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Chem 1004 > Week 1 B - what happens to drugs after we take them? > Flashcards

Week 1 B - what happens to drugs after we take them? Flashcards

1
Q

Routes of Administration

A
  • Oral ingestion (most common)
  • Inhalation
  • Injection (needle and powder) see Liska p105
  • Body orifices (use your imagination!)
  • Skin application (transdermal patches)
  • Implantable drug delivery systems (contraceptives)
  • Microsponges
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2
Q

Orally Ingested Drugs

A
  • Expected to disintegrate in the stomach (pH~2) and enter bloodstream by absorption from stomach or small intestine
  • Enterically coated aspirin: designed not to dissolve in stomach acid due to potential irritation (bleeding)
  • Some drugs (antibiotics) are to be taken with food to minimize any irritant effect the drug may have on the stomach lining
  • Disadvantages: some drugs (ie insulin) are destroyed by digestive juices, and must be injected
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3
Q

Inhaled drugs

A
  • Rapidly absorped due to large number of blood vessels in lungs and nasal region (ie cocaine: faster access to the brain)
  • Nasal decongestants work by shrinking the nasal mucous membrane
  • Some non-volatile drugs (proteins) can be inhaled in the form of a fine aerosol spray
  • Drawbacks include possible drug induced irritation (and in the extreme, destruction) of mucous membrane
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4
Q

Parenteral (by Injection)

A
  • Hyperdermic injection into muscle, veins, beneath skin etc.
  • Advantage is rapid access to bloodstream, hence rapid action and can be stopped if necessary
  • Disadvantages: possible pain, need for sterility, and need to put drug into an injectable form-thus injectables usually cost more than other drug forms
  • Also possible contamination if non sterile needles used!
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5
Q

Powder Injections:painless!

A

Hand held, pressed against skin
A jet of He gas accelerates fine particles of tiny amounts (1-2 mg) of vaccine into outer skin layer (epidermis)
Small quantities present a serious limitation

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6
Q

Body orifices

A

Eye, ear, nose drops
Sublingual tablets
Rectal suppositories: aspirin for severely nauseated
Buccal cavity (between teeth and cheek): tobacco (baseball players!): Andean porters (coca leaves); nitroglycerine(for angina pain)

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7
Q

Skin applications of Drugs

A

Petroleum based creams (Topical antibiotics) : polysporin
Oil in water emulsions
Some aerosol sprays (topical pain relief)

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8
Q

Transdermal skin patches

A

New trend!: slow absorption into bloodstream from a patch placed in a convenient area of the body
Scopalamine (vs. motion sickness) : Transderm SCOP-ideally suited since a large dose all at once is toxic
OrthoEvras (contraceptive skin patch)
Nicotine patches for nicotine withdrawal
Best for potent drugs, which are taken for long periods
Drug must have significant solubility in both oil and water to pass thro the semipermeable membrane in the patch and the skin

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9
Q

Where can contraceptives be worn?

A
  • abdomen
  • upper outer arm
  • upper torso
  • buttocks
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10
Q

Implantable Drug Delivery

A

Pellets, reservoirs or pumps can be used
Applications to insulin, morphine,antibiotics, contraceptives are now common
Subcutaneous contraceptive implants: slow release

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11
Q

Microsponges:imp for cosmetics

A

Available OTC acne medication: benzoyl peroxide microsponge

High porosity of sponge permits large surface area to be filled with drug

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12
Q

Tablet treatments

A

Some foil wrapped to keep out moisture
Almost all contain binders to hold the active ingredient together:gelatine to aid swallowing
Sometimes enterically coated to dissolve in the small intestine rather than the stomach
Aspirin most common:stomach bleeding side effect

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13
Q

Aspirin

A

often enterically coated

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14
Q

Bayer Advanced Aspirin (2011)

A

Smaller particle sizes by a factor of ~10 make it faster acting for pain relief since it dissolves 6x faster than previous formulation
New formulation has been patented
Patients claim that pain relief starts in ~ 16 minutes vs 100 minutes with previous type
Increased surface area (smaller particle size) increases rates of chemical processes (such as dissolution) and reactions

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15
Q

Time release pills

A

May contain different spherical particle sizes
Higher surface area (smaller particles) react faster
Polymer based coverings with different solubilities can be used

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16
Q

Liquid medications

A

Cough syrups:dosages (volumes important to know!)
Sometimes aqueous solutions (shelf life decreases, may need to refrigerate)
Heat, light and oxygen (air) can cause degradation

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17
Q

How Drugs get to their target

A

Process by which drugs: (i) enter the body

(ii) move through it (iii) interact with their target and finally (iv) undergo elimination is called Pharmacokinetics.

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18
Q

Pharmacokinetics

A

Study of rates of change of drug concentrations in the body

Factors involved are rates of (i) absorption (ii) distribution (iii) metabolism and (iv) excretion

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19
Q

(i) Absorption

A

Starts in the “unloading area called the capillary bed
Rich network of tiny blood vessels in lung, stomach, intestinal walls etc
Drugs can enter or leave the bloodstream via the capillary bed.

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20
Q

(ii) Distribution: after absorption…delivery to target

A

To other body fluids, cells, tissues or specific molecular targets in fluids

Some target fluids: 1. intracellular 2. extracellular 3. CSF: cerebrospinal fluid 4.placental blood supply 5. intraocular fluid
6. synovial fluid: inside bony joints 7. urine

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21
Q

Body Tissue targets

A

Muscle
Fat (normally ~20% of body mass):varies greatly!!-see BMI scale
Bone
Body organs: liver, heart, brain, kidney..

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22
Q

Body Mass Index (BMI)

A

Weight in kg/height in m2.
So..for 100 kg mass at 2 m height (a big guy)

BMI=100/4 =25

Healthy range is 20-26

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23
Q

Molecular targets within fluids

A

Some drugs are targeted to albumins and other blood proteins (perhaps heme proteins such as myoglobin and hemoglobin)
The future!

24
Q

Barriers to absorption

A

The blood-brain barrier
As a general rule, fat soluble drugs penetrate this more easily than water soluble materials
Transport across the barrier is a complex biochemical process (beyond the scope of Chem 1004)

25
Q

Drugs that easily penetrate B-B barrier

A

Tranquilizers, barbiturates, LSD, narcotics (opioids), marijuana
Alcohol:instantaneous absorption into the stomach lining & rapidly metabolized (oxidized) in the liver using alcohol dehydrogenase enzyme (Liska p241)
Oxidation products of alcohol cause a “dysfunction” of the BB barrier-can increase effects of other drugs:DANGER

26
Q

Glucose (blood sugar) gets to the brain!

A

Glucose (C6H12O6) is highly water soluble
Gets to the brain by “mediated transport”
Carrier molecules and channel forming chemicals shepherd it across the B-B barrier
Recall..glucose is the most abundant organic compound on earth!

27
Q

Distribution:Fat soluble drugs

A

Non polar molecules (few OH,COOH or charged functional groups)
Remain in the body longer than polar ones such as ethyl alcohol
Thus, THC’s (cannabinoids in MJ) stay in the body for a long time; Half life=24hr
Fat soluble vitamins (all except Band C) are stored in adipose tissue

28
Q

Like dissolves like

A

Water dissolves polar molecules, salts, alcohols, acids

Fat (vegetable oil) or hexanes; Dissolves molecules with few polar groups (Mostly C, H), steroids (cholesterol)

29
Q

The importance of Biological Membranes

A

Membranes hold cells together
All foods and drugs must enter the cell through the membrane
Metabolic products leave thro’ them

30
Q

Effects of cell membranes

A 
Some cell functions occur in or on the membrane
Some enzymes (biological catalysts) are embedded in the cell membrane
Some (but not all) drug receptor sites are in or on the cell membrane
31
Q

Penetration of membranes by Organic Molecules

A

(i) Passive diffusion: most drugs cross membranes by Diffusion from an area of high to low concentration-ie from the GI tract for an orally administered drug to the blood. Highly pH dependent
(ii) Active transport: rare for drugs (only L-Dopa) . But common for dietary sugars and amino acids , due to their highly hydrophilic (water loving) character.
By definition, active transport involves a series of chemical interactions between the transported substance and components of the membrane, which involves use of energy (ie Glucose across the blood brain barrier)

32
Q

Drug Absorption and Transport

A

Most drugs are either weak acids or bases
Un-ionized molecules have greater lipid solubility and thus diffuse across the lipid barrier of the cell membrane easier than the ionized form
In the human GI system, pH increases from stomach on down!
Stomach fluids: pH is 1-3; in small intestine pH is 5-7, in colon pH is ~8
Thus stomach acid has optimal pH for absorption by passive diffusion of weak organic acids such as aspirin

33
Q

Basic molecules (ie amines) with higher pH

A

Get protonated in the stomach by gastric acid, thus not absorbed
In more basic duodenum (upper part of small intestine) more likely to get absorption by passive diffusion
N. B. Alcohol (ethanol), a neutral molecule, has an appropriate partition coefficient to have significant absorption across the stomach wall as well as the intestinal wall!
But..in general, the stomach is poorly designed for efficient absorption of its contents

34
Q

Other factors affecting drug absorption

A

The lumen of the human intestine can contain many materials, including ions.
Calcium ions react with tetracycline antibiotics to form a complex which cannot be absorbed
Thus calcium rich dairy foods inhibit tetracycline absorption

35
Q

Other possible absorption sites

A

Lungs, skin, subcutaneous and intramuscular, and rectal (for unconscious or vomitting patients) when oral is not practical
All governed by the same lipophilicity and partition coefficient requirements as for GI tract absorption

36
Q

The placental barrier

A

Almost all the drugs taken by the mother cross over the placental barrier
BUT, the placenta is an effective barrier to the passage of bacteria, high MW proteins and the anticoagulant drug heparin

37
Q

Transport across placental membrane

A

Transport of drugs and their metabolites from mother to fetus occurs mainly by passive diffusion: thus THC, heroin, cocaine, caffeine are easily transported
shortest time for a drug to equilibrate between maternal blood and fetal tissue is ~40 minutes
Greatest concern is chronic medication
NB . Ethanol readily penetrates the placental barrier!!
Thus, ingestion of even moderate amounts of alcohol increases the risk of fetal alcohol syndrome (FAS)

38
Q

Fetal alcohol Syndrome

A

Major source of mental retardation and some physical abnormalities

39
Q

Mammalian vs. Bacterial Cell Membranes

A

Bacterial Cell membranes are more complex structurally than mammalian ones
Thus, bacteria can survive in mammalian host environments
NB: Antibiotic Drugs act by destroying bacterial cell walls

40
Q

Metabolism of Drugs

A

Most important organ is the liver , but kidneys, Gastrointestinal tract and blood plasma also play a part.
Most drugs are foreign substances to the body and thus can be termed “xenobiotic”
Other xenobiotics could be toxins such as pesticides—accidentally ingested
Human body must be able to break down xenobiotics, so that they can be eliminated

41
Q

CYP enzymes most important

A

Cytochrome P-450 (CYP) enzymes found primarily in the liver
Assume the bulk of the responsibility for breaking down xenobiotics, so that they can be eliminated in urine and feces.
Generally, metabolites of xenobiotics are less active than their precursor and are quickly eliminated from the body

42
Q

Liver Enzymes

A

Enzymes are biological catalysts (increase reaction rates) but are not affected themselves in the reaction
Cytochrome P-450 “mixed function” oxidase is key
Catalyze the metabolism of 1000’s of substances ie alcohol, barbiturates, fatty acids, chlorinated hydrocarbons etc..

43
Q

Initial metabolic effects on drugs

A
  1. Hydrolysis: addition of water may cleave an ester function for example to an alcohol and a carboxylic acid-ie acetylsalicylic acid (ASA)
  2. Chemically linked to an amino acid such as glycine to inactivate it or make it more readily excreted by the kidneys
  3. Oxidation or salt formation to become more soluble in urine
44
Q

Individual differences

A

Cytochrome P-450 levels differ
Thus rapid and slow metabolizers!
Cytochrome P-450 is a high MW protein
Drug or food being acted upon is the “substrate”
Enzyme-substrate interactions are often “lock and key” mechanisms

45
Q

Drug Half life

A

Denoted by t1/2.
Time needed for initial level of the drug in the blood to fall to ½ of this value
Depends on molecular structure
and the individual (to a lesser extent)
Methadone (used to help heroin addicts recover) has 24 hr half life.

46
Q

Getting the dose right

A 
Drugs are tested on animals and then humans during their development
Effective dose  (ED50) is the dose of a drug that causes the desired effect in 50% of all test subjects
Toxic dose (TD50) is the dose of a drug that causes 50% of all test subjects to experience toxic effects
47
Q

Therapeutic Index (TI) of a drug

A

TI is the ratio of TD50 to its ED50.

So…… TI= TD50/ ED50.

Higher values mean higher drug safety

TI is …so important that it is repeated here!!

48
Q

How does one know the “effective dose”?

A

Sometimes can be measured quantitively (ie cholesterol levels in blood) , blood pressure etc (graded response)
Some studies do not yield numerical scientific data
trials of a new sleeping pill (patient either does or does not fall asleep)
Here ED50 would be the concentration at which 50% of subjects fell asleep

49
Q

5 Effects of Age on Drug Metabolism

A
  1. As we age, we dessicate (lose water) and increase fat levels (normally) and lose muscle mass
    Thus.. fat soluble drugs stay in the body longer
  2. level of cytochromeP-450 enzyme decreases. Also alcohol dehydrogenase levels decrease, thus lower tolerance to alcohol
  3. Kidney function diminishes, so drugs remain in system longer
  4. Protein levels in blood decrease, thus ability to form conjugates in metabolic 1st step goes down
  5. There is generally enhanced brain and organ sensitivity to drugs
50
Q

3 types of Drug tolerance

A
  1. Metabolic: liver makes more enzyme to cope with increased dose
  2. cellular-adaptive: receptor sites lose their sensitivity to the drug. Tissues simply get accustomed to the drug and do not respond as much to its presence
  3. Behavioral tolerance: user learns how to handle the drug in a way a non user cannot
51
Q

Drug-Drug Interactions

A

Particularly a problem for seniors who are on several drugs simultaneously

52
Q

2 major types of Drug:Drug interactions

A
  1. Synergism: 2 drugs may act on each other to enhance each other’s effects
    Barbiturates and alcohol: Both CNS depressants: can cause death by respiratory depression
    Also alcohol can increase the potency of tranquillizers, antihistamines and sedatives-leads to drowsiness
53
Q

Avoid if on any medication which satisfies 3 criteria

A

Taken orally

  1. has low bioavailablity
  2. involve metabolism with the enzyme cytochrome P450 3A4
54
Q

Drug:food interactions

A 
Grapefruit juice (or ½ a grapefruit) - very common culprit
Also other citrus fruits such as Seville oranges (in marmalade) , limes and pomelos can affect bloodstream concentrations of drugs
These citrus fruits contain compounds called “furanocoumarins” that irreversibly block the active site of the cytochrome P45o enzyme
Avoid grapefruit, pomelos, limes, Seville Oranges  if taking any oral prescription  medication
55
Q

Overdose hazards

A

These fruits can cause much higher blood concentrations of the drug, than if the medication was taken with water
“taking 1 tablet with a glass of grapefruit juice is like taking 20 tablets with a glass of water” D
Research by David Bailey, clinical pharmacologist at Lawson Health Research Institute (London ON) 2012 paper

56
Q

What about timing?

A

Interactions can occur even if grapefruit is consumed many hours before taking the drug
Grapefruit for breakfast can still affect the efficacy of a drug take after the evening meal

57
Q

Finally : Excretion of Drugs

A

Via urine, feces, breath, perspiration, saliva

Or if ill in vomit

But…for nursing mothers….drugs such as nicotine, laxatives, aspirin, have been found in breast milk!…so minimize the use of any drug during lactation

Chem 1004 (15 decks)

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