Intro, Pharmacodynamics, Pharmacokinetics and ADME Flashcards
What is pharmacodynamics?
Study of molecular, biochemical and physiological EFFECTS of drugs on the body systems, AND mechanisms of action
What is Pharmacokinetics?
Study of ADME of drugs (fate)
Pharmacogenomics
Genetic influences on the effectiveness and fates of drugs
Toxicology
Adverse effects of drugs and other toxic agents
Percentage of drugs from the natural world
63% (eg Taxol, anticancer drug from Yew tree)
Where do drugs come from? (5 categories)
- Extract from plants and herbs
- From microorganisms
- From the body itself (endogenous)
- Chemical modification of body’s own hormones/chemical regulators
- Chemical synthesis of novel compounds with desirable properties
Examples of drugs from plants and herbs
- Opium Poppy (morphine, painkiller, early 1900s)
- Digoxin from foxglove leaves (reverse inhib of Na/K ATPase used to treat congestive heart failure, lethal at high doses)
Examples of drugs from microorganisms
Penicillin (antibiotics) b-lactam, interferes with bactrial cell wall synthesis
Examples of endogenous drugs
Hormones eg insulin, throxine, growth hormone (most now produced by recombinant tech or chemical synthesis)
Examples of chemical modification of endogenous
Hormonal drugs eg ethinyl estradiol (readily absorbed estrogen form)
Anticancer drugs eg 6hercaptopurine, modified base component of DNA to interfere with DNA symth
Examples of chemical synthesis of novel compounds
Eg indomethacin and celecoxib - COX inhibitors (NSAIDS) eg cimetadine (histamine receptor modulator) eg Simvastatin (HMG CoA reductase inhibitor for high cholesterol)
Examples of drugs discovered by chance
eg antidepressants monoamine oxidase inhibitors and tricyclic antidepressants (faled TB treatments) eg cisplatin (platinum containing, used to treat cancers, was for bacteria)
4 most common proteins that drugs bind to
- Enzmes
- Carrier proteins
- Ion channels
- Receptors
Features of receptors
At least one binding site
Binding of exogenous ligands results in signal transduction (efficacy)
How do drugs act on receptors?
Drugs act by promoting or inhibiting the process of signal transduction. Must bind with specificity / selectivity (shapes important)
Affinity
Attraction of a ligand for receptor
Efficacy
Effect of ligand binding. Max = 1, no effect = 0
Agonists
Affinity and efficacy (mimics ligand)
Antagonists
Affinity but NO efficacy (prevents signal)
Histamine specificity
H1 = allergic reactions, skin H2 = stomach acid secretion H3 = CNS, ileum, cardiac tissue, often presynaptic and autoregulatory (WIDESPREAD)
What is selectivity>
Preferential binding to certain subtype. Greater effect at that subtype than others. (eg sabutamol at B2 (lungs) rather than B1 (heart), or selectivity of H1 antihistamines)
Lack of selectivity / specificity in NSAIDS
Universally inhibit COX.
COX2 selective for inducible, little effect on constitutive form (rofecoxib, celecoxib)
COX1 = homeostatic mechanisms COX2 = antiinflammatory
Rate theory
Drug effect is proportional to RATE of occupancy
Floating receptor model
the D-R complex may interact with variety of effectors in the membrane to produce effect (cause different signals depending on what exposed to in microenvironment)
Receptor occupancy theory
Drug effect is proportional to NUMBER of receptors occupied (michaelis-menten equilibrium D + R D-R )
Receptor plasticity
Number and states of receptors changes - mouldability, due to pharmacological, physiological, pathological states. Responsibel for changes in drug effectiveness over time.
2 state receptor model
Resting state R Activated state R*
NO LIGAND
Equilibrium favours R
FULL AGONIST (efficacy =1) Strongly shifted to R*
PARTIAL AGONIST (efficacy 0-1) Partly shifted to R*
ANTAGONIST (affinity and NO efficacy = 0)
Equilibrium not shifted, no preference for active/inactive. Binds to and inactivates receptors
4 types of receptor families
- Ionotropic (ion channels)
- Metabotropic (GPCR)
- Catalytic (kinases)
- Nuclear/intracellular (transcription)
Structure of ionotropic receptor
extracellular N
Extracellular ligand binding domain
4 TM domains (form pore)
extracellular C domain
Structure of GPCRs
EC N, IC C domain
EC binding domain
IC GProt coupling domain
7 TM domains
Structure of kinase-linked receptors
EC N domain, binding domain
1 TM domain
IC C domain, catalytic domain
Structure of nuclear receptors
NOT MEMBRANE EMBEDDED
Binding domain by C
middle DNA binding domain (Zn fingers)
Ionotropic receptors (eg, speed, mechanism)
eg nACh, GABA
VERY FAST
Binding causes conf change, ion channel opening
(increase in opening time for nAChR and increase in channel conductance for GlutamateR)
GPCRs (eg, speed, mechanism)
eg mAChR, adrenoreceptors
FAST (milliseconds)
Binding causes activation -> opnening or closing of ion channel or generation of second messengers eg cAMP for biol effect
Gs, Gi, Gq
Protein Kinases (eg, speed, mechanism)
eg tyrosine kinase receptors
ACTION TAKES MINUTES TO DAYS
Receptor triggers a kinase cascade (intrinsic or associative). Attach phosphates to proteins for change in structure and function - cell growth and differentiation (regulate gene expression)
Example of kinase pathway: Ras/Raf/MAP Kinase
For cell differentiation GF binds, conformational change. Receptor dimerisation Tyrosine autophosphorylation Phosphorylation of Grb2 Activation of Ras (GDP/GTP exchange) -> Raf -> Mek -> MAP Kinase -> various transcription factors act on nucleus - GENE TRANSCRIPTION
Example of kinase pathway: Jak/Stat
For inflammation Cytokine binds, conformational change Binding of Jak intracellularly Phosphorylation of receptor and Jak Binding and phos of SH2-domain protein (Stat) Dimerisation of Stat Acts on nucleus for gene transcription
Intracellular receptors (eg, time, mechanism)
eg Steroid hormone receptors (oestrogen, cortisol, vitamin A)
ACTION SLOW (hours) AND LONG LASTING
Ligands penetrate PM so lipid-soluble
Bind to highly conserved DNA regions (ligand binding and transcriptional control domains)
Alteration in gene transcription and protein synthesis
Agonist potency
EC50
Lower value = greater potency
Effective concentration that produces 50% of the maximum effect
PD2
PD2
-log(EC50)
higher value is greater potency
AGONIST
Competitive reversible antagonism
Antagonist competes directly with agonist for receptor binding
Parallel rightwards curve shift - no depression, but max response occurs at higher agonist concentration
PA2
Measurement of potency of competitive reversible antagonism
PA2 (parallel right shift)
PA2 = -log[antagonist] + log((EC50pres/EC50abs) - 1)
Example of competitive reversible antagonism
Propranolol at B1 receptors
Atropine at M
Competitive irreversible antagonism
Antag competes directly for receptor binding, binds with greater affinity (doesn’t let go)
Non-parallel rightwards shift of concentration-response curve. Spare receptors?
Potency measure PD2’
eg Phenoxybenzamine at H1 receptors
Non-competitive antagonism
Doesnt bind to same receptor as agonist, or alter agonist binding.
Interfere with cascade of events eg ca2+ channel blockers
Non-parallel rightwards shift in curve, depression of max response
Potency PD2’
Partial agonists
ACT AS ANTAGONISTS to full agonists
Efficacy less thn 1 so don’t elicit maximum response
Key characteristic is crossover. At high conc, response diminishes
2-state: hold some receptors in the inactive state so can’t bind as well.
Inverse agonists
Binds receptor and has negative efficacy - turns receptor off - constitutive activity.
Get in the way of agonist binding, like competitive reversible antagonism
HOmologous desensitisation
acts on itself
Phosphorylation of serine by BARK on adenylate cyclase
Heterologous desensitisation
One agonist triggers response that desensitises response to different agonist (eg PKA and PKC)
Chronic agonist administration leads to…
DOWN REGULATION of receptors
eg chronic salbutamol, internalisation of receptors, less available for stimulation, decreased bronchodilation
CHronic antagonist administration leads to…
UP REGULATION of receptors
Eg chronic propranolol leads to increased synthesis of B1 receptors in heart, less antagonism, decreased drug effect.
Clinical significance of receptor population changes
Tolerance
Adverse effects
Therapeutic effects (time to build up the effect)
Examples of enzymes as drug targets
COX and NSAIDS (treat pain and inflammation)
ACE and ACE Inhibitors (captopril, enalaprilat) treat hypertension
Drugs that interact with carrier proteins
drugs that act on monoamine neurotransmitter uptake proteins
Fluoxetine (Prozac) SSRI
Sibutramine (Reductil) SNRI
Fluoxetine mechanism
Block reuptake of 5HT for increased conc in synapses. Depression is thought to be from decreased 5HT so antidepressive effect
Serotonin
IOn channel blocker examples
Anaesthetics (local) Na+ blockers
Cardiovascular conditions Ca2+ blockers (verapamil, nifedipine)
Major organs involved in ADME
- GI tract (absorption)
- Liver (metabolism)
- Kidney (excretion)
- Lungs (absorb / excrete volatile gases)
4 main methods of membrane transport
- Passive transport
- Facilitated diffusion
- Active transport
- Endocytosis
Passive diffusion
Non polar drugs (lipid soluble)
Conc gradient drives
No energy
Facilitated diffusion
Move faster than expected Oscillating carrier protein Concentration gradient! No energy Usually substrates are sugars and AAs
Active transport
Proceed against conc gradient REQUIRES ATP Satuable Liver, kidney, BBB, gut epithelium Allows accululation, waste removal, protection against toxins
Endocytosis
Internalise large molecules >1000 (cytokines, hormones, nanoparticles)
Substrate binds to receptor, invag of complex, budding off and delivery
Filtration
Some drugs pass BETWEEN not through cells
Blood capillary fenestrations, rapid exchange with IF
Glomerular capillaries in kidneys, extremely porous allowing passage of all plasma except >30,000
What is absorption / bioavailablility?
Passage of drug from administration to general circulation (bloodstream)
IV absorbed completely (100% bioavailability)
Orally has barriers so absorbtion delayed and incomplete
Rate of absorption
How rapidly does durg reach general circulation?
Extent of absorption
How much of administered dose enters general circulation (BIOAVAILABILITY - F)
Bioavailabilty = area under concentration-time curve
Routes of drug administration
Enteral Oral Sublingual Rectal Parenteral IV SC Intradermal (into skin) Intramusclular Lungs (volatile anaesthetics)
IV Administration (+/-)
(+)
Rapid, precise control (100% bioavailability), avoid absorption/breakdown before entering blood, good for bad drugs too irritating to be taken by mouth eg anticancer drugs
(-) Skill required (air emb), careful preparation of sterile materials, no recall so hazardous
Oral Administration
(+)
Safest, most convenient, economic
(-)
Slow effect, unpredictable rate, extent, reproducibility (change day to day, between people)
Factors influencing oral bioavailability
Decomposition in Gastric juices (acidic) Decomposition in hydrolytic gut enzymes Degradation by gut micro-organisms Food in gut Metabolism by gut wall enzymes Metabolism by liver enzymes prior to reaching systemic circulation
MOST ARE INVOLVED IN EXTENT
Rate limiting step of drug absorption
Stomach emptying
Patient factors inflencing absorption
Stomach emptying rate! (increase in hunger, metoclopramide. Decrease hot meals, narcotics, anticholinergics, TCA anti-depressants)
Intestinal motility (increased due to gastroenteritis, diarrhoea. Decreased by various drugs (narcotics, anticholinergics, tricyclics)
Interactions with foods (chelation of tetracycline with metal ions, becomes insoluble and so is not absorbed)
Only kind of drugs to diffuse across BBB
Lipid-soluble
Additional layer of glial cells in BBB
Body fluid compartments. How much intracellular fluid?
28L
Body fluid compartments. How much Extracellular fluid?
11L ECF + 3L Plasma = 14L
Sites of drug metabolusm
LIVER GI tract - gut bacteria and proteases Intestinal wall - CYPs Plasma - esterases Specialised tissues (monoamine oxidases in nerve endings, noradr to adrenaline)
Result of drug metabolism
More H2O soluble metabolite
Less likely to diffuse into cells to have action (decreased lipid solubiluty)
Increased excretion (urine or bile)
Usually abolishes activity
UNLESS prodrug (promotes) eg Zidovudine
OR no change in activity (valium diazepam to nordiazepan has v similar activity)
OR produces toxic metabolites, paracetamol
Phases of Drug Metabolism
- Addition / uncovering rective group (oxidation / reduction / hydrolysis - make more susceptible to phase 2)
- Conjugation of endogenous molecule to drug (glucuronide, sulphate, GSH, acetylation/methylation - makes molecule more polar, ideal for active transport and EXCRETION)
Most important Phase 1 Metabolism Reaction
OXIDATION
Cytochrome P450 mixed oxidases (smooth ER)
Requires O2, NADPH, CP450 Reductase
Metabolism of Phenytoin
- Hydroxylation by CYP (now slightly water soluble)
2. Conjugation by UDP glucuronosyl transferase (now very soluble in water)
Factors influencing drug metabolism
Organ function (kidney, liver, heart, gut).
Diseases, other drugs.
Diet, cigarrettes, alcohol
Age, sex, pregnancy
Induction of drug metabolism
Enzyme synth initiated within 24h of exposure, increasing over 5 days, decreases over 1-3w afer inducing agent discontinued
Environmental factors:
Cigarette smoking, eating BBQ meat, cruciferous veges, high protein diet, ethanol, insecticides.
Other drugs: barbiturates, phenytoin, rifampicin, st John’s wort (potent inducers of drug metabolising enzymes)
Reversible inhibitors of drug metabolusm
cimetidine, ketoconazole, quinolone antibiotics, HIV protease inhibitors, grapefruit juice
Lead to EXAGGERATED RESPONSE with increased risk of toxicity.
Smokers and Caffeine
Smokers have an increased ability to metabolise some drugs and chemicals. Smokers have to drink 50% more coffee to get same effect
Reason for variability in therapeutic benefit among population
Different ability to metabolise drugs
Excretion
Compounds are removed from the body to the external environment
Site of excretion
Kidney - important
biliary excretion - some large drugs >400 and ionised eg glucuronides
Lungs - anaesthetic gases
The kidney’s role in excretion
Removes H2O soluble drugs and metabolites
3 main mechanisms of drug excretion by the kidney
- Glomerular filtration of unbound drug (130mL/min ~10% RBF)
- Active secretion of free and prot-bound drug by transporters (anions and cations) (Prox tubule)
- Filtrate 100fold concentrated in tubules for favourable conc gradient for reabsorption by passive diffusion (LOH)
Factors influencing renal excretion
Gender (f 80% RF)
Age (decreases 50% 25-75_
Pregnancy (increases 50%)
Disease (renal disease,heart failure)
Alteration of renal excretion of drugs
- Comp inhibition of tubular secretion (RC of penicillin decreased 90% by probenecid to just filtration percent)
- Influence of pH (Sodium bicarbonate for increasing ionisation of weak acids and decreasing reabsorption (salicylate, methotrexate). Ammonium chloride used to acidify urine to enhance excretion of basic drugs (amphetamines)
- Influence of urinary flow rate (increase decreases conc gradient for passive reabsorption - flush drug out. Dehydration has opposite effect)
Amphetamine overdose
Treat with Ammonium chloride to make urine acidic and increase excretion of amphetamine in overdose
Prolong amphetamine effects
Take baking soda to increase pH of urine and decrease the excretion of amphetamine, prolonging the effect
PD2’
Competitve irreversible antagonism
