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Drug Mechanisms and Reactions

Phase 1: Drug Metabolism The whole range of biochemical processes that occur within an organism, Metabolism consists both of anabolism and catabolism (the buildup and breakdown of substances, respectively). The biochemical reactions are known as metabolic pathways and involve enzymes that transform one substance into another substance, either breaking down a substance or building a new chemical substance. The term is commonly used to refer specifically to the breakdown of food and its transformation into energy.
The liver is the principal site of drug metabolism. Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically active sometimes even more than the parent compound. An inactive or weakly active substance that has an active metabolite is called a pro-drug, especially if designed to deliver the active moiety more effectively.
Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization, whatever the process, the goal is to make the drug easier to excrete. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver.
Drug metabolism rates vary among patients. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not reached, in others, metabolism may be so slow that usual doses have toxic effects. Individual drug metabolism rates are influenced by genetic factors, coexisting disorders (particularly chronic liver disorders and advanced heart failure), and drug interactions (especially those involving induction or inhibition of metabolism).
For many drugs, metabolism occurs in two phases:
Phase I reactions: Which involve formation of a new or modified functional group or cleavage, these reactions are nonsynthetic.
Phase II reactions Which involve conjugation with an endogenous substance, these reactions are synthetic. Metabolites formed in synthetic reactions are more polar and more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions. Some drugs undergo only phase I or phase II reactions, thus, phase numbers reflect functional rather than sequential classification.
Phase I Drug Metabolism Phase I metabolism includes oxidation, reduction, hydrolysis and hydration reactions, as well as other rarer miscellaneous reactions. Oxidations performed by the microsomal, mixed-function oxidase system (cytochrome P450-dependent) is considered separately because of its importance and the diversity of reactions performed by this enzyme system.
Classification of Phase I Reactions: Oxidation
Reduction
Hydrolysis
Hydration
Dethioacetylation
Isomerization
Oxidations involving cytochrome P450 (the microsomal mixed-function oxidase) The mixed-function oxidase system found in microsomes (endoplasmic reticulum) of many cells (notably those of liver, kidney, lung and intestine) performs many different functionalisation reactions.
CYP 450: The cytochrome P450(CYP) enzyme system consists of a superfamily of hemoproteins that catalyse the oxidative metabolism of a wide variety of exogenous chemicals including drugs, carcinogens, toxins and endogenous compounds such as steroids, fatty acids and prostaglandins. The CYP enzyme family plays an important role in phase-I metabolism of many drugs. The broad range of drugs that undergo CYP mediated oxidative biotransformation is responsible for the large number of clinically significant drug interactions during multiple drug therapy.
All of these reactions require the presence of molecular oxygen and NADPH as well as the
complete mixed-function oxidase system (cytochrome P450, NADPH-cytochrome
P450 reductase and lipid).
All reactions involve the initial insertion of a single oxygen atom into the drug molecule. A subsequent rearrangement and/or decomposition of this product may occur, leading to the final products formation.
(i) Aromatic hydroxylation: This is a very common reaction for drugs and xenobiotics containing an aromatic ring. In this example the local anaesthetic and antidysrhythmic drug, lignocaine, is converted to its 3-hydroxy derivative.
(ii) Aliphatic hydroxylation: Another very common reaction, e.g. pentobarbitone hydroxylated in the pentyl side chain.
(iii) Epoxidation: Epoxides are normally unstable intermediates but may be stable enough to be isolated from polycyclic compounds (e.g. the precarcinogenic polycyclic hydrocarbons). Epoxides are substrates of epoxide hydrolase (discussed later), forming dihydrodiols, but they may also spontaneously decompose to form hydroxylated products or quinones. It has been suggested that epoxide formation is the first step in aromatic hydroxylation.
(iv) Dealkylation: This reaction occurs very readily with drugs containing a secondary or tertiary amine, an alkoxy group or an alkyl substituted thiol. The alkyl group is lost as the corresponding aldehyde. The reactions are often referred to as N-, O- or S-dealkylations, depending on the type of atom the alkyl group is attached to.
(v) Oxidative deamination: Amines containing the structure -CH(CH3)-NH2 are metabolised by the microsomal mixed-function oxidase system to release ammonium ions and leave the corresponding ketone. As with dealkylation, oxidative deamination involves an intermediate hydroxylation step with subsequent decomposition to yield the final products.
The product of the oxidative deamination of EPI or NE is 3,4-didydroxyphenylclycoaldehyde (DOPGAL). DOPGAL is subject to reduction to the corresponding alcohol (3,4-dihydroxyphenylethylene glycol, DOPEG) or oxidation to the corresponding carboxylic acid (3,4-dihydroxymandelic acid, DOMA), the latter being the major pathway.
(vi) N-oxidation: Hepatic microsomes in the presence of oxygen and NADPH can form N-oxides. These oxidation products may be formed by the mixedfunction oxidase system or by separate flavoprotein N-oxidases. The enzyme involved in N-oxidation depends on the substrate under study. Many different chemical groups can be N-oxidised including amines, amides, imines, hydrazines and heterocyclic compounds.
(vii) S-oxidation: Phenothiazines can be converted to their S-oxides (sulfoxides (S¼O) and sulfones (¼S¼O)) by the microsomal mixed-function oxidase system.
(viii) Phosphothionate oxidation: The replacement of a phosphothionate sulfur atom with oxygen is a reaction common to the phosphothionate insecticides, e.g. parathion. The product paraoxon is a potent anticholinesterase and gives the potent insecticide action as well as the toxicity in humans.
Oxidations not catalysed by cytochrome P450 (Non-Microsomal) A number of enzymes in the body not related to cytochrome P450 can oxidize drugs.
(i) Alcohol Oxidation by Alcohol dehydrogenase: This enzyme catalyses the oxidation of many alcohols to the corresponding aldehyde and is localised in the soluble fraction of liver, kidney and lung cells. This enzyme uses NAD as co-factor and is a true dehydrogenase.
(ii) Aldehyde oxidation: Aldehydes can be oxidised by a variety of enzymes involved in intermediary metabolism, e.g. aldehyde dehydrogenase, aldehyde oxidase and xanthine oxidase (the latter two being soluble metalloflavoproteins).
(iii) Oxidation by Xanthine oxidase: This enzyme will metabolise xanthine-containing drugs, e.g. caffeine, theophylline and theobromine, and the purine analogues to the corresponding uric acid derivative.
Metabolic Reduction (i) Azo- and nitro-reduction can be catalysed by cytochrome P450 (but can also be catalysed by NADPH-cytochrome P450 reductase).
(ii) Ring cleavage: Epoxides can be converted back to the parent hydrocarbon, e.g. benzo(a)anthracene- 8,9-epoxide whereas some heterocyclic compounds can be ring cleaved by reduction.
(iii) Reductive defluorination: Fluorocarbons of the halothane type can be defluorinated by liver microsomes in anaerobic conditions.
Metabolic Hydrolysis Esters, amides, hydrazides and carbamates can readily be hydrolysed by various enzymes.
(i) Ester hydrolysis: The hydrolysis of esters can take place in the plasma (nonspecific acetylcholinesterases, pseudocholinesterases and other esterases) or in the liver (specific esterases for particular groups of compounds). Procaine is metabolised by the plasma esterase, whereas pethidine (meperidine) is only metabolised by the liver esterase.
(ii) Amide hydrolysis: Amides may be hydrolysed by the plasma esterases (which are so non-specific that they will also hydrolyse amides, although more slowly than the corresponding esters) but are more likely to be hydrolysed by the liver amidases. Ethylglycylxylidide, the N-deethylated phase 1 product of lignocaine, is hydrolysed by the liver microsomal fraction to yield xylidine and ethylglycine.
(iii) Hydrazide and carbamate hydrolysis: Less common functional groups in drugs can also be hydrolysed, such as the hydrazide group in isoniazid or the carbamate group in the previously used hypnotic, hedonal.
Factors Affecting Metabolism Many factors can affect liver metabolism, such as:
In aging, the numbers of hepatocytes and enzyme activity declines.
Diseases that reduce hepatic blood flow like heart failure or shock can also reduce the metabolic potential of the liver.
Also the use of other drugs as well as dietary and environmental factors can influence liver metabolic function.
Metabolism can also be altered due to a genetic deficiency of a particular enzyme.
Differences in metabolism that result from functional genetic polymorphisms can be accommodated by knowing the frequency of different genotypes, and by modifying either the enzyme abundance (null alleles, for example, in the case of CYP2D6 ‘poor metabolizers’) or the intrinsic enzyme activity (for example, CYP2C9 variants). Data on developmental changes in the abundance and activity of different CYPs can also be incorporated into the models to predict hepatic clearance in neonates, infants and children.
Conclusion Metabolism is the breakdown of Drugs inside the body, to disable their activity, forming inactive metabolites, however some drugs are either not affected by metabolism or activated by it, some even form toxic metabolites Examples:
Imipiramine not affected by metabolism:
Paracetamol produce Toxic Metabolite
Metabolism occurs in two phases, Phase I Metabolism, and Phase II Metabolism.
Phase I Metabolism converts the drug into metabolite by formation of a new functional group or modifying it, while phase II Metabolism or reactions involve conjugation with indigenous substance.
Phase I Reactions Include:
Oxidation, reduction, hydrolysis and hydration reactions, and other rare miscellaneous reactions.
Oxidation can be divided into Microsomal or non Microsomal according to whether it involves mitochondrial CYP 450 enzymes.
Oxidation involves:
Microsomal Aromatic Hydroxylation, Aliphatic Hydroxylation, Epoxidation, Dealkylation, oxidative deamination, N- oxidation, S-oxidation and Phosphothionate oxidation.
Non-Microsomal Alcohol Oxidation by Alcohol dehydrogenase, Aldehyde Oxidation and Oxidation by Xanthine oxidase.
Reduction involves: Azo- and nitro-reduction, Ring cleavage, Reductive defluorination
Hydrolysis involves: Ester hydrolysis, Amide hydrolysis, Hydrazide and carbamate hydrolysis

Skin Functions, Structure and Relationship with the Body

The main function of the skin, its structure and the relationship between the skin, circulatory and nervous system Draw a label diagram of the skin and describe its structures and key parts
(See diagram attached)
The skin is the largest organ in the human body. It has three layers; the epidermis, dermis and subcutaneous layer.
The epidermis
Google images (2016)
“The upper or outer layer of the two main layers of cells that make up the skin. The epidermis is mostly made up of flat, scale-like cells called squamous cells. These cells produce melanin, which gives the skin its colour” (MedicineNet.com 2016).
The epidermis is the outmost layer of the skin, the skin we can see. This layer differs in thickness; it is thinner on the eyelids and nipples than it is on the soles of feet and palms of hands. This layer has water resistant properties and protects us from cuts and injuries. The epidermis contains the pigment melanin which gives us our skin tone.
The dermis
Google images (2016)
“Lying underneath the epidermis-the most superficial layer of our skin-is the dermis. The dermis is a tough layer of skin.” (Boundless.com N/D).
The dermis is the layer beneath the epidermis; this layer is attached to the blood and nerve supply. It consists of sweat glands and hair follicles and connective tissues.
The subcutaneous layer
(Google Images 2016)
“The bottom layer of skin is the subcutaneous fat layer.” (American Academy of Dermatology 2016).
The subcutaneous layer is made up of fatty tissues or bundles of adipose tissue. This layer is responsible for retaining heat in the body. The smaller these bundles of adipose tissue are, the less over weight you are likely to be.
Functions of the skin
Protection: The skin helps to protect us from things such as dehydration, harmful microorganisms, bacteria and UV rays from the sun.
Absorption: The skin can absorb substances that the body need such as oxygen and nitrogen. Some medications/ointments may be applied to and absorbed by the skin for muscle pain, for example, deep heat or oriental tiger balm.
Sensation: Receptors in the skin allow us to touch and feel pain, heat and cold.
Temperature Regulation: Sweating begins at around 37°C. The sweat comes to the surface of the skin and evaporates, causing the body to reduce the heat, as well as this, the hair on our arms lie down to allow the heat to escape. When we are cold the opposite happens: the hairs stand up and goose bumps form to trap any heat in the body in order to warm us up again.
Immunity: The skin and the immune system work together to make the immune to microorganisms and bacteria.
Movement and growth: The skin is stretchy because of its elastic properties and this allows the covering of the whole body and the movement of the individual.
Excretion: The skin allows materials such as urea, excess water and ammonia out of the skin. By-products that aren’t wanted or needed by the skin are released through sweat glands in the form of sweat. Excretion is an important function to note about the skin (New Health Advisor 2014).
Vitamin production: Upon exposure to ultraviolet light (the sun), the skin produces vitamin D. This is important for the growth and strengthening of bone (Curran 2016).
The relationship between the skin, circulatory system and the nervous system. The skin
The skin is the largest organ in the body and is wide spread throughout the whole body. The skin absorbs essential nutrients and oils through the pores and this provides moisture to the skin. The skin consists of three layers: The dermis, epidermis and subcutaneous layer.
The dermis is the layer beneath the epidermis; this layer is attached to the blood and nerve supply. It consists of sweat glands and hair follicles and connective tissues.
The epidermis is the outmost layer of the skin, the skin we can see. This layer differs in thickness; it is thinner on the eyelids and nipples than it is on the soles of feet and palms of hands. This layer has water resistant properties and protects us from cuts and injuries. The epidermis contains the pigment melanin which gives us our skin tone.
The subcutaneous layer is made up of fatty tissues or bundles of adipose tissue. This layer is responsible for retaining heat in the body. The smaller these bundles of adipose tissue are, the less over weight you are likely to be.
Functions of the skin
Protection: The skin helps to protect us from things such as dehydration, harmful microorganisms, bacteria and UV rays from the sun.
Absorption: The skin can absorb substances that the body need such as oxygen and nitrogen. Some medications/ointments may be applied to and absorbed by the skin for muscle pain, for example, deep heat or oriental tiger balm.
Sensation: Receptors in the skin allow us to touch and feel pain, heat and cold.
Temperature Regulation: Sweating begins at around 37°C. The sweat comes to the surface of the skin and evaporates, causing the body to reduce the heat, as well as this, the hair on our arms lie down to allow the heat to escape. When we are cold the opposite happens: the hairs stand up and goose bumps form to trap any heat in the body in order to warm us up again.
Immunity: The skin and the immune system work together to make the immune to microorganisms and bacteria.
Movement and growth: The skin is stretchy because of its elastic properties and this allows the covering of the whole body and the movement of the individual.
Excretion: The skin allows materials such as urea, excess water and ammonia out of the skin. By-products that aren’t wanted or needed by the skin are released through sweat glands in the form of sweat. Excretion is an important function to note about the skin (New Health Advisor 2014).
Vitamin production: Upon exposure to ultraviolet light (the sun), the skin produces vitamin D. This is important for the growth and strengthening of bone (Curran 2016).
The nervous system
The nervous system consists of the brain, spinal cord and all of the nerves that connect to these organs to the rest of the body. The cells in the nervous system are known as neurons and they transmit impulses along the nerves to carry messages between the brain and the body via the spinal cord. When the brain receives the information, it processes it before sending out the demands for the body. Neurons contain a long axon which is protects by myelin sheath as well as tiny branches called dendrons which branch out into smaller parts called dendrites ( BBC 2017).
(BBC 2017).
The autonomic nervous system regulates some body processes like blood pressure and breathing which work without any effort from the person. The somatic system consists of the nerves that are connected to the receptors in the skin. This is the system that protects us form getting burnt when holding or hand on a hot surface because the brain sends signals via the spinal cord to tell us to lift the hand off the surface.
The circulatory system
The circulatory system consists of the heart, blood containing oxygen and carbon dioxide and the blood vessels including veins, arteries and capillaries. These blood vessels have muscles inside their walls in which the blood flows through and these muscles are controlled by the nervous system. The circulatory system is responsible for providing blood, hormones, nutrients and oxygen to all the cells in the body. This system also fights infection through white blood cells and antibodies and aid in the clotting of blood through platelets which form scabs on the surface of the skin when cut and exposed to oxygen.
(Google Images 2017)
The relationship between the skin, nervous system and circulatory system
The skin, nervous system and circulatory system work together in order to ensure the body is functioning the way it should. The somatic nervous system works with the central nervous system to protect the skin. It does this by telling us to lift our hand off a hot surface to avoid burning ourselves. The nervous system and circulatory system are connected by the lymphatic system and work together to maintain blood pressure and regulation of the heart. The nervous system “tells” the circulatory system to pump blood around the body. The nervous system and circulatory system needs to function correctly and work together to ensure the rest of the body is functioning properly. The nervous system controls all functions of the body. The circulatory system provides blood flow and regulates body temperature. The skin works together with it to regulate the body temperature. When too hot the blood vessels dilate, the hairs lie down and we sweat to allow excess heat to escape the body. When we are too cold the hairs stand up and goose bumps form to trap any heat in the body. If blood flow is restricted, the skin becomes pale. If one of these systems became damaged in any way, the body would have abnormal functioning (Curran 2017).
(iii) Using the table format give examples of viral, bacterial, fungal skin diseases.
Viral
Bacterial
Fungal
Gastroenteritis
Pneumonia
Athletes foot
Common cold
Meningitis
Cutaneous Candidiasis
Flu
Food Poisoning
Tinea Versicolor
Cold sores
Impetigo
Onychomycosis
Chicken Pox
Cellulitis
Tinea Capitis
Herpes
Boils
Ringworm
(Native Remedies 2016)
(On Health 2016)
(Remedies health communities 2016)

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