Intro, Pharmacodynamics, Pharmacokinetics and ADME Flashcards
1
Q
What is pharmacodynamics?
A
Study of molecular, biochemical and physiological EFFECTS of drugs on the body systems, AND mechanisms of action
2
Q
What is Pharmacokinetics?
A
Study of ADME of drugs (fate)
3
Q
Pharmacogenomics
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Genetic influences on the effectiveness and fates of drugs
4
Q
Toxicology
A
Adverse effects of drugs and other toxic agents
5
Q
Percentage of drugs from the natural world
A
63% (eg Taxol, anticancer drug from Yew tree)
6
Q
Where do drugs come from? (5 categories)
A
- 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
7
Q
Examples of drugs from plants and herbs
A
- 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)
8
Q
Examples of drugs from microorganisms
A
Penicillin (antibiotics) b-lactam, interferes with bactrial cell wall synthesis
9
Q
Examples of endogenous drugs
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Hormones eg insulin, throxine, growth hormone (most now produced by recombinant tech or chemical synthesis)
10
Q
Examples of chemical modification of endogenous
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Hormonal drugs eg ethinyl estradiol (readily absorbed estrogen form)
Anticancer drugs eg 6hercaptopurine, modified base component of DNA to interfere with DNA symth
11
Q
Examples of chemical synthesis of novel compounds
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Eg indomethacin and celecoxib - COX inhibitors (NSAIDS) eg cimetadine (histamine receptor modulator) eg Simvastatin (HMG CoA reductase inhibitor for high cholesterol)
12
Q
Examples of drugs discovered by chance
A
eg antidepressants monoamine oxidase inhibitors and tricyclic antidepressants (faled TB treatments) eg cisplatin (platinum containing, used to treat cancers, was for bacteria)
13
Q
4 most common proteins that drugs bind to
A
- Enzmes
- Carrier proteins
- Ion channels
- Receptors
14
Q
Features of receptors
A
At least one binding site
Binding of exogenous ligands results in signal transduction (efficacy)
15
Q
How do drugs act on receptors?
A
Drugs act by promoting or inhibiting the process of signal transduction. Must bind with specificity / selectivity (shapes important)
16
Q
Affinity
A
Attraction of a ligand for receptor
17
Q
Efficacy
A
Effect of ligand binding. Max = 1, no effect = 0
18
Q
Agonists
A
Affinity and efficacy (mimics ligand)
19
Q
Antagonists
A
Affinity but NO efficacy (prevents signal)
20
Q
Histamine specificity
A
H1 = allergic reactions, skin H2 = stomach acid secretion H3 = CNS, ileum, cardiac tissue, often presynaptic and autoregulatory (WIDESPREAD)
21
Q
What is selectivity>
A
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)
22
Q
Lack of selectivity / specificity in NSAIDS
A
Universally inhibit COX.
COX2 selective for inducible, little effect on constitutive form (rofecoxib, celecoxib)
COX1 = homeostatic mechanisms COX2 = antiinflammatory
23
Q
Rate theory
A
Drug effect is proportional to RATE of occupancy
24
Q
Floating receptor model
A
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)
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Receptor occupancy theory
Drug effect is proportional to NUMBER of receptors occupied (michaelis-menten equilibrium D + R D-R )
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Receptor plasticity
Number and states of receptors changes - mouldability, due to pharmacological, physiological, pathological states. Responsibel for changes in drug effectiveness over time.
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2 state receptor model
Resting state R Activated state R*
NO LIGAND
Equilibrium favours R
```
FULL AGONIST (efficacy =1)
Strongly shifted to R*
```
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PARTIAL AGONIST (efficacy 0-1)
Partly shifted to R*
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ANTAGONIST (affinity and NO efficacy = 0)
Equilibrium not shifted, no preference for active/inactive. Binds to and inactivates receptors
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4 types of receptor families
1. Ionotropic (ion channels)
2. Metabotropic (GPCR)
3. Catalytic (kinases)
4. Nuclear/intracellular (transcription)
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Structure of ionotropic receptor
extracellular N
Extracellular ligand binding domain
4 TM domains (form pore)
extracellular C domain
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Structure of GPCRs
EC N, IC C domain
EC binding domain
IC GProt coupling domain
7 TM domains
31
Structure of kinase-linked receptors
EC N domain, binding domain
1 TM domain
IC C domain, catalytic domain
32
Structure of nuclear receptors
NOT MEMBRANE EMBEDDED
Binding domain by C
middle DNA binding domain (Zn fingers)
33
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)
34
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
35
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)
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Example of kinase pathway: Ras/Raf/MAP Kinase
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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
```
37
Example of kinase pathway: Jak/Stat
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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
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38
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
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Agonist potency
EC50
Lower value = greater potency
Effective concentration that produces 50% of the maximum effect
PD2
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PD2
-log(EC50)
higher value is greater potency
AGONIST
41
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
42
Measurement of potency of competitive reversible antagonism
PA2 (parallel right shift)
| PA2 = -log[antagonist] + log((EC50pres/EC50abs) - 1)
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Example of competitive reversible antagonism
Propranolol at B1 receptors
| Atropine at M
44
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
45
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'
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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.
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Inverse agonists
Binds receptor and has negative efficacy - turns receptor off - constitutive activity.
Get in the way of agonist binding, like competitive reversible antagonism
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HOmologous desensitisation
acts on itself
| Phosphorylation of serine by BARK on adenylate cyclase
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Heterologous desensitisation
One agonist triggers response that desensitises response to different agonist (eg PKA and PKC)
50
Chronic agonist administration leads to...
DOWN REGULATION of receptors
| eg chronic salbutamol, internalisation of receptors, less available for stimulation, decreased bronchodilation
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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.
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Clinical significance of receptor population changes
Tolerance
Adverse effects
Therapeutic effects (time to build up the effect)
53
Examples of enzymes as drug targets
COX and NSAIDS (treat pain and inflammation)
| ACE and ACE Inhibitors (captopril, enalaprilat) treat hypertension
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Drugs that interact with carrier proteins
drugs that act on monoamine neurotransmitter uptake proteins
Fluoxetine (Prozac) SSRI
Sibutramine (Reductil) SNRI
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Fluoxetine mechanism
Block reuptake of 5HT for increased conc in synapses. Depression is thought to be from decreased 5HT so antidepressive effect
Serotonin
56
IOn channel blocker examples
Anaesthetics (local) Na+ blockers
| Cardiovascular conditions Ca2+ blockers (verapamil, nifedipine)
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Major organs involved in ADME
1. GI tract (absorption)
2. Liver (metabolism)
3. Kidney (excretion)
4. Lungs (absorb / excrete volatile gases)
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4 main methods of membrane transport
1. Passive transport
2. Facilitated diffusion
3. Active transport
4. Endocytosis
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Passive diffusion
Non polar drugs (lipid soluble)
Conc gradient drives
No energy
60
Facilitated diffusion
```
Move faster than expected
Oscillating carrier protein
Concentration gradient!
No energy
Usually substrates are sugars and AAs
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Active transport
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Proceed against conc gradient
REQUIRES ATP
Satuable
Liver, kidney, BBB, gut epithelium
Allows accululation, waste removal, protection against toxins
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Endocytosis
Internalise large molecules >1000 (cytokines, hormones, nanoparticles)
Substrate binds to receptor, invag of complex, budding off and delivery
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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
64
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
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Rate of absorption
How rapidly does durg reach general circulation?
66
Extent of absorption
How much of administered dose enters general circulation (BIOAVAILABILITY - F)
Bioavailabilty = area under concentration-time curve
67
Routes of drug administration
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Enteral
Oral
Sublingual
Rectal
Parenteral
IV
SC
Intradermal (into skin)
Intramusclular
Lungs (volatile anaesthetics)
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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
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(-)
Skill required (air emb), careful preparation of sterile materials, no recall so hazardous
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Oral Administration
(+)
Safest, most convenient, economic
(-)
Slow effect, unpredictable rate, extent, reproducibility (change day to day, between people)
70
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
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MOST ARE INVOLVED IN EXTENT
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Rate limiting step of drug absorption
Stomach emptying
72
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)
73
Only kind of drugs to diffuse across BBB
Lipid-soluble
| Additional layer of glial cells in BBB
74
Body fluid compartments. How much intracellular fluid?
28L
75
Body fluid compartments. How much Extracellular fluid?
11L ECF + 3L Plasma = 14L
76
Sites of drug metabolusm
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LIVER
GI tract - gut bacteria and proteases
Intestinal wall - CYPs
Plasma - esterases
Specialised tissues (monoamine oxidases in nerve endings, noradr to adrenaline)
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77
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
78
Phases of Drug Metabolism
1. Addition / uncovering rective group (oxidation / reduction / hydrolysis - make more susceptible to phase 2)
2. Conjugation of endogenous molecule to drug (glucuronide, sulphate, GSH, acetylation/methylation - makes molecule more polar, ideal for active transport and EXCRETION)
79
Most important Phase 1 Metabolism Reaction
OXIDATION
Cytochrome P450 mixed oxidases (smooth ER)
Requires O2, NADPH, CP450 Reductase
80
Metabolism of Phenytoin
1. Hydroxylation by CYP (now slightly water soluble)
| 2. Conjugation by UDP glucuronosyl transferase (now very soluble in water)
81
Factors influencing drug metabolism
Organ function (kidney, liver, heart, gut).
Diseases, other drugs.
Diet, cigarrettes, alcohol
Age, sex, pregnancy
82
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)
83
Reversible inhibitors of drug metabolusm
cimetidine, ketoconazole, quinolone antibiotics, HIV protease inhibitors, grapefruit juice
Lead to EXAGGERATED RESPONSE with increased risk of toxicity.
84
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
85
Reason for variability in therapeutic benefit among population
Different ability to metabolise drugs
86
Excretion
Compounds are removed from the body to the external environment
87
Site of excretion
Kidney - important
biliary excretion - some large drugs >400 and ionised eg glucuronides
Lungs - anaesthetic gases
88
The kidney's role in excretion
Removes H2O soluble drugs and metabolites
89
3 main mechanisms of drug excretion by the kidney
1. Glomerular filtration of unbound drug (130mL/min ~10% RBF)
2. Active secretion of free and prot-bound drug by transporters (anions and cations) (Prox tubule)
3. Filtrate 100fold concentrated in tubules for favourable conc gradient for reabsorption by passive diffusion (LOH)
90
Factors influencing renal excretion
Gender (f 80% RF)
Age (decreases 50% 25-75_
Pregnancy (increases 50%)
Disease (renal disease,heart failure)
91
Alteration of renal excretion of drugs
1. Comp inhibition of tubular secretion (RC of penicillin decreased 90% by probenecid to just filtration percent)
2. 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)
3. Influence of urinary flow rate (increase decreases conc gradient for passive reabsorption - flush drug out. Dehydration has opposite effect)
92
Amphetamine overdose
Treat with Ammonium chloride to make urine acidic and increase excretion of amphetamine in overdose
93
Prolong amphetamine effects
Take baking soda to increase pH of urine and decrease the excretion of amphetamine, prolonging the effect
94
PD2'
Competitve irreversible antagonism
