Learning outcome 1 Flashcards
Thalidomide
Sedative that caused phocomelia (birth defect - gross malformation or absence of limbs)
Randomized controlled trials (RCT) three distinguishing features
Use of controls, randomization, blinding
Use of controls in RCTs
Pts are given new drug, others are given a placebo or an already standard treatment. (Standard or placebo pts are controls)
Randomization in RCT
Subjects randomly assigned to treatment or control group.
Blinded in RCT
Single blind means only subjects don’t know who’s getting what, double blind means they both don’t know
Preclinical testing
Done in animals. Take 1 to 5 years. If approved for clinical testing by FDA, drug is awarded investigational
Phase I
Done in healthy patients unless the drug has severe sides like cancer drugs
Phase I three goals
Evaluating drug metabolism, pharmacokinetics, biologic effects
Phase II and III
Testing patients. Object is to determine therapeutic effects, dosage range, safefty, and effectiveness
Phase IV
If approved, it gets released for general use permitting observation in a large population.
Failure to detect in clinical trials
Relatively small number use the drug, patients are carefully selected and don’t fully represent the population, pts take drug for limited time
Effects which show up after clinical trial
Infrequent effects, long term effects, effects in certain populations only (1/2 drugs have serious adverse effects not found until after release)
Chemical name of drug
A description of the drug using chemistry nomenclature
N-acetyl-para-aminophenol
Generic name
Or nonproprietary. A name assigned, each drug has only one.
Acetaminophen
The final syllables may indicate a class
Cillin suffix means
Belongs to the penicillin class
Statin suffix
HMG-CoA reductase inhibitor.
Lowers cholesterol
Trade name
Proprietary or brand name.. Must be approved. Tylenol
olol
Beta-adrenergic blocker htn and angina
barbital
barbiturate
pril
ACE inhibitor
sartan
Angiotensin II receptor blocker
dipine
Didropyridine calcium channel blocker
triptan
Serontonin 1B/1D receptor agonist
Migraine
parin
low-molecular wait heparin
afil
PDE-5 inhibitor
glitazone
Thiazlidinedione for NIDDM
Prazole
Proton pump inhibitor
dronate
Bisphosphonate for osteoporosis
floxacin
Fluoroquinolone antibiotic
Non equivalent trade names
Pts taking dilantin got switched to generic phenytoin and had seizures
Pharmacokinetics
Study of drugs moving throughout the body. It includes drug metabolism and excretion.
4 basic pharmacokinetic properties
Absorption, distribution, metabolism, excretion
Absorption
Movement of a drug from its site of administration into the blood
Distribution
Drug movement from blood to interstitial space of tissues, and from there into the cells
Metabolism
Enzymatically mediated alteration of a drug
Excretion
Movement of drugs and metabolites out of the body
Metabolism plus excretion is called
elimination
3 ways drugs pass membranes
Passage through channels or pores, passage with aid of transport system, through the membrane itself
Channels and pores
Not many drugs go through as they are took big, usually for things under 200 daltons like Na+ and K+
Transport system
May or may not use energy
Are selective
P-glycoprotein
Aka multidrug transporter protein. Transports many drugs OUT of cells.
Present liver, kidney, placenta, intestine, capillaries in brain.
P-glycoprotein in organs
Transports drugs for bile elimination.
In kidneys it pumps drugs out for excretion
Placenta transports back to maternal blood
Intestine transports to intestinal lumen (and can reduce absorption into blood because of this)
Direct penetration of the membrane
Most drugs depend on this because they are too big for channels or pores, often lack transport system to help them cross all of the membranes that separate them from their sites of action, metabolism and excretion
Likes disolve
likes
NOT lipid soluble are
Polar and ion
Polar molecules
E.g gentamicin because of hydorxyl groups.
Polar molecules have no net charge.
Ions
Net positive or negative charge. Can’t cross membrane unless tiny
Quaternary Ammonium Compounds
At least one atom of nitrogen, and carry a positive charge all the time.
pH-dependent Ionization
Weak acids and bases can contain or not contain a charge.
If an acid is in an acid it is less likely to give up its H+ (therefore gaining a negative charge) and can still cross the membrane
Ion trapping
Or pH partitioning. Acids stay on acidic side, bases stay on basic bitch side
Factors affecting absorption
Rate of dissolution
Surface area - small intestine has more surface area (microvilli) so oral drugs normally absorbed here not stomach
Blood flow - large gradient maintained by rapid blood flow
Lipid solubility - lipid soluble = more rapid (as a rule)
pH Partioning
Enteral
Via the GI tract
IV advantages
No absorption barrier Instantaneous absorption pattern Rapid onset Precise control Permits large fluid volumes Permits use of irritant drugs
IV disadvantages
Irreversible, expensive, inconvenient, difficult to do, risk of fluid overload, infection risk, emoblism
IM/SUB absorb/ advtanges
Cap wall barrier to absorption Rapid with water soluble drugs Slow with poorly soluble drugs Permits use of poorly soluble drugs Depot preparations
IM/ Sub Q disadvantages
Discomfort, inconvenient, injury potential
Oral barriers to absorption and absorption pattern
Epithelial lining of GI tract, cap wall
Slow and variable absorption
Advantages PO
Easy, convenient, cheap, potentially reversible
Disadvantages of PO
Variability
GI inactivation
N/V
Pt needs to be conscious and cooperative
Slow IVP
CNS toxicity occurs after 15 seconds with IV therefore only 25% has gone in if you’re pushing over 1 minute
IV embolism
Hypotonic and hypertonic kill RBCs, which can cause emoblism. Also obviously the trauma to the vessel wall.
Also drugs not fully disolved (don’t give cloudy drugs or ones with visible particles)
IM absorption
Big spaces in cells that make cap wall, so not much of a barrier to get through
Water soluble drugs absorb much more rapidly.
Good for drugs which dissolve poorly
Chemical equivalence
Contain the same amount of the identical chemical compound
Equal in bioavailability
Same drug is absorbed at the same rate
Not possible to for drugs to be chemically equivalent but differ in bioavailability
Tablets
Drug plus binders and fillers compressed together.
Enteric coated
Drugs covered with a material designed to be digested by the intestine but not stomach
Protect drug from stomach and stomach from drug.
Absorption is even more variable due to delays in gastric emptying or not desolving
Materials used for enteric coating
Fatty acids, waxes, shellac.
Sustained release preparations
Capsule contains spheres with active drug inside, spheres dissolve at different rates
Potential for variable absorption and expensive
Distribution defined as
Movement of drugs throughout the body
Three major factors of drug distribution
Blood flow, ability of drug to exit the vascular system, and ability of drug to enter cells
Two pathologic conditions effecting blood flow
Abscesses - no blood flow so antiobiotics can’t reach, must be drained first
Tumors - Limited blood supply, blood flow becomes less as you can inward in a tumor. Limited blood flow is a major reason tumors are resistant to drugs
Typical capillary beds
Drugs move between cap cells rather than through them, therefore leaving is easy
BBB
Unique caps in CNS, as they have tight junctions between, so dougs need to pass through cap membrane and therefore need to be lipid soluble or have a transport system.
CNS also has P-glycoprotein to pump back out any drugs that get in
Can impede antiobiotics
Newborns and BBB
BBB not fully evolved, vulnerable to CNS toxicity
Placental drug transfer
Drugs which are highly polar, ionized, or protein bound cannot pass. Same with substrates for P-glycoprotein
Protein bonds
Albumin most abundant. 69,000 daltons so stays in blood.
Ablumin
Warfarin binds 99%, gentamicin 10%.
Bound drugs are restricted because Albumin is so big. Also drugs won’t be metabolized while bound.
Also two drugs competing for albumin increases the free concentration of the one getting bumped
Entering cells
Some drugs must enter cells to reach site of action (some bind to external receptors)
All drugs must enter cells to undergo metabolism
CYP 450
12 CYP families, first three metabolize drugs, other 9 metabolize endogenous compounds like steroids and fatty acids
6 possible consequences of drug metabolism
Accelerated renal excretion Drug inactivation Increased therapeutic action Activation of prodrugs Increased toxicity Decreased toxicity
Accelerated renal drug excretion
Most important consequence of metabolism.
Kidneys are unable to excrete highly lipid soluble drugs, and most convert to hydrophilic.
Two main conversions to increase renal drug excretion
Adding a hydroxyl group, or glucuronidation (add glucuronic acid) (may enter enterohepatic recirc)
Age and drug metabolism
Up till 1 year liver is not developed and so infants are very sensitive to drugs
Old people lose ability to metabolize and dosages need to be reduced to prevent toxicity
Malnourishment
May mean lack of co factors in liver for metabolism
Competition for metabolism
If two drugs are metabolized by one limited resource drugs may accumulate
Enterohepatic reciruclation
Liver to duodenum (via bile duct) and back to liver (via portal blood)
Only glucorinidated drugs.
Beta-glucuronidase breaks the glucorinated acid from the drug, where it is again lipid soluble so it absorbs across intestinal wall, goes back to liver, and starts again
*Not all glucuronidated drugs do this
Renal drug excretion
Most important for removing drugs, therefore with renal failure excretion is all badness
1) Glomerular filtration, 2) passive tubular reabsoprtion, 3)active tubular secretion
Glomerular filtration
Only drugs small enough to enter can be excreted (not ones bound to proteins like albumin)
Passive tubular reasoprtion
Fat soluble drugs re enter at distal tubule
Active tubular secretion
P-glycoproteins can pump drugs from blood into urine, as can two transport systems, one for organic acids and one for organic bases
pH dependent ionization
Drugs ionized at pH of tubular urine will remain in tubule and be excreted. Therefore manipulating urinary pH is a way to clear drugs out.
Giving a drug to make urine more basic is a way to clear ASA out of children (acids ionize in bases, and therefore less is reabsorbed)
Competition for active tubular transport
Probenecid uses the same pumps penicillin does and can be used to prolong the time penicillin stays in the body, as it is normally rapidly excreted
Used when penicillin was very expensive
Age and kidneys
Newborns underdeveloped kidneys have a hard time excreting drugs, as to old people.
Breast milk excretion
Lipid soluble drugs have ready access to baby boobie juice
Minimum Effective Concentration
Below which, therapeutic effects will not occur
Therapeutic Range
Between MEC and toxic
Time to plateau
Four half lives
Three techniques to reduce fluctuations
Administer via continuous infusion
Administer a depot preparation
Reduce size and interval of each dose
Decline from Plateau
94% will be eliminated in four half lives
Pharmacodynamics
Study of biochemical and physiologic effects of drugs, or what drugs do to the body and how
Dose responses are
Graded, as the dosage increases, the response becomes progressively larger
Phase I II III dose response
I is before an effect occurs (flat line)
II Is the upward curve, increased dose = increased response
III threshold response has been hit, more drug does not illicit more response
Potency
The amount of drug needed to illicit a response. It is rarely important (you can just give less in terms of units)
*has nothing to do with max efficiancy
Receptor definition
Any functional macromolecule in a cell to which a drug binds to produce its effects.
Receptors are on or off.
General equation for drug interactions with their receptors
D = drug
R = receptor
D+RD-R Complex –> Response
4 primary families of receptors
Cell membrane-embedded
Ligand-gated ion
G protein-coupled
Transcription factors
Cell Membrane-Embedded Enzymes
Span the cell membrane, ligand-binding domain is located on cell surface, enzymes catalytic side is inside.
Response occurs in seconds
E.g insulin
Ligand-Gated Ion Channels
Also span cell membrane, regulated ions. When an endogenous ligand or agonist binds the channels open. Responses are extremely fast, milliseconds
E.g ACTH, GABA
G-Protein-Couple receptors
Made of the receptor itself, the G-protein (its GTP) and effector (ion channel or enzyme)
Binding of endogenous ligand or agonist activates receptor, which activates G protein, which activates the effector
Responses happen rapidly
E.g NE, serotonin, histamine, many peptides.
Receptors transverse membrane 7 times
Transcription Factors
Only one within the cell, delayed response compared to the rest. Must be lipid soluble to activate
E.g thyroid hormone, all steroid hormones
Simply occupancy theory
The intensity of the response to a drug is proportional to the number of receptors occupied by that drug and a maximal response will occur when all available receptors have been occupied.
Modified occupancy theory
Affinity refers to strength of attraction between drug and receptor
Intrinsic refers to ability of drug to activate receptor
These are independent properties and explain why drugs can have different potency and maximal effects
Affinity
Strength of attraction between a drug and its receptor.
Drugs with high affinity are potent
Intrinsic activity
Ability of drug to activate receptor.
Intrinsic activity is its max efficiency.
Agonists/Antagonists
Agonist have affinity and high intrinsic
Antagonist have affinity and no intrinsic
Noncompetitive antagonists
Bind irreversibly. Also called insurmountable.
Receptor modulation
Receptors can be destroyed or modified to respond less
Drugs without receptors
React through physical or chemical interactions with other small molecules
Antacids, saline laxatives, chelating agents
ED50
Dose required to produce a defined therapeutic response in 50% of the population
It can be considered a standard dose
LD50/ED50 =
TI. For a drug to be truly safe, the highest dose required to produce therapeutic effects must be substantially lower than the lowest dose to produce death
First ‘merican law to regulate drugs
Federal Pure food and Drug Act in 1906
Canada food and drug act
- To review safety/efficiancy before marketed and decide script or no script.
Controls labeling
Controlled drug act canada
1997
Schedules 1 examples
Opiates
Schedule 2
Cannabis
Sched 3
Amphetamines
Sched 4
Sedative-hypnotics like benzons and barbs
Sched 5
Propylhexadine
Sched 6
Precursors for controlled substances
Schedule 7 and 8
Cannabis resin 3k then 1g for 8
Mary j 3k then 30g
Years to create new drug
10-15 years, 20% ever get approval.
Preclinical testing
On animals, 1-5 years
Stages of clinical testing (takes 2-10years)
1 volunteers for pharmokinetics/dynamics
2 pts 500-5000 for therapuetic dose and effect
3 pts 500-5000 Safety and efficiancy, application is made at conclusion
4 post market surveliance
Potentiative
One drug intensifies another
Unique response
Two drugs can make a third unique response (antabuse with booze creates N/V syncope tachycardia SOB headaches circulatory collapse)
A g coupled protein receptor is also known as a
Metabotropic
Jeopardy ligand
Any molecule which binds to another (polar molecules, ions etc)
3 components of a G protein coupled receptor
Receptor on cell surface activated by ligand
G protein, the serpentine structure
An effector, ion channel or enzyme
