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Pharmacology 3 > Week 4 > Flashcards

Week 4 Flashcards

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1
Q

There are many different routes of administration (RoA) of drugs, but they can be split into two classes. What are they?

A
  • Enteral: Involves the GI tract (most common but least predictable
  • Parenteral: Independent of the GI tract
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2
Q

Enteral administration consists primarily of oral administration. What are some pros and cons of oral administration?

A

Pros:
- Convenient
- Prolonged absorption along the whole length of the GI tract
- Cheap

Cons:
- Irritation of the gut
- Destruction of drugs by gastric acid
- Interaction with food
- Sometimes inefficient
- FIRST PASS EFFECT

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3
Q

What is the First Pass Effect? What is its relationship to drug bioavailability?

A
  • The first pass effect is the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation
  • The greater the first pass effect, the less a drug will reach systematic circulation (i.e., there is an inverse correlation between the FPE and bioavailability)
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4
Q

The magnitude of the first pass hepatic effect can be calculated using an equation, what is it?

A

ER = Cl / Hepatic Blood Flow

ER = Extraction ratio
Cl = Hepatic clearance

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5
Q

Give some estimated drug delivery times of different RoAs

A
  • Intravenous: 30-60 seconds
  • Inhalation: 2-3 mins
  • Sublingual: 3-5 mins
  • Intramuscular: 10-20 mins
  • Subcutaneous: 15-30 mins
  • Rectal: 5-30 mins
  • Oral: 30-90 mins
  • Transdermal (topical): variable (mins-hours)
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6
Q

What are some factors that influence the rate of absorption?

A
  • Routes of administration
  • Dosage forms
  • Concentration of the drug
  • Physiochemical properties of the drug
  • Protein binding
  • Types of transport
  • Circulation at the site of absorption
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7
Q

What are some barriers to absorption of drugs in humans?

A
  • Mucous layers
  • Protein binding
  • Fat isolation
  • Placenta
  • Blood-brain barrier (exceptions: Area postrema, median eminence of hypothalamus)
  • First, and most ubiquitous barrier is the cell membrane
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8
Q

The relative solubility of a drug depends on 3 things, what are they? think acidity

A
  • pH of the drug
  • pH of the environment
  • pKa of the drug
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9
Q

What is the equation for pH?

A

pH = -log10[H+]

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10
Q

What actually is pKa?

A

The pH at which 50% of a drug is ionised (ionisation ratio = 1)

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11
Q

What are the effects of ionisation on drug absorption?

A
  • Non-ionised drugs are absorbed better than ionised drugs
  • Drugs that are weak acids become highly ionised as pH increases (more alkaline)
  • Drugs that are weak bases become highly ionised as pH decreases (more acidic)
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12
Q

In terms of absorption, in what medium are the following best absorbed?
a) Acidic drugs
b) Basic drugs

Remember, drugs become concentrated where they are most ionised!

A

a) Acidic solution
b) Basic solution

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13
Q

Where are the primary sites of biotransformation
a) in the body
b) in the cell

A

a)
- Liver
- Kidneys
- Lungs
- Intestine

b)
- Cytosol
- Mitochondria
- Lysosomes
- Smooth ER

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14
Q

There are 3 different consequences of biotransformation. What are they? an give examples where necessary. (hint = activation)

A
  • Inactivation to produce an inactive metabolism
  • Production of an active metabolite from an inactive prodrug
    Example: Tamoxifen —[CYP3A4]—> Endoxifen = active
  • Production of an active metabolite from an active drug
    Example: Codeine —> Morphine
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15
Q

There are 2 phases of biotransformation, Phase I and Phase II. What are they and what sort of reactions constitute these phases?

A

Phase I
- Catabolic
- Oxidation/Reduction, Hydrolysis reactions
- May create sites of phase II reactions (“functionalisation”)

Phase II
- Anabolic
- Conjugation reactions, addition of substituent groups

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16
Q

Phase I reactions include oxidation, reduction and hydrolysis. Where are the sites of each of these, the system that breaks them down and an example of a drug that is metabolised in that specific way?

A

Oxidation:
Site: Liver
System: Cytochrome p450 system
Example drug: Benzodiazepines

Reduction:
Site: Liver
System Cytochrome p450
Example drug: Methadone

Hydrolysis:
Site: Not the liver
System: -
Example: Oxytocin

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17
Q

What is a common example of an oxidation reaction? v common

A

Ethanol –> Acetaldehyde –> Acetate

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18
Q

What is an example of Oxidative deamination?

A

Amphetamine –> Phenylacetone

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19
Q

CYP enzymes metabolise most drugs, with CYP3A4 responsible for metabolism of 60% of this.

As such, modifiers of CYP3A4 activity can have dramatic effects on drug action in the body. What are the 2 types (with examples) of CYP3A4 modifiers?

A

Inhibitors:
- Prolong action of drugs
- Or inhibit action of drugs that need to be bio-transformed into active agents
- Example: Grapefruit juice contains CYP3A4 inhibitors that can prolong the action of drugs such as the antihypertensive felodipine (a Ca2+ channel blocker)

Inducers:
- Shorten the action of drugs
- Or increase effects of those bio-transformed to active agents
- Example: St Johns Wort promotes CYP3A4 activity.

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20
Q

What TCA is hydrolysed by the enzyme CYP2D6?

A

Imipramine

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21
Q

Phase II reactions involve the conjugation of a drug with an endogenous chemical to form an ionised drug that can be readily excreted.

What are the 3 types of Phase II reactions? With examples of a drug that is processed in that way

A
  • Glucuronide conjugation (morphine)
  • Acetylation (sulphonamindes)
  • Methylation (adrenaline, histamine)
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22
Q

Outline the process of glucuronide conjugation

A
  • The microsomal enzyme glucuronyl transferase conducts the donation of glucuronic acid from the endogenously synthesised UDPGA to various substrates
  • Not all phase II reactions are about deactivating drugs!

Example:
Morphine-3-glucuronide = inactive
Morphine-6-glucuronide = active

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23
Q

Phase II metabolism does have its limits. An example of this is Paracetamol (Acetaminophen) overdose. Why does this happen?

Study These Flashcards
A
  • Most of acetominophen (~90%) is metabolised by glucuronidation and sulphation
  • A fraction (<5-10%) is metabolised by CYP2E1 to N-acetyl-p-benzoquinoeimine (NAPQ), a toxic metabolite.
  • Under normal conditions, NAPQI is detoxified through conjugation with glutathione
  • If the above route is saturated/busy, you get toxic effects
24
Q

Phase II metabolism can involve microsomal enzymes and non-microsomal enzymes
What are the features of both?

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A

Microsomal enzymes:
- Catalyse glucuronide conjugation and most oxidation reactions
- Located in the liver
- Lack specificity - requiring only that the drug be lipid soluble
- Inducible by drugs / other substances

Non-microsomal enzymes:
- Catalyse the other types of conjugation reactions and most hydrolysis reactions
- Widely distributed in plasma
- Degrade polar substances
- Not inducible

25
What is the principle organ of excretion of drugs?
The kidney
26
How do changes in urinary pH affect the excretion of drugs?
- Acidic drugs are excreted in basic urine Basic drugs are excreted in acidic urine
27
What is the kinetics of drug elimination when a drug follows a) Zero order kinetics? b) First order kinetics? Give an example of a drug that is excreted in this way.
a) - Constant amount of the drug is eliminated per unit time. - Usually happens when the substrate concentration exceeds the capacity of the enzyme - E.g., Ethanol b) - Rate of removal is proportional to the plasma concentration of the substrate. - A constant fraction of the drug is removed per unit time - Half life is only a thing in drugs that follow first order kinetics
28
The time to reach steady state is a)_________ of the dose rate but b)__________ on the half life in the drug
a) independent b) dependent
29
What is the topology of GPCRs?
- 7 Transmembrane domains - helices of hydropathic amino-acids - Extracellular N-terminal domains - Extracellular loops - some maintained by disulphide bonds - Intracellular loops - g-protein interaction - Intracellular C terminal domain - regulatory phosphorylation sites and g-protein interaction
30
There are 3 main classes of GPCRs. What are they? (Think Alphabet)
- Class A: Rhodopsin-like (276) - Class B: Secretin R-like - 53 - Class C: GABA(b)R / mGluR-like - 19
31
What is the structure of Class A GPCRs? Give some examples of them
Structure: - Short extracellular N-terminal tail, ligand binds between TM helices (amines) or to extracellular loops - Several strongly conserved motifs - Often palmitoylated in proximal C-terminal tail Examples: - Visual pigments - Neurotransmitter receptors - Peptide receptors - Glycoproteins - Protease-activated receptors
32
What is the structure of Class B GPCRs? Give some examples of them
Structure: - Extended extracellular N-terminal tail which contributes to binding of ligands (peptide hormones) Examples: - Calcitonin - Corticotropin-releasing factor (CRF) - Glucagon - Parathyroid hormone - Pituitary adenylate cyclase-activating peptide
33
What is the structure of Class C GPCRs? Give some examples of them
Structure: - Very large extracellular N-terminal tail, fully responsible for ligand binding (Venus fly-trap domain) Examples: - Metabotropic glutamate (mGlu) - Gamma-aminobutyric acid type B (GABAb) - Calcium-sensing receptor
33
GPCRs undergo conformational changes upon activation. An example of this is Rhodopsin in the retina. What happens in this example?
- The captive ligand, retinal, is bound to TM VII Lys296 of Rhodopsin - Light causes cis to trans isomerism of retinal GPCR and therefore conformational change in rhodopsin - This causes the activation of the G protein transducin, prompting GDP to exchange for GTP, causing the dissociation of the G-protein into its alpha and beta/gamma subunits
34
beta-2 AR**
35
What is the process of the G-protein activation cycle?
1) Resting State - GDP bound to alpha-subunit 2) Ligand binding and nucleotide exchange (GDP is expelled and GTP binds) 3) Dissociation of alpha-subunit from beta-gamma-subunits and receptor itself 4) Active State - GTP bound: Signalling occurs 5) Activation of GTPase 6) GTP Hydrolysis: Facilitated by RGS proteins
36
Important one! What are the main roles of the alpha-subunit of the G-protein? Also list the 4 main families of alpha subunit and their functions (hard).
- GTP/GDP-binding subunit with intrinsic GTPase activity - Principle role in intracellular signalling 4 main families: - Ga - activate adenyl cyclase to produce 2nd messenger cAMP - Gai/Gao - Inhibit adenyl cyclase - Gaq/Ga11 - Activate phospholipase C to produce dual 2nd messengers IP3 (Ca2+ mobilisation) and DAG - Ga12/Ga13 - Activate small G protein Rho to cause cytoskeleton changes
37
What are the roles of the Beta/Gamma subunits of G proteins?
- Also have signalling roles. E.g., various beta subunits regulate K+ channels and some isoforms of AC and PLC - Specific roles of individual beta and particularly gamma subunits are generally poorly understood
38
Summarise how GPCRs are switched off in a sentence.
Homologous desensitisation occurs through the co-ordinated action of G protein-coupled receptor kinases (GRKs) and Arrestins
39
What is the mechanism through which GRKs and Arrestins deactivate GPCRs
- The basal state of arrestin is folded, with only a modest affinity for GPCRs - GRK phosphorylation of the GPCR tail leads to a 10-30 fold increase in affinity for arrestin - Arrestins lock onto to phospho-tail and prevent further signalling - Phospho-GPCR tail invades the polar core of arrestin leading to conformational change, newly exposing regions that bind strongly to intracellular loops of GPCR and thereby obstruct G-protein binding
40
There is substantial evidence that GPCRs can exist as homo- and hetero-dimers. An example of a heterodimer GPCR is the GABAB receptor. Describe the structure and function of the GABAB receptor
- Consists of two slightly different parts: GABAB-R1 and GABAB-R2 - Both are needed for functional signalling - They have a distinct protein-protein interaction called coiled-coil interactions - GABA binds to the GABAB-R1 N terminus, resulting in a conformational change in the GABAB-R2 protein. This allows recruitment of G-proteins and subsequent signalling
41
G Proteins: G proteins are a family of proteins that are resident in the a) (cytoplasm/cell membrane/nucleus) of cells. Their function is to recognise activated GPCRs and transduce their signal to effector systems. G proteins interact with b) (guanine/cytosine/ adenosine) nucleotides called c)_____________
a) cell membrane b) guanine c) GTP and GDP
42
A single pool of G proteins can produce a distinct cellular response through variation in molecular makeup of the subunits involved. The types of G protein are below: - Gs - Gi/o - G12 - Gq - G(beta/gamma) What do these influence / do?
Gs: - Adenylate cyclase - Increase cAMP Gi/o: - Adenylate cyclase - Decrease cAMP G12: - Rhodopsin - Rhokinase G(beta/gamma): - As for Gi/o - Also activates potassium channels, activates GCPR kinases, activates MAP kinase cascade
43
IMPORTANT What is the role of adenylate cyclase and how does it influence cAMP?
- Adenylate cyclase is a membrane-bound enzyme - It converts ATP to cAMP - cAMP activates protein kinase A (PKa) - PKa then proceeds to produce an effect
44
How is cAMP deactivated?
Phosphodiesterase's (PDEs) hydrolyse cAMP to make 5'-AMP, deactivating it.
45
What is the effect of adenylate cyclase/cAMP on smooth muscle?
- PKa phosphorylates myosin light-chain kinases (MLCKs) - This leads to muscle relaxation
46
How is smooth muscle contracted in terms of adenylate cyclase and cAMP?
- MLCKs aren't phosphorylated - Causes contraction of smooth muscle
47
What do phosphodiesterase inhibitors do?
- Inhibit phosphodiesterase enzymes responsible for breaking down cAMP and cGMP within cells - Leads to prolonged intracellular signalling - This affects different cell types differently (increased cGMP in smooth muscle = relaxation whereas in cardiac muscle it leads to contraction)
48
What are some clinical uses of phosphodiesterase inhibitors?
- Cardiovascular disorders (arterial hypertension, heart failure) - Viagra (PDE5 inhibitor) causes vasodilation - Asthma
49
What is phospholipase C?
- An enzyme involved inn signal transduction pathways within cells - Plays a crucial role in the hydrolysis of a membrane phospholipid called PIP2 - Can be activated by GPCRs and receptor tyrosine kinases (RTKs)
50
PLC cleaves PIP2 into 2 second messengers, what are they?
- IP3 - Diacyl glycerol (DAG)
51
What does IP3 do?
- Bind to IP3 receptors on the endoplasmic reticulum, leading to the release of intracellular Ca2+ - This is crucial for various cell processes such as smooth muscle contraction, secretion and enzyme activity
52
What does DAG do?
- DAG remains in the cell membrane and, along with Ca2+, activates protein kinase C (PKC) - Activated PKC then phosphorylates target proteins, regulating cellular processes such as gene expression, metabolism, cell growth and differentiation
53
Signal integration refers to the integration of information from several distinct pathways. In the context of ACh, integration is crucial. How does ACh mediate vascular tone regulation?
- ACh binds to muscarinic receptors on endothelial cells triggering the release of Nitric Oxide (NO) through activation of PLC and subsequent activation of NO synthase - NO is a potent vasodilator - Vasodilation is modulated by other processes as well tho, hence integration
54
What is Guanylate cyclase? and roles does it have?
- GC is an enzyme that catalyses the conversion of GTP into cyclic cGMP, a crucial second messenger Roles: 1) cGMP production 2) Signal transduction 3) Cellular responses: - Vasodilation (mediated by cGMPs ability to activate PKG) - Neurotransmitter release - Smooth muscle relaxation

Pharmacology 3 (7 decks)

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