Principle Seminars

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Carbohydrate

Monomer = Monosaccharide (1 sugar unit, 3-7C atoms) e.g. (hexose) glucose, fructose, galactose; (pentose) ribose, deoxyribose; (triose) glyceraldehyde

Linked together by glycosidic bonds during condensation reactions to make Disaccharides (2 sugar units) e.g. maltose, lactose, sucrose

Name of the glycosidic bond depends on where the bond formed e.g. in maltose = a 1,4 glycosidic bond but in cellulose its b 1,4 glycosidic bond

Repeated condensation reactions between sugar units can result in a macromolecular polysaccharide (many sugar units) structure e.g. glycogen, cellulose, starches

Most carbohydrates exist as polysaccharides

Lipids

4 classes of lipids:

fatty acids and their derivatives

fatty acids - COOH group with hydrocarbon chain that is either saturated (C-C only) or unsaturated (C=C)

prostaglandins (eicosanoids - polyunsaturated FAs with 20C) made from arachidonic acid (20:4) via COX; inflammatory and platelet homeostasis

leucotrienes (eicosanoid) made from arachidonic acid via LOX; inflammatory, neutrophil adhesion

lipids containing glycerol

charged - phospholipids = phosphate + glycerol + 2FAs; amphipathic (hydrophobic tails and hydrophilic head); make up membranes

neutral:

mono-acylglycerols - breakdown product of TAG in fat digestion

di-acylglycerols - intracellular signaller, mobilise Ca 2+

tri-acyglycerols - energy storage in adipose tissue; 3FAs joined to glycerol in a series of 3 condensation reactions (ester links)

lipids not containing glycerol

steroids e.g. cholesterol - 27C in 4 rings (3 x 6C, 1 x 5C), OH group; metabolic precursor (vit D, bile acids, steroid hormones); structural role in membranes

sphingolipids = sphingosine + FA + R e.g. sphingomyelin - type of phospholipid

Terpenoids (pigments in plants)

lipoproteins and lipopolysaccharides

lipoproteins - spherical: hydrophobic core of cholesteryl esters + triacylglycerols + phospholipid layer associated with cholesterol and proteins

lipopolysaccharides - in gram neg bacteria = endotoxin, produces a large inflammatory response in humans

Proteins

primary structure - amino acid sequence

peptide/amide bonds between NH2 of one amino acid and COOH of another amino acid

condensation reactions (H2O eliminated with bond formation)

secondary structure - H bonding form as a result of partial charges between amino acids

alpha helices

H bond every 4 a.acids

3.6 a.acid residues per turn

beta pleated sheets

H bonding between backbones of different regions of the same polypeptide chain that has turned back on itself

resulting structure looks like a zig zag

tertiary structure - interactions of a.acid R groups

H bonding

between R groups of certain a.acid subunits

Ionic interactions

between R group with unit + charge and R group with unit - charge

Hydrophobic interactions

tendency of non-polar R groups to be excluded by the surrounding water

associate with the interior of the globular structure

quaternary structure - interactions of R groups from a.acids in different polypeptide chains (some proteins don't have this level of organisation)

Protein structure is highly ordered and is linked closely with its function. A change in lower levels of organisation results in an overall change in conformation which can result in denaturation.

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Question 9 - Compare and contrast Ipratropium and Salbutamol in the treatment of patients with bronchoconstriction. Use your knowledge of agonists and antagonists to explain how these drugs serve to alter sympathetic tone in the lungs.

Salbutamol

B adrenergic agonist

Agonists are ligands/chemicals that bind to receptors and causes a biological response

There are two types of adrenergic receptor: alpha and beta and they are further divided into subtypes:

B1 - heart and cerebral cortex, activation increases rate and force of contraction of the heart

B2 - lungs, smooth muscle and cerebellum, activation stimulates smooth muscle relaxation and bronchodilation

B3 - adipose tissue, activation stimulates increased lipolysis

Salbutamol affects B1 and B2 adrenergic receptors

29x more selective to B2 receptors than to B1, therefore higher specificity for pulmonary B receptors than cardiac B receptors

Racemic mixture of R- and S- isomers

R-isomer has 150x higher affinity for B2 than S-isomer

S-isomer is associated with toxicity --> led to development of pure drug of just R-isomer, levalbuterol. Disadv: very expensive

Overall effects of this drug is smooth muscle relaxation, vasodilation, and reduction in BP

Mechanism of Action:

Upon inhalation it causes relaxation of bronchial smooth muscle (or bronchodilation) by increasing cAMP activity via G-protein linked activation of adenylyl cyclase

Inhibits mediator release from mast cells

May also increase mucocilliary clearance

Administration by inhalation

Adv: increased patient compliance, drug is delivered directly to the site of therapeutic interest i.e. avoids first pass metabolism, many more active drug molecules are able to give their therapeutic effects to target site

Can increase amount of drugs delivered to the lungs with the use of a spacer (reduces velocity so less drug molecules impact on the back of the throat, also reduces side effects of oral thrush)

Short-acting, with half-life of 2-3 hours

Adv: quick acting and can be used to give almost immediate relief for patients suffering an attack

Side Effects:

Arrhythmia

Tachycardia

Headache

Tremor

Hypokalaemia

Muscle Cramps

Ipratropium

Is a muscarinic antagonist

There are 5 types of muscarinic receptors of which ipratropium acts on M3 - smooth muscle of the lungs

An antagonist is a chemical/ligand that binds to a receptor and inhibits the biological response as it blocks agonists from binding to the receptor.

Overall effect is to produce bronchodilation and decrease mucous secretion by this mechanism:

The muscarinic receptor is coupled to a G-protein. This is called 'GQ'

The G protein regulates phospholipase C and couples to a calcium second messenger system (when ACh binds --> increased DAG and IP3 --> more calcium channels open, influx calcium, contraction)

Ipratropium blocks this so;

Less phospholipase C is produced

Less DAG and less IP3

Less calcium channels open, there is little to no influx of calcium ions, which is needed to bind to tropomyosin

Airway remains relaxed --> increased airway diameter --> reduction of airway resistance

Administered by inhalation (like salbutamol)

Slower acting than B2 agonists

Disadv: will not work fast enough to treat a bronchospasm attack that has already begun

Side Effects:

Dizziness, headache

Stuffy nose, sinus pain, dry mouth, cough, hoarseness

Nausea, stomach upset, constipation

Back pain

Fever, chills, body ache, flu symptoms

In summary, Salbutamol is a B agonist while Ipratropium is a muscarinic antagonist, so the former induces a response in contrast, the latter prevents a response from occurring. Both act on G-protein linked receptors. Both are administered by inhalation and avoid first pass metabolism. Finally, because Salbutamol and Ipratropium act on different receptors, they can be used in conjunction with each other as they will not have inhibitory effects against one another. This is an advantage because it will have better therapeutic effects.