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MEP2 Pharmacology Midterm > Lecture 2 - Sept 16 > Flashcards

Lecture 2 - Sept 16 Flashcards

1
Q

Pharmacodynamics

A

-biological effect of drugs on the body
-drugs only modify underlying biochemical and physiological processes (they do not create new effects)
-most drugs act on more than 1 type of cell/receptor which can lead to multiple effects in body (ex nicotine acts on CNS, blood vese;s and bowel)
-some drugs can act specifically (ex penicillin)

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2
Q

Drugs work via..

A
  1. receptors or on cell membranes (ex oxytocin)
  2. enzymes within cells or ECF (ex NSAIDs)
  3. non-specific actions (ex. antacids)
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3
Q
  1. drugs work on receptors or on cell membranes
A

Drug + receptor ←> drug-receptor complex → biological response
-lock and key only correctly size key fits in hole to unlock

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4
Q

Second messengers

A

-why do we need them?
-main reason = ligand cannot penetrate the cell, because cell membrane is a lipid-bilayer and most drugs are water soluble, also the signal from the receptor on the surface of the cell needs to be translated inside
-amplification - only a few 1st messengers are needed to make many second messengers until the ligand attaches
-integration of information - second messengers can help coordinate pathways
-fine tuning of responses: calls can fine tune their repsonse by regulating synthesis and degradation of 2nd messengers
-multiple downstream targets: 2nd messengers can have an impact o multiple factors within a cell (expands scope of signal transmission)

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5
Q

families of receptors slide 9

A
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6
Q

Ligand gated ion channels

A

ligands DONT lead to the manufacture of 2nd messengers
-binding of ligand opens a membrane-bound ion channel to allow specific ion to travel down concentration gradient
-response is VERY fast milliseconds

-ex - lagnad gated Na+ channels
-nicotinic acetylcholine repceotn found at neuromuscular junctions and autonomic ganglia in cns
-binding of ACh causes NA+ to enter through channel and cell interior becomes more positive and voltage decreases

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7
Q

Nuclear Receptors

A

-ligand crosses cell membrane, activates intracellular receptor causing gene transcription and trasltaion
-lasts hours-days

-ex. thyroid hormone receptors
-thyroid hormones are lipopilic and very small so can penetrate cell membrane

-ex. steroid hormone receptors
-steroids are lipophilic and do not need cell surface receptor –> penetrate cell directly and interact with hormone response elements on DNA

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8
Q

G protein coupled receptors

A

-g proteins are large proteins embedded in cell membranes
-intermediary between many repos and their effects
-can activate or inhibit production of 2nd messengers
-responses last several seconds to minute

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9
Q

Some g protein subgroups

A

Gs - stimulates adenylate cyclase
-Gi – inhibits adenylate cyclase
-Gq - stimulates phospholipase c

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10
Q

Mode of Action of G Proteins

A

-ligand binds to receptor → G protein stimulate the effector
-effector = small molecule that selectively binds to a protein and regulates its biological activity - acts as a ligand that can increase (activate) or decrease (inhibit) enzyme activity, cell signalling, gene expression
-the effects can be:
1. Ion channels: binding of ligand to its receptor activates G protein –> g protein opens ion channel (no 2nd messenger made)
2. adeylate cyclase: males cAMP from ATP cAMP is 2nd messenger)
3.phospholipase C (PLC): cleaves PIP to yield IP3 and DAG (IP3 and DAG and the 2nd messengers)

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11
Q

G Protein linked ion channels

A

-ion channels: binding of a ligand to its receptor activates G protein
-g protein opens ion channel
-no second messenger made
-ion produces the effect (usually hyperpolarization of cell)

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12
Q

slide 14

A
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13
Q

G protein coupled receptors (adyenylate cyclase)

A

-adenylate cylase converts ATP to cAMP

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14
Q

2nd messenger cAMP

A

-receptor is extracellular
1. Drug binds to receptor
2. Receptor becomes activates and binds to g protein
3. G protein becomes activated and then activates adenylate cyclase
4. Adenylate cyclase converts ATP to cAMP (the 2nd messenger)
5. cAMP activates a prtoein kinase which then tirggers a cellular response

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15
Q

Gs and Gi

A

Gs activates adenylate cyclase: increases [cAMP] –> activates a response

Gi inhibits adenylate cyclase: decreases [cAMP] –> inhibits a response

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16
Q

Drug that Activates Gs

A

-salbutamol (ventolin) bronchodilator used to treat asthma:
-binds to beta 2 adrenoceptor activating G2 (activates adenylate cyclase)
-increase [cAMP] sequesters CA2+ intp sarcoplasmic reticulum
lower [Ca+2] –> relaxation of bronchial smooth muscle

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17
Q

what happens in salbutamol is given to a pregnant person

A

-salbutamol works on Beta 2 adrenoreceptors
-uterus has beta 2 andrenoreceptors
-therefore would prevent contractions or lessen in pregnancy

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18
Q

slide 18

A
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19
Q

Drug That Activates Gi

A

-misoprostol (Cytotec) causes uterine contractions
-commonly used as an abortifacient and for treatment of postpartum haemorrhage

-bids to EP1 and EP3 receptors un uterus
-EP3 binds to Gi
-Gi inhibits adenylate cyclase –> decreases [cAMP]
-leaves Ca2+ in cytoplasm available for muscle contractions
-see figure 4-3 and video link?

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20
Q

g protein coupled receptors 2 main targets

A

1.adenylate cylase converts ATP to cAMP
2. phospholipase C (PLC): produces IP3 (2nd messenger)

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21
Q

g protein coupled receptos (phospholipase c PLC)

A

phospholipase C (PLC): produces IP3 (2nd messenger)

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22
Q

Second Messenger - IP3

A

-receptor is extracellular
1. Drug binds to receptor
2. Receptor becomes activated and binds to a g protein (Gq)
3. Gq protein becomes activated and then activates phospholipase C
4. Phospholipase c cleaves the phospholipids in membrane releasing IP3 (the 2nd messenger)
5. IP3 binds to calcium channels on the ER and opens channels
6. calcium enters the cytosol and causes a response in target cell

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23
Q

Drugs that activate Gq

A

-oxytocin causes uterine contractions
(binds to oxytocin receptor, Gq activated PLC, makes IP3, opens Ca2+ channels on the sarcoplasmic reticulum → stimulate contractions), half life of 3.5 min (via IV)

-carbetocin (DURATOCIN): analogue of oxytocin and agonized oxytcoin receptors
-used to control bleeding after birth, often post cesarean
-long half life of 85-100min

-ergonovine
-binds to a1 adrenroreceptirs coupled to Gq protein
-causes contraction of the uterus (used to treat postpartum haemorrhage)
-causes contraction of blood vessels (huge increases in blood pressure may result)
-never give ergonovine for hypertension

-misoprostol
-binds to EP1 receptors on uterus
-EP1 binds to Gq
-Gq activates PLC → increases IP3
-IP3 opens calcium channels in ER
-leading to contractions
-misoprostol, binds to EP1 and EP3 receptors, so it activate Gi and inhibits cAMP, and stimulates Gq and affects calcium channels at the same time

-if oxytocin does not treat PPH then you can use a drug that works by a different pathway

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24
Q

review muscle contractions from 1st year anatomy

A
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25
Q

Regulation of Receptors

A

-receptors not only initiate regulation of physiological and biochemical function but are themselves subject of many regulatory control
-protect cell from excessive stimulation
-controls include regulation of synthesis and degradation of the receptors by multiple mechanisms:
-desensitisation
-down regulation

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26
Q

receptor desensitization

A

-repeated use of a drug can turn off the receptor (ex IP3 pathways, too much calcium kills the cell) and receptor becomes desensitized

-desensitization = alteration of receptro making it unable to send signal

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27
Q

receptor downregulation

A

-number of receptors in cell surface can change in response to presence of drug
-receptors are either:
-recycled (restores sensitivity)
-degraded → need new receptor synthesis

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28
Q

slide 33-34?

A

-prostaglandins are important proinflammatory mediators
-tissue damage = COX enzymes convert arachidonic acid into prostaglandins
-prostaglandins help make protect mucus lining enteric system, help with platelet aggregation
-we don’t have any drugs that block only COX 2 enzymes
-look up cox enzymes and consecutively expressed (always turned on)
**2 charts in slides

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29
Q

Non specific action drugs

A

-these drugs work as a result of their physicochemical properties rather a specific shape of molecule

-ex. antacids like dosium bicarobante or aluminum hydroxide neutralzie gastic secretions without acting on cells of the body

-saline solutions to add fluid

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30
Q

slide 37 nervous system chart

A
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31
Q

Somatic Nervous System

A

-voluntary control
-one nerve between the CNS and the effector (striated muscle)
-no ganglia (collection of nerve bundles)
-1 neurotransmitter, acetylcholine, interact with nicotine receptor
-the receptors on striated (voluntary muscles) are nicotinic cholinergic receptors

-examples of drugs that interfere with the somatic motor system:
-neuromuscular blocking agents are drugs that block acetylcholine between motor nerve and nicotinic receptors on skeletal muscle (used in surgery to facilitate tracheal intubation and complete muscle relaxation)
-vecuronium/norcuron: stops cntractions of striate musle, used in NICU for controlled ventilation, competitive antagonsit to nicotinc reeptors, effects can be reversed with anticholinesterase

32
Q

autonomic nervous system

A

-maintains homeostasis in body
-works autonomously/autmoatic

-2 divisions
Sympathetic (fight/flight)
Parasympathetic (SLUDD)

-the autonomic motor nerve is under involuntary control
-2 nerves between CNS and effector
First neuron: preganglionic neuron, myelinated
-acetylcholine released in ganglion and interacts with nicotine receptors
2nd neuron: postganglionic neuron, unmyelinated
-acetylcholine released and interacts with muscarinic receptor OR norpeinephrine released and interacts with adrenergic receptor

33
Q

Sympathetic Functions

A

-responds to stressful situations (trauma, fear, hypoglycemia, cold and exercise)
-stimulation of SNS causes;
-increase heart rate, increase blood pressure, increased blood flow to muscles and heart, dilation of pupils and bornchioles, decreases GI motiltiy

-fight/flight mode triggered by sympathic stimulation and epinpehrine (from adrenal medulla) - epinephine enters bloodstream and stimulatees organs with adreneric recptos

34
Q

Parasympathetic Functions

A

-maintaining homeostasis in the body and essential bodily functions
-usually acts to oppose or balance sympathetic division
-dominates most of the time in rest/digest mode
-eye: contraction of iris sphincter and cilairy msucle for near vision
-trachea and bronchilels constricted and increased secretions
-heart rate decrease and contractiltiy
increased motility of GI tract

35
Q

Innervation of Organs by ANS

A

-most organs are innervated by both divisions of ANS

-heart:
sympathetic input increases heart rate (tachycardia)
parasymapthic decreases heart for rest

organs such as adrenal medulla, kiney, sweat glands and visceral blood vessels only receive sympathetic innervation

36
Q

Receptors in ANS

A

-2 types of receptors
Cholinergic: in sympahtic and parasympathetic ganglia, and postganglionic parasympathtic organs
Adrenergic recpetors only in postgnglioninc sympathtic organs

37
Q

slide 47

A
38
Q

Cholinergic Receptors

A

-2 types of cholinergic receptors

nicotinic and muscarinic
muscarinic mostly parasymp

-m1,m3 = gq
-m2 = gi
-g protein coupled receptors: M1, M2, M3
-M2 bound to Gi - inhibits adenylate cyclase - decreases heart rate
-short time of activation becasue ACh is rapidly broken down by acetylcholinesterase

39
Q

Cholinergic Drugs

A

-agonists mimic ACh effects
-ex bethanechol stimulates urination, used post-operatively for urine retention

-antagonsits:
atropine used to treat IBS (decrease GI motility) and during surgery to decrease respiratory secretion

40
Q

Adrenergic Receptors

A

-the postganglionic sympathetic nerve terminals release norepinephrine
-long term activation of neurons (slow breakdown of norepinephrine vs ACH) and widespreead effect on organs leads to long lasting sympatheic effects

41
Q

drugs that stimulate SNS

A

are called sympathomimetic (ex. epinephrine)

42
Q

drugs that inhibit SNS

A

are called sympatholytic (ex. beta blocker like propranolol)

43
Q

alpha and beta recepetors genreally..

A

alpha receptors generally stimulate contractions
beta receptors generally inhibit contractions/relax (except heart contractility)

44
Q

Adeneric Receptor Subtypes

A

a (mostly contraction):
-a1 = causes smooth muscle contraction, mostly in blood vessels of viscera except heart
-a2 = promotes clotting

b(mostly relaxation except in heart muscle)
-b1 = tachycardia and increased contrctility in heart, relaxes heart blood vessles
-b2 = relaxes bronchioles, uterus, and most sympathetic organs
-b3 = increases lipolysis

45
Q

Alpha-1 adrenergic receptors

A

-a1 receptors are found on blood vessels, the uterus and a few other places
-a1 stimulation activates PLC → makes IP3 –> increased [Ca2+]
-constiction in blood vessles (Aka vasoconstrcitor), epinephrine constrcist blood vessels to increase blood pressure
-ergonovine causes contraction of smooth uterine muscle

46
Q

Beta 1 Adrenergic receptors

A

-b1 receptro binding causes activation of adenylate cyclase therfore increased [cAMP] in cell –> activates protein kinases –> phosphorylate proteins that contract cardiac and some other smooth muscles

-b1 receptor agonists increase HR, increase renin and increase fat metabolsim

47
Q

b1 adrenoceptor antagonists

A

-b1 antagonists (b1 blockers or sometimes just beta blockers) decrease the heart rate and this diastole is longer and the heart fills more completely (increases efficienty of heart)

-ex metoprololl is a beta 1 blcoker and used as an antihypetensive

ex labetalol is a nonselective bet blocker for pregnant people with gestational hypertension

48
Q

Beta 2 Adrenoceptors

A

-b2 agonsits stimulate adenylate cyclase and increase [cAMP] –> activation of protein kinases –> phosphorylate proteins that relax smooth muscle

-ex salbutamol is a specifc b2 receptor agonist that relaxes airway smooth msucle for acute asthamtic attack relief

49
Q

Pharmacokinetics

A

-what dose body do to the drug - how it gets in, where it goes, and how it’s excreted

50
Q

Metabolism

A

-the combination of all chemical reaction that maintain body systems
-energy production and storage
-removal of waste products
-substances taken into body undergo a series of chemical reactions (components that can be used are gathered and the rest are eliminated)
-overall goal of physiologic homeostasis
-main site of metabolism is liver (but also kidneyes and gut wall)

51
Q

Drug Clearance

A

-once a drug enters body it is seen as a toxin and needs to be removed (plasma clearance)
-process of elimination had 3 major routes:
1. hepatic metabolism
2. elimination in bile
3. elimination in urine

52
Q

slide 59-60

A
53
Q

Drug Metabolism - the liver

A
  • carried out by enzymes
    -these enzymes are found in the microsomes (fragments of the endoplasmic reticulum) of hepatocytes
    -the liver is the most important organ in drug metabolism
    -liver dysfunction will increase life of many drugs in the body
    -tylenol and alcohol will persist for a long time if hepatic disease because they are completely metabolized by liver

-most is excreted by kidneys, some in bile
-bile excretion for lipophilic materals
-bile exits through common bile duct to duodenum

54
Q

enterohepatic recycling

A

-can occur
-when metabolized dugs are reasborbed from Gi tract
-ex in bilirubin excretion, bilirubin diglucuronide (conjuagted form) has the glucucronide residues removed in the intestines and thus can be reasborbed into blood
-then the portal circulation takes drug back to liver

55
Q

biliary excretion

A

-active transport over passive diffusion
-drug goes from liver-bile-intestines-eliminated in feces

56
Q

slide 68/64 liver anatomy

A
57
Q

Drug metabolism has 2 parts

A

-phase 1 = drugs are oxidized or hydrolyzed
-phase 2 = drugs are conjugated

58
Q

Phase 1 reactions of metabolism

A

-convert parent compound into more polar (charge: hydrophilic) metabolite
-adding or unmasking functional groups (OH< SH< NH2, COOH)
-drugs are oxidzied or hydrolyzed
-these metabolites are often pharmacologically inactive
-may be sufficiently polar (hydrophilic) to be excreted after phase 1

59
Q

phase 1 reactions: oxidation

A

-oxidation = loss of an elecrton/hydrogen, gain of oxygen bonds

Oxidation
Is
Loss

60
Q

phase 1 reactions: hydrolysis

A

-hydrolysis = a chemical reaction in which the addition of a water molecule leads to the breakdown of the molecule
-ex. Ester groups are broken down in this fashion
-enzymes = esterases, procain is broken down this way

61
Q

enzymes involved in phase 1 reactions

A

-the enzymes that carry out phase 1 reactions are called cytochromes (CYPs)
-greatest concentration in liver, also in gut lungs and other tissues
-at least 12 CYPs important for drug metabolism
-biological functions include conversion of testosterone to oestrogen (CYP19 also called aromatase)
-many interact with drugs and food - can lead to drug interactions
-ketoconazole, grapefruit juice binds to and inhibits CYP3A4 → inhibits metabolism of domperidonne and other drugs

62
Q

factors effecting CYPs (in phase 1 reactions)

A

-levels on CYPs can vary betwen people and result in hyper or hyprsensitivty to drugs
-enzyme induction = factors increasing level.activity of CYPs = nutrition, alcojol, drugs, smoking, pregnancy

63
Q

moving to phase 2 (if need)

A

if drug is hydrophilic after phase 1 it can be excreted by kidneys, but if not, then phase 2 required

64
Q

phase 2 reactions

A

-definition: coupling of a drug molecule to one or several molecules to yield greater water solubility

-conjugation with an endogenous substrate to increase solubility
-conjugation with glucuronide, sulfate, acetate, amino acids and other compounds
-carried out by enzymes called transferases
-generally follow phase 1 reactions

65
Q

slide 79/75

A
66
Q

most metabolic products are usually less pharmacologically active

A

however exceptions are:
carcinogenic:
1. benzene gets metabolized by liver, ring opens, causes leukemia
2.alfatoxin: fungal contaminated peanutsm metabolized by liver, causes tumors

toxic metabolites
1. acetaminophen metabolite is toxic but at low doses it is detoxified by conjugation, but at high doses of acetaminophen toxic metabolite cannot be cojjuagted and remains toxic
-alcohol increases enzyme that breaks down acetaminpohen
-alcohol and acetompinpohen shoudlnt be mxied

67
Q

prodrugs (metabolism)

A

-prodrug is a drug given in inactive form that is later metabolized into an active compound (bioactivation)
-designed with metabolism in mind - can get drugs accross normally impermeable membrans and avoid 1st pass metabolism

  1. nitrofurantoin: antibiotic for uti, bacterial prodrug
  2. erythromycin: easuly destriyed by GI acidity but add an ester and it increases lipid solubiluty for better absoprtion, ester needs to by hydrolyzed for antibacterial activity
68
Q

codeine as a prodrug

A

CYP2D6 (liver enzyme) carries out the conversion (a methyl group is snipped off of the oxygen of the codeine)
-some people carry a genetic variation for CYP2D6 that cause the enzyme to carry out this reaction to a greater extent - there people are called ultra-rapid metabolizers
-if you are an ultra-rapid metabolizer of codeine, much more, possibly toxic amounts will sow in your blood and milk

69
Q

valacyclovir as a prodrug

A

-valacyclovir/valtrex is a potent antivrial (for hsv 1 and 2)
-valacyclovir is converted to the active antiviral acyclovir/zovirax by removal of an ester group
-this de-esterification in the gut wall and liver is importent because valacyclovir is 5x more orally available then acyclovir

70
Q

Drug Elimination - The Kidney facts

A

-most important organ in elimination of drugs and drug metabolites
-any decrease in kindey finction will vastly increase the life of many drugs in the body
-the neworn kidney only filter 4-6% of cardiac output vs 25% in adults (adult level reach at 6 months of age)
-drus that rely on renal filtration will have extended t1/2 in newborns (half life)

71
Q

anuria

A

-less/absence of urine produced by kidneys (less than 100mL a day)
-anuria will increase drugs life by 25%
-in anuria drug gentamycin goes from 2h to 35-50h

72
Q

drug’s half life in pregnancy (increased gfr)

A

-glomerular filtration rate is kidneys filtering blod to remove water, salts, substances to produce urine

therefore increased drug clearnace, shortened half life, sometimes dose adjusmtents can be increased

73
Q
  1. glomerular filtration (kidneys removal of drug)
A

slide 81

73
Q

kidneys 3 ways of interacting with drugs

A
  1. glomerular filtration
  2. tubular secretion
  3. tubular reabsorption
74
Q

2, tubular secretion (kidneys removal of drug)

A

slide 82

75
Q
  1. tubular reabsorption (kidneys removal of drug)
A

slide 83

MEP2 Pharmacology Midterm (12 decks)

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