1 Pharmacology

Front 1

5 steps of drug development

Back 1

1. Drug discovery, compound testing
2. Pre-clinical testing - animals
3. Clinical trials phase I-III
4. FDA submission
5. FDA approval and phase IV

Front 2

Clinical testing phase I (how many people)

Back 2

Health people for safety and pharmacokinetics
20-100 people

Front 3

Clinical testing phase II (how many people)

Back 3

Patients, testing for efficacy
100-500 people

Front 4

Clinical testing phase III (how many people)

Back 4

Testing against placebo
Thousands

Front 5

Clinical testing phase IV

Back 5

Anything learned about the drug after approval

Front 6

Pre-clinical vs clinical testing (who are subjects and what are objectives)

Back 6

Pre-clinical: on animals testing toxicity and pharmacokinetics
Clinical: on humans to test efficacy

Front 7

Drug potency

Back 7

Drug A is more potent than drug B if it can achieve the same efficacy w/ less dose (A's dose response curve would be shifted left)
The fraction of Emax attained (eg, partial agonists have lower efficacy because they dont attain Emax

Front 8

Drug efficacy

Back 8

The degree to which different agonists produce varying responses even when occupying the same proportion of receptors

Front 9

EC50

Back 9

Molar concentration of drug that produces 50% of maximal effect

Front 10

ED50

Back 10

Dose of drug that produces 50% of maximal effect

Front 11

Complete vs partial agonists

Back 11

Complete agonists reach full effiacy
Partial agonists, even when applied at high enough concentrations to occupy all receptors, do not have as large an effect as full agonist

Front 12

Competitive antagonists and dose response graphs

Back 12

Competitive can be overcome by adding more agonist
On graph, peak efficacy is still the same but dose needed to reach it is higher

Front 13

Noncompetitive antagonists and dose response graphs

Back 13

Antagonism is insurmountable
Efficacy (% response) is lower

Front 14

LD50

Back 14

Dose of drug that produces 50% death in population of test animals

Front 15

Therapeutic Index

Back 15

Ratio of LD50/ED50
Usually higher is better because it means more separation between effective therapeutic doses and lethal doses
High can still be bad if the response curves are so spread out that there is overlap

Front 16

Formula for determining relative amounts of ionized drug given pH and pKa (for acid and base)

Back 16

Acid:
[HA]/[A-] = 10^(pKa-pH)

Base:
[B]/[BH+] = 10^(pH-pKa)

Front 17

Formula for determining ratio of drug in two compartments given pHs and pKa

Back 17

Acid:
(1+10^(pH-pKa))plasma/(1+10^pH-pKa))tissue

Base:
(1+10^(pKa-pH))plasma/(1+10^(pKa-pH))tissue

Front 18

Ion trapping

Back 18

For example:
Aspiring (pKa 3.4) is in HA form in stomach, so can pass through membrane to plasma (pH 7.4) where it is deprotonated. As A- it cannot pass back through plasma so is trapped

Front 19

Acetaminophen metabolism

Back 19

Normally detoxified by conjugation to glucuronide sulfate
CYP enzymes can metabolize to toxic intermediate that is inactivated to glutathione conjugate
Toxic intermediate's innocuous metabolism can be inhibited by alcohol/starvation, which leads to toxic intermediate causing cell toxicity and death

Front 20

3 ways toxicity is increased in acetaminophen metabolism

Back 20

1. Anything that increases CYP and bioactivation (ethanol, anticonvulsants)
2. Anything that depletes glutathione
3. Anything that impairs detoxification

Front 21

Where does a drug go after IV or oral dose?

Back 21

IV dose: straight to systemic circulation
Oral dose: GI tract mucosa -> portal circulation -> liver -> systemic circulation

Front 22

First-pass effect (presystemic extraction)

Back 22

When an orally administered drug, on its way to systemic circulation is metabolised by GI tract mucosa or liver, so only a fraction of dose reaches systemic circ

Front 23

Phase I vs Phase II drug metabolism

Back 23

Phase I : exposes functional group resulting in more polar molecule (oxidations, azo/nitro reductions)
Phase II: results in water soluble molecule (glucuronidation, acetylation, sulfate conjugation, methylation)

Front 24

P-glycoprotein (MDR1)

Back 24

Membrane transporter that eliminates drugs from cells
Active in GI tract and blood brain barrier

Front 25

Major actions of sympathetic nervous system

Back 25

Pupil dilation
Bronchi dilation
Sphincter tone up

Front 26

Urinary bladder and ANS

Back 26

SNS relaxes detrusor muscle and constricts sphincter -> retention
PNS has opposite effects -> void

Front 27

Pupil and ANS

Back 27

NE causes dilation
Ach causes constriction
Lung tumor can block cervical ganglion causing unilateral constriction on only one side

Front 28

Sweat gland innervation

Back 28

SNS postganglionic neuron releases Ach onto muscarinic receptors

Front 29

Succinylcholine

Back 29

Cholinomimetic depolarizing NMJ blocker
Used preoperatively

Front 30

Bethanechol (3)

Back 30

Cholinomimetic
Causes GI bladder contraction
Resistant to AchE so is used post op after GI surgery to jump-start muscles

Front 31

Effects of antagonizing a muscarinic receptor (5 effects)

Back 31

Interferes w/ PNS
Dry mouth, blurred vision, urinary retention, constipation, increased heartrate

Front 32

Physostigmine

Back 32

Achase inhibitor that can cross BB barrier
Treat atropine overdose

Front 33

Organophosphates (and antidote)

Back 33

Irreversible Achase inhibitors
Antidote - pralidoxime w/ atropine

Front 34

Myasthenia gravis treatment

Back 34

Block Achase activity and add azothioprine to block Ab production

Front 35

Why is carbidopa used?

Back 35

Carbidopa inhibits catecholamine synth
Used in parkinson's treatment because there is a dopamine lack
Can't give DA cause it doesnt cross BB barrier
So give dopa that be used to synth dopamine
But dopa would spread to whole body, so give carbidopa which only blocks dopa synth peripherally, so more dopa goes to brain

Front 36

Sequence of events in catecholamine secretion (8)

Back 36

1. Active tyrosine uptake pump
2. Catecholamine synth
3. Transport of NE and DO into vesicles
4.Only in Ad. Medulla: NE transport out of vesicles and methylation to E and uptake back into vesicles
5. NE release via exocytosis (Ca stimulates, Mg inhibits)
6. NE binding to pre and post receptors
7. Active NE reuptake
8. Catabolism of NE and DA by monoamine oxidases

Front 37

How do most anti depressants work? (tricyclics vs SSRIs)

Back 37

By inhibiting the catecholamine reuptake pump
Tricyclics inhibit NE and 5HT uptake
SSRIs only inhibit 5HT uptake

Front 38

Catecholaminomimetics (5)

Back 38

Indirect CNS stimulants
Amphetamine, cocaine, ephedrine, MAO inhibitors, tricyclics

Front 39

False transmitters

Back 39

Any molecule that can displace NE or E from synaptic vesicle but has little action once released

Front 40

Tyramine and MAOs

Back 40

Tyramine is normally metabolized in liver by MAO
If tyramine is ingested w/ MAO inhibitors -> hypertensive crisis
Because tyramine will displace NE and E

Front 41

Clonidine

Back 41

alpha2 receptor agonist on presynaptic neurons causing auto inhibition of NE and E synthesis and release so can be used as an anti hypertensive

Front 42

adrenergic receptors and adenylate cyclase

Back 42

β activate
α2 inhibits

Front 43

Serotonin biosynthesis

Back 43

Tryptophan is precursor
End metabolite is 5-HIAA which is measured in urine

Front 44

Biological actions of serotonin (4)

Back 44

1. Constriction of GI and bronchial smooth muscles
2. Constriction of cranial vessels leading to migraines
3. Dilation of skeletal muscle blood vessels (flushing)
4. Stimulation of sensory nerve endings

Front 45

Carcinoid syndrome

Back 45

Tumor produces high serotonin levels and causes symptoms: flushing, hypertension, diarrhea, right side heart failure

Front 46

What 3 things does mast cell activation lead to?

Back 46

Vasodilation, inflammation, nociceptive

Front 47

Glucocorticoids and inflammation

Back 47

Stabilize plasma membrane so that arachidonic acid is not released and thus inhibits synth of prostaglandins

Front 48

Cyclooxygenase inhibitors

Back 48

NSAIDs are unspecific and inhibit COX-1 and COX-2
COX-2 inhibitors block PGI2 synthesis so release platelet inhibition

Front 49

Prostaglandin synthesis

Back 49

From arachidonic acid + cyclooxygenase

Front 50

Prostaglandin properties (3)

Back 50

Vasodilators/constrictors
Promote platelet aggregation (except PGI2)
Bronchial constriction except PGE2

Front 51

Prostacyclin (PGI2)

Back 51

Most potent endogenous inhibitor of platelet aggregation
Also vaso/broncho dilator

Front 52

Thromboxanes (synth and properties)

Back 52

Synthesized from PGH2
Platelet aggregation

Front 53

Leukotriene synthesis

Back 53

From arachidonic acid via lipoxygenase

Front 54

Platelet activating factor (2)

Back 54

Promotes platelet aggregation
Bronchoconstriction

Front 55

Leukotriene properties (2)

Back 55

Potent bronchoconstrictors
Key mediators in asthma

Front 56

Kinins synthesis + physiologic effects (4)

Back 56

Synthesized from kininogens
Vasodilation
Bronchial/intestinal smooth muscle contraction
Mast cell activation
Pain

Front 57

Histamine physiologic effects (2)

Back 57

Vasodilation
Increased capillary permeability

Front 58

Histamine receptors

Back 58

H1 - responsible for allergy symptoms, in blood vessels, H1 receptors in CNS cause drowsieness
H2 - localized to parietal cells to cause increased gastric acid secretion

Front 59

What physiologic effect do serotonin agonists have?

Back 59

Vasoconstriction (headache relief)