Clinical Sciences 2 Week one review activities

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Review:

Pharmacokinetics

There are four pharmacokinetic

processes depicted in the diagram. These determine how much drug reaches the

site of action. Provide a brief

definition of each process and ways a drug could move through membranes:

Absorption

The movement of a drug from its site of administration into the blood

Distribution

Drug movement from the blood to the interstitial space of tissues and from there into cells

Metabolism

is defined as enzymatically mediated alteration of drug structure

Excretion

The movement of drugs and their metabolites out of the body

There are three ways in which drugs can cross membranes

Passage through channels and Pores

Very few drugs cross membranes via channels or pores. The channels in membranes are extremely small (aprox 4 angstroms) and are specific for certain molecules. Consequently, only the smallest of compounds (molecular weight below 200) can pass through these channels, and then only if the channel is the right one. Compounds with the ability to cross membrane via channels include small ions such as potassium and sodium

Passage with the aid of a transport system

Transport systems are carriers that can move drugs from one side of the cell membrane to the other. Some transport systems require the expenditure of energy; other do not. All transport systems are selective: They will not carry just any drug. Wether a transporter will carry a particular drug depends on the drugs structure.

Direct penetration of the membrane itself

For most drugs, movement throughout the body is dependent on the ability to penetrate membranes directly. Why? Because most drugs are too large to pass through channels or pores and most drugs lack transport systems to help them cross all of the membranes that separate them from their sites or action, metabolism, and excretion. In order to directly penetrate membranes,a drug must be posed primarily of lipids. Consequently, if drug is to penetrate membrane, it must be able to dissolve into the lipids the membrane is made of.

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The pharmacokinetic processes

influence plasma drug concentration as observed in the next slide.

1.

Define the terms toxic and minimum effective concentrations as well as

therapeutic range.

Minimum Effective concentration (MEC) is defined as the plasma drug level below which therapeutic effects will not occur. Hence, to be of benefit, a drug must be present in concentrations at or below MEC.

Toxicity occurs when plasma drug levels climb too high. The plasma level at which toxic effect begin is termed the toxic concentration. Doses must be kept small enough so that the toxic concentration is not reached

2.

What would the dose response curve look like if drug absorption, metabolism and

excretion were very rapid?

3.

Often drugs are taken repeatedly over days or weeks. Explain why drug half-life

is important to determine dosage frequency.

Drug half life is defined as the time required for the amount of drug in the body to decreased by 50%. It is important to know so that dosage frequency can be determined so that enough drug remains in the system to provide efficacy.

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Consider receptor interactions:

1.

Explain what receptors are and where they are found.

Any functional macromolocule in a cell to which a drug binds to promote its effects, located on the cell surface membrane or within the cytoplasm

2.

Describe the 4 primary receptor families in the next slide.

Cell Membrane embedded enzyme

Receptors of this type span the cell membrane. The ligand binding domain is located on the cell surface, and the enzymes catalytic site is inside. Binging of the endogenous regulatory molecule or agonist druge (one that mimics the acton of the endogenous reglatory molecukle) activates the enzyme, therby increasing its catalytic activity. Responses to activation of these receptors occur in seconds. Insulin is a good example of an endogenous ligand that acts through this type of receptor

Ligand-gated ion channel

Ligand-gated ion channels span the cell membrane. The function of these receptors is to regulate flow of ions into and out of cells. Each ligand-gated channel is specific of a particular ion (eg Na+, Ca++). The liganding-binding domain is on a cells surface. When an endogenous ligand or agonist drug binds to the receptor, the channel opens, allowing ions to flow inward or outward (the direction of flow is determined bu the concentration gradient of the ion across the membrane). Responses to activation of a ligand-gated ion channel are extremely fast usually occurring in milliseconds. Several neurotransmitters, including acetylcholine and gamma-aminobutyric acid (GABA), act through this type of receptor.

G protein-coupled receptor system

There are there are three components; the receptor, G protein and an effector (typically an ion channel or an enzyme). These systems work as follows; binding of an endogenous ligand or agonist drug activate the receptor, which in tern activates G protein, which in turn activates the effector. Responses to activation of this type of system develop rapidly, Numerous endogenous ligands including NE serotonin, histamine and many peptide hormones act through G proteins0cupled receptor systems.

As shown in figure 5-4, the receptors that couple to G proteins are serpentine structures that transverse the cell membrane 7 times. For some of these receptors the ligand binding domain is on the cell surface. For others the ligand-binding domain is located in a pocket accessible from the cell surface

Transcription Factor

Transcription factors aare found within the cell rather then on the surface. and responses to activation of these receptors are delayed. Transcription factors activation are situated on DNA in the cell nucleus. Their function is to regulated protein synthesis, Activation of these receptors by endogenous ligands or by agonist drugs stimulates transcriptions of messenger RNA molecules, which then act as templates for synthesis of specific proteins. The entire process - from activation of the the transcription factor through completion of protein synthesis may take hours or even days. Because transcription factors are intercellular, they can be activated only by ligands that are sufficient;u lipid soluble to cross the cell membrane. Endogenous ;ligandsthat act through transcription factors include thyroid hormone and all d the steroid hormones.

https://www.youtube.com/watch?v=GPoDNQhP0Mg (Incorporar)

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Locally

Released Mediators

Mediator

Source

Function

Histamine

Mast cells and basophils

Dilation and increase permebility

Serotonin

platelets

similar

to histamine

Prostaglandins

leukocytes,

platelets

potentiate histamine

Leukotrienes

leukocytes

similar

to histamine, chemotaxis

PAF

leukocytes,

endothelial cells

platelet

aggregation

Nitric

oxide

macrophages

vasodilation

Cytokines

lymphocytes,

macrophages

fever,

promote neutrophils

Enzymes

neutrophils,

macrophages

protein

breakdown

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Tissue

SNS

PNS

Receptor

Action

Receptor

Action

Heart

β1

↑HR

M

↓ HR

Kidney

β1

↑ Renin release

Arterioles: heart, lung, SM

β2

Dilatation

Bronchi

β2

Dilatation

M

Contraction

Uterus

β2

Relaxation

Eye

α1

↑ Pupil size

M

↓ Pupil size

Bladder

α1

↓ Voiding

M

↑ Voiding

Penis

α1

Ejaculation

M

Erection

GIT

α1

↓ Blood flow

M

↑ secretions, motility, defecation reflex

Arterioles: Skin, viscera, Mucous Membranes

α1

Constriction

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1. The

presence of β2 receptors on blood vessels to

skeletal muscles during “fight or flight”, and the presence of α1 receptors on the resistance vessels

that control blood pressure.

Answer:

Refer to

sympathetic neurotransmitters that interact with special structures in the cell

membrane called receptors.

Refer to Slide

35, which

describes the responses of effector organs to sympathetic and parasympathetic

impulses. The “flight” response would cause vasodilation of these muscles,

aiding in providing additional arterial flow/oxygen during this time through

the β2 receptors, some of which are

located on the blood vessels that provide blood flow to the skeletal muscles: a

physiologic advantage. With regard to the α receptors located on the resistance

vessels that control blood pressure, the flight response would cause

vasoconstriction of these vessels, aiding in providing an increased cardiac

output—also a physiologic advantage

The presence of acetylcholine receptors on

sweat glands that allow for evaporative loss of body heat during “fight or

flight”, and the presence of α1 receptors that constrict the skin

vessels that control blood flow to the skin.

Answer: The sympathoadrenal

system also can discharge as a unit when there is a critical threat to the

integrity of the individual—the so-called fight-or-flight response. During a

stress situation, the heart rate accelerates; blood pressure rises; blood flow

shifts from the skin and gastrointestinal tract to the skeletal muscles and

brain; blood sugar increases; the bronchioles and pupils dilate; the sphincters

of the stomach and intestine and the internal sphincter of the urethra

constrict; and the rate of secretion of exocrine glands involved in digestion

diminishes.

3.The presence of β2 receptors relaxing the detrusor muscle

of the bladder during “fight or flight”, and the presence of α1 receptors that produce a contraction of

smooth muscle in the internal sphincter of the bladder.

Answer:

Your

answer should include the role both β2

and α1 receptors play in the control of

bladder function. The parasympathetic nervous system is concerned with bladder

emptying, the sympathetic concerned with bladder filling. Remember "Sympathetic

is for storage, Parasympathetic

is for peeing."

However,

during

“fight or flight” it is not uncommon for someone to experience urine loss

during times of panic or extreme anxiety.

It

is thought that the first response released in any stressful event is a parasympathetic

response, then shortly thereafter sympathetic takes over. For a brief period of time

parasympathetic firing occurs first, prior

to sympathetic domination. Thus,

when extremely

scared

you may briefly wet yourself and your "heart stops"

(parasympathetic) but then shortly after you no longer have the urge to urinate and your

"heart races”

(sympathetic). α1 receptors

are found in

postsynaptic

effector sites; mediating responses in vascular smooth muscle. β1-adrenergic

receptors

are found primarily in the heart, bronchioles,

and other β-mediated sites. In bladder

smooth muscle,

excitation

of

α receptors causes vaso-constriction,

and excitation of β receptors causes vasodilation.

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•The renin-angiotensin-aldosterone

system

(RAAS) helps regulate blood pressure, blood volume, and fluid and electrolyte

balance. The RAAS exerts its effects through angiotensin

II

and aldosterone.

•The most prominent actions of

angiotensin II are vasoconstriction and stimulation of aldosterone release.

•Angiotensin II acts directly on

vascular smooth muscle (VSM) to cause contraction. Vasoconstriction is prominent in arterioles and

less so in veins.

•In addition to its direct action on

blood vessels, angiotensin II can cause vasoconstriction indirectly by acting

on (1) sympathetic neurons to promote noradrenaline release, (2) the adrenal medulla to

promote adrenaline

release,

and (3) the central nervous system to increase sympathetic outflow to blood vessels.

•Angiotensin II acts on the adrenal

cortex to promote synthesis and secretion of aldosterone.

•After release from the adrenal

cortex, aldosterone acts on the distal tubules of the kidney to cause retention

of sodium

and excretion of potassium and hydrogen. Aldosterone can

promote cardiac remodeling and fibrosis.

•Angiotensin II may cause pathologic

structural changes in the heart and blood vessels. In the heart, it may cause hypertrophy (increased cardiac mass) and remodelling (redistribution of mass within the

heart).

•The RAAS, acting through

angiotensin II, raises blood pressure through two basic processes: vasoconstriction and renal

retention

of

water and sodium.