Lecture notes for pharmacology

1. Memorizing notes- Pharmacology 1
Intro into pharmacology (Module 1)
- Pharmacodynamics: Site of action and mode of action
- Pharmacokinetics: Way in which the drug
concentration changes with time (ADME, quantitively
pharmacokinetics).
- Osmotic diuretics (mannitol) or osmotic laxatives
(sorbitol) will bind to water (TARGET) in the kidney
- Antacids will bind to acid (TARGET) in the stomach
- Unscheduled drugs can be sold through other retail
outlets
- Receptors are macromolecular structures in or on the cell surface with which drugs interact to
produce effects:
o Change in structure can change activity of drug
o The type of chemical interaction with the receptor can influence the action of the drug
o A high degree of specificity can result in fewer toxic side effects.
- Receptor example: sensing elements for chemical communication (hormone, neurotransmitter,
nonhormones)
o D2 dopamine: agonist dopamine, antagonist: chlorpromazine
- Ion channels: may be blocked by a drug or the gating operation may be modulated
o Local anesthetics: physically block the voltage gated sodium channel
o Benzodiazepines bind to a region of the GABA receptor/chloride channel complex
- Enzymes: drugs may be competitive or non-competitive
- Pumps: Drugs may inhibit the action of carrier molecules: proton pump inhibitors
- Binding to DNA: some anti-tumor alkylating drugs
- Counterfeit substrates: Antihypertensive agent alpha-methyldopa substitutes for normal
substrates in the synthesis of noradrenaline resulting in a less active end product.
- Potency: Inherent ability of drug to combine with receptors. Important for dosage but
unimportant for clinical purposes
- ED50 is a measure of potency
- Emax measure of efficacy

2. 2
Agonists, antagonist and drug toxicity (Module 1)
- Bethanechol mimics action of Ach- muscarinic Ach receptors
- Atropine competitively inhibits the action of ACH at the muscarinic receptors
- Agonists- affinity and intrinsic activity
- Antagonists- affinity but lack intrinsic activity
- Buprenorphine (partial agonist at μ opioid receptor) produces less analgesia than morphine (full
agonist)
- Reversible competitive: increased concentration agonist can reverse blockade. ED50 increased
o Atropine
- Irreversible: antagonist dissociates slowly or not at all. Blockade cannot be reverses
o ED50 same, Emax decreased
o Methysergide (5-HTreceptorantagonist) used in Rx of migraine
o Neurotoxins from snake venom (nicotinic receptor antagonist)
- Non-competitive: ED50 increased Emax decreases
o Suxamethonium (depolarizing muscle relaxant) desensitizes nicotinic receptor ion
channel
Calcium antagonists (e.g. verapamil and nifedipine) non-specific block of contractions by
other drugs
- Physiological antagonism: Blockade of effect due to production of an effect in the opposite
direction, opposing receptors.
o In gut - ACh contraction mediated through muscarinic receptor antagonised by
noradrenaline (Nad) relaxation mediated through beta receptor
- Desensitization and tachyphylaxis: a drug effect which gradually diminishes over a few seconds to
minutes. Caused:
o Change in receptors: Receptor resulting in tight binding of agonist without opening of
ion channel
o Exhaustion of mediators: secondary messengers
o Increased metabolic degradation
o Physiological adaptation: side effects
o Translocation of receptors: Receptor may be internalized by endocytosis: EG:
gonadotrophin-releasing hormone inhibits gonadotropin release by continuous receptor
simulation used in prostatic cancer.
- LD50/ED50 gives an idea of the relative margin of safety of a drug
- Greater this ratio the safer the drug

3. 3
Drug admiration and absorption (Module 2)
- Low lipid solubility- poorly absorbed from gut
- Most drugs or their salts are weak acids/bases
- Ionized drugs are not very lipid soluble, only non-
ionized form of drug crosses membrane readily
- If pKa= pH, compound is 50% ionized and 50%
non-ionized
- Gastric pH=3
- Plasma pH=7.4
- Urine pH=8
- Drugs cross lipid membranes mainly by passive diffusion
- Only the uncharged species (the protonated form for a
weak acid, the unprotonated form for a weak base) can
diffuse across lipid membranes; this gives rise to pH
partition.
- Weak acids tend to accumulate in compartments of
relatively high pH
- Oral route: most common
o First pass metabolism: Thus, drugs that are
highly metabolised by the liver may attain very low circulating levels relative to those
attained after parenteral administration
o Drugs taken orally are absorbed in stomach and small intestine
o Blood vessels take the drug directly to the liver
o Drug passes through liver before being distributions round the body
o Irregular absorption: delayed gastric emptying, alter stomach pH due to food,
decreased splanchnic blood flow in heart failure, complex formation
o Gastrointestinal irritation
o Low pH may inactive certain drugs
o Particle size
o Require patient compliance
- Oral bioavailability: Fraction of orally administered drug that reaches the systemic circulation
- Sublingual- avoids first pass metabolism, rapid absorption
- Intravenous
- IM and subcutaneous
- Rectal
- Spinal
- Topical

4. 4
Drug distribution, metabolism and excretion (module 3)
- Drug distribution depends on: permeability across barriers,
binding within compartments, pH portion, fat: water portion
- If the free fraction (FF, unbound) is <10% apparently slight
variations in FF can have important consequences: potential
for drug interactions
- As FF becomes larger (eg 10-25%) binding becomes less important
- If 2 drugs compete for the same site, then stronger affinity will transiently displace weaker affinity
- Phenylbutazone displaces warfarin and also inhibits warfarin
metabolism → internal bleeding
- aspirin displaces methotrexate and also reduces its renal secretion → GIT and kidney toxicity
Quinidine/verapamil/amiodarone displace digoxin and reduce
its renal excretion → severe dysrhythmias
-
Loading dose = target plasma conc. x Volume of distribution (Vd)
1. The drug must be instantaneously distributed, and no metabolism should have occurred
2. No portion of the drug should have been excreted
3. No portion of the drug should have been sequestered (thiopentone, being lipid
soluble is sequestered into fat)
- Ionised drugs (which are filtered or actively secreted in proximal tubule) undergo little
reabsorption and are excreted
- POINT TO METABOLISM IS TO MAKE THE COMPOUND MORE WATER NOT
LIPID SOLUBLE
- Lipophilic drugs diffuse back (reabsorbed) into blood
therefore not eliminated
- Drugs bound to plasma proteins are unable to be
filtered but are subject to tubular secretion (eg.
penicillin)
Aspirin undergoes phase 1 and phase 2 glucuronidation
Paracetamol undergoes phase 2 only

5. 5
Renal excretions
- Nearly all drugs cross the glomerular filter
freely
- They will be efficiently excreted (ie. remain in
tubular fluid) unless they are lipid soluble and
can be re-absorbed into the blood
- The key function of metabolism is to make the drug molecule less lipid soluble (more water
soluble/more charged)
- Drugs excreted unchanged: digoxin gentamicin, methotrexate

6. 6
Quantitative pharmacokinetics (module 4)
- Clearance (CL) is the volume of plasma cleared of drug
per unit time (L/hr)
- Relates rate of drug elimination to its plasma
concentration (Cp) (mg/L)
- Rate of drug elimination = Cp x CL (mg/hr)
- For most individuals at therapeutic concs CL is the same
at different drug doses (Q) (NB: not in overdose)
Small or large volume of distribution, results in the
same clearance

7. 7
- 2 opposing forces at work
- Patient compliance
- Fluctuations in plasma concentration- less often the
drug is given, greater the fluctuation in Cp
2 compartment model
- A fast and slow phase of loss of drug from plasma is noted
- The fast phase is characterized as distribution from plasma to the
tissue
- The slow phase equates to elimination from the plasma
- Most drugs are described by a 2-compartment model

8. 8
- Rate of eliminated is independent of drug starting concentration
- t1/2 is dependent on drug starting concentration
- Eg. Ethanol = 4 mmol/hr
- Once the Cp producing the maximal rate of metabolism is exceeded, the Cp will, in principle,
increase indefinitely and a steady state Cp will not be reached
- Therefore, Cp should be regularly measured

9. 9
Adverse drug reactions
- Noxious and unintended and that occurs at doses normally used in humans
- The TGA evaluates therapeutic goods before they are marketed and monitors products once on
the market
- All serious ADRs are documented by the time a drug is marketed
- It is difficult to determine if a drug is responsible
- ADRs should only be reported if absolutely certain
- One reported case can’t make a difference
Main causes of variability are:
- Age (neonatal vs adult vs elderly)
- Pharmacogenetics (genetic factors)
- Disease (kidney or liver disease)
- Idiosyncratic reactions (rare fatal reactions)
Age
- Cardiac output decreases with a decreased proportion of blood flow to kidney/liver
- GFR decreases with age with a reduced creatine clearance rate
- [Albumin] decline with age so less plasma protein binding and greater free drug
- GFR in the newborn is 20% of adults
- Decrease in GFR not reflected in plasma [creatinine] as creatinine synthesis decline with age.
- Enzymes have low activity in neonates and elderly
- Includes: CYP450, glucuronyltrasferase, acetyltransferase, plasma ChE
- Slow hepatic conjugation of:
o Chloramphenicol in babies –‘grey baby’ syndrome
o Morphine during labour –respiratory depression in newborns
- The same plasma drug concentration can cause different effects in young and old:
- Benzodiazepines produce more confusion and less sedation in elderly than in young patients
- Hypotensive drugs cause postural hypotension more commonly in elderly than in young adults
Pharmacogenetics
- Administered to dizygotic twins (fraternal) and monozygotic (identical) twins. Much less
variation in the half-life in identical twins. First evidence for the role of genes in drug
metabolism (pharmacokinetics)
- People with an inherited deficiency in the enzyme glucose-6-dehydrogenase (G6PD) can develop
haemolytic anaemia after eating broad beans (Phythagoras)

10. 10
- A large amount of individual variability to drugs is genetically determined
o Half-life of antipyrine and warfarin are 6-22 times less variable
in identical than in fraternal twins
- Gene polymorphisms can affect an individuals susceptibility to ADRs
o Pharmacokinetic (eg. polymorphisms in genes encoding
CYP450)
o Pharmacodynamic (eg. polymorphisms in drug targets such as receptors and enzymes)
Abacavir- Hla gene test
- Is a reverse transcriptase inhibitor that is highly effective in treating HIV infection.
- Its use has been limited by severe rashes.
- Susceptibility to this adverse effect is closely linked to the human leukocyte antigen (HLA)
variant HLAB*5701,
- Testing for this variant is used widely
Trastuzumab
- Is a monoclonal antibody that antagonises epidermal growth factor (EGF) by binding to one of
its receptors (human epidermal growth factor receptor 2 – HER2) which can occur in tumour
tissue
- It is used in patients with breast cancer whose tumour tissue overexpresses this receptor. Other
patients do not benefit from it.
- Liver and kidney disease: Prolonged drug effects –
toxicity: Reduction in protein binding, liver/kidney blood
flow, liver capacity
- Migraine and diabetic neuropathy: Slowed drug absorption
due to gastric stasis
- Heart failure: Reduced liver perfusion – toxicity: Mucosal
oedema – reduced absorption
- Hyperthyroidism: Increased sensitivity to pethidine (mechanism?)
- Hypothermia: Reduced drug clearance

11. 11
Idiosyncratic reactions
- Harmful, sometimes fatal, reactions that occur in a small minority of individuals
o Qualitatively abnormal
o Rare
o eg. Chloramphenicol induced aplastic anemia (bone marrow
depression) in ~1 in 50,000 patients
- Reactions may occur with low doses
- Sometimes genetic factors may be responsible
o Primaquine, dapsone, doxorubicin, some sulfonamides and
Vicia fava beans cause severe anemia in G6PD deficient
Afro-Carribean men (deficiency in the antioxidant glutathione)
-
CYP2Cs
- Major substrates include some nonsteroidal anti-inflammatory drugs, warfarin, phenytoin, PPIs
- Dramatic interracial polymorphism e.g. CYP2C19

12. 12
o CYP2C19 activity is genetically determined, and its genetic polymorphism shows marked
interracial difference.
o The incidence of the poor metaboliser phenotype is markedly higher in Asian
populations (13–23%) than in white populations (2–5%)
- Substrate in relation to metabolism refers to a drug which
undergoes metabolism by a specific enzyme (e.g.
CYP3A4)
- However, a drug can be a substrate to multiple enzymes
- fluoxetine (substrate) is metabolized by both CYP2D6
and CYP3A4
- warfarin is a substrate for 1A2, 2A6, 2C19, 3A4
- One enzyme has many different substrates and these will
compete with one another
- Drugs can be substrates and inducers or inhibitors
concurrently
- 3A4 and 2D6 are the isoenzymes responsible for the
metabolism of most commonly used drugs

13. 13
Drugs in pregnancy (Module 6)
- Plasma volume increases (increased Vd)
- Maternal plasma albumin concentration is reduced to 70-80%-decreased protein binding
(albumin conc. Rises in fetus)
- Cardiac output is increased-increased GFR-increased clearance of free drug
- Hormones alter liver enzymes
- Gastric pH increases
- Smaller molecules transfer across the placenta faster. Greater than 1000 Da will not cross
- Lipophilic drugs cross faster
- Foetal pH more acidic-so weak acids and bases will become more ionized and tend to accumulate
- 40% of drugs are taken during the critical period
- Teratogenesis=the production of gross physical malformations
- Teratogen- toxic agent that increase the occurrence of a structural defect/abnormality
- Effect varies depending upon amount and length of exposure, genetic factors, additive effects of
- Effect of agents on somatic cells
- Lack toxicity in the mother but produce malformations in fetus
- Blastocyst formation: cytotoxic drugs and alcohol; resistant to teratogenic effects- may cause
miscarriage
- Organogenesis: Teratogens
- Histogenesis and functional maturation: Miscellaneous drugs
- Probability of structural defect is greatest during organogenesis
- Structural organisation of fetus occurs in a sequence: Brain, Heart and major vessels, Skeleton
and limbs, Ears and eyes, Palate, Genitourinary system
- Type of malformation depends on time of exposure
- Drugs enter embryonic bloodstream by passive diffusion
- Fetal liver has 20-40% of adult activity for phase 1 reaction
- Category A: taken by many women-no evidence of causing malformation. Controlled studies
- Category B: Divided into 3 groups (B1, B2, B3) with all having only been taken by limited
number of women (pregnant or childbearing age) with no increased incidence of malformation
or effects on fetus. Differences range from no effects in animals (B1) to evidence of fetal damage
in animals (B3)
- Category C: No data available or suspected harmful effects
- Category D: suspected increased incidence of malformation- benefits may be acceptable despite
risk. Category x: high risk
- Most medications are assigned to category C
- Thalidomide: sedative, was originally deemed safe, amelia, phocomelia
o Lesson: low maternal toxicity and low toxicity in animals may have high teratogenic
potential

14. 14
Drug receptors
- Ligand gated ion channel: trigger is agonist binding
- Location: membrane
- Effector: ion channel
- Coupling: direct
- Examples: Nicotinic acetylcholine (ACh), g-Aminobutyric
acid (GABA), Excitatory amino acids (eg. NMDA,
aspartate),Glycine
- Timescale: extremely rapid cell activation with a time scale
of milliseconds
- 2 ACH molecules is needed
- Voltage gated: trigger is change in membrane potential
- G-protein-couple receptors:
- Location: membrane
- Effector: channel or enzyme
- Coupling: G-protein (affinity for guanyl nucleotides (GDP/GTP)
- Examples: Muscarinic Ach Adrenoceptors
- Timescale: slow cell activation with a time scale of seconds
- Amplification of signal: one receptor can activate many G-proteins
- Active G-proteins can cause effector enzymes to produce many intracellular second messengers
- Principal second messengers: 1. Cyclic adenosine monophosphate (cAMP), 2. Ca2, 3.
phosphoinositides (eg IP3 and DAG)
- Active=GTP bound
- Inactive= GDP bound
- G-proteins provide link between ligand-activated receptor and effector
- G-proteins have intrinsic GTPase activity which spontaneously hydrolyses bound GTP to bound
GDP
- Gi=inhibitory. Gs=stimulatory
- Kinase-linked receptor:
- Location: membrane
- Effector: protein kinases
- Coupling: direct
- Examples: Insulin Growth factors eg.Epidermal growth
factor (EGF), nerve growth factor, platelet derived growth
factor (PDGF)
Cytokine receptors eg. interferon-gamma (IFN-g)
- Timescale: cell activation with a time scale of minutes to hours

15. 15
- Enzyme is usually a protein tyrosine kinase, but can be a protein serine kinase, a protein
threonine kinase or guanyl cyclase (activation of receptor by phosphorylation)
- Nuclear receptors:
- Location: intracellular
- Effector: gene transcription
- Coupling: via DNA
- Examples: Sex steroids, eg. Testosterone, Glucocorticoids eg cortisol, Mineralocorticoids eg
aldosterone, Hormones and vitamins eg. Vitamin D and thyroid
hormone
- Timescale: cell activation with a time scale of hours
- Agonist-receptor complex acting on DNA resulting in
- 1. transcription and translation of mediator proteins or
- 2. repression of expression of certain genes with inhibition of production of specific proteins

16. 16
Precision Medicine
- Assumption that one size fits all: disease subtypes, clinical features, risk profiles for particular
groups and demographics, environmental effects, socio-economic effects and the use of
biomarkers
- Precision medicine includes: Genomics and Omics (e.g. proteomics), Lifestyle, Preferences,
Compliance, Health History, Medical Records, Other exogenous factors
- Karyotyping is extremely valuable
- Single nucleotide polymorphisms: changes in the nucleotide sequence
- The CFTR protein is composed of 1,480 amino acids—the building blocks of all proteins—and
is located on the surface of many cells in the body
- It plays an important role in transporting chloride ions in and out of the cell
- This is caused when a defective in CTFR, obstructs the normal flow of water and mineral ions in
and out of cells.
- When this occurs in the sweat glands, it prevents sodium from being reabsorbed into cells and
causes chloride to accumulate in the sweat ducts. As the excessive amounts of sodium and
chloride get pushed close to the surface of the skin, they combine to form salt.
1. Find a mutation that influence the activity of a protein
2. Obtain cells with the desired mutation
3. Develop a high-throughput screening method for protein activity
4. Screen thousands of compounds and look for activity in cell lines
5. Check if it works in patients through clinical trials
- F508del mutations lead to little to no trafficking of the CFTR, but of the small amount of protein
that gets to the surface is like G551D and non-functional.
- Augmentation therapy is the use of alpha-1 antitrypsin protein (AAT) from the blood plasma of
healthy human donors to augment (increase) the alpha-1 levels circulating in the blood and lungs
of AATD patients diagnosed with emphysema.
- AATD patient survival after lung transplantation who received augmentation therapy prior show
worse 10-year survival rates relative to AATD without prior augmentation as well as to those
with general COPD.
- Despite being on inhaled corticosteroids treatment is able to further reduce the inflammation by
restoring AAT activity.
- Depending on the AATC genotype augmentation therapy may or may not help
Protospacer Adjacent Motif (PAM)-is a short DNA sequence (~3 base pairs) that follows the DNA
region targeted for cleavage by the CRISPR system.
• CRISPR RNAs (crRNA)- transcribed from this CRISPR locus matching the virus sequence
• (TracrRNA)- partially complementary to pairs with a pre-crRNA forming an RNA duplex.

17. 17
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