FUNDAMENTALS 2 10:00-11:00Scribe: ANGI GULLARD

November 29, 2010Proof: KRATIKA PAREEK

Dennis PillionDRUG TARGETS and CLASSESPage1 of 5

  1. Drug Targets and Classes[S1]
  2. Drugs targets and classes and antihistamines. We will cover some ground today that we will see over and over again – the way we treat people with drugs, how we use drugs. How do drugs interact in the body?
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  4. Combine anatomy, physiology, and biochemistry to understand pharmacology.
  5. Hormones, catecholamines are in the bloodstream, looking for receptors on particular organs, some organs have receptors, others don’t.
  6. For example: Imagine a pen being jabbed through your hand. What would happen? What type of receptors would be involved in the response?

i.Eyes: get larger- pupils dilate (mydriasis)

  1. Why? Look for route of escape or ways of defense

ii.Breathing: increases

iii.Heart Rate: increases

iv.Possible screaming

  1. How does all of this happen in a second? There are muscles, nerves, and receptors involved.

i.Using pharmacology, all of these things (receptors) can be blocked with drugs, antagonists of natural drugs (endogenous chemicals) or agonists of the drugs that have the opposite effect.

ii.There are two systems at work inside the human body, the sympathetic and parasympathetic, which oppose each other. These systems are in a balance, which can be altered with certain drugs to accentuate one system or the other.

  1. Agonistic and antagonistic drugs work by having a three-dimensional shape that binds to a receptor site that also has a three-dimensional shape. The fit of the drug to the receptor has to be just right.

i.One analogy is a key going into a door lock. The key has to be the right size and the right shape.

ii.Drugs are the same way. They can bind to a receptor and have no effect or they can bind to a receptor and have an effect.

iii.Another analogy is putting balls (drug) into a golf hole (receptor) – illustrates dose-response, one of the cardinal responses of pharmacology. The more of something you give, the larger response – 1, 10, 60, 1,000 golf balls per minute. There is a maximal response.

  1. If a man takes Viagra, he gets a particular response with 1 pill, how much of a response with 10 or 100 pills? It’s not 10 or 100-fold more, there is a dose-response that occurs.
  2. Do drugs work by interacting with a receptor? Yes
  3. Do drugs work by inhibiting an enzyme? Yes

i.For example, MAOIs – monoamine oxidase inhibitors

  1. Do drugs work by changing ion flow through an ion channel? Yes

i.Example: Proton pump inhibitors – taken for acid reflux

ii.Example: Pain medications – give someone a lot of alcohol, interfere with sodium or chloride channels

  1. Identify the Targets[S3]

6 examples of classes of drugs

1) Beta blockers– lower heart rate, were used for glaucoma therapy

i.Target: beta adrenergic receptors; Normal agonist: adrenaline/epinephrine

ii.Beta 1 receptors in heart

iii.Beta 2 receptors in lung

iv.Can give drugs to target beta1 over beta2 receptors (or vice versa) –look at differences in receptor binding chemistry and make drug molecule that can differentiate between binding to receptors; new drug is chemical cousin of normal chemical but has specificity for what it binds to

2) Antihistamine– bind histamine receptors

i. H1 and H2 receptors – nasal decongestion drugs bind H1 r eceptors

3) ACE inhibitors – block angiotensin converting enzyme (ACE) , which converts angiotensin I to II, converts precursor from inactive to active molecule; inhibitor blocks the enzyme

4) Statins – Atorvastatin; treat high cholesterol; block cholesterol synthesis, block HMG-CoA reductase – make less cholesterol

5) Loop diuresis – loop of Henle – causes diuresis by binding to and blocking ion channels that reabsorb sodium, so if block sodium reabsorption, more sodium causes more urine production

i. Someone with hypertension gets loop diuretics to increase urine output and thereby lower blood pressure; drug target is kidney ion channel

6) Local anesthetics – Lidocaine blocks sodium channels in nerves that form nocireceptors – prevent pain

  1. Concepts for you to learn [S4]
  2. Structure and function of drugs: polarity, charge, size
  3. Dose-response, toxicity – too much of anything can be harmful (Example: Viagra – too much causes dangerous drop in blood pressure)
  4. Therapeutic level of drug - how much is needed for a therapeutic action? Toxic reaction? How do avoid toxicity?
  5. Absorption, Distribution, Metabolism Elimination (ADME) – principal concept of pharmacology

i.If you take 2 aspirin, you can track how much is in the bloodstream, how much relief you get in treating pain or fever – can do dose-response relationship to determine how many aspirin to get complete relief

  1. Potency and efficacy – will be tested on the difference between these!
  1. Structure/Function Relationship [S5]
  2. It’s all about three-dimensional shapes, like key and lock analogy; drugs can be modified
  1. DOSE-RESPONSE [S6]
  2. As the drug concentration increases, the number of receptors occupied by the drug increases, and the response to the drug increases.
  3. At very high drug concentrations, the response to the drug reaches a maximum.
  4. At the highest response, you have max efficacy of the drug

i.Efficacy is the max response, how much of an effect you see

ii.Potency is how much you use to get a particular effect

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  2. Graph on left: dose response curve with an arithmetic x-axis
  3. Graph on right: dose response curve with log scale on x-axis

i.Take more drug A, get more of a response

ii.At 50%, you get the maximal response, which is called the EC50, effective concentration 50

i.We have determined an EC50 for each drug, can compare the EC50 of different drugs

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  2. Two drugs with equal efficacy produce the same maximal response, but they may have different potency
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  2. In this graph, we are looking atheadache relief when comparing 4 drugs – look at log of drug that is used

A. Ibuprofen

B.Diphenhydramine

C.Aspirin

D.Acetaminophen

  1. Get maximal relief (efficacy) with drugs A, C, and D have max efficacy, but not with B (Diphenhydramine or Benadryl), so Benadryl won’t give complete relief

i.With drug D (Acetaminophen), you get relief but you need more of the drug to get the desired effect

ii.3 of 4 drugs have equal efficacy, but unequal potency

  1. Potency is how much of the drug is needed to get the half-max effect

i.Drug A concentration that gives half-max effect is different from the concentration of Drug B, C, or D

ii.Each drug has a different EC50

  1. UNDERSTAND FOR THE EXAM!

i.D has the highest EC50, so it is least potent – it takes more of the drug to get a half-maximal effect

ii.B is the least efficacious, not the least potent

  1. Headache Relief [S10]
  1. Which drug(s) is/are the most efficacious?[S11]
  2. 4. A,C,D
  1. Which drug(s) is/are the most potent? [S12]
  2. 2. B (Diphenhydramine) – the lowest amount of drug gives a half-max effect, so it has the has lowest EC50; a lower EC50 means the drug is more potent
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  2. Full agonist - drug that gives the maximal response at high enough concentration
  3. Partial agonist - gives less than maximal response, a partial effect

i.Diphenhydramine was a partial agonist; Acetominophen, Aspirin, Ibuprofen – full agonists

ii.Why would a partial agonist be useful? For a beta adrenergic receptor, a partial agonist is good because it does not increase the heart rate too much

i.Tumors that secrete pulses of high levels of adrenaline – cause tachycardia, seizures; give partial agonist to occupy receptors that is only partially agonistic, but system cannot be turned on any higher, so it is a protective mechanism

  1. Antagonists [S14]
  2. Antagonists are drugs that bind to receptors and block activity of normal agonist or prevent agonist from having its action

i.Can be competitive or noncompetitive (like enzyme kinetics and inhibitors)

  1. Competitive antagonist reversibly binds to the active site, can be overcome when ligand concentration is raised

i.There is a right and a wrong key trying to lock the door - for the competitive antagonist, there is a mass action phenomenon, so more antagonist causes blocking while more agonist allows for normal function, the curve for this system has a characteristic shape (more agonist overcomes the effect of the antagonist)

  1. Noncompetitive antagonist binds to a different site; it is like a deadbolt on the door; a working key in the lock would not change the effect

i.It prevents the receptor from responding at all; its effect cannot be overcome by adding more agonist

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  2. Cartoon shows membrane, phospholipid bilayer, with an ion channel and an agonist-binding site.
  3. This might be a GABA receptor , which is a chloride ionophorethat has a binding site for GABA, alcohol, barbiturates, and benzodiazepines – drugs can be used to put someone to sleep

i.There are binding sites for natural agonist and for allosteric antagonist

ii.Agonist would be GABA, binds, opens chloride channel, allows chloride to enter the cell and depolarizes it, so nerve cell doesn’t fire

iii.Competitive antagonist could compete with GABA for the binding site; cell won’t open and chloride won’t enter cell

iv.Non-competitive antagonist binds at downstream or other non-agonist-binding site. Agonist can bind but nothing happens; chloride channel will not open

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  2. Dose-response curves: In the upper graph, the competitive antagonistis the black line versus agonist alone (blue); add competitive antagonist – get different response

i.If you add more and more of the agonist, can overcome the antagonistic effect and get a complete response – mass action phenomenon

  1. In the lower graph, with a noncompetitive antagonist (black line), you cannot overcome the effect in order to get anormal response (blue line)

i.If add enough noncompetitive antagonist, you would get a flat line

ii.You can get a response but you cannot overcome the antagonisticeffect

  1. If we see these curves on the exam or boards, we need to be able to distinguish competitive and noncompetitive antagonists!!!
  1. Table – Summary of Agonist and Antagonist Action [S17]
  2. Fun facts for home reading: We won’t see an inverse agonist much anymore – it stimulates the opposite effect of the agonist’s effect
  3. Antagonist classes: competitive, noncompetitive, and allosteric noncompetitive
  4. The noncompetitiveantagonist active site is chemically modified to look like the agonist, bind to the receptor, and covalently attach to receptor and never let go – this type of compound would be very unstable and is not used much, occasionally listed though
  5. Competitive antagonists and noncompetitive allosteric antagonists are more common
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  2. Therapeutic index: effective dose ED50 is like EC50
  3. TD50 – concentration that gives toxic response in 50% of people treated
  4. LD50 is the dose that gives a lethal response – this data is not collected much
  5. The TD50 data is collected for drugs and it can be different things for the same drug
  6. The toxic effect is what you want to consider

i.For example, aspirin can causes ringing inthe ears, higher doses - GI bleeding, and coma

ii.The TD50 of aspirin depends on which toxic effect you talk about–ringing in ears, GI bleed, or coma

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  2. This graph shows what happens when a drug is given to animals
  3. The graph has a log scale on the x-axis, with 4 and a half log doses, so let’s say there is a 10,000 fold difference in concentration of drug
  4. For particular therapeutic effect, ED50 of say 3mg gives a certain amount of therapeutic, toxic, and lethal effect

i.When you give 3 mg, you reach the ED50

ii.At 30mg, you reach the TD50

iii.At 3,000mg of the drug, you reach the LD50

  1. Drugs with an ED50 and TD50 close to each other (as in this graph) are dangerous and need to be monitored carefully, especially anti-clotting drugs such as warfarin

i.If you have a heart attack or hip implant, you need to prevent a thrombotic event from happening, so you prescribe warfarin – the ED50 and TD50 would be right next to each other (terribly dangerous but life-saving drug)

ii.These drugs are used a lot but you have to be very careful how much is given

i.Even the type of food the patient eats can cause a toxic situation to occur

  1. Examples of receptors that are drug targets [S20]
  2. Histamine 1 and 2 receptors
  3. Adrenergic receptors – we will need to know the distribution of receptors

i.Beta 1

ii.Beta 2

iii.Alpha1 –on vascular tissue, smooth muscle cells

iv.Alpha 2 – on presynaptic membrane where norepinephrine is released; helps bind and autoregulate norepinephrine by reuptake – this system is commonly intervened by drugs (heart rate and blood pressure)

  1. Cholinergic – there are muscarinic and nicotinic receptors; Acetylcholine receptors
  2. GABA-ergic receptors have lots of binding sites; targeted for pain, use anesthesia to block them

i.These drugs resemble shape of natural ligands

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  2. Drugs affect the signaling pathways that occur afterdrug binds to the receptor

i.Beta-adrenergic receptor: after binding of epinephrine/norepinephrine binds beta1 receptor in heart, what happens? Adenylate cyclase activity goes up  cAMP goes up phosphorylation cascades, protein kinase A, controls other enzymes in cellfor glycolysis, ATP production, phosphodiesterase (breaks down cAMP, like caffeine’s action)

  1. Protein Binding [S22]
  2. Drugs that are more lipid-soluble are better able to cross cell membranes and are better able to enter the brain
  3. More lipid-soluble drugs are uncharged and get into CNS:

i.Atropine methylsulfate will not gain access to the brain and therefore, have no effect on CNS

ii.Atropine will cross the membrane to enter brain and have a CNS effect

iii.One needs to think of uncharged drugs to give for headaches, dizziness, nausea

iv.A charged drug is intentionally made to keep it out of the brain

  1. The larger a drug, the less likely it will enter brain, so size and charge matters
  2. Drugs that get into bloodstream are bound to carrier proteins and have longer half-lives – Need to know and understand this!!
  3. If a drug that goes in the mouth, goes to stomach, intestine gets absorbed into the bloodstream, will it be soluble in water in bloodstream?

i.No – charged drugs goes into solution readily; polar compounds or drugs (sugar) are water-soluble; if drug is uncharged, it won’t be dissolved

i.Uncharged drugs have a problem in the bloodstream; they do not get absorbed in bloodstream, so they bind to albumin in the blood

ii.Proteins have amino acids with some positive, negative and neutral R groups; the protein folds so that opposite charges avoid each other and the protein becomes more structured

iii.In the shape, a nonpolar or lipid-soluble drug can bind to albumin in order to avoid water around them

  1. When the drugs reach the kidney, they get filtered and excreted in urine, but if the drug is bound to albumin, it won’t get filtered and excreted, so the concentration and half-life of the drug is extended – this makes a big difference, such as in taking a daily birth control pill – would take a pill every hour if it was excreted very readily

i.Question: Does this mean the potency is higher? Potency is a stand-alone term, not to be applied here; the situation explained refers to the concentration of the drug in the bloodstream and how long the drug will be there

ii.More lipid-soluble drugs are metabolized by the liver to a form that is more water-soluble

  1. For two 50-year old men (one is an alcoholic) if you prescribe a drug, keep in mind that the alcoholic will have compromised liver function and not metabolize the drug as quickly, so the drug would stay in the bloodstream longer, attached to albumin, would have more of an effect that would accumulate if you give the normal dosing regimen - so you need to give him a less concentrated drug, otherwise he would develop a toxic level of the drug because it would not be processed and excreted as rapidly as in a non-alcoholic

i.Need to understand drug removal from the system

  1. Signal Transduction [S23]
  2. We won’t finish antihistamines – slides should be self-explanatory; the drugs we need to know are on the slides
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  2. There are a number of different signal transduction pathways for different drugs
  3. Left: 1) G-protein coupled receptor family (GPCR) also involves scaffolding proteins and effectors
  4. There are 5 families to think about
  5. 2) Receptors can have enzyme activity, such as the insulin receptor, growth hormone receptor, and drugs interacting in thecAMP/cGMP pathway

i.3) Intracellular level of calcium: muscle cells sequester calcium in sarcoplasmic vesicles that release calcium when stimulated  allows for muscle contraction, some drugs interact with this system

ii.Sarcoplasmic vesicles store calcium that is released in muscle contraction

  1. 4) Ion channels – some cholinergic drugs interact with ion channels

i.Serotonin – treat depression with selective serotonin reuptake inhibitors – interact with ion channels

  1. 5) Estrogens, androgens, and adrenocorticosteroids - interact with receptors that are in the cytoplasm or nucleus of the cell, so it takes more time for drug to have an effect because protein synthesis is the response

i.Response may take hours or sometimes weeks or months for full effect

[End 48:01 mins]