic and post-ganglionic neurones (post is not myelinated
- 3 anatomical divisions, sympathetic, parasympathetic and enteric
- Neurotransmitters and co-transmitters: Ach (parasympathetic neurones and preganglionic sympathetic neurones) and NorAdrenaline (post-ganglionic
sympathetic neurones)

- Some non-adrenergic non-cholinergic transmitters (NANC), include ATP, GABA,
-

dopamine and serotonin
Cholinesterases break down acetylcholine, short-acting, medium acting and
irreversible/long-acting anticholinesterases
nicotinic and muscrinic receptors
Depolarising blockers and non-depolarising blockers
Adenoreceptors
a blockers and b blockers
MAO and COMT inhibitors

Uptake inhibitors
9 Cardiovascular Pharmacology: drugs that affect the heart and vascular muscle
contraction

- Coronary heart disease
- Vascular disease
- Myocardinal infarctions: pre hospital aspirin, in hospital long term aspirin, beta
blocker, ACE inhibitor, statins

- Nitrates: relieve angina pectoris, also relieved by resting, venodilator (reduce preload), arterial dilator so increase coronary flow and improve oxygen supply

- Nitric Oxide (NO) produced by many cells in body, drugs can mimic its actions
- Nitric oxide stimulates cGMP formation, which activates protein kinase G, affecting
contractile proteins and Ca2+ regulation

- Diuretics: Increase urine output by kidney, reduce pre-load
...
Thiazides inhibit sodium-chloride transporter on the distal
tubule
...

Reduce preload and after load by blocking formation of angiotensin II or
blocking AII receptors

- B blockers and calcium channel blockers: reduce cardiac rate/contractility
- Calcium channel blockers also reduce after load, arterial dilator, increase coronary
-

flow/oxygen supply improved
...
B blockers bind to B-adrenoceptors
...


-

B2 receptors are responsible for causing smooth muscle relation in many organs
CHF: reduce preload and afterload, normalise tissue perfusion, prevent oedema
B blockers used in heart failure with systolic dysfunction
Statins lower lipids in the blood: HMG-CoA reductase inhibitors

- Primary prevention: no CV disease, Secondary prevention: Existing CV disease
10 Respiratory Pharmacology: Disorders of respiratory function and drugs used to
treat asthma and COPD

-

Signalling via Gqa: Gy, Gb, PLCb, PIP2, DAG, IP3
B2-adrenoceptor agonists, produce bronchodilation, act on b2 adrenoceptors
Predominantly inhaled, sometimes oral or intravenous if necessary
Short-acting B2 agonists used on an as-needed basis
Long-acting used in addition to inhaled corticosteroids, prophylactic treatment
(control)

- PDE4 inhibitors (phosphodiesterase 4), bronchodilators with anti-inflammatory
effects, usually taken orally, can cause bad side effects
Anti-cholinergics, muscarinic receptor antagonists

- Corticosteroids useful in asthma
- HPA axis: hypothalamus, anterior pituatary, adrenal cortex, negative feedback
mechanism
Transactivation vs Transrepression

- LABAs and PDE inhibitors
- Anti-leukotrienes, Mucolytics, Oxygen, Antibiotics/vaccination
11 Introduction to toxicology and drugs of abuse
- Toxicology: Mechanistic toxicology (biochemical, behavioural, carcinogenesis,
tetarogenesis, mutagenesis), forensic, economic, environmental, analytical,
regulatory, Applied toxicology: Clinical (ie overdoses, attempted suicides,
emergency)

- Irreversible: carcinogen (cancer), mutagen (chromosome damage), reproductive
-

hazard (damage to reproductive system), teratogen (causes birth defects)
May or may not be reversible: Dermatotoxic, haemotoxic, hepatotoxic,
nephrotoxic, neurotoxic, pulmonotoxic

- Classified by nature, effect or length of exposure needed to have an effect
- Nature: Chemicals (alcohols, phenols, heavy metals), physical (radiation),
-

biological (venom)
Effect: Systemic toxicant, an agent affecting entire body/many organs rather than
a specific site; Target organ toxicant, affect only specific tissues/organs while
not damaging body as a whole i
...
hepatotoxic
Length: Acute toxicity: almost immediate, hours/days after single dose or series of
doses received within 24hrs, death is a concern, activated charcoal can bind to
toxin and reduce adsorption; Subchronic toxicity (reversible), results from
repeated exposure over weeks/months, common human exposure pattern for
some pharmaceuticals/environmental agents

- Toxicants can also 1
...
directly
damage DNA, 3
...
3mL/min to 100

-

Problems with alkalisation include hypokalemia and poor renal function
Extracorporeal removal
Clinical trials
Alkaloids examples: amphetamines, cocaine, opiates and cannabidinoids
Alcohol - affects nervous system especially the brain
Arsenic detected by Marsh test
Heroin, opioids derived from opioid poppy, alkaloids derived include morphine
Acts on opioid receptors
Normal dose, overdose, consequences of dependance and withdrawal
Cannabis, inhaled
Pharmacology of cannabis: CB1 (in CNS) and CB2 (peripheral tissue/lymphoid
tissue) receptors
Acute, chronic and withdrawal

- Cocaine, crack and regular
- Stimulant, uptake inhibitor of monoamines/catecholines, increased concentration
at synaptic cleft

- MDMA and Amphetamines
- Increase of monoamines, pharmacology not clear
- LSD, synthesised from lysergic acid



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